Product Information safety updates - year table

4.8 - Adverse effects (undesirable effects).

• Added nausea, vomiting, diarrhoea.
• Added arthralgia.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Use for Sedation During Intensive Care'. Life-threatening adverse events known as Propofol Infusion Syndrome (PRIS), occurring together or in combinations, of cardiac failure, arrhythmias, metabolic acidosis, rhabdomyolysis Brugada-type ECG (elevated ST-segment and coved T-wave) and/or rapidly progressive cardiac failure (in some cases with a fatal outcome), hyperkalaemia, hepatomegaly, hyperlipidaemia and renal failure associated with propofol when used for sedation during intensive care. There have been very rare reports of occurrence of PRIS (in some cases with a fatal outcome) in adults treated for more than 48 hours with propofol infusions in excess of 5 mg/kg/hour. These reports have mainly (but not exclusively) been in patients with serious head injuries treated with high doses of propofol, inotropes and vasoconstrictors. The following appear to be major risk factors for the development of these events: decreased oxygen delivery to tissues; serious neurological injury and/or sepsis; high dosages of one or more of the following pharmacological agents: vasoconstrictors, steroids, inotropes and/or propofol. If these adverse events occur propofol administration must immediately be discontinued.

4.8 - Adverse effects (undesirable effects).

• Added new adverse effect under subheading 'Propofol Infusion Syndrome (PRIS)'. Symptoms include metabolic acidosis, notably lactic acidosis, hyperlipidaemia, hyperkalaemia, rhabdomyolysis typically indicated by a marked increase of the blood creatine phosphokinase, renal impairment or failure, Brugada type ECG, hepatomegaly and cardiac failure not responding to inotropic medication. Cases of fatal outcome have been reported. Propofol Infusion Syndrome may present with varying combinations of these symptoms.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Potentiation of radiation toxicity'. Cases of radiation recall and radiation sensitisation have been reported in patients treated with radiation either prior, during or subsequent to treatment with trametinib in combination with dabrafenib. Most cases were cutaneous in nature, but some cases involved other locations including the spinal cord. Trametinib in combination with dabrafenib should be used with caution when given concomitantly or sequentially with radiation treatment.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Radiation treatment'. Potentiation of radiation treatment toxicity has been reported in patients receiving trametinib in combination with dabrafenib.

4.8 - Adverse effects (undesirable effects).

• Added potentiation of radiation toxicity in combination with Tafinlar, with a frequency of common.

4.8 - Adverse effects (undesirable effects).

• Panniculitis.

4.8 - Adverse effects (undesirable effects).

• Added rash.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Potentiation of radiation toxicity'. Cases of radiation recall and radiation sensitisation have been reported in patients treated with radiation either prior, during or subsequent to treatment with dabrafenib as monotherapy or in combination with trametinib. Most cases were cutaneous in nature, but some cases involved other locations including the spinal cord. Dabrafenib should be used with caution when given concomitantly or sequentially with radiation treatment.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Radiation treatment'. Potentiation of radiation treatment toxicity has been reported in patients receiving dabrafenib as monotherapy or in combination with trametinib.

4.8 - Adverse effects (undesirable effects).

• Added potentiation of radiation toxicity with a frequency of common.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Patients with known or suspected mitochondrial diseases'. In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.
• Added new warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added reduction of TSH level in patients with treated or untreated hypothyroidism has been reported with postmarketing use of metformin.

4.8 - Adverse effects (undesirable effects), postmarketing experience.

• Added oedema.
• Added peripheral oedema.

4.8 - Adverse effects (undesirable effects).

• Trichoglossia reported in post-marketing experience.

4.4 - Special warnings and precautions for use.

• Cases of asymptomatic subretinal fluid in the paediatric population.
• Retinal pigment epithelial detachment (RPED)/ central serous retinopathy (CSR).

4.8 - Adverse effects (undesirable effects).

• Retinal pigment epithelium.
• Central serous chorioretinopathy.
• Serous retinal detachment.
• Serous retinopathy.
• Retinal detachment.

4.4 - Special warnings and precautions for use.

• Stimulants, including non-pharmacotherapeutics (e.g., energy drinks, caffeine) should be used with caution.

4.8 - Adverse effects (undesirable effects).

• Side effects in the paediatric population is similar to that of the adult population.

4.4 - Special warnings and precautions for use.

• Constipation in patients predisposed to constipation look for new or worsening symptoms during treatment.

4.4 - Special warnings and precautions for use.

• Haemophagocytic lymphohistiocytosis (HLH).
• Progressive multifocal leukoencephalopathy (PML).

4.8 - Adverse effects (undesirable effects).

• Haemophagocytic lymphohistiocytosis (HLH).
• Progressive multifocal leukoencephalopathy (PML).

4.4 - Special warnings and precautions for use.

• Updated withdrawal of CNS depressants.

4.5 - Interactions with other medicines and other forms of interactions.

• Posaconazole.
• Antivirals abacavcir, amprenavir, darunavir, lopinavir, indinavir, nelfinavir, saquinavir.
• HIV-protease inhibitors.
• Etoposide, irinotecan.
• Folic acid supplements.
• Stiripentol.

4.8 - Adverse effects (undesirable effects).

• Circulatory disorders.
• Blood count changes such as eosinophilia, leucocytosis, leucopenia.
• Gingival enlargement.
• Upper abdominal discomfort.
• Disorders of sexual function.
• Allergic cross-reactions with other antiepileptics.
• Renal failure.
• Reduction of serum concentrations of thyroid hormones.

4.3 - Contraindications.

• Severe renal impairment.

4.4 - Special warnings and precautions for use.

• Timing of administration.

4.5 - Interactions with other medicines and other forms of interactions.

• In vivo interaction study.
• Products that may potentiate or attenuate hypoglycaemia.

4.7 - Effects on ability to drive and use machines.

• Updated ability to drive or operate machinery.

4.9 - Overdose.

• Updated overdose treatment.
• Specific information for paediatric overdose.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Gastrointestinal hypomotility with severe complications'. Early diagnosis and treatment of constipation at the start of clozapine therapy is important in preventing serious gastrointestinal-related complications (e.g. appendicitis). Appendicitis, including perforated appendicitis, have been reported in post-marketing cases in patients treated with clozapine of any duration, regardless of age or gender. Some of these cases have reported fatal outcomes. Appendicitis and perforated appendicitis require intervention with medicine and surgery.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction, concomitant treatment of clozapine and valproic acid may increase the risk of clozapine-induced myocarditis. If concomitant use of clozapine with valproic acid is necessary, careful monitoring for this event is required.

4.8 - Adverse effects (undesirable effects).

• Added appendicitis*.
• Added appendicitis perforated*. *May be fatal.

4.8 - Adverse effects (undesirable effects).

• Added liver injury with a frequency with not know.
• Relocated the following adverse events under SOC 'Hepatobiliary disorders': Alanine aminotransferase increased, Aspartate aminotransferase increased and Gamma-glutamyltransferase increased.

4.4 - Special warnings and precautions for use.

• Updated co-infection with HIV.

4.3 - Contraindications.

• Updated contraindications for daclatasvir, sofosbuvir, telaprevir and lurasidone.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interactions with lurasidone, sofosbuvir, daclatasvir, telaprevir, cabotegravir, fostemsavir and lenacapavir.
• Added simeprevir.

4.4 - Special warnings and precautions for use.

• Arterial occlusive events.

4.4 - Special warnings and precautions for use.

• Hypersensitivity reactions which progressed to Kounis syndrome.
• False positive direct Coombs test.

4.8 - Adverse effects (undesirable effects).

• Linear IgA disease.
• Updated wording to'Tubulointerstitial nephritis'.

4.2 - Dose and method of administration.

• Food or milk changed to milk or dairy products.

4.4 - Special warnings and precautions for use.

• Additional information about contraception.
• Added Neuromuscular agents.
• Added Posterior reversible encephalopathy syndrome (PRES).

4.6 - Fertility, pregnancy and lactation.

• Additional information about contraception.

4.8 - Adverse effects (undesirable effects).

• Posterior reversible encephalopathy syndrome (PRES).
• Cardiac dysfunction.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated CYP2C9 and CYP3A4 inhibitors and inducers.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity.

4.4 - Special warnings and precautions for use.

• Interstitial lung disease.

4.2 - Dose and method of administration.

• Reduction of total daily dose from 600 mg to 400 mg for TRAMAL solution for injection for postoperative pain.

4.2 - Dose and method of administration.

• Addition of information on administration of goserelin implant.

4.4 - Special warnings and precautions for use.

• Interstitial lung disease (ILD).

4.5 - Interactions with other medicines and other forms of interactions.

• Androgen deprivation treatment may prolong the QT interval.

4.8 - Adverse effects (undesirable effects).

• Drug fever.

4.8 - Adverse effects (undesirable effects).

• Drug fever.

4.8 - Adverse Effects (undesirable effects).

• Added alopecia with a frequency not known.
• Added dysaesthesia with a frequency not known.
• Added non-arteritic anterior ischaemic optic neuropathy (NAION)* with a frequency not known. *Cases of NAION have been reported with GLP-1 RAs, including liraglutide. A sudden loss of vision should lead to ophthalmological examination.

4.8 - Adverse effects (undesirable effects).

• Exacerbation of Darier's disease.

4.5 - Interactions with other medicines and other forms of interactions.

• In patients with reduced activity of both UGT2B17 and CYP2C19, coadministration of WELIREG with CYP3A4 inhibitors may increase the risk of adverse reactions of WELIREG.

4.4 - Special warnings and precautions for use.

• Anti neutrophil cytoplasmic antibody (ANCA) associated vasculitis.

4.6 - Fertility, pregnancy and lactation.

• Must not be used for the treatment of diabetes during pregnancy.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypogammaglobulinaemia'. Hypogammaglobulinaemia has been reported in patients receiving TALVEY. Immunoglobulin levels should be monitored during treatment with TALVEY. Intravenous or subcutaneous immunoglobulin therapy was used to treat hypogammaglobulinaemia patients. Patients should be treated according to local institutional guidelines, including infection precautions, antibiotic or antiviral prophylaxis, and administration of immunoglobulin replacement.

4.4 - Special warnings and precautions for use.

• Crystalluria (including acute renal injury) observed very rarely in patients with reduced urine output.
• May cause false test results for Aspergillus infection.

4.5 - Interactions with other medicines and other forms of interactions.

• Penicillins may reduce the excretion of methotrexate causing a potential increase in toxicity.
• Interaction with Mycophenolate mofetil.

4.6 - Fertility, pregnancy and lactation.

• Breastfeeding diarrhoea and fungus infection of the mucous membranes are possible in the breast-fed infant.

4.8 - Adverse effects (undesirable effects).

• Drug reaction with eosinophilia and systemic symptoms (DRESS).
• Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE).

4.8 - Adverse effects (undesirable effects), post-marketing experience.

• Added multiple acyl-coenzyme A dehydrogenase deficiency (MADD)-like disorder with a frequency of unknown.

4.4 - Special warnings and precautions for use.

• Due to risk of hepatoxicity, monitor more frequently during the first two months.

4.8 - Adverse effects (undesirable effects).

• In clinical studies, incidence and severity of transaminase elevations were higher in Japanese patients.

4.4 - Special warnings and precautions for use.

• Presence of sodium metabisulfite.

4.4 - Special warnings and precautions for use.

• Presence of sodium metabisulfite.

4.3 - Contraindications.

• Severe pulmonary insufficiency.
• Myasthenia gravis.
• Spinal or cerebellar ataxia.

4.4 - Special warnings and precautions for use.

• Updated withdrawal.
• Updated amnesia.
• Updated psychiatric and paradoxical reactions.
• Thyroid disease may affect the levels of oxazepam.
• Worsening hepatic encephalopathy.

4.5 - Interactions with other medicines and other forms of interactions.

• Oxazepam with opioids increases the risk of sedation, respiratory depression, coma, death.

4.6 - Fertility, pregnancy and lactation.

• Updated use in pregnancy.
• Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines.

4.8 - Adverse effects (undesirable effects).

• Coma.
• Extrapyramidal disorder.
• Convulsion.
• Amnesia.
• Tremor.
• Vertigo.
• Dysarthria.
• Hypothermia.
• Paradoxical drug reaction (anxiety).
• Ataxia.
• Confusional state.
• Dizziness.

4.9 - Overdose.

• Flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines.

4.8 - Adverse Effects (undesirable effects).

• Added dysaesthesia.
• Added alopecia.
• Added non-arteritic anterior ischaemic optic neuropathy (NAION)*. With description *cases of NAION have been reported with GLP-1 RAs, including liraglutide. A sudden loss of vision should lead to ophthalmological examination.

4.4 - Special warnings and precautions for use.

• Restricted therapeutic indications for rifampicin oral syrup.
• Contraception for males and females.
• Genotoxicity statement for rifampicin oral syrup.

4.6 - Fertility, pregnancy and lactation.

• Contraception for males and females.
• Genotoxic potential in animals.

4.4 - Special warnings and precautions for use.

• Expand drug reaction with eosinophilia and systemic symptoms (DRESS) precaution to include additional severe cutaneous adverse reactions (SCARs).

4.8 - Adverse effects (undesirable effects).

• Acute generalised exanthematous pustulosis (AGEP).
• Toxic epidermal necrolysis (TEN).
• Stevens-Johnson Syndrome (SJS).

4.8 - Adverse effects (undesirable effects).

• Panniculitis.

4.2 - Dose and method of administration.

• Added instructions on how to inject Increlex.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Thrombotic microangiopathy (TMA)'. TMA, including thrombotic thrombocytopaenic purpura (TTP), have been associated with the use of regorafenib. The diagnosis of TMA should be considered in patients presenting with haemolytic anaemia, thrombocytopenia, fatigue, fluctuating neurological manifestation, renal impairment, and fever. Regorafenib therapy should be discontinued in patients who develop TMA and prompt treatment is required. Reversal of the effects of TMA has been observed after treatment discontinuation.

4.8 - Adverse effects (undesirable effects), post-marketing experience.

• Added cases of thrombotic microangiopathy have been reported. (frequency rare).

4.4 - Special warnings and precautions for use.

• Hypertensive crisis in patients with phaeochromocytoma.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity observed for rocuronium and for rocuronium-sugammadex complex.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated warning under subheading 'Clozapine'. Concomitant treatment of valproate and clozapine may increase the risk of clozapine-induced myocarditis. If concomitant use of valproate with clozapine is necessary, careful monitoring for this event is required.

4.4 - Special warnings and precautions for use.

• Added new warning 'Thromboembolic events'. Thromboembolic events, including pulmonary embolism, were reported in patients treated with CDK4/6 inhibitors in combination with endocrine therapy. Patients at risk of thromboembolic events should be closely monitored while receiving KISQALI.

4.8 - Adverse effects (undesirable effects).

• Added thrombosis.

4.4 - Special warnings and precautions for use.

• Updated gastrointestinal effects and dehydration.
• Added patients with gastroparesis may experience more serious or severe gastrointestinal effects.
• Added non-arteritic anterior ischaemic optic neuropathy (NAION).

4.8 - Adverse effects (undesirable effects).

• More serious or severe gastrointestinal effects for patients with gastroparesis.
• Non-arteritic anterior ischaemic optic neuropathy (NAION).
• Alopecia.
• Cholecystitis.

4.3 - Contraindications.

• Renal disfunction, G6PD deficiency, acute porphyria.

4.4 - Special warnings and precautions for use.

• Updated peripheral neuropathy, renal impairment, pulmonary reactions.
• Added hepatotoxicity.
• Added clostridium difficile-associated diarrhoea.
• Added galactose intolerance, total lactase deficiency or glucose-galactose malabsorption warning.
• Added information for patients.
• Updated use in elderly.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated antacids.
• Added carbonic anhydrase inhibitors, urine alkalinising agents, quinolone antimicrobials, oral typhoid vaccines.

4.6 - Fertility, pregnancy and lactation.

• Updated pregnancy.
• Updated breastfeeding information.

4.8 - Adverse effects (undesirable effects).

• Aplastic anaemia.
• Nervous system disorders.
• Asthma.
• Pseudomembranous colitis, dyspepsia, constipation, flatulence.
• Angioedema.
• Malaise, myalgia.
• Increased AST (SGOT), increased ALT (SGPT), decreased haemoglobin, increased serum phosphorus.

4.4 - Special warnings and precautions for use.

• Updated QTc interval prolongation warning.
• Added decrease in bone mineral density in premenopausal women warning.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction with other medicines known to cause QT prolongation.

4.8 - Adverse effects (undesirable effects).

• Decreased bone mineral density.
• QT prolongation.

4.8 - Adverse Effects (undesirable effects), post-marketing experience.

• Added acute disseminated encephalomyelitis (causality not confirmed) with a frequency of very rare.

4.8 - Adverse effects (undesirable effects).

• Weight decreased.
• Hypotension.

4.8 - Adverse effects (undesirable effects).

• Squamous cell carcinoma.

4.4 - Special warnings and precautions for use.

• Dystonic reactions.

4.2 - Dose and method of administration.

• Added instructions for patients to discontinue H2 antagonists 24 hours prior to test.

4.4 - Special warnings and precautions for use.

• Added instructions for patients to discontinue H2 antagonists 24 hours prior to test.

4.5 - Interactions with other medicines and other forms of interactions.

• Histamine H2-receptor antagonists (such as cimetidine, famotidine, nizatidine, and ranitidine) are known to supress H. Pylori and ingestion within 24 hours of testing may give false negative result.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Serious Skin Reactions'. Serious skin reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing experience. A majority of the reported cases involved the concomitant use of other drugs, including antiepileptic drugs, that are associated with serious skin reactions. SJS/TEN/DRESS could be associated with a fatal outcome. Patients should be closely monitored for signs or symptoms of SJS/TEN/DRESS, especially during the first 8 weeks of treatment. These commonly present as a combination of the following symptoms: extensive cutaneous rash or exfoliative dermatitis, fever, lymphadenopathy, and possible eosinophilia. Clobazam should be immediately discontinued when SJS/TEN/DRESS is suspected. If signs or symptoms suggest SJS/TEN/DRESS, use of this drug should not be resumed and alternative therapy should be considered.

4.8 - Adverse effects (undesirable effects).

• Added drug reaction with eosinophilia and systemic symptoms syndrome.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Myasthenia gravis'. Gabapentin should be used with caution in patients with myasthenia gravis as post-marketing cases of exacerbation of myasthenia gravis have been reported with gabapentin.

4.8 - Adverse effects (undesirable effects).

• Added exacerbation of myasthenia gravis.

4.4 - Special warnings and precautions for use.

• Added new warning. Appropriate medical treatment should always be readily available in case of an anaphylactic event following the administration of the vaccine.

4.8 - Adverse effects (undesirable effects), post-marketing data.

• Added anaphylactic reaction with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Updated warning on Progressive multifocal leukoencephalopathy (PML) and added instructions for situations when PML is suspected or confirmed.

4.8 - Adverse Effects (undesirable effects), post-marketing data.

• Added skin granuloma associated with vaccine derived rubella virus with a frequency of unknown.

4.8 - Adverse Effects (undesirable effects).

• Added nephrolithiasis with a frequency of common.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypertension'. Development of hypertension and worsening of pre-existing hypertension have been reported following the use of calcitonin gene-related peptide (CGRP) antagonists, including EMGALITY, in the post-marketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalisation. Hypertension may occur at any time during treatment but was most frequently reported within 7 days of therapy initiation. The CGRP antagonist was discontinued in many of the reported cases. Monitor patients treated with EMGALITY for new-onset hypertension or worsening of preexisting hypertension, and consider whether discontinuation of EMGALITY is warranted if evaluation fails to establish an alternative aetiology or blood pressure is inadequately controlled.

4.8 - Adverse effects (undesirable effects), post-marketing data.

• Added hypertension with a frequency of unknown.

4.2 - Dosage and Method of Administration.

• Added new subsection 'Reconstitution before administration of Act-HIB vaccine'. Each single dose vial of Act-HIB contains freeze-dried powder which needs to be dissolved in 0.5 - mL of the diluent for Act-HIB. Slowly inject the entire contents of the diluent pre-filled syringe into the centre of the stopper on the vial. Shake vigorously until the freeze-dried powder is completely dissolved and a colourless solution is visible. Withdraw the entire contents of the reconstituted vaccine into the syringe and administer the total volume (about 0.5 - mL) via the intramuscular or subcutaneous route. Aseptic technique must be used for withdrawal of each dose.

4.8 - Adverse Effects (undesirable effects), post-marketing data.

• Added skin granuloma associated with vaccine derived rubella virus with a frequency of unknown.

4.4 - Special warnings and precautions for use.

• Updated cardiovascular events to include risk of arrhythmia, myocardial infarction and cardiovascular mortality associated with macrolides including erythromycin.

4.8 - Adverse effects (undesirable effects).

• Added vasculitis.

4.6 - Fertility, pregnancy and lactation.

• Added new safety information under subheading 'Use in pregnancy (Category B2)'. BEYFORTUS is not indicated for use in females of reproductive potential.

4.8 - Adverse Effects (undesirable effects).

• Added new adverse event under subheading 'Eye Disorders'. Events of non-arteritic anterior ischaemic optic neuropathy (NAION), a rare condition associated with the potential for decreased vision including permanent loss of vision, have been reported in patients treated with products with GLP-1 receptor agonist activity. A sudden loss of vision should lead to ophthalmological examination.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Tacrolimus'. Flucloxacillin (a CYP450 inducer) may decrease tacrolimus whole blood trough concentrations and increase the risk of rejection. Monitor tacrolimus whole blood trough concentrations and increase tacrolimus dose if needed. Monitor graft function closely.

4.8 - Adverse effects (undesirable effects).

• Added mouth ulceration.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypertension'. Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including VYEPTI, in the post-marketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension, and in some cases hospitalisation. Hypertension may occur at any time during treatment, but was most frequently reported within 7 days of therapy initiation. The CGRP antagonist was discontinued in many of the reported cases. Monitor patients treated with VYEPTI for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of VYEPTI is warranted if evaluation fails to establish an alternative aetiology or blood pressure is inadequately controlled.

4.8 - Adverse effects (undesirable effects).

• Added hypertension with a frequency of unknown.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on. TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.
• Added new warning under subheading 'Patients with known or suspected mitochondrial diseases'. In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of. metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic. evaluation should be performed.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added reduction of TSH level in patients with treated or untreated hypothyroidism.

4.8 - Adverse Effects (undesirable effects).

• Added new adverse event under subheading 'Eye disorders' Events of non-arteritic anterior ischaemic optic neuropathy (NAION), a rare condition associated with the potential for decreased vision including permanent loss of vision, have been reported in patients treated with products with GLP-1 receptor agonist activity. A sudden loss of vision should lead to ophthalmological examination.
• Added Dysaesthesia.
• Added Dysgeusia.
• Added Alopecia.

4.9 - Overdose.

• Updated management information.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event under subheading 'Metformin'. Reduction of TSH level in patients with treated or untreated hypothyroidism.

4.4 - Special warnings and precautions for use.

• Acute kidney injury.

4.8 - Adverse effects (undesirable effects).

• Acute kidney injury.

4.4 - Special warnings and precautions for use.

• Kounis syndrome related to aspirin use.

4.4 - Special warnings and precautions for use.

• Updated concomitant use of beta-blockers with sulfonylureas.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated concomitant use of beta-blockers with sulfonylureas.

4.2 - Dose and method of administration.

• Haemophagocytic lymphohistiocytosis (HLH).

4.4 - Special warnings and precautions for use.

• Haemophagocytic lymphohistiocytosis (HLH).

4.8 - Adverse effects (undesirable effects).

• Haemophagocytic lymphohistiocytosis (HLH).

4.8 - Adverse effects (undesirable effects).

• Acute paronychia.
• Exanthema.
• Increase in rheumatic nodules.
• Pericardial tamponade.
• Dyspepsia.
• Inflammation and ulceration of the urinary bladder.
• Inflammation and ulceration of the vagina.
• Gynaecomastia.
• Electrolyte disturbances.
• Bronchial asthma.
• Pleural effusion.
• Depression.
• Confusion.
• Retinopathy.
• Impaired vision.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Flucloxacillin'. Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk.

4.8 - Adverse effects (undesirable effects).

• Anaphylactic shock.

4.8 - Adverse effects (undesirable effects).

• Added Jaundice with a frequency of not known.
• Added hepatic failure with a frequency of not known.
• Added hepatitis with a frequency of not known.

4.8 - Adverse effects (Undesirable effects).

• Added Henoch-Schonlein purpura, with transient renal involvement in certain cases.
• Added rash.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event under subheading 'Reduction of TSH level'. Reduction of TSH level in patients with treated or untreated hypothyroidism.

4.4 - Special warnings and precautions for use.

• Added warning under subheading 'Cardiovascular '. Unmasking of Brugada syndrome has been reported in patients treated with nortriptyline. Brugada syndrome is a rare hereditary disease of the cardiac sodium channel with characteristic ECG changes (ST segment elevation and T wave abnormalities in the right precordial leads), which may lead to cardiac arrest and/or sudden death. Nortriptyline should generally be avoided in patients with Brugada syndrome or those suspected of having Brugada syndrome. Caution is advised in patient with risk factors such as a family history of cardiac arrest or sudden death.

4.8 - Adverse effects (Undesirable effects).

• Added Brugada Syndrome (unmasking).
• Added Hyponatraemia.

4.9 - Overdose.

• Added Brugada syndrome (unmasking) and Brugada ECG pattern (BEP) have been reported in post-marketing surveillance in association with nortriptyline overdose.

4.4 - Special warnings and precautions for use.

• Updated slipped capital femoral epiphysis and osteonecrosis of the femoral head.

4.8 - Adverse effects (undesirable effects).

• Avascular necrosis of the femoral head (including Legg-Calve-Perthes disease).
• Revision of frequency of slipped capital femoral epiphyses to unknown due to post-market reports.

4.4 - Special warnings and precautions for use.

• Updated existing warning under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated the existing safety information under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.4 - Special warnings and precautions.

• Updated warning under subheading 'Hypersensitivity to cephalosporins, penicillins or other drugs'. There have been reports of hypersensitivity reactions which progressed to Kounis syndrome (acute allergic coronary arteriospasm that can result in myocardial infarction).

4.8 - Adverse effects (undesirable effects).

• Added Kounis Syndrome with a frequency of not known.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity including anaphylactic reaction, angioedema, rash, urticaria, pruritus.

4.4 - Special warnings and precautions for use.

• Added warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added Reduction of TSH level in patients with treated or untreated hypothyroidism with a frequency of unknown.

4.4 - Special warnings and precautions.

• Updated warning under subheading 'Cardiac arrhythmias including atrial fibrillation and flutter'. Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. In the combined safety database of 1478 patients with haematological malignancies treated with CALQUENCE monotherapy, atrial fibrillation and atrial flutter of any grade occurred in 7.4% of patients and. Grade 3 or higher occurred in 2.3% of patients. Monitor for symptoms of cardiac arrhythmia, including atrial fibrillation and atrial flutter, (e.g., palpitations, dizziness, syncope, chest pain, dyspnoea) and obtain an ECG as appropriate.
• Added new warning under subheading 'Hepatotoxicity, including drug-induced liver injury'. Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE. Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

4.8 - Adverse effects (Undesirable effects).

• Added cardiac arrhythmias.
• Added hepatotoxicity.
• Added drug-induced liver injury.

4.8 - Adverse effects (undesirable effects).

• Acute generalized exanthematous pustulosis (AGEP).

4.4 - Special warnings and precautions for use.

• Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS).

4.6 - Fertility, pregnancy and lactation.

• Excretion in breastmilk.

4.8 - Adverse effects (undesirable effects).

• Haematopoietic and lymphatic systems:
• Haemolytic anaemia.
• Haemophagocytic lymphohistiocytosis/macrophage activation syndrome.
• Anaphylaxis.
• Angioneurotic oedema.
• Serum sickness-like syndrome.
• Hypersensitivity vasculitis.

4.8 - Adverse effects (undesirable effects).

• Added hyaline occlusive glomerular microangiopathy.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity reactions in patients with alpha-gal syndrome, allergy to mammalian meat or meat products, or anti-alpha-gal IgE.

4.8 - Adverse effects (undesirable effects).

• Addition of panniculitis as a post-marketing adverse effect with frequency 'not known'.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Ketoacidosis'. Ketoacidosis and glucosuria may be prolonged after discontinuation of QTERN in some patients, i.e. it may last longer than expected based on the plasma half-lives of dapagliflozin. Consider monitoring for ketoacidosis and glucosuria in patients on dapagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with QTERN should be ceased prior to major surgery or procedures associated with prolonged fasting. An increase in other glucose lowering agents may be required during this time.
• Added new warning under heading 'Effects on laboratory tests', subheading 'Increased Haematocrit'. Increased haematocrit has been observed with dapagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Updated adverse event under subheading 'Genital infections'. Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genital infections and in some cases, circumcision was required.
• Added Increased haematocrit with a frequency of common.
• Added Tubulointerstitial nephritis with a frequency of very rare.

4.4 - Special warnings and precautions for use.

• Mood alterations and depression.
• Allergic-type reactions from colouring agent.

4.4 - Special warnings and precautions for use.

• Updated existing warning under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated the existing safety information under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.4 - Special warnings and precautions for use.

• Addition of information under sub-heading 'Hyperkalaemia'. To avoid Hyperkalaemia, do not infuse Baxter Potassium Chloride and Sodium Chloride IV Infusion rapidly.

4.8 - Adverse effects (undesirable effects).

• Hepatitis.
• Acute hepatic failure.

4.8 - Adverse effects (undesirable effects).

• Polyuria in association with hypernatraemia.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Serum lipids and blood glucose'. Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

4.2 - Dose and method of administration.

&.

4.4 - Special warnings and precautions for use.

&.

4.8 - Adverse effects (undesirable effects).

• Removal of NTRK indication and information pertaining to the indication.

4.4 - Special warnings and precautions for use.

• Updated existing warning under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, teriflunomide plasma levels must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated fetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated the existing safety information under subheading 'Use in males'. Teriflunomide (A771726) is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, teriflunomide plasma levels must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated fetal toxicity is considered very low.

4.4 - Special warnings and precautions for use.

• Updated angioedema.

4.4 - Special warnings and precautions for use.

• Updated existing warning under subheading 'Use in males'. Teriflunomide (A771726), the active metabolite of Arava, is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Arava and undergo a washout procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated the existing safety information under subheading 'Use in males'. Teriflunomide (A771726), the active metabolite of Arava, is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Arava and undergo a washout procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite (A771726) must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.4 - Special warnings and precautions for use.

• Updated angioedema.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypothyrodism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.
• Added new warning under subheading 'Patients with known or suspected mitochondrial diseases'. In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added reduction of TSH level in patients with treated or untreated hypothyroidism.

4.8 - Adverse effects (undesirable effects).

• Necrotising oesophagitis.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Ketoacidosis'. Ketoacidosis and glucosuria may be prolonged after discontinuation of FORXIGA in some patients, i.e. it may last longer than expected based on the plasma half-lives of dapagliflozin. Consider monitoring for ketoacidosis and glucosuria in patients on dapagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with FORXIGA should be ceased prior to major surgery or procedures associated with prolonged fasting. An increase in other glucose lowering agents may be required during this time.
• Added new warning under heading 'Effects on laboratory tests', subheading 'Increased Haematocrit'. Increased haematocrit has been observed with dapagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Updated adverse event under subheading 'Genital infections'. Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genital infections and in some cases, circumcision was required.
• Added Increased haematocrit with a frequency of common.
• Added Tubulointerstitial nephritis with a frequency of very rare.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Endocrine effects'. Thyrotoxic Periodic Paralysis (TPP) can occur in patients with hyperthyroidism and with methylprednisolone-induced hypokalaemia. TPP must be suspected in patients treated with methylprednisolone presenting signs or symptoms of muscle weakness, especially in patients with hyperthyroidism. If TPP is suspected, levels of blood potassium must be immediately monitored and adequately managed to ensure the restoration of normal levels of blood potassium.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Endocrine effects'. Thyrotoxic Periodic Paralysis (TPP) can occur in patients with hyperthyroidism and with methylprednisolone-induced hypokalaemia. TPP must be suspected in patients treated with methylprednisolone presenting signs or symptoms of muscle weakness, especially in patients with hyperthyroidism. If TPP is suspected, levels of blood potassium must be immediately monitored and adequately managed to ensure the restoration of normal levels of blood potassium.

4.8 - Adverse effects (undesirable effects).

• Addition of panniculitis as an Adverse effect with frequency 'unknown'.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Serum lipids and blood glucose'. Serum lipid and blood glucose levels may increase during antiretroviral therapy. Disease control and life style changes may also be contributing factors. Consideration should be given to the measurement of serum lipids and blood glucose. Lipid disorders should be managed as clinically appropriate.

4.4 - Special warnings and precautions for use.

• Addition of warning on Thyrotoxic Periodic Paralysis (TPP) in patients with hyperthyroidism and with prednisone-induced hypokalaemia.

4.8 - Adverse effects (undesirable effects).

• Addition of panniculitis as an AE with a frequency 'not known'.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Myocarditis and pericarditis'. Very rare cases of myocarditis and pericarditis have been observed following vaccination with COMIRNATY. Cases have occurred following first and second vaccinations and following booster doses. These cases have primarily occurred within 14 days following vaccination, more often after the second vaccination, and more often, but not exclusively in younger males (adolescents and young adults). There have been reports in females. Based on accumulating data, the reporting rates of myocarditis and pericarditis after primary series in children ages 5 through <12 years are lower than in ages 12 through 17 years. Rates of myocarditis and pericarditis in booster doses do not appear to be higher than after the second dose in the primary series. Available data indicate that most cases recover but some cases have rarely been associated with severe outcomes including death. Some patients diagnosed with COVID-19 vaccine associated myocarditis have reported persistent cardiac symptoms or had abnormalities detected on cardiac imaging months following diagnosis, though there is improvement over time. The significance of these findings is not yet known. Further guidance is found in the Australian Immunisation Handbook.

4.2 - Dose and method of administration.

• Updated wording on reconstitution and formatting of pictogram.

4.4 - Special warnings and precautions for use.

• Updated increased risk of breast cancer.

4.8 - Adverse effects (undesirable effects).

• Symptoms of hereditary and acquired angioedema.
• Risk of coronary artery disease.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Myocarditis and pericarditis'. Very rare cases of myocarditis and pericarditis have been observed following vaccination with COMIRNATY. Cases have occurred following first and second vaccinations and following booster doses. These cases have primarily occurred within 14 days following vaccination, more often after the second vaccination, and more often, but not exclusively in younger males (adolescents and young adults). There have been reports in females. Based on accumulating data, the reporting rates of myocarditis and pericarditis after primary series in children ages 5 through <12 years are lower than in ages 12 through 17 years. Rates of myocarditis and pericarditis in booster doses do not appear to be higher than after the second dose in the primary series. Available data indicate that most cases recover but some cases have rarely been associated with severe outcomes including death. Some patients diagnosed with COVID-19 vaccine associated myocarditis have reported persistent cardiac symptoms or had abnormalities detected on cardiac imaging months following diagnosis, though there is improvement over time. The significance of these findings is not yet known. Further guidance is found in the Australian Immunisation Handbook.

4.4 - Special warnings and precautions for use.

• Expanded information on additional monitoring.

4.5 - Interactions with other medicines and other forms of interactions.

• Interaction between azathioprine and allopurinol.

4.6 - Fertility, pregnancy and lactation.

• Cholestasis of Pregnancy.

4.8 - Adverse effects (undesirable effects).

• Tremor, sialoadenitis, non-cirrhotic portal hypertension, porto-sinusoidal vascular disease.

4.8 - Adverse Effects (Undesirable Effects).

• Added new description of selected adverse reaction 'Injection site reaction (pain* and discomfort, site nodule, induration) in table 6: Adverse Reactions. *May rarely result in temporary gait disturbance.

4.6 - Fertility, Pregnancy and Lactation.

• Updated information under subheading 'Use in Lactation'. Limited data from case reports have shown that cladribine is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, breast-feeding is contraindicated during treatment with MAVENCLAD and for 1 week after the last dose.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Ketoacidosis'. Ketoacidosis and glucosuria may be prolonged after discontinuation of SIDAPVIA in some patients, i.e. it may last longer than expected based on the plasma half-lives of dapagliflozin. Consider monitoring for ketoacidosis and glucosuria in patients on dapagliflozin, even if drug treatment has been interrupted or. discontinued.
• Updated warning under subheading 'Surgery'. Treatment with SIDAPVIA should be ceased prior to major surgery or procedures associated with prolonged fasting. An increase in other glucose lowering agents may be required during this time.
• Added new warning under heading 'Effects on laboratory tests', subheading 'Increased Haematocrit'. Increased haematocrit has been observed with dapagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Updated adverse event under subheading 'Genital infections'. Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genital infections and in some cases, circumcision was required.
• Added new adverse event Increased haematocrit with a frequency of common.
• Added new adverse event Tubulointerstitial nephritis with a frequency very rare.

4.4 - Special warnings and precautions for use.

• Concomitant use of temazepam and opioids may result in sedation.
• Warning regarding lactose intolerance these products contains lactose.

4.5 - Interactions with other medicines and other forms of interactions.

• The concomitant use of temazepam with opioids increases the risk of sedation, respiratory depression, coma and death due to additive CNS depressant effect.

4.4 - Special warnings and precautions for use.

Wording under subheading 'Tumours' relocated from 5.3 - Preclinical safety data subheading 'Carcinogenicity',

The most important risk factor for cervical cancer is persistent human papillomavirus (HPV) infection. Some epidemiological studies have indicated that long-term use of COCs may further contribute to this increased risk but there continues to be controversy about the extent to which this finding is attributable to confounding effects, e.g. cervical screening and sexual behaviour including use of barrier contraceptives.

A meta-analysis from 54 epidemiological studies reported that there is a slightly increased relative risk (RR = 1.24) of having breast cancer diagnosed in women who are currently taking COCs. The excess risk gradually disappears during the course of the 10 years after cessation of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the overall risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users, the biological effects of COCs or a combination of both. The breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

In rare cases, benign liver tumours, and even more rarely, malignant liver tumours have been reported in users of COCs. In isolated cases, these tumours have led to life-threatening intra-abdominal haemorrhages. A liver tumour should be considered in the differential diagnosis when severe upper abdominal pain, liver enlargement or signs of intra-abdominal haemorrhage occur in women taking COCs.

Malignancies may be life-threatening or may have a fatal outcome.

4.4 - Special warnings and precautions for use.

• Added reports of mood alterations including depressed mood, depression and suicidal ideation in patients treated with another oral 5-alpha reductase inhibitor (5-ARI).

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Patients with known or suspected mitochondrial diseases, Metformin hydrochloride', In patients with known mitochondrial diseases such as Mitochondrial Encephalomyopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternally Inherited Diabetes and Deafness (MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologic complications which may lead to worsening of the disease. In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation should be performed. Updated warning under subheading 'Diabetic ketoacidosis'. Consider monitoring for ketoacidosis. This is recommended for all patients on empagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with XIGDUO XR should be ceased at least 48 hours prior to major surgery or procedures associated with prolonged fasting. An increase in other glucose lowering agents may be required during this time.
• Updated warning under subheading 'Ketoacidosis', Ketoacidosis and glucosuria may be prolonged after discontinuation of XIGDUO XR in some patients, i.e. it may last longer than expected based on the plasma half-lives of dapagliflozin. Consider monitoring for ketoacidosis and glucosuria in patients on dapagliflozin, even if drug treatment has been interrupted or. discontinued.
• Added new warning under heading 'Effects on laboratory tests', subheading 'Increased Haematocrit'. Increased haematocrit has been observed with dapagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Updated adverse event under subheading 'Genital infections'. Cases of phimosis/acquired phimosis have been reported with dapagliflozin concurrent with genital infections and in some cases, circumcision was required.
• Added new adverse event Increased haematocrit with a frequency of common.
• Added new adverse event Tubulointerstitial nephritis with frequency very rare.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of warning regarding interactions with ioflupane.

4.4 - Special warnings and precautions for use.

• Addition of Capillary Leak Syndrome.

4.8 - Adverse effects (undesirable effects).

• Addition of Capillary Leak Syndrome in post-marketing experience.

4.2. Dose and method of administration.

Added new warning TRANEXAMIC ACID MUST NOT BE USED FOR INTRATHECAL OR EPIDURAL ADMINISTRATION.

4.3. Contraindications.

Added new contraindication, Intrathecal and epidural administration of tranexamic acid is contraindicated.

4.4. Special warnings and precautions for use.

Added new warning, Serious events including death and cardiac arrythmias were reported in patients erroneously treated with tranexamic acid via intrathecal or epidural injection.

4.4 - Special warnings and precautions for use.

• Inclusion of maculopapular exanthema.
• Added specific contraindication against rechallenge for patients who have experienced Stevens-Johnson syndrome or toxic epidermal necrolysis.
• Lactose warning added.

4.5 - Interactions with other medicines and other forms of interactions.

• 6-mercaptopurine and azathioprine.
• Ace inhibitors.
• Diuretics.

4.8 - Adverse effects (undesirable effects).

Updates to:

• Generalised hypersensitivity: chills, nausea, vomiting, DRESS/DIHS (drug reaction with eosinophilia and systemic symptoms) and multi-organ hypersensitivity. Fever, rash, vasculitis, lymphadenopathy, pseudolymphoma, arthralgia, leukopenia, eosinophilia, hepatosplenomegaly, abnormal liver function tests, and vanishing bile duct syndrome.
• Gastrointestinal disorders: diarrhoea, stomatitis, changed bowel habit, intermittent abdominal pain.
• General disorders: erectile dysfunction, fever, aseptic meningitis, angioedema.
• Laboratory parameters: liver function test abnormal, increased blood thyroid stimulating hormone and rise in urea.

4.4 - Specials warnings and precautions for use.

• Interaction with St. John's wort added.

4.5 - Interactions with other medicines and other forms of interactions.

• Interaction with St. John's wort coadministration may lead to a decrease in ciclosporin blood levels.

4.4 - Special Warnings and Precautions for Use.

Updated information under subheading 'Carcinoma of the Breast and Cervix', A meta-analysis from 54 epidemiological studies showed that there is a slightly increased relative risk (RR= 1.24) of having breast cancer diagnosed in women who are currently using COCs (with ethinylestradiol as the estrogen component), compared to never-users. The increased risk gradually disappears during the course of the 10 years after cessation. of COC use. Because breast cancer is rare in women under 40 years of age, the excess number of breast cancer diagnoses in current and recent COC users is small in relation to the lifetime risk of breast cancer. These studies do not provide evidence for causation. The observed pattern of increased risk may be due to an earlier diagnosis of breast cancer in COC users (due to more regular clinical monitoring), the biological effects of COCs or. a combination of both. Breast cancers diagnosed in ever-users tend to be less advanced clinically than the cancers diagnosed in never-users.

4.1 - Therapeutic indications.

Deleted the lapsed provisionally registered indication for MCL and updated to the following:

CALQUENCE is indicated for the treatment of patients with chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL).

4.4 - Special warnings and precautions for use.

Revised warning under the subheading 'Cardiac arrhythmias including atrial fibrillation and flutter' Serious cardiac arrhythmias have occurred in patients treated with CALQUENCE. In the combined safety database of 1040 patients with haematologic malignancies treated with CALQUENCE monotherapy, Grade 3 atrial fibrillation and atrial flutter occurred in 1% of patients and Grade 1 or 2 in 3% of patients. Monitor for symptoms of cardiac arrhythmia, including atrial fibrillation and atrial flutter, (e.g., palpitations, dizziness, syncope, chest pain, dyspnoea) and obtain an ECG as appropriate.

Added a new warning under the subheading 'Hepatotoxicity, including drug-induced liver injury'.

Hepatotoxicity, including severe, life-threatening, and potentially fatal cases of drug-induced liver injury (DILI), has occurred in patients treated with Bruton tyrosine kinase inhibitors, including CALQUENCE.

Evaluate bilirubin and transaminases at baseline and throughout treatment with CALQUENCE. For patients who develop abnormal liver tests after CALQUENCE, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold CALQUENCE. Upon confirmation of DILI, discontinue CALQUENCE.

4.8 - Adverse effects (Undesirable effects), Post-marketing experience.

Added new adverse effects 'cardiac arrhythmias', 'hepatotoxicity' and 'drug-induced liver injury'.

4.8 - Adverse effects (undesirable effects).

• Addition of new adverse events: Psychiatric disorders including abnormal dreams, depression, anxiety, panic attacks, crying, nightmares, psychotic disorders.

4.4 - Special warnings and precautions for use.

• Use with oral oestrogen therapy.
• Updated neoplasms.
• Antibodies.
• Pancreatitis.
• Benzyl-alcohol.

4.5 - Interactions with other medicines and other forms of interactions.

• Warning for women on oral oestrogen replacement therapy.

4.6 - Fertility, pregnancy and lactation.

• Updated use in pregnancy.

4.8 - Adverse effects (undesirable effects).

• Updated Slipped capital femoral epiphyses (SCFE), and Legg-Calve-Perthes disease.
• Reduced serum cortisol levels.
• Gynecomastia.
• Hypothyroidism.
• Headache.
• Formation of antibodies.

4.5 - Interactions with other medicines and other forms of interactions:

Added new interaction under the heading of 'Antifungal agents such as posaconazole, voriconazole, ketoconazole and itraconazole', as alltrans retinoic acid (ATRA) is metabolised by the hepatic cytochrome P450 enzymes, notably CYP3A4, concomitant administration with strong inhibitors of CYP3A4, including posaconazole, may lead to increased exposure to tretinoin resulting in an increased toxicity (especially hypercalcaemia). Serum calcium levels should be monitored and, if needed, appropriate dose adjustments of tretinoin should be considered during the treatment with CYP3A4 inhibitors like posaconazole, and during the following days after treatment.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Effects on liver function'. Drug-induced liver injury, including liver enzyme increase (≥ 3 x upper limit of normal (ULN)) and elevation of total bilirubin levels (≥ 2 x ULN) can result from treatment with dimethyl fumarate. The time to onset can be directly, several weeks or longer. Resolution of the adverse reactions has been observed after treatment was discontinued. Assessment of serum aminotransferases (e.g. alanine aminotransferase (ALT), aspartate aminotransferase (AST)) and total bilirubin levels are recommended prior to treatment initiation and during treatment as clinically indicated.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of warning regarding interactions with ioflupane.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Use in Males'. Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated warning under subheading 'Use in Males'. Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male mediated foetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of Teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated foetal toxicity is considered very low.

4.4 - Special warnings and precautions for use.

• Updated life threatening reactions, respiratory toxicity reactions, skin reactions including SJS, TEN, DRESS, use in renal and hepatic impairment.
• Added Immune thrombocytopenia.
• Added Circulatory shock.

4.8 - Adverse effects (undesirable effects).

• Updated Allergic, Endocrine and Metabolism, Gastrointestinal, Haemotologic, Hepatic and Neurologic adverse effects.
• Added Musculoskeletal, Ophthalmologic, Psychiatric, Respiratory, Skin and subcutaneous tissue disorders, Vascular disorders adverse effects.
• Added Circulatory shock.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Use in Males'. Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite must be verified to be less than 0. 02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated fetal toxicity is considered very low.

4.6 - Fertility, pregnancy and lactation.

• Updated warning under subheading 'Use in Males'. Teriflunomide is detected in human semen. Animal studies to specifically evaluate the risk of male mediated fetal toxicity have not been conducted. To minimise any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of teriflunomide and undergo an accelerated elimination procedure or wait 2 years after treatment cessation. In either case, plasma levels of the active metabolite must be verified to be less than 0.02 mg/L on two separate tests at an interval of at least 14 days apart. If the plasma concentration is less than 0.02 mg/L on both tests, and after a waiting period of at least 3 months, the risk of male-mediated fetal toxicity is considered very low.

4.8 - Adverse effects (Undesirable effects).

• Added nail psoriasis.

4.8 - Adverse effects (undesirable effects).

• Addition of Post-marketing adverse reaction blood creatine phosphokinase increased.

4.8 - Adverse effects (Undesirable effects).

• Added new description to footnote relating to interstitial lung disease in Table 2 Adverse drug reactions reported in ADAURA, FLAURA, FLAURA2 (monotherapy arm) and AURA studies. Cases of eosinophilic pneumonia have additionally been reported in the post-marketing setting.
• Added Myopathy-related events such as myositis and rhabdomyolysis.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Renal'. Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients treated with ibuprofen over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

4.8 - Adverse Effects (Undesirable effects).

• Added renal tubular acidosis with a frequency of not known.
• Added hypokalaemia with a frequency of not known.
• Added new description of selected adverse reaction under subheading 'Post Marketing Experience'. Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of ibuprofen at higher than recommended doses.

4.9 - Overdose.

• Added prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness.

4.8 - Adverse effects (undesirable effects).

• Addition of 'Injection site urticaria' as a postmarketing ADR with unknown frequency.

4.8 - Adverse effects (undesirable effects).

• Addition of 'seizure' and 'renal cortical necrosis'.

4.4 - Special warnings and precautions for use:

• Added new warning under subheading 'Pulmonary veno-occlusive disease'. Cases of pulmonary oedema have been reported with vasodilators, including nitric oxide, when used in patients with pulmonary veno-occlusive disease. Consequently, if signs of pulmonary oedema occur when INOmax is administered in patients with pulmonary arterial hypertension, the possibility of pulmonary veno-occlusive disease should be considered. If confirmed, the treatment is to be discontinued.

4.4 - Special warnings and precautions for use.

• Added Hypertensive crisis in patients with phaeochromocytoma.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity with rocuronium and rocuronium-sugammadex complex added in postmarketing.

4.5 - Interactions with other medicines and other forms of interactions.

• Added Digoxin test interference.

4.8 - Adverse Effects (Undesirable Effects).

• Added new description of selected adverse reaction 'Injection site reaction (pain and discomfort, site nodule, induration) in table 9: Tabulated summary of adverse drug reactions. May rarely result in temporary gait disturbance.

4.8 - Adverse effects (undesirable effects), Postmarketing Experience:

• Added Stevens-Johnson syndrome.
• Added toxic epidermal necrolysis.
• Added pleural effusion.
• Added serositis.

4.4 - Special warnings and precautions for use.

• Addition of warning for use in pregnant women and nursing women.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated interaction with methylprednisolone.
• Addition of interaction with immunosuppressants.
• Addition of interaction with substrates eliminated by CYP2C9, CYP3A4 and glucuronidation.

4.8 - Adverse effects (undesirable effects).

• Updates to Highly and Moderately emetogenic chemotherapy topics including the addition of multiple adverse effects.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse dander allergies.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Venous thromboembolism'. Venous thromboembolic events were reported in patients treated with IBRANCE. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism, and treated as medically appropriate.

4.8 - Adverse effects (undesirable effects).

• Added venous thromboembolism.

4.4 - Special warnings and precautions for use.

• Additional warning statements pertaining to angioedema of the head, neck and extremities.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse dander allergies.

4.4 - Special warnings and precautions for use.

• Addition of Insulin Autoimmune Syndrome and Angioedema.

4.8 - Adverse effects (undesirable effects).

• Addition of Immune system disorders.

4.1 - Therapeutic indications.

• Added new statement limited data are available for the use of ENGERIX-B in patients over 60 years of age.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Use in the elderly'. Clinical studies of ENGERIX-B did not include sufficient numbers of subjects aged 65 years and older to determine whether they responded differently from younger subjects. However, in a later study it has been shown that a diminished antibody response and seroprotective levels can be expected in persons older than 60 years.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Cardiovascular Thrombotic Events'. Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.
• Added new warning under subheading 'Renal'. Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients taking ibuprofen products over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

4.8 - Adverse effects (undesirable effects).

• Added Renal tubular acidosis with a frequency of not known.
• Added Kounis syndrome with a frequency of not known.
• Added Hypokalaemia with a frequency of not known.
• Added new description of selected adverse reaction under subheading 'Post Marketing Experience'. Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of ibuprofen at higher than recommended doses.

4.9 - Overdose.

• Added prolonged use at higher than recommended doses may result in severe hypokalaemia and renal tubular acidosis. Symptoms may include reduced level of consciousness and generalised weakness.

4.4 - Special warnings and precautions for use.

• Addition of warning related to Severe cutaneous adverse reactions (SCARs).
• Updated pseudotumour cerebri (PTC) / idiopathic intracranial hypertension (IIH).

4.8 - Adverse effects (undesirable effects).

• Addition of Severe cutaneous adverse reactions (SCARs) to Adverse Reactions tables for use in men and children.

4.1 - Therapeutic indications.

• Added new statement limited data are available for the use of HAVRIX 1440 in elderly patients.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Use in the elderly'. Clinical studies of HAVRIX did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Other reported clinical experience from Hepatitis A vaccines has not identified differences in overall safety between these subjects and younger adult subjects.

4.4 - Special warnings and precautions for use.

• Addition of vasculitis under Autoimmunity.

4.2 - Dose and method of administration.

• Added new advice to Table 6 Rybrevant dosage modifications for the adverse reaction 'Infusion-related reactions (IRR)'. Permanently discontinue for any Grade anaphylaxis / anaphylactic reactions.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Infusion-related reactions'. IRRs including anaphylaxis may occur in patients treated with RYBREVANT. The most frequent signs and symptoms include chills, nausea, dyspnoea, flushing, chest discomfort, and vomiting. Give RYBREVANT infusions in a monitored setting with appropriate medical support for the treatment of IRRs, including cardiopulmonary resuscitation medication and equipment. Interrupt infusion if IRR is suspected, and reduce infusion rate or permanently discontinue RYBREVANT based on severity. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT.

4.8 - Adverse effects (undesirable effects).

• Added Infusion-related reactions, including anaphylaxis/anaphylactic reactions.

4.4 - Special warnings and precautions for use.

Addition of warnings:

• Psychiatric events following discontinuation or dose reduction.
• Suitability for childhood gastrooesophageal reflux disease.
• Suitability for chemotherapy-orradiotherapy or post-operative nausea and vomiting.
• Additional information on prolongation of QT intervals with potent CYP3A4 inhibitors, and patients underlying cardiovascular disease.
• Additional information on electrolyte disturbance and risk of arrythmias.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of interaction with apomorphine.

4.7 - Effects on ability to drive and use machines.

• Addition of warning to use caution if driving or operating machinery.

4.8 - Adverse effects (undesirable effects).

Addition of:

• Angiodema.
• Dizziness.
• Urinary retention.
• Blood prolactin increased.

4.3 - Contraindications.

• Added meningioma or history of meningioma as a contraindication.

4.4 - Special warnings and precautions for use.

• Addition of Warning Combined oestrogen-progestogen therapy, Oestrogen-only, Ischaemic stroke and Other Conditions.
• Additional Information included under Warning Venous Thromboembolism (VTE).
• Additional warning included – Meningioma, Endometrial hyperplasia and Carcinoma.
• Additional warning included under ALT elevations.

4.5 - Interactions with other medicines and other forms of interactions.

• Additional information about Interaction Interactions with HCV combination drug regimen included.

4.4 - Special warnings and precautions for use.

• Additional warning statements pertaining to angioedema of the head, neck and extremities.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

Addition of:

• HIV antibody testing to be recommended for all patients.
• HIV/HBV co-infected patients receiving concomitant antiretroviral therapy.
• Resistance and specific precaution for lamivudine-refractory patients.
• Update to:
• Lactic acidosis and severe hepatomegaly with steatosis.
• Exacerbations of hepatitis.
• Use in renal impairment.
• Decompensated liver disease.

4.6 - Fertility, pregnancy and lactation.

Update to:

• Use in pregnancy recommendation to women of childbearing potential to use effective contraception.

4.7 - Effects on ability to drive and use machines.

Addition of:

• Dizziness, fatigue and somnolence as common side effects that may impair ability to drive and use machines.

4.8 - Adverse effects (undesirable effects).

Addition of side effects:

• Upper abdominal pain.
• Pancreatitis.
• Leukopenia.
• Neutropenia.
• Platelet count decreased.
• Hypersensitivity and drug hypersensitivity.

4.4 - Special warnings and precautions for use.

Addition of:

• HIV antibody testing to be recommended for all patients.
• HIV/HBV co-infected patients receiving concomitant antiretroviral therapy.
• Resistance and specific precaution for lamivudine-refractory patients.

  Update to:

• Lactic acidosis and severe hepatomegaly with steatosis.
• Exacerbations of hepatitis.
• Use in renal impairment.
• Decompensated liver disease.

4.6 - Fertility, pregnancy and lactation.

Update to:

• Use in pregnancy recommendation to women of childbearing potential to use effective contraception.

4.7 - Effects on ability to drive and use machines.

Addition of:

• Dizziness, fatigue and somnolence as common side effects that may impair ability to drive and use machines.

4.8 - Adverse effects (undesirable effects).

Addition of side effects:

• Upper abdominal pain.
• Pancreatitis.
• Leukopenia.
• Neutropenia.
• Platelet count decreased.
• Hypersensitivity and drug hypersensitivity.

4.3 - Contraindications.

• Added new contraindication under subheading 'Metoprolol'. Fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Metoprolol used in cardiac failure'. Risk of metoprolol adverse events including excessive bradycardia, may be increased because of an inhibition of its metabolism by fluoxetine.

4.8 - Adverse effects (undesirable effects).

Addition of:

• Takotsubo cardiomyopathy (Stress cardiomyopathy).
• Obsessive-compulsive disorder (OCD) (including trichotillomania and dermatillomania).
• Dry eye.

4.9 - Overdose.

Addition of:

• Takotsubo cardiomyopathy (Stress cardiomyopathy).

4.4 - Special warnings and precautions for use.

• Update to include warning statement related to increased blood sugar levels.

4.8 - Adverse effects (undesirable effects).

• Updated to include unpleasant taste under common Nervous System disorder.
• Updated to include statement on paediatric safety.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Diabetic ketoacidosis'. Consider monitoring for ketoacidosis. This is recommended for all patients on empagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with JARDIAMET should be ceased at least 48 hours prior to major surgery or procedures associated with prolonged fasting. An increase in other glucose lowering agents may be required during this time.
• Added new warning under subheading 'Hypothyroidism'. Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism. Regular monitoring of TSH levels is recommended in patients with hypothyroidism. Studies have shown that metformin reduces plasma TSH levels, often to subnormal levels, when it is administered to patients with untreated hypothyroidism or to hypothyroid patients effectively treated with Levothyroxine. The metformin-induced reduction of plasma TSH levels is not observed when metformin is administered to patients with normal thyroid function. Metformin has been suggested to enhance the inhibitory modulation of thyroid hormones on TSH secretion. Levothyroxine can reduce the hypoglycaemic effect of metformin. Careful monitoring of blood glucose levels is recommended in patients with hypothyroidism treated with Levothyroxine, especially when thyroid hormone therapy is initiated, changed, or stopped.
• Added new warning under heading 'Effects on laboratory tests', subheading 'Increased Haematocrit'. Increased haematocrit has been observed with empagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Levothyroxine'. Levothyroxine can reduce the hypoglycaemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated, changed, or stopped, and dosage adjusted as necessary.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event under subheading 'Empagliflozin'. Tubulointerstitial nephritis with frequency very rare.
• Added new adverse event under subheading 'Metformin'. Reduction of TSH level in patients with treated or untreated hypothyroidism.
• Updated adverse event under subheading 'Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection'. Cases of phimosis/acquired phimosis have been reported with empagliflozin concurrent with genital infections and in some cases, circumcision was required.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hypertension'. Development of hypertension and worsening of pre-existing hypertension have been reported following the use of CGRP antagonists, including AJOVY, in the post-marketing setting. Some of the patients who developed new-onset hypertension had risk factors for hypertension. There were cases requiring initiation of pharmacological treatment for hypertension and, in some cases, hospitalisation. Hypertension may occur at any time during treatment but was most frequently reported within 7 days of therapy initiation. Use of CGRP antagonists, including AJOVY, were discontinued in many of the reported cases. Monitor patients treated with AJOVY for new-onset hypertension or worsening of pre-existing hypertension, and consider whether discontinuation of AJOVY is warranted if evaluation fails to establish an alternative aetiology or blood pressure is inadequately controlled.

4.8 - Adverse effects (undesirable effects).

• Added hypertension with a frequency of unknown.

4.4 - Special warnings and precautions for use.

• Update to the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse-dander allergies.

4.3 - Contraindications.

• Added new contraindication under subheading 'Metoprolol', fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

• Added verapamil and diltiazem, hypotension and heart failure to calcium channel blocking drugs, ibutilide, and dofetilide and other antiarrhythmics, rebound hypertension after discontinuation of clonidine.

4.5 - Interactions with other medicines and other forms of interactions.

• Added Epinephrine, phenylpropanolamine, use of mefloquine, ergotamine, sympathomimetics, theophylline, tropisetron, proton pump inhibitors and drugs which antagonise the hypotensive effects of sotalol.

4.6 - Fertility, pregnancy and lactation.

• Added placental perfusion warning.

4.7 - Effects on ability to drive and use machines.

• Added fatigue.

4.8 - Adverse effects (undesirable effects).

• Added additional patient conditions for sotalol, blood and lymphatic system disorder, dyspnoea and bronchospasm.

4.8 - Adverse effects (undesirable effects).

• Added drug rash with eosinophilia and systemic symptoms (DRESS).

4.8 - Adverse effects (undesirable effects).

• Added hyaline occlusive glomerular microangiopathy (Table 2 under Vascular Disorders in post-marketing adverse effects).

4.4 - Special warnings and precautions for use.

• Inclusion of St. John's wort, carbamazepine, phenytoin under existing section on strong inhibitors, inducers of CYP3A4 (previously classified as moderate).

4.5 - Interactions with other medicines and other forms of interactions.

• Update the classification of selected CY3A4 inducers from moderate to strong and changes to section as a result.

4.3 - Contraindications.

• Added new contraindication under subheading 'Metoprolol', fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.4 - Special warnings and precautions for use.

• Update to include warning on iatrogenic botulism.

4.9 - Overdose.

• Updated to include spread of toxin.

4.8 - Adverse effects (undesirable effects).

• Added Glaucoma and Increased Intraocular Pressure as post marketing adverse effect.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of drug-drug interaction between vadadustat and rosuvastatin.

4.8 - Adverse effects (undesirable effects).

• Addition of new adverse reaction: injection site induration.

4.4 - Special warnings and precautions for use.

• Added Kounis syndrome.

4.8 - Adverse effects (undesirable effects).

• Added Haemolytic anaemia, alanine aminotransferase and aspartate aminotransferase.

4.4 - Special warnings and precautions for use.

• Added Neuroleptic malignant syndrome and akathisia/psychomotor restlessness.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated to include Inducers of CYP1A2, serotonergic agents, oral contraceptives and other steroidal agents.
• Updated MAOIs and anticoagulants and antiplatelet agents.

4.6 - Fertility, pregnancy and lactation.

• Updated to include two large observational studies in the US and EU.

4.9 - Overdose.

• Updated to include cases of overdose with doses of 5400mg.
• Updated to include information regarding Gastric lavage for overdose management.

4.3 - Contraindications.

• Added new contraindication, fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Bone Fractures'. Epidemiological studies, mainly conducted in patients 50 years of age and older, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. The mechanism leading to the risk is unknown.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Metoprolol used in cardiac failure'. Risk of metoprolol adverse events including excessive bradycardia, may be increased because of an inhibition of its metabolism by fluoxetine.
• Added new interaction under subheading 'Mequitazine'. Risk of mequitazine adverse events (such as QT prolongation) may be increased because of an inhibition of its metabolism by fluoxetine.
• Added new interaction under subheading 'Drugs that cause QT interval prolongation'. Pharmacokinetic and pharmacodynamic studies between fluoxetine and other medicinal products that prolong the QT interval have not been performed. An additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, coadministration of fluoxetine with medicinal products that prolong the QT interval should be used with caution.

4.8 - Adverse effects (undesirable effects).

• Added headache with frequency very common.
• Added bone fractures.

4.4 - Special warnings and precautions for use.

• Added precaution for use with pemetrexed.

4.8 - Adverse effects (Undesirable effects).

• Updated information under subheading 'Post marketing data'. The following ADRs are derived from post-marketing experience with KISQALI via spontaneous case reports and literature cases. As these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure, therefore the frequency is categorised as not known.
• Added erythema multiforme.

4.3 - Contraindications.

• Added new contraindication, fluoxetine is contraindicated in combination with metoprolol used in cardiac failure.

4.3 - Contraindications.

• Added advice to review further information found in the Australian Immunisation Handbook when vaccinating in immunocompromised patients.

4.4 - Special warnings and precautions for use.

• Updated warning in relation to children and young adults infected with HIV with or without evidence of immunosuppression that further information can be found in the Australian Immunisation Handbook.
• Added new warning under subheading 'Encephalitis'. Encephalitis has been reported during post-marketing use of live attenuated measles, mumps, rubella and varicella vaccines. In a few cases fatal outcomes have been observed, especially in patients who were immunocompromised. Vaccinees/parents should be instructed to seek prompt medical attention if they/their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

4.8 - Adverse effects (Undesirable effects).

• Added new adverse event under subheading 'Post-marketing safety surveillance'. Complications of varicella from vaccine strain including herpes zoster and disseminated disease such as aseptic meningitis and encephalitis have been reported in immunocompromised and immunocompetent individuals. A few cases of encephalitis with a fatal outcome have been observed following vaccination with live attenuated varicella vaccines, especially in immunocompromised people.

4.4 - Special warnings and precautions for use.

• Added glucose-6-phosphate dehydrogenase deficiency, Aortic aneurysm and dissection, and heart valve regurgitation/incompetence.

4.5 - Interactions with other medicines and other forms of interactions.

• Added vitamin K antagonists.

4.7 - Effects on ability to drive and use machines.

• Added information on effects on ability to drive and use machines.

4.8 - Adverse effects (undesirable effects).

• Added back pain, chest pain, pain, pain in extremities, candidiasis, phlebitis, decreased appetite, hypoglycaemic coma, albuminuria, hematuria, abnormal kidney function, acute kidney failure, vaginal discharge, nephritis interstitial, urinary retention, vaginitis, vaginal candidiasis, SIADH, aortic aneurysm and dissection, sometimes complicated by rupture and of regurgitation/incompetence of heart valves.

4.3 - Contraindications.

• Added contraindication for concomitant use of lopinavir/ritonavir with suzetrigine.

4.5 - Interactions with other medicines and other forms of interactions.

• Added suzetrigine drug-drug interaction with lopinavir/ritonavir.

4.3 - Contraindications.

• Added contraindication for suzetrigine with concomitant use of ritonavir.

4.5 - Interactions with other medicines and other forms of interactions.

• Added suzetrigine drug-drug interaction with ritonavir.

4.3 - Contraindications.

• Added advice to review further information found in the Australian Immunisation Handbook when vaccinating in immunocompromised patients.

4.4 - Special warnings and precautions for use.

• Updated warning in relation to children and young adults infected with HIV with or without evidence of immunosuppression that further information can be found in the Australian Immunisation Handbook.
• Added new warning under subheading 'Encephalitis'. Encephalitis has been reported during post-marketing use of live attenuated varicella vaccines. In a few cases fatal outcomes have been observed, especially in patients who were immunocompromised. Vaccinees/parents should be instructed to seek prompt medical attention if they/their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

4.8 - Adverse effects (Undesirable effects).

• Added new description of adverse event under subheading 'Complications associated with varicella'. Complications of varicella from vaccine strain, including herpes zoster and disseminated disease such as aseptic meningitis and encephalitis have been reported in immunocompromised and immunocompetent individuals. A few cases of encephalitis with a fatal outcome have been observed following vaccination with live attenuated varicella vaccines especially in immunocompromised people.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Hepatotoxicity, including drug-induced liver injury (DILI)'. Severe liver toxicity, such as hepatic failure (Grade 3 and 4 elevations in ALT and AST) and DILI, including fatal events, have occurred in the post-marketing setting in patients taking ibrutinib. The time to onset was variable (5 days – 3 months after commencing ibrutinib) and monitoring of liver function tests is recommended. These events were very rare and in most cases resolved upon dose modification. Ibrutinib treatment should be interrupted if ≥ Grade 3 liver function abnormalities develop. Liver function status, including bilirubin and transaminase, should be assessed before initiating treatment with IMBRUVICA. Patients should be monitored for signs and symptoms (such as vomiting and jaundice) and periodically for changes in liver function parameters during treatment. For patients who develop abnormal liver tests after IMBRUVICA, monitor more frequently for liver test abnormalities and clinical signs and symptoms of hepatic toxicity. If DILI is suspected, withhold IMBRUVICA. Upon confirmation of DILI, discontinue IMBRUVICA.

4.8 - Adverse effects (undesirable effects).

• Updated hepatotoxicity to include 'Drug-induced liver injury'.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event of diffuse alveolar haemorrhage: haemoptysis, shortness of breath with chest X-ray findings, and increasing aliquots of frank blood on bronchoalveolar lavage have been reported following exposure to sevoflurane and in the absence of airway obstruction. The incidence and attribution of sevoflurane to these events cannot be established with certainty.

4.2 - Dose and method of administration.

• Added warning that the ZOLADEX syringe cannot be used for aspiration.

4.5 - Interactions with other medicines and other forms of interactions.

• Caution recommended when using ZOLADEX with medicines known to prolong the QT interval.

4.4 - Special warnings and precautions for use.

• Addition of MELAS and MIDD warning in Section 4.4 - Special warnings and precautions for use with Metformin.
• Warning added for patients with hypothyroidism.

4.5 - Interactions with other medicines and other forms of interactions.

• Effect of levothyroxine with metformin.

4.8 - Adverse effects (undesirable effects).

• Adverse effects in patients with hypothyroidism.

4.4 - Special warnings and precautions for use.

• Updated to include additional safety information including risk of posterior reversible encephalopathy syndrome (PRES), severe bullous skin reactions (DRESS), risk of inflammatory bowel disease (IBD), Gonococcal infection, enhanced neurological warnings, updated monitoring recommendations in general, and added precautions regarding development of drug-resistant bacteria.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated interactions with lithium, disulfiram, hepatic enzyme inducers and inhibitors and added Vecuronium.

4.6 - Fertility, pregnancy and lactation.

• Updated pregnancy precautions to include information regarding safety of use of.
• Metronidazole and short high dose regimes.

4.7 - Effects on ability to drive and use machines.

• Added drowsiness.

4.8 - Adverse effects (undesirable effects).

• Added dyspepsia, dry mouth and coated tongue in Gastrointestinal, DRESS in body as a whole, drowsiness in nervous system disorders, gynaecomastia in reproductive system and breast disorders, burning in genitourinary tract.

4.4 - Special warnings and precautions for use.

• Added Hypersensitivity reactions.
• Added Cholestatic hepatitis.
• Updated effect on tendons.

4.5 - Interactions with other medicines and other forms of interactions.

• Drugs known to prolong QT interval.
• Updated caffeine containing medications.

4.6 - Fertility, pregnancy and lactation.

• Updated use in lactation.

4.8 - Adverse effects (undesirable effects).

• Added adverse events observed in clinical trials.
• Added post-marketing adverse events.

4.2 - Dose and method of administration.

• Added Injection site infections.

4.4 - Special warnings and precautions for use.

• Added Injection site infections.

4.8 - Adverse effects (undesirable effects).

• Added: Injection site infection, cellulitis, necrosis, and abscess.

4.6 - Fertility, pregnancy and lactation.

• Update to duration of contraception after cessation of treatment.

4.4 - Special warnings and precautions.

• Updated using disulfiram and ethanol together, and the effect on drug-induced liver injury.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated interactions involving isoniazid, phenytoin, benzodiazepines and paraldehyde.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Photosensitivity Reaction'. Posaconazole may cause increased risk of photosensitivity reaction. Patients should be advised to avoid sun exposure during treatment without adequate protection such as protective clothing and sunscreen with a high sun protection factor (SPF).

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'All-trans retinoic acid (ATRA) or tretinoin'. As ATRA is metabolised by the hepatic CYP450 enzymes, notably CYP3A4, concomitant administration with posaconazole, which is a strong inhibitor of CYP3A4, may lead to increased exposure to tretinoin, which may lead to hypercalcaemia. Serum calcium levels should be monitored and, if needed, appropriate dose adjustments of tretinoin should be considered during the treatment with posaconazole, and during the following days after treatment.

4.8 - Adverse effects (undesirable effects).

• Added photosensitivity reaction with frequency not known.

4.3 - Contraindications.

Addition of information relating to:

• Increased risk of malignant hyperthermia, ventricular dysrhythmias and cardiac arrest secondary to acute rhabdomyolysis with hyperkalaemia.
• Cross reference to any excipients in section 6.1.
• Major trauma or severe burn.
• Patients need to be fully anaesthetised.
• Monitoring requirements over prolonged use.
• Immobilised patients, neurological deficits, myofibrillar contractions, inherited or low serum levels of pseudocholinesterase, cerebral palsy, neuromuscular blockade, personal or family history of congenital myotonic diseases.

4.4 - Special warnings and precautions for use.

• Patients with cachectic, acid-base disturbances, parenchymatous, obstructive jaundice, carcinomatosis, certain insecticides, neurological disorders, muscular disease.
• Use in patients with fractures or muscle spasms.
• Use as an infusion.
• Effects on autonomic ganglia and muscarinic receptors and hyperkalemia.
• Cross sensitivity with pseudocholinesterase.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of interaction with: enflurane, desflurane, isoflurane, diethylether and methoxyflurane, aminoglycosides, clindamycin, vancomycin, piperacillin, chlorpromazine, morphine, morphine antagonists, pethidine, procainamide, procaine, cocaine, chloroprocaine, chlorethamine, tretamine triethylene-melamine, bambuterol, diphenhydramine, ketamine and propanidid, cardiac glycosides, edrophonium, galantamine, organophosphorous insecticides and metriphonate, oestrogens, liver disease, cancer, pregnancy, dehydration, electrolyte imbalance and overdosage (due to excessive production of succinylmonocholine).

4.8 - Adverse effects (undesirable effects).

• Addition of prolonged respiratory depression, excessive salivation, skin flushing, anaphylactic reactions, transient blood potassium increase.

4.3 - Contraindications.

• Addition of a contraindication: Not to be used for the augmentation of labour.

4.6 - Fertility, pregnancy and lactation.

• Must not be used for the induction or augmentation of labour.

4.8 - Adverse effects (undesirable effects).

• Added palpitations under post-marketing adverse reactions.

4.8 - Adverse effects (undesirable effects).

General disorders and administration site:

• Injection site pain. Injection site pain is transient.

4.4 - Special warnings and precautions for use.

• Hypothyroidism Metformin induces a reduction in thyrotropin (thyroid stimulating hormone (TSH)) levels in patients with treated or untreated hypothyroidism.
• Mitochondrial diseases Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes (MELAS) syndrome.
• Maternal inherited diabetes and deafness (MIDD).

4.5 - Interactions with other medicines and other forms of interactions.

• Levothyroxine can reduce the hypoglycaemic effect of metformin.

4.6 - Fertility, pregnancy and lactation.

• Updated warning about use in pregnancy.

4.8 - Adverse effects (undesirable effects).

• May increase the risk of lactic acidosis and adversely affect renal function.
• Added adverse effects in patients with hypothyroidism.

4.4 - Special warnings and precautions for use.

• Under immune mediated reactions additional information has been added relating to myocarditis-myositis-myasthenia gravis overlap syndrome.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Skeletal Muscle'. The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. atorvastatin) and daptomycin. Consideration should be given to temporarily suspend LIPITOR in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. If co- administration cannot be avoided, CK levels should be measured 2-3 times per week and patients should be closely monitored for any signs or symptoms that might represent myopathy.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Daptomycin'. Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. atorvastatin) co-administered with daptomycin. If co-administration cannot be avoided, appropriate clinical monitoring is recommended.

4.8 - Adverse effects (undesirable effects).

• Added lichenoid drug reaction.
• Added vasculitis.

4.4 - Special warnings and precautions for use.

• Update to use in renal impairment not recommended for use in moderate renal impairment. No dose adjustment required for mild renal impairment.

4.4 - Special warnings and precautions for use.

• Added new warning, Encephalitis has been reported during post-marketing use of live attenuated varicella vaccines including VARILRIX. Fatal outcomes have been observed, especially in patients who were immunocompromised. Vaccinees or parents should be instructed to seek prompt medical attention if they or their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

4.8 - Adverse effects (Undesirable effects).

• Added new description of selected adverse reaction, Encephalitis has been observed following vaccination with live attenuated varicella vaccines. Fatal outcome was reported in a few cases, especially in immunocompromised people.

4.4 - Special warnings and precautions for use.

• Added new warning, Encephalitis has been reported during post-marketing use of live attenuated measles, mumps, rubella and varicella vaccines including PRIORIX-TETRA. Fatal outcomes have been observed, especially in patients who were immunocompromised. Vaccinees or parents should be instructed to seek prompt medical attention if they or their child experience, after vaccination, symptoms suggestive of encephalitis such as loss or reduced levels of consciousness, convulsions or ataxia accompanied by fever and headache.

4.8 - Adverse effects (Undesirable effects).

• Added new description of selected adverse reaction, encephalitis has been observed following vaccination with live attenuated measles, mumps, rubella and varicella vaccines. Fatal outcome was reported in a few cases, especially in immunocompromised people.

4.4 - Special warnings and precautions for use.

• 'Hepatoxicity' section, additional warning for alcohol consumption and drug-induced injury.
• 'Hypoproteinaemia' section added.
• 'Infections' section additional information relating to tuberculosis.
• 'Skin reactions' section added information relating to onset psoriasis and skin ulcers.
• 'Switching to or from Teriflagio' additional precaution included.
• 'Peripheral neuropathy' section, age-related information included.
• 'Pancreatitis' section added.
• 'Use in males' section revised.

4.6 - Fertility, pregnancy and lactation.

• 'Use in males' section revised.

4.8 - Adverse effects (undesirable effects).

• Revised to align with international product information and to improve readability.

4.4 - Special warnings and precautions for use.

• Added warning about pulmonary oil microembolism.

4.5 - Interactions with other medicines and other forms of interactions.

• Added warning about elevated haematocrit levels (risk of erythrocytosis) with concomitant SGLT-2 inhibitors.

4.8 - Adverse effects (undesirable effects).

• Added pulmonary oil microembolism.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Cardiac and Pulmonary Disease'. Limited data from the pivotal clinical study in patients with a known history of cardiovascular or pulmonary disease showed a significantly increased incidence of cardiac events with azacitidine. It is therefore advised to exercise caution when prescribing azacitidine to these patients.

4.8 - Adverse effects (undesirable effects).

• Added pericardial effusion with frequency common.
• Added pericarditis with frequency uncommon.
• Added new adverse event under subheading 'Cardiac Events'. Data from a clinical study allowing enrolment of patients with known history of cardiovascular or pulmonary disease showed an increase in cardiac events in patients with newly diagnosed AML treated with azacitidine.

4.4 - Special warnings and precautions for use.

• Updated hypersensitivity reactions.

4.8 - Adverse effects (undesirable effects).

• Added hypersensitivity reactions.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Skeletal Muscle'. The risk of myopathy and/or rhabdomyolysis may be increased by concomitant administration of HMG-CoA reductase inhibitors (e.g. atorvastatin) and daptomycin. Consideration should be given to temporarily suspend CADUET in patients taking daptomycin unless the benefits of concomitant administration outweigh the risk. If co- administration cannot be avoided, CK levels should be measured 2-3 times per week and patients should be closely monitored for any signs or symptoms that might represent myopathy.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Daptomycin'. Cases of myopathy and/or rhabdomyolysis have been reported with HMG-CoA reductase inhibitors (e.g. atorvastatin) co-administered with daptomycin. If co-administration cannot be avoided, appropriate clinical monitoring is recommended.

4.8 - Adverse effects (undesirable effects).

• Added lichenoid drug reaction.
• Added vasculitis.

4.4 - Special warnings and precautions for use.

• Added pre-existing psychosis, phaeochromocytoma, priapism, peripheral vasculopathy (including Raynaud's Phenomenon).
• Amended Seizures, Cardiovascular events and anxiety.

4.5 - Interactions with other medicines and other forms of interactions.

• Added anti-hypertensive drugs, Pressor agents or drugs that increase blood pressure.
• Added information for interaction with other QT prolonging medicine and seizure under Beta-Adrenergic Receptor Agonists.

4.4 - Special warnings and precautions for use.

• Addition of severe cutaneous adverse reactions.

4.8 - Adverse effects (undesirable effects).

• Addition of toxic epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Ketoacidosis'. Consider monitoring for ketoacidosis. This is recommended for all patients on empagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with JARDIANCE should be ceased prior to major surgery or procedures associated with prolonged fasting.
• Added to warning under subheading 'Increased Haematocrit'. Increased haematocrit has been observed with empagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Updated adverse effect under subheading 'Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection'. Cases of phimosis/ acquired phimosis have been reported with empagliflozin concurrent with genital infections and in some cases, circumcision was required.
• Added Tubulointerstitial nephritis with frequency very rare.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Diabetic Ketoacidosis'. Consider monitoring for ketoacidosis. This is recommended for all patients on empagliflozin, even if drug treatment has been interrupted or discontinued.
• Updated warning under subheading 'Surgery'. Treatment with GLYXAMBI should be ceased prior to major surgery or procedures associated with prolonged fasting.
• Added to warning under subheading 'Increased Haematocrit'. Increased haematocrit has been observed with empagliflozin treatment. Patients with pronounced elevations in haematocrit should be monitored and investigated for underlying haematological disease.

4.8 - Adverse effects (undesirable effects).

• Added Tubulointerstitial nephritis with frequency very rare.
• Updated adverse effect under subheading 'Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection'. Cases of phimosis/ acquired phimosis have been reported with empagliflozin concurrent with genital infections and in some cases, circumcision was required.

4.5 - Interactions with other medicines and other forms of interactions:

• Added new interaction under subheading 'Posaconazole'. Flucloxacillin (a CYP450 inducer) may decrease plasma posaconazole concentrations. Concomitant use of posaconazole and flucloxacillin should be avoided unless the benefit to the patient outweighs the risk.

4.4 - Special warnings and precautions for use.

• Added warning related to aggravation of MELAS (Mitochondrial Encephalopathy with Lactic Acidosis, and Stroke-like episodes) syndrome and MIDD (Maternal inherited diabetes and deafness) in patients taking metformin with known mitochondrial diseases.

4.4 - Special warnings and precautions for use.

• Update to the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

• Update to the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Cerebellar Syndrome'. Cerebellar syndrome which may include abnormal motor coordination presenting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, has been reported in post-marketing case reports with the use of isoniazid. Most cases of cerebellar syndrome involved patients with chronic kidney disease (CKD), however, cerebellar syndrome was also reported in patients without CKD. Discontinue isoniazid if symptoms or signs of cerebellar syndrome occur.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event under subheading 'Nervous system'. Cerebellar syndrome, which may include abnormal motor coordination manifesting as gait, trunk, and limb ataxia, dysmetria and dysdiadochokinesia, intention tremor, dysarthria, or nystagmus, have been reported in post marketing case reports.

4.4 - Special warnings and precautions for use.

• Added warning for patients on metformin hydrochloride with known or suspected mitochondrial disease.

4.4 - Special warnings and precautions for use.

• Added myocarditis-myositis-myasthenia gravis overlap syndrome.

4.8 - Adverse effects (undesirable effects).

• Added myocarditis-myositis-myasthenia gravis overlap syndrome as a postmarketing adverse effect.

4.4 - Special warnings and precautions for use.

• Update the section to strengthen wording around horse and horse-dander allergies.

4.4 - Special warnings and precautions for use.

• Added a warning that iatrogenic botulism has been reported following injection of botulinum toxin products and action for patients and caregivers to take in the event of signs or symptoms consistent with spread of botulinum toxin effect.

4.8 - Adverse effects (undesirable effects).

• Updated warning regarding toxin spread.

4.9 - Overdose.

• Updated to amend a warning in order to include management where spread of toxin is suspected.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Cardiovascular and cerebrovascular effects'. Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.
• Added new warning under subheading 'Renal'. Renal tubular acidosis and hypokalaemia may occur following acute overdose and in patients treated with ibuprofen over long periods at high doses (typically greater than 4 weeks), including doses exceeding the recommended daily dose.

4.8 - Adverse effects (undesirable effects).

• Added Kounis syndrome with frequency not known.
• Added hypokalaemia* with frequency not known.
• Added renal tubular acidosis* with frequency not known. * Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of ibuprofen at higher than recommended doses.

4.9 - Overdose.

• Added prolonged use at higher than recommended doses or overdose may result in renal tubular acidosis and hypokalaemia. Symptoms may include reduced level of consciousness and generalised weakness.

4.3 - Contraindications.

• Updated contraindication for use in paediatric patients less than two years of age because of potential for psychiatric and CNS (central nervous system) events.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Paediatric use' with potential for psychiatric and CNS events in patients two years of age and older.

4.8 - Adverse effects (Undesirable effects).

• Added new adverse event under subheading 'CNS'. Children less than 6 years of age also experienced aggression, hallucination and psychomotor hyperactivity.

4.9 - Overdose.

• Added new overdose symptoms under subheading 'symptoms'. They are characterised in children by various combinations of excitation, ataxia, incoordination, athetosis and hallucinations, reversible intellectual disability and cognition deficit in children less than 6 years of age, while adults may become drowsy and lapse into coma. Convulsions may occur in both adults and children: coma or excitement may precede their occurrence.

4.4 - Special warnings and precautions for use.

• Addition of warning statement regarding doxylamine use and QT interval prolongation.

4.8 - Adverse effects (undesirable effects).

• Added Hypersensitivity and Erythema multiforme in the post-marketing data.

4.4 - Special warnings and precautions for use.

• Updated angioedema information that angioedema can occur at any time during treatment.
• Added sensitivity reactions with thiazides.

4.4 - Special warnings and precautions for use.

• Added new warning for hypogammaglobulinaemia under subheading'Serious infections'. Hypogammaglobulinaemia has also been reported in patients receiving epcoritamab. Immunoglobulin (Ig) levels should be monitored prior to and during treatment. Patients should be treated according to local guidelines, including infection precautions and antimicrobial prophylaxis.

4.8 - Adverse effects (undesirable effects).

• Added hypogammaglobulinaemia.

4.4 - Special warnings and precautions for use.

• Added increased risk of severe hypoglycaemia with concurrent beta-blockers and sulfonylureas.

4.5 - Interactions with other medicines and other forms of interactions.

• Added increased risk of severe hypoglycaemia with concurrent beta-blockers and sulfonylureas.

4.4 - Special warnings and precautions for use.

• Addition of Infusion Site Extravasation Injury.

4.8 - Adverse effects (undesirable effects).

• Addition of Infusion Site Extravasation Injury and Post Marketing Experience.

4.4 - Special warnings and precautions for use.

• Addition of Anti-Thymocyte Globulin and Thrombotic Microangiopathy.

4.4 - Special warnings and precautions for use.

• Addition of statement to specify that severe cutaneous adverse reactions (SCAR) such as SJS, TEN, DRESS and AGEP has been reported in patients taking ceftaroline.

4.8 - Adverse effects (undesirable effects).

• Correction of adverse event frequencies for c-reactive protein and hypersensitivity/anaphylactic reactions for urticaria.

4.3 - Contraindications.

Added:

• Acute gastric or duodenal ulcer.
• Cerebral haemorrhage.
• Severe cerebro-spinal trauma.
• Diabetic or haemorrhagic retinopathy.
• Proximal use of spinal/epidural anaesthesia.

4.4 - Special warnings and precautions for use.

Updated:

• Haemoglobin symptom.
• Information on acute stent thrombosis.
• Information on gamma brachytherapy. Added:
• Cardiac surgery.
• Warning for nursing women.

4.5 - Interactions with other medicines and other forms of interactions.

Added:

• Information on heparin.
• Pregnancy interactions.

4.8 - Adverse effects (undesirable effects).

• Added additional information on HORIZON's Trial; Platelets, bleeding and clotting.

4.3 - Contraindications.

• Added active, severe infections. immunocompromised patients, severe heart failure and severe, uncontrolled cardiac disease.

4.4 - Special warnings and precautions for use.

• Updated progressive multifocal leukoencephalopathy (PML), infusions-related reactions, infections, and immunisation.

4.2 - Dose and method of administration.

• Updated wording to prevent medication errors, do not substitute KANJINTI for or with trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is KANJINTI (trastuzumab) and not trastuzumab emtansine or trastuzumab deruxtecan.

4.2 - Dose and method of administration.

• Added reason for rotating injection site weekly.

4.4 - Special warnings and precautions for use.

• Updated existing warning for 'Epiphyseal disorders'.

4.5 - Interactions with other medicines and other forms of interactions.

• Added content related to oral estrogen and dosing.

4.8 - Adverse effects (undesirable effects).

• Added lipoatrophy as ADR identified post-marketing with frequency not known.
• Added epiphysiolysis (including slipped capital femoral epiphysis) with frequency not known.

4.3 - Contraindications.

• Updated contraindication for glaucoma (may increase intra-ocular pressure).

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interactions with medicines: antimuscarinics, anti-arrhythmics, antidepressants, antifungals, antihistamines, metoclopramide.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated AUC value for drug-drug interaction with ticagrelor and rosuvastatin.
• Added drug-drug interactions with belumosudil and momelotinib with rosuvastatin.
• Corrected AUC value for drug-drug interaction between enasidenib with rosuvastatin.

4.8 - Adverse effects (undesirable effects).

• Added pericardial effusion to the Post-marketing Experience section.

4.4 - Special warnings and precautions for use.

• Added warning statement section for musculoskeletal disorders.

4.8 - Adverse effects (undesirable effects).

• Added renal and urinary disorders for patients with high cumulative exposure to pegylated liposomal doxorubicin.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Retinal vein occlusion'. Retinal vein occlusion has been reported in patients treated with JAK inhibitors, including upadacitinib. Patients should be advised to promptly seek medical care in case they experience symptoms suggestive of retinal vein occlusion.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event, semen discolouration, under subheading 'Post Marketing Experience'. Reports of semen discolouration (blue or green) have occurred in patients taking RINVOQ. Most reports occurred with RINVOQ 45 mg. Discolouration intensity decreased or resolved after dose reduction or discontinuation. There were no clinically meaningful adverse events reported with the semen discolouration.

4.4 - Special warnings and precautions for use.

• Caution for patients with known or suspected mitochondrial diseases.

4.4 - Special warnings and precautions for use.

• Caution for patients with known or suspected mitochondrial diseases.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Cardiovascular and cerebrovascular effects'. Cases of Kounis syndrome have been reported in patients treated with ibuprofen. Kounis syndrome has been defined as cardiovascular symptoms secondary to an allergic or hypersensitive reaction associated with constriction of coronary arteries and potentially leading to myocardial infarction.

4.8 - Adverse effects (Undesirable effects).

• Added Kounis syndrome with a frequency of unknown.

4.4 - Special warnings and precautions for use.

• Strengthened warning regarding possibility of HIV transmission.

4.6 - Fertility, pregnancy and lactation.

• Updated lactation topic regarding the transmission of HIV.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading 'Other interactions'. Androgens may potentiate the effects of ciclosporin and increase risk of nephrotoxicity. The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation; thus these active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema.

4.8 - Adverse effects (Undesirable effects).

• Added the following adverse events with a frequency of unknown. Increased appetite, hypercholesterolaemia, blood triglycerides increased, blood cholesterol increased, emotional disorder, migraine, tremor, bronchitis, sinusitis, snoring, urine flow decreased, urinary retention, urinary tract disorder, nocturia, dysuria, dry skin, muscle disorder (muscle spasm, muscle strain), musculoskeletal stiffness, aspartate aminotransferase increased, glycosylated haemoglobin increased, estradiol increased, blood creatine phosphokinase increased, prostate examination abnormal, benign prostatic hyperplasia, prostatic dysplasia, prostate induration, prostatitis, prostatic disorder, breast induration and breast pain.

4.2 - Dose and method of administration.

• Updated wording under subheading'General'. Do not substitute Herceptin SC for or with trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is Herceptin SC (trastuzumab) and not trastuzumab emtansine or trastuzumab deruxtecan.

4.2 - Dose and method of administration.

• Updated wording under subheading'General'. Do not substitute OGIVRI for or with trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is Trastuzumab (OGIVRI) and not another Trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

Boxed warning.

• Updated warning to be clearer and prevent medication errors.

4.2 - Dose and method of administration.

• Updated wording to prevent medication errors; do not substitute Kadcyla for or with trastuzumab or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is Kadcyla (trastuzumab emtansine) and not trastuzumab or trastuzumab deruxtecan.

4.3 - Contraindications.

Added:

• Severe hepatic impairment.
• Colonic ulceration.
• Chronic intestinal disease.
• Diabetic ketoacidosis.

4.4 - Special warnings and precautions for use.

• Added warnings about coadministration of antacids, fulminant hepatitis, severe hepatic impairment and renal impairment.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction with colestyramine.

4.8 - Adverse effects (undesirable effects).

• Added acute generalised exanthematous pustulosis (post-marketing).

4.9 - Overdose.

• Updated overdose warning (no specific antidote known).

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Hypersensitivity Reactions, including Anaphylaxis'. In addition, serious cutaneous reactions, including Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported in patients with autoinflammatory conditions treated with Actemra.

4.8 - Adverse effects (undesirable effects).

• Added Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS).

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Viral Reactivation'. At least one confirmed case of progressive multifocal leukoencephalopathy (PML) has been reported in RA patients receiving tofacitinib in the post marketing setting. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.

4.2 - Dose and method of administration.

• Updated wording under subheading'General'. Do not substitute HERZUMA® for or with trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors it is important to check the vial labels to ensure the medicine being prepared and administered is HERZUMA® (trastuzumab) and not trastuzumab emtansine or trastuzumab deruxtecan.

4.2 - Dose and method of administration.

• Updated wording to prevent medication errors; do not substitute TRAZIMERA for or with trastuzumab emtansine or trastuzumab deruxtecan. In order to prevent medication errors, it is important to check the vial labels to ensure the medicine being prepared and administered is TRAZIMERA (trastuzumab) and not another trastuzumab-containing product (e.g. trastuzumab emtansine or trastuzumab deruxtecan).

4.4 - Special warnings and precautions for use.

• Added risk of liver injury.

4.6 - Fertility, pregnancy and lactation.

• Update to the benefit-risk of ofatumumab use during pregnancy and lactation.

4.8 - Adverse effects (undesirable effects).

• Update to Table 2: Adverse drug reactions from spontaneous reports. and literature (frequency not known) to include Hepatobiliary. Disorders: Liver injury.

4.4 - Special warnings and precautions for use.

Added:

• Coronary artery disease (CAD).
• Combined estrogen-progestogen therapy.
• Estrogen-only.
• Ischaemic stroke.
• Updated Venous thromboembolism (VTE).
• Added no safety data to support oral doses of estradiol > 2 mg.
• Update to Hypothyroidism.
• Update drug interaction information under the ALT elevations topic.

4.5 - Interactions with other medicines and other forms of interactions.

• Additional information added on metabolism of progesterone and effect on uterine bleeding profile.
• Additional drug interaction information added to other interactions.

4.6 - Fertility, pregnancy and lactation.

• Additional information related to occurrence of pregnancy during treatment.

4.8 - Adverse effects (undesirable effects).

Added:

• Haemolytic anaemia.
• Hypertension, peripheral vascular disease, varicose vein, venous thromboembolism added to Vascular disorders.
• Leg cramps.
• Back pain.
• Pelvic pain.
• Change in cervical secretion and menorrhagia.
• Asthenia.
• Oedema/peripheral oedema. Frequency updated:
• Headache.
• Abdominal pain / nausea.
• Breast pain.
• Dysmenorrhoea.

4.3 - Contraindications.

• Added coadministration of posaconazole with rivaroxaban or apixaban is contraindicated as posaconazole may increase the plasma concentration of these medicines, which may increase the risk of bleeding.

4.5 - Interactions with other medicines and other forms of interactions.

• Added 'rivaroxaban' and 'apixaban' under the contraindicated column of table 2.
• Added interaction under subheading 'Effects of Posaconazole on other drugs'. Rivaroxaban and Apixaban: Posaconazole inhibits CYP3A4 and may have an inhibitory effect on P-gp, and therefore it may increase plasma concentrations of rivaroxaban and apixaban to a clinically relevant degree which may lead to an increased bleeding risk.

4.3 - Contraindications.

• Expanded contraindications with other medicines.

4.4 - Special warnings and precautions for use.

• Added cardiac dysrhythmias.
• Updated use in CHF, hepatic and renal impairment and in immunocompromised patients.
• Added disorders of carbohydrate metabolism.
• Added interaction potential.
• Added monitoring and laboratory tests.

4.8 - Adverse effects (undesirable effects).

• Added hypersensitivity, oedema, leukopenia, serum sickness, angioneurotic oedema, anaphylactic reaction, hypertriglyceridaemia, tremor, paraesthesia, hypoaesthesia, dysgeusia, visual disturbance (including diplopia and blurred vision), transient or permanent hearing loss, tinnitus, congestive heart failure, tinnitus, dyspnoea, pancreatitis, serious hepatotoxicity (including some cases of fatal acute liver failure), hyperbilirubinaemia, toxic epidermal necrolysis, Stevens-Johnson Syndrome, acute generalised exanthematous pustulosis, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, alopecia, photosensitivity, blood creatine phosphokinase increased serum sickness, angioneurotic oedema, anaphylactic reaction, psuedoaldosteronism.

4.4 - Special warnings and precautions for use.

• Added Drug-induced liver injury (DILI).

4.8 - Adverse effects (undesirable effects).

• Added Metabolism and nutrition disorders Hypokalaemia.
• Added Hepatobiliary disorders Drug-induced liver injury.

4.3 - Contraindications.

• Addition of Cockayne syndrome as a contraindication.

4.4 - Special warnings and precautions for use.

• Updated frequency of viral shedding.
• Updated risk of transmission in the use of genital herpes.

4.5 - Interactions with other medicines and other forms of interactions.

• Added tenofovir, cimetidine, probenecid and mycophenolate mofetil.

4.6 - Fertility, pregnancy and lactation.

• Added malformative or foetal / neonatal toxicity Reproductive toxicity.

4.8 - Adverse effects (undesirable effects).

• Updated hepato-biliary disorders to include bilirubin and liver enzymes.

4.8 - Adverse effects (undesirable effects).

• Added rash.

4.8 - Adverse effects (undesirable effects).

• Postmarketing Thrombocytopenia and neutropenia included when amivantamab is used in combination with carboplatin and pemetrexed.

4.8 - Adverse effects (undesirable effects).

• Added 'hyponatraemia' to the tabulated list of adverse reactions, with a frequency of 'uncommon'.

4.3 - Contraindications.

• Added new contraindication, CIZINATE is contraindicated for use in children under 6 years of age because of the potential for fatal respiratory depression, psychiatric and CNS (central nervous system) events.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Paediatric use'. CIZINATE is contraindicated for use in children under 6 years of age because of the potential for fatal respiratory depression, psychiatric and CNS events.

4.8 - Adverse effects (undesirable effects).

• Added new adverse event. Children less than 6 years of age also experienced aggression, hallucination and psychomotor hyperactivity.

4.9 - Overdose.

• Added new overdose symptom information. Symptoms are characterised in children by various combinations of excitation, ataxia, incoordination, athetosis and hallucinations, reversible intellectual disability and cognition deficit in children less than 6 years of age, while adults may become drowsy and lapse into coma. Convulsions may occur in both adults and children: coma or excitement may precede their occurrence. Tachycardia may develop.

4.4 - Special warnings and precautions for use.

• Updated information relating to signs and symptoms of idiopathic intracranial hypertension.
• Updated information relating to metabolic syndrome in the post market setting.
• Added Severe Cutaneous Adverse Reactions (SCARs) and recommendation to discontinue if confirmed.

4.8 - Adverse effects (undesirable effects).

• Added Stevens Johnson Syndrome / Toxic epidermal necrolysis, Toxic skin Eruption, erythema multiforme, diabetes to Table 3 under Skin and subcutaneous tissue disorders group.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction. Androgens may potentiate the effects of ciclosporin and increase risk of nephrotoxicity.

4.4 - Special warnings and precautions for use.

• Addition of warning on Circulatory shock.

4.8 - Adverse effects (undesirable effects).

• Added hypersensitivity of the respiratory tract.
• Added acute and delayed lung injury.
• Added circulatory shock.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading'Moderate CYP3A4 inhibitors'. Co-administration with moderate CYP3A4 inhibitors such as calcium channel blockers (verapamil and diltiazem) will increase the exposure to colchicine, which may lead to colchicine induced toxicity including fatalities. If treatment with a moderate CYP3A4 inhibitor is required in patients with normal renal and hepatic function, a reduction in colchicine dosage or interruption of colchicine treatment is recommended.

4.4 - Special warnings and precautions for use.

• Additional detail on anaphylactic reactions.

4.8 - Adverse effects (undesirable effects).

• Addition of Hypersensitivity reactions.

4.8 - Adverse effects (undesirable effects).

• Update to Immune System Disorders in Post-marketing experience, 'Rheumatoid Arthritis' and 'Inflammatory Bowel Disease' added to 'New onset paradoxical drug-induced immune disorders'.
• Added to Post-marketing experience, 'Musculoskeletal and connective tissue disorders', 'Rheumatoid arthritis' with a frequency unknown.

4.4 - Special warnings and precautions for use.

• Update to Other immune-related adverse reactions section to include cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with ipilimumab. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.
• .

4.8 - Adverse effects (undesirable effects).

• Update to Postmarketing experience section to include Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome associated with the use of ipilimumab in combination with nivolumab.

4.4 - Special warnings and precautions for use.

• Cases of Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome (presenting as an overlap of either two or all three conditions), some with fatal outcome, have been reported with nivolumab and nivolumab in combination with ipilimumab. Early recognition and aggressive management are essential to address associated morbidity and risk of mortality.

4.8 - Adverse effects (undesirable effects).

• Update to Postmarketing experience section to include Myocarditis-Myositis-Myasthenia Gravis Overlap Syndrome.

4.8 - Adverse effects (undesirable effects).

• Post-marketing experience: added pyrexia as a non-serious adverse reaction.

4.4 - Special warnings and precautions for use.

• Added new information to enhance the existing warning regarding pulmonary oily microembolism. The patient should be observed during and immediately after each injection in order to allow for early recognition of possible signs and symptoms of pulmonary oily microembolism.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction under subheading'Effects of androgens on other drugs'. Androgens may potentiate the effects of ciclosporin and increase risk of nephrotoxicity. The concurrent administration of testosterone with ACTH or corticosteroids may enhance oedema formation; thus these active substances should be administered cautiously, particularly in patients with cardiac or hepatic disease or in patients predisposed to oedema.
• Added new interaction under subheading'Insulin and other anti-diabetic medicines'. Androgens may improve glucose tolerance and decrease the need for insulin or other antidiabetic medicines in diabetic patients. Patients with diabetes mellitus should therefore be monitored especially at the beginning or end of treatment and at periodic intervals during Reandron 1000 treatment. Concomitant use of testosterone replacement therapy and sodium-glucose co-transporter 2 (SGLT-2) inhibitors has been associated with an increased risk of erythrocytosis. Since both substances may independently elevate haematocrit levels, a cumulative effect is possible. Monitoring of haematocrit and haemoglobin levels is recommended in patients receiving both treatments.

4.8 - Adverse effects (undesirable effects).

• Added pulmonary oil microembolism with a frequency of rare.

4.4 - Special warnings and precautions for use.

• Addition of warning regarding risk of Thrombotic thrombocytopenic purpura (TTP).

4.8 - Adverse effects (undesirable effects).

• Addition of Thrombotic thrombocytopenic purpura (TT) of unknown frequency under 'Blood and lymphatic system disorders'.

4.3 - Contraindications.

• Cardiogenic shock, unstable angina, clinically significant aortic stenosis.
• Acute angina attacks or for secondary prevention of myocardial infarction.
• Severe hypotension.
• History of gastro-intestinal obstruction, oesophageal obstruction, or and degree of reduced intestinal lumen diameter of the intestinal tract. It must not be used in patients with a Kock pouch (ileostomy after proctocolectomy), inflammatory bowel disease or Crohn's disease.
• .

4.5 - Interactions with other medicines and other forms of interactions.

• Updated digoxin interaction.

4.8 - Adverse effects (undesirable effects).

• Cardiovascular system, vascular disorders, digestive system, nervous system and immune system disorders.
• Post-marketing AE updated for Respiratory, thoracic, and mediastinal disorders.
• .

4.5 - Interactions with other medicines and other forms of interactions.

• Concomitant use of mavacamten is contraindicated.

4.4 - Special warnings and precautions for use.

• Addition of liver injury as warning and precaution.

4.8 - Adverse effects (undesirable effects).

• Addition of liver injury as adverse drug reactions from post-marketing experience.

4.4 - Special warnings and precautions for use.

• Monitoring for recurrence of neuromuscular blockade.
• Prolonged neuromuscular blockade.
• Adequate ventilation.
• Caution in patients receiving anticoagulation.
• Depth of anaesthesia, awareness under surgical anaesthesia.
• Caution for use with rocuronium or vecuronium.

4.8 - Adverse effects (undesirable effects).

• Dysgeusia, headache, nausea, urticaria, pruritus, dizziness, vomiting and abdominal pain.
• In post-marketing reports, hypersensitivity events.
• Cardiac disorders.
• Respiratory, thoracic, and mediastinal disorders adverse effects.
• Severe systemic disease.
• .

4.4 - Special warnings and precautions for use.

• Addition of information relating to:
• Institute alternative antibacterial therapy in cSSSI or RIE.
• Severe cutaneous adverse reactions.
• Symptoms of Tubulointerstitial Nephritis (TIN).
• Discontinuation in presence of unexplained muscle symptoms.
• Peripheral neuropathy.
• Increased CPK and renal impairment.
• Treatment failure in non-susceptible organism and Clostridioides difficile-associated diarrhoea (CDAD).
• Revised myopathy information.

4.5 - Interactions with other medicines and other forms of interactions.

• Interactions in renal impairment.
• Interference between daptomycin and assay reagents of prothrombin time/international normalised ratio (PT/INR).

4.8 - Adverse effects (undesirable effects).

• Addition of adverse effects:
• Thrombocythaemia, thrombocytopaenia,
• Infusion reaction: tachycardia, wheezing, pyrexia, rigors, systemic flushing, vertigo, syncope and metallic taste.
• Supraventricular tachycardia, extrasystole.

4.3 - Contraindications.

• Bronchial asthma.
• Depolarizing muscle relaxants.

4.4 - Special warnings and precautions for use.

• Addition of the following warnings:
• Severe cholinergic reaction in hyperreactive patients.
• Cyclopropane or halone anaesthesia.
• Use of anticholinesterase agents in patients with intestinal anastomoses.
• .

4.5 - Interactions with other medicines and other forms of interactions.

• Non-depolarising muscle relaxants.

4.8 - Adverse effects (undesirable effects).

• Addition to Post marketing: decreased cardiac conduction; cholinergic syndrome; myasthenia gravis, increase intestinal motility; muscle spasm; hypersensitivity; angioedema; hyperhidrosis, increased lacrimation.

4.3 - Contraindications.

• Added:
• Acute pulmonary oedema.
• Cardiac decompensation.

4.4 - Special warnings and precautions for use.

• Added:
• Glaucoma.
• G6PD deficiency.
• Heart failure.
• Decrease of blood pressure.

4.5 - Interactions with other medicines and other forms of interactions.

• Added:
• Dapoxetine and other medical products that may increase potassium levels.
• NSAIDs.

4.7 - Effects on ability to drive and use machines.

• Added blood pressure lowering effects and weakness.

4.4 - Special warnings and precautions for use.

• Additional monitoring for long-term therapy.
• Additional monitoring for ARDs and pulmonary oedema.

4.7 - Effects on ability to drive and use machines.

• Added Dizziness.
• Added Ataxia.

4.4 - Special warnings and precautions for use.

• Updated use in hepatic impairment.

4.5 - Interactions with other medicines and other forms of interactions.

• Monitoring liver enzymes added to Ciclosporin topic.

4.8 - Adverse effects (undesirable effects).

• Additional adverse effects to align with the SmPC relating to the following:
• Clinical adverse experiences in adult patients added (Table 4 added).
• Clinical adverse experiences in paediatric patients added (Table 9 added).
• Laboratory values updated.
• Post-marketing experience updated with following new reactions:
• Hepatic necrosis.
• Erythema multiforme, skin exfoliation.
• Angioedema.
• Pancreatitis.
• Clinically significant renal dysfunction.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Liver Injury'. Clinically significant liver injury, without findings of viral hepatitis, has been reported in the post marketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including BRIUMVI. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred weeks to months after administration. Patients treated with BRIUMVI found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3x the upper limit of normal (ULN) with serum total bilirubin greater than 2x ULN, are potentially at risk for severe drug-induced liver injury. Obtain liver function tests prior to initiating treatment with BRIUMVI and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue BRIUMVI.

4.8 - Adverse effects (undesirable effects).

• Added Liver injury with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Kounis syndrome.

4.8 - Adverse effects (undesirable effects).

• Kounis syndrome.
• Cutaneous vasculitis.
• Symmetrical drug-related intertriginous and flexural exanthema.

4.4 - Special warnings and precautions for use.

• Kounis syndrome.

4.8 - Adverse effects (undesirable effects).

• Kounis syndrome.
• Cutaneous vasculitis.
• Symmetrical drug-related intertriginous and flexural exanthema.

4.3 - Contraindications.

• Update to use in pregnancy.

4.4 - Special warnings and precautions for use.

• Added Adrenal insufficiency.
• Added Endocrine effects.
• Added Neonatal withdrawal syndrome.
• Added hepatobiliary disorders.
• Added Gastrointestinal toxicity.
• Kounis syndrome added under Cardiovascular and cerebrovascular effects topic.
• SCARs.
• Added Hypokalaemia and renal tubular acidosis to Hazardous and harmful use topic.

4.5 - Interactions with other medicines and other forms of interactions.

• Added Gabapentinoids interaction.

4.6 - Fertility, pregnancy and lactation.

• Neonatal withdrawal syndrome added to the Use in Pregnancy topic.
• Full pregnancy contraindication.

4.8 - Adverse effects (undesirable effects).

Following adverse effects added to table:

• Hypotension added at frequency very rare.
• Adrenal insufficiency and androgen deficiency added under Endocrine Disorders at frequency Not known.
• Hypokalaemia added at frequency Not known.
• Kounis syndrome added at frequency Not known.
• Central sleep apnoea syndrome added at frequency Not known.
• Pancreatitis added at frequency Not known.
• Spasm of sphincter of Oddi added at frequency Not known.
• Severe Cutaneous Adverse Reactions (SCARs) added at frequency Very rare.
• Renal tubular acidosis added at frequency Not known.
• Irritability added at frequency Not known.
• Antitussive therapy added at frequency Not known.

4.9 - Overdose.

• Toxic leukoencephalopathy.

4.3 - Contraindications.

• Update to use in pregnant women and with immunosuppressive therapy.

4.4 - Special warnings and precautions for use.

• Update to use in pregnant women and with immunosuppressive therapy.

4.6 - Fertility, pregnancy and lactation.

• Update to use in pregnant women and with immunosuppressive therapy.

4.3 - Contraindications.

• Update to use in pregnant women and with immunosuppressive therapy.

4.4 - Special warnings and precautions for use.

• Update to use in pregnant women and with immunosuppressive therapy.

4.6 - Fertility, pregnancy and lactation.

• Update to use in pregnant women and with immunosuppressive therapy.

4.4 - Special warnings and precautions for use.

• Generalised bullous fixed drug eruption,

4.8 - Adverse effects (undesirable effects).

• Generalised bullous fixed drug eruption,

4.9 - Overdose.

• Added Desvenlafaxine is the major active metabolite of venlafaxine. Hypoglycaemia has been reported in association with venlafaxine overdose.

4.3 - Contraindications.

• Patients with a history of photoallergy or phototoxic reaction.

4.4 - Special warnings and precautions for use.

• Updated concomitant use with HMG-CoA reductase inhibitors.
• Muscle disorders.
• Concomitant use with CYP2C8, CYP2C29, CYP2C19, CYP1A2, UGTA1, UGTA3 and OATP1B1 substrates.

4.5 - Interactions with other medicines and other forms of interactions.

• Selexipag.
• Enzalutamide.
• Colchicine.
• Expanded HMG-CoA reductase inhibitors.

4.4 - Special warnings and precautions for use.

• Monitoring of patients requiring surgery for infectious and non-infectious complications.

4.4 - Special warnings and precautions for use.

• Generalised bullous fixed drug eruption.

4.8 - Adverse effects (undesirable effects).

• Fixed drug eruption.
• Generalised bullous fixed drug eruption.

4.8 - Adverse effects (undesirable effects).

• Tachycardia.

4.8 - Adverse effects (undesirable effects).

• Added hallucinations with a frequency of uncommon.

4.8 - Adverse effects (undesirable effects).

• Added under subheading 'Orphenadrine citrate' hallucinations with a frequency of less common.

4.4 - Special warnings and precautions for use.

• Addition of warning on acute myopathy.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of interaction between corticosteroids, and anticholinergics and neuromuscular blocking agents.

4.9 - Overdose.

• Added new overdose event, hypoglycaemia, under subheading 'Signs and Symptoms'.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Suicidal behaviour and ideation'. Suicidal behaviour and ideation have been reported with GLP-1 receptor agonists.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with PALEXIA should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as PALEXIA may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of tapentadol by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Biodone Forte has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added drug dependence with a frequency of not known. Repeated use of PALEXIA can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.2 - Dose and method of administration.

• Updated statement under subheading 'Dosage (dose and interval)'. If Prolia treatment is discontinued, consideration should be given to transitioning to an alternative antiresorptive therapy.

4.4 - Special warnings and precautions for use.

• Updated statement under subheading 'Osteonecrosis of the jaw'. In patients who develop ONJ during treatment with Prolia, a temporary interruption of Prolia treatment should be considered based on individual risk/benefit assessment until the condition resolves.
• Updated warning under subheading 'Multiple vertebral fractures (MVF) following discontinuation of Prolia treatment'. MVF may occur following discontinuation of treatment with Prolia, particularly in patients with a history of vertebral fracture. New vertebral fractures occurred as early as 7 months after the last dose of PROLIA. Patients being treated with Prolia, should be advised not to interrupt Prolia therapy without prior consultation with their treating physician. The individual benefit/risk should be evaluated before discontinuing treatment with Prolia. If Prolia treatment is discontinued, consideration should be given to transitioning to an alternative antiresorptive therapy.

4.5 - Interactions with other medicines and other forms of interactions.

• Interaction with methotrexate.

4.4 - Special warnings and precautions for use.

• Updated haematological effect for renal impairment.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated information regarding drug impacts for bone marrow depressants.

4.8 - Adverse effects (undesirable effects).

• Nausea.
• Vomiting.
• Specifying hepatobiliary disorders.

4.4 - Special warnings and precautions for use.

• Sarcoidosis.
• Addition of warning statements for immune-mediated adverse reactions including the co-occurrence of myositis, myocarditis, and myasthenia gravis (Triple-M syndrome).

4.8 - Adverse effects (undesirable effects).

• Sarcoidosis.

4.8 - Adverse effects (undesirable effects).

• Safety data for Study TRAILBLAZER-ALZ-6 at 76 weeks.

4.4 - Special warnings and precautions for use.

• Acute myopathy with high doses.
• Caution use in osteoporosis.

4.8 - Adverse effects (Undesirable effects).

• Panniculitis.
• Rhabdomyolysis.

4.8 - Adverse effects (undesirable effects).

• Psoriasis/psoriasis aggravation.

4.2 - Dose and method of administration.

• Deletion of information regarding the opening of capsules. Relocation of handling instructions to section 6.6.

4.4 - Special warnings and precautions for use.

• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Biodone Forte should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as Biodone Forte may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of methadone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Biodone Forte has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Psychiatric disorders'. Suicidal behaviour and ideation have been reported with GLP-1 receptor agonists. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behaviours, and/or any unusual changes in mood or behaviour. Consider the benefits and risks for individual patients prior to initiating or continuing therapy in patients with suicidal thoughts or behaviours or have a history of suicidal attempts.

4.8 - Adverse effects (undesirable effects).

• Added dysaesthesia.

4.8 - Adverse effects (undesirable effects).

• Added anaphylactic reaction with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Proladone should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids, such as Proladone, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of oxycodone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or noncardiac chest pain.
• Added new warning under subheading 'Hepatobilary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Proladone has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

4.6 - Fertility, Pregnancy and Lactation.

• Updated information under subheading 'Use in Pregnancy'. During labour, narcotic analgesics may cause respiratory depression in the newborn infant. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of Proladone during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Update to infusion reactions frequency.

4.8 - Adverse effects (undesirable effects).

• Meningococcal infections as a MedDRA grouped term.

4.8 - Adverse effects (undesirable effects).

• Corneal decompensation.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, ACTIQ has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Updated warning under subheading 'Endocrine Effects'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.2 - Dose and method of administration.

• Addition of hepatotoxicity as adverse reaction with dose modification. Hepatotoxicity (Grade 3-4): Withhold LAZCLUZE and amivantamab. Upon recovery to ≤ Grade 1, resume both medicinal products at the same dose or consider dose reduction, preferentially reducing the dose of amivantamab first.

4.8 - Adverse effects (undesirable effects).

• Added hepatotoxicity as adverse reaction in Table 3.
• Added description of hepatotoxicity. Hepatotoxicity-related reactions occurred in 47% of patients treated with lazertinib in combination with amivantamab. Most events were Grade 1-2, with Grade 3-4 hepatotoxicity occurring in 9% of patients. Most events were related to elevations of serum transaminases (36% alanine elevations of transaminases were able to continue study treatment without modification of study treatment while a small number were managed with a dose interruption or with a dose reduction. There were no cases of liver failure or fatal cases of hepatotoxicity in clinical studies.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading'Severe cutaneous adverse reactions (SCARs)'. SCARs such as erythema multiforme (EM), Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) which can be life-threatening or fatal, have been reported very rarely in association with omeprazole treatment. Patients should be advised of the signs and symptoms of the severe skin reaction EM/SJS/TEN/DRESS and should seek medical advice from their prescriber immediately when observing any indicative signs or symptoms. Omeprazole should be discontinued immediately upon signs and symptoms of severe skin reactions and additional medical care/close monitoring should be provided as needed. Rechallenge should not be undertaken in patients with EM/SJS/TEN/DRESS.

4.8 - Adverse effects (undesirable effects).

• Psoriasis/psoriasis aggravation.

4.8 - Adverse effects (undesirable effects).

Nervous system disorders:

• Aseptic meningitis.
• Hyperkinesia.

4.4 - Special warnings and precautions for use.

• Hypokalaemia.

4.8 - Adverse effects (undesirable effects).

• Anaemia,
• Eosinophilia,
• Increase frequency of Candida infection to common,
• Erythema multiforme,
• Toxic epidermal necrolysis (TEN),
• Encephalopathy and convulsions (class effect).

4.9 - Overdose.

• Discontinue treatment.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading'Hepatotoxicity'. Serious cases of drug induced liver injury (DILI) including hepatitis, acute hepatitis and hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of erlotinib. Risk factors may include pre-existing liver disease or concomitant hepatotoxic medications. Periodic liver function testing is recommended during treatment with erlotinib. The frequency of monitoring of liver function should be increased in patients with pre-existing hepatic impairment or biliary obstruction. Prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury. Erlotinib is not recommended for use in patients with severe hepatic dysfunction.

4.8 - Adverse effects (undesirable effects).

• Added hepatitis with a frequency of rare.
• Added acute hepatitis with a frequency of unknown.
• Added pneumatosis intestinalis with a frequency of rare.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading'Hepatotoxicity'. Serious cases of drug induced liver injury (DILI) including hepatitis, acute hepatitis and hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of erlotinib. Risk factors may include pre-existing liver disease or concomitant hepatotoxic medications. Periodic liver function testing is recommended during treatment with erlotinib. The frequency of monitoring of liver function should be increased in patients with pre-existing hepatic impairment or biliary obstruction. Prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury. Erlotinib is not recommended for use in patients with severe hepatic dysfunction.

4.8 - Adverse effects (undesirable effects).

• Added hepatitis with a frequency of rare.
• Added acute hepatitis with a frequency of unknown.
• Added pneumatosis intestinalis with a frequency of rare.

4.4 - Special warnings and precautions for use.

• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, fentanyl has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with fentanyl should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as fentanyl, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been reported after opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

4.4 - Special warnings and precautions for use.

• Amended language under Hypothyroidism to include additional precaution for patients with insufficient response to substitution with T4.

4.8 - Adverse effects (undesirable effects).

• Post-marketing data: Stevens-Johnson Syndrome.

4.8 - Adverse effects (undesirable effects).

• Tattoo associated skin reaction.

4.3 - Contraindications.

• Natural or acquired idiosyncrasy to barbiturates.

4.4 - Special warnings and precautions for use.

• Additional contraception methods.
• Delirium.

4.5 - Interactions with other medicines and other forms of interactions.

• Posaconazole,
• Etoposide,
• Abacavir,
• Pyridoxine,
• Folic acid,
• Folinic acid,
• Carbamazepine,
• Lamotrigine,
• Tiagabine,
• Zonisamide,
• Primidone,
• Ethosuximide,
• Stripentol.
• Updated: anti-arrhythmics, calcium channel blockers.

4.6 - Fertility, pregnancy and lactation.

• Should not be used during pregnancy unless the potential benefit outweighs the risks.

4.8 - Adverse effects (undesirable effects).

• Headache,
• Blood count changes,
• Circulatory disorders accompanied by arterial hypotension or even shock,
• Intolerance reactions (fever, hepatic disorders, hepatitis, lymph node swelling, leucocytosis, lymphocytosis,
• Increased sensitivity to light (photosensitivity),
• Allergic cross reactions with other antiepileptics,
• Drug rash with eosinophilia and systemic symptoms (DRESS syndrome),
• Pemphigus vulgaris (severe skin disease with formation of blisters),
• Renal damage,
• Disorders of sexual function (reduced libido, impotence),
• Upper abdominal discomfort,
• Gingival enlargement,
• Tiredness (sleepiness, weariness, muziness, prolonged reaction time),
• Reduction of serum concentrations of thyroid hormones,
• Reduction in folic acid levels,
• General joint pain.
• Cholestasis.

4.8 - Adverse effects (undesirable effects).

• Tattoo associated skin reaction.

4.4 - Special warnings and precautions for use.

• Sleep-related breathing disorders.
• Adrenal insufficiency.
• Endocrine effects.
• Hepatobiliary disorders.
• Gastrointestinal toxicity.
• Caution for use in patients with pheochromocytoma or in patients with obstructive and inflammatory bowel disease.

4.8 - Adverse effects (undesirable effects).

• Antidiuretic hormone release.
• Adrenal insufficiency.
• Androgen deficiency.
• Drowsiness.
• Vertigo.
• CNS depression.
• Serotonin syndrome.
• Miosis.
• Peripheral vasodilation.
• Hypotension.
• Central sleep apnoea.
• Coughing at induction of anaesthesia.
• Hypercapnia.
• Pulmonary oedema.
• Sweating.
• Dysphagia.
• Constipation.
• Ileus.
• Pancreatitis.
• Spasm of sphincter of Oddi.
• Urine retention.
• Habituation.
• Drug withdrawal syndrome.
• Pyrexia.
• Delirium.
• Tolerance.
• Dependence.

4.6 - Fertility, pregnancy and lactation.

• Breast-feeding restriction for 1 week after completing treatment.

4.8 - Adverse effects (undesirable effects).

• Increase of frequency of ketoacidosis from'rare' to'uncommon.'.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with oxycodone/naloxone modified release tablets should be considered.
• Updated warning under subheading 'Endocrine Effects'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of oxycodone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Updated warning under subheading 'Biliary tract disorders'. Therefore, oxycodone/naloxone modified release tablets has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Psychiatric disorders'. Suicidal behaviour and ideation have been reported with GLP-1 receptor agonists. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behaviours, and/or any unusual changes in mood or behaviour. Consider the benefits and risks for individual patients prior to initiating or continuing therapy in patients with suicidal thoughts or behaviours or have a history of suicidal attempts.

4.8 - Adverse effects (undesirable effects).

• Added under subheading 'PADCEV as monotherapy', skin hyperpigmentation, skin discoloration, pigmentation disorder with a frequency of not known.
• Added under subheading 'PADCEV in combination with pembrolizumab', skin hyperpigmentation, skin discoloration, pigmentation disorder with a frequency of not known.

4.8 - Adverse effects (undesirable effects).

• Skin hyperpigmentation.
• Skin discoloration.
• Pigmentation disorder.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading'Hepatotoxicity'. Serious cases of drug induced liver injury (DILI) including hepatitis, acute hepatitis and hepatic failure and hepatorenal syndrome (including fatalities) have been reported during use of erlotinib. Risk factors may include pre-existing liver disease or concomitant hepatotoxic medications. Periodic liver function testing is recommended during treatment with erlotinib. The frequency of monitoring of liver function should be increased in patients with pre-existing hepatic impairment or biliary obstruction. Prompt clinical evaluation and measurement of liver function tests should be performed in patients who report symptoms that may indicate liver injury. Erlotinib treatment should be interrupted or discontinued if changes in liver function are severe. Erlotinib is not recommended for use in patients with severe hepatic dysfunction.

4.8 - Adverse effects (undesirable effects).

• Added hepatitis with a frequency of rare.
• Added acute hepatitis with a frequency of unknown.
• Added pneumatosis intestinalis with a frequency of rare.

4.4 - Special warnings and precautions for use.

• Added new warning 'Idiopathic intracranial hypertension (pseudotumor cerebri) has been reported in patients receiving mesalazine. Patients should be warned for signs and symptoms of idiopathic intracranial hypertension, including severe or recurrent headache, visual disturbances or tinnitus. If idiopathic intracranial hypertension occurs, discontinuation of mesalazine should be considered'.
• Updated warning under subheading 'Use in renal impairment'. Mesalazine treatment should be discontinued immediately if renal function deteriorates.

4.8 - Adverse effects (undesirable effects).

• Added Idiopathic intracranial hypertension with a frequency of not known.

4.8 - Adverse effects (undesirable effects).

General disorders and administration site conditions.

• Hypothermia.
• Hyperthermia.

4.8 - Adverse effects (undesirable effects).

General disorders and administration site conditions.

• Hypothermia.
• Hyperthermia.

4.3 - Contraindications.

• Rhabdomyolysis with renal dysfunction secondary to myoglobinuria.

4.5 - Interactions with other medicines and other forms of interactions.

• Telmisartan may increase antihypotensive effect of other antihypertensive agents.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, buprenorphine has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with buprenorphine should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Hormonal changes, including androgen deficiency, may present with low libido, impotence, erectile dysfunction, amenorrhea, or infertility.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added sphincter of Oddi dysfunction with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• DRESS complicated by HLH, including MAS.
• HLH/MAS.

4.8 - Adverse effects (undesirable effects).

• Pulmonary nodule.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Updated warning under subheading 'Endocrine Effects'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of oxycodone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Psychiatric disorders'. Suicidal behaviour and ideation have been reported with GLP-1 receptor agonists. Monitor patients for the emergence or worsening of depression, suicidal thoughts or behaviours, and/or any unusual changes in mood or behaviour. Consider the benefits and risks for individual patients prior to initiating or continuing therapy in patients with suicidal thoughts or behaviours or have a history of suicidal attempts.

4.5 - Interactions with other medicines and other forms of interactions.

• Update to interaction between ticagrelor and rosuvastatin.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as NORSPAN/BUPREDERMAL may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of buprenorphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth. Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.6 - Fertility, pregnancy and lactation.

• Update to remove reference to “oral or intravenous” clindamycin.

4.8 - Adverse effects (undesirable effects).

• Haemophagocytic lymphohistiocytosis.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of fentanyl by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, DUROGESIC has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency with a frequency of not known.

4.6 - Fertility, pregnancy and lactation.

• Possibility of miscarriage.
• Warning for use in first trimester.

4.6 - Fertility, pregnancy and lactation.

• Possibility of miscarriage.
• Warning for use in first trimester.

4.3 - Contraindications.

• Anaphylaxis.

4.4 - Special warnings and precautions for use.

• Hypersensitivity.
• Anaphylaxis.

4.6 - Fertility, pregnancy and lactation.

• Excretion in human breast milk.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity.
• Anaphylaxis.

4.9 - Overdose.

• Updated to report a fatal case of overdose.

4.2 - Dose and method of administration.

• Updated information relating to skin-to-skin transfer.

4.4 - Special warnings and precautions for use.

• Update to statement on patients suffering severe cardiac, hepatic or renal insufficiency or ischaemic heart disease.
• Update to statement regarding antidiabetic medication.
• Spermatogenesis.
• Gynecomastia.
• Update to Excipient with known effect section (ethanol).
• Update to potential testosterone transfer.
• Ethanol and risk in neonates.

4.5 - Interactions with other medicines and other forms of interactions.

• Use with sunscreens.

4.8 - Adverse effects (undesirable effects).

• Post marketing adverse events:
• Hot flushes/flushing.
• Pruritis.
• Hirsutism.
• PSA increased.
• Nausea.
• Hypertension.
• Parathesia generalised.
• Headache.
• Anxiety.
• Decreased libido.
• Emotional lability.
• Gynaecomastia.
• Prostate abnormalities.
• Prostatomegaly.
• Prostatic disorders.
• Spermatogenesis.
• Semen disorders.
• Testicular atrophy.

4.2 - Dose and method of administration.

• Recommendation for discontinuing or restarting therapy if severe local inflammatory response develops.

4.4 - Special warnings and precautions for use.

• Use not recommended in severe nodular or deep nodulocystic acne.
• Contains polysorbate 80 (E433).

4.4 - Special warnings and precautions for use.

• Severe cutaneous adverse reactions (SCARs).

4.8 - Adverse effects (undesirable effects).

• Drug reaction with eosinophilia and system symptoms (DRESS).
• Erythema multiforme.

4.8 - Adverse effects (undesirable effects).

• Sepsis.
• Neutropenic sepsis.

4.4 - Special warnings and precautions for use.

• Falsely elevated serum levels in patients receiving enzalutamide.

4.5 - Interactions with other medicines and other forms of interactions.

• Interaction with enzalutamide.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with FENTANYL MEDSURGE should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as FENTANYL MEDSURGE, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, FENTANYL MEDSURGE has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with SUBLIMAZE should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as SUBLIMAZE, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, SUBLIMAZE has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.

4.8 - Adverse effects (undesirable effects).

• Encephalitis,
• Meningitis and.
• Meningoencephalitis.

4.4 - Special warnings and precautions for use.

• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with RAPIFEN should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as RAPIFEN may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, RAPIFEN has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Pancreatitis.

4.8 - Adverse effects (undesirable effects).

• Pancreatitis.

4.8 - Adverse effects (undesirable effects).

• Increased blood triglycerides.

4.4 - Special warnings and precautions for use.

• ALT elevations with concomitant antiviral treatment for HCV infections.

4.5 - Interactions with other medicines and other forms of interactions.

• ALT elevations with concomitant antiviral treatment for HCV infections.

4.4 - Special warnings and precautions for use.

• Ophthalmic evaluation within 3-4 months of starting treatment for all patients.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as codeine may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, codeine has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Added under subheading 'Use in Pregnancy', neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of codeine during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Increased risk of cardiac failure.

4.5 - Interactions with other medicines and other forms of interactions.

• Enzalutamide interference with the Chemiluminescent Microparticle Immunoassay (CMIA), resulting in falsely elevated digoxin plasma level results.

4.4 - Special warnings and precautions for use.

• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Fentanyl Juno should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as Fentanyl Juno may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Fentanyl Juno has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.

4.5 - Interactions with other medicines and other forms of interactions.

• Concomitant use of heparin with andexanet alfa may reduce the effectiveness of heparin.

4.8 - Adverse effects (undesirable effects).

• Hypersensitivity.

4.2 - Dose and method of administration.

• Reduce maximum daily dose (200 mg).

4.5 - Interactions with other medicines and other forms of interactions.

• Removed of information related to taking tablets with food (as prescribers are now instructed to refer to the Product Information of the Protease Inhibitor for further information).

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Endocrine Effects'. Opioids such as Tramal may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of tramadol by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Tramal has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administer with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Added under subheading 'Use in Pregnancy', neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Tumour Lysis Syndrome (TLS)'. TLS has been reported in patients receiving epcoritamab. Patients at an increased risk for TLS are recommended to receive hydration and prophylactic treatment with a uric acid lowering agent. Patients should be monitored for signs or symptoms of TLS, especially patients with high tumour burden or rapidly proliferative tumours, and patients with reduced renal function. Patients should be monitored for blood chemistries and abnormalities should be managed promptly.
• Added new warning under subheading 'Tumour flare'. Tumour flare has been reported in patients treated with epcoritamab. Manifestations could include localised pain and swelling. Consistent with the mechanism of action of epcoritamab, tumour flare is likely due to the influx of T-cells into tumour sites following epcoritamab administration. There are no specific risk factors for tumour flare that have been identified; however, there is a heightened risk of compromise and morbidity due to mass effect secondary to tumour flare in patients with bulky tumours located in close proximity to airways and/or a vital organ. Patients treated with epcoritamab should be monitored and evaluated for tumour flare at critical anatomical sites.

4.4 - Special warnings and precautions for use.

• Added new subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with fentanyl should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as fentanyl may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, fentanyl has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Updated warning under subheading 'Endocrine Effects', with androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of hydromorphone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administer with caution in patients with pancreatitis and diseases of the biliary tract.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added adrenal insufficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose and can present hours, days, or weeks after apparent recovery from the initial intoxication.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Dopamine Dysregulation Syndrome'. Dopamine Dysregulation Syndrome (DDS) is an addictive disorder resulting in excessive use of dopaminergic agonists, including SIFROL. Before initiation of treatment, patients and caregivers should be warned of the potential risk of developing DDS.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Sleep-related Breathing Disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with ASPALGIN should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as ASPALGIN, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary Disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, ASPALGIN has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or noncardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Updated subheading 'Use in Pregnancy'. Regular use of codeine during pregnancy may cause physical dependence in the fetus, leading to withdrawal symptoms in the neonate also known as neonatal withdrawal syndrome.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added central sleep apnoea syndrome with a frequency of not known.

4.9 - Overdose.

• Added Toxic leukoencephalopathy.

4.4 - Special warnings and precautions for use.

• Increases in gamma GT.
• Increases in alkaline phosphatase.
• Increases in bilirubin.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Endocrine Effects and adrenal insufficiency'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, fentanyl has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of uncommon.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Hemolytic Anaemia Associated with G6PD Deficiency.

4.4 - Special warnings and precautions for use.

• Psychiatric disorders.

4.8 - Adverse effects (undesirable effects).

• Compulsive eating.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Updated warning under subheading 'Endocrine Effects'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of morphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added pancreatitis with a frequency of not known.

4.8 - Adverse effects (undesirable effects).

• Pancreatitis.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administer with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Added updated subheading ' Use in Lactation'. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of codeine during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administer with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Added updated subheading ' Use in Pregnancy'. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of codeine during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Updated subheading ' Gastrointestinal'. Cases of oesophageal disorder (e.g. oesophageal motility disorder, lower oesophageal sphincter relaxation impaired, oesophageal peristalsis decreased) have been reported with opioid therapy'.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added central sleep apnoea syndrome with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Updated wording under subheading'Psychiatric disorders'. Suicidal behaviour and ideation have been reported with GLP-1 receptor agonists.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated interaction under subheading 'Oral contraceptives'. Reduced efficacy of oral contraceptives cannot be excluded, it is therefore advised that patients using oral hormonal contraceptives switch to a non-oral contraceptive method or add a barrier method of contraception for 4 weeks after initiation and for 4 weeks after each dose escalation with MOUNJARO.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading'Endocrine effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of morphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea. or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Renal insufficiency or acute renal failure.

4.5 - Interactions with other medicines and other forms of interactions.

• Concomitant theophylline use.

4.6 - Fertility, pregnancy and lactation.

• Largely reversible adverse effects on spermatogenesis in rats and dogs.

4.8 - Adverse effects (undesirable effects).

• Alopecia,
• Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis,
• Crystalluria, peripheral oedema,
• Myalgia, visual abnormalities,
• Diarrhea, gastrointestinal distress and nausea.

4.4 - Special warnings and precautions for use.

• Patients with cardiac arrhythmias, a history of cardiac arrhythmias or with risk factors for cardiac arrhythmias.

4.8 - Adverse effects (undesirable effects).

• Cardiac arrhythmias.

4.4 - Special warnings and precautions for use.

• Patients with cardiac arrhythmias, a history of cardiac arrhythmias or with risk factors for cardiac arrhythmias.

4.8 - Adverse effects (undesirable effects).

• Cardiac arrhythmias.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Updated subheading 'Gastrointestinal Disorders'. Cases of oesophageal disorder (e.g. oesophageal motility disorder, lower oesophageal sphincter relaxation impaired, oesophageal peristalsis decreased) have been reported with opioid therapy.
• Added central sleep apnoea syndrome with a frequency of not known.
• Added adrenal insufficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.8 - Adverse effects (undesirable effects).

• Added pneumonia.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, administer with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added pancreatitis with a frequency of not known.
• Added central sleep apnoea syndrome with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Off-label, chronic use and in high dose'. TEMGESIC is indicated for the short-term treatment of severe pain and should not be used for longer than 7 days. Chronic use of buprenorphine, especially in high doses beyond Temgesic's maximum daily dose, as well as other opioids, may lead to the following safety issues;
• Added new warning under subheading 'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of buprenorphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth. Due to the long half-life of buprenorphine, neonatal monitoring for several days should be considered to prevent the risk of respiratory depression or withdrawal syndrome in neonates.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, opioids have to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.8 - Adverse effects (undesirable effects).

• Panniculitis.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with SUBOXONE FILM should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as SUBOXONE FILM may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, SUBOXONE FILM has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.2 - Dose and method of administration.

• Co-administration with moderate CYP3A4 inhibitors.

4.8 - Adverse effects (undesirable effects).

• Update of ADR frequencies.
• Hypokalaemia,
• Pyrexia,
• Decrease in weight.

4.8 - Adverse effects (undesirable effects).

• Anaemia.
• Hyperbilirubinaemia.

4.4 - Special warnings and precautions for use.

• Added a new warning under subheading 'Serious Gastrointestinal Reactions'. Serious gastrointestinal reactions, including perforation, ulceration, haemorrhage, and obstruction, some with fatal outcomes, have been reported in the post-marketing setting with the use of fumaric acid esters, including TECFIDERA, with or without concomitant aspirin use. The majority of these events have occurred within 6 months of fumaric acid ester treatment initiation. In controlled clinical trials, the incidence of serious gastrointestinal adverse events was 1% in patients treated with TECFIDERA; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain.

4.4 - Special warnings and precautions for use.

• Added a new warning of under subheading 'Serious Gastrointestinal Reactions'. Serious gastrointestinal reactions, including perforation, ulceration, haemorrhage, and obstruction, some with fatal outcomes, have been reported in the post-marketing setting with the use of fumaric acid esters, including VUMERITY, with or without concomitant aspirin use. The majority of these events have occurred within 6 months of fumaric acid ester treatment initiation. In controlled clinical trials, the incidence of serious gastrointestinal adverse events was 1% in patients treated with VUMERITY; these events, none of which were fatal, included vomiting (0.3%) and abdominal pain (0.3%).

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with REMIFENTANIL VIATRIS should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as REMIFENTANIL VIATRIS may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Neonatal withdrawal syndrome'. Chronic use of remifentanil by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Added under subheading 'Use in Pregnancy', neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of remifentanil during pregnancy.

4.8 - Adverse effects (undesirable effects), post-marketing experience.

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added Toxic leukoencephalopathy.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with SUBUTEX should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids such as SUBUTEX may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, SUBUTEX has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.2 - Dose and method of administration.

• Guidance for withholding drug if neutropenia associated with infection or sepsis present.

4.4 - Special warnings and precautions for use.

• Contraception update.

4.6 - Fertility, pregnancy and lactation.

• Contraception update.

4.7 - Effects on ability to drive and use machines.

• Update based on possible adverse events.

4.4 - Special warnings and precautions for use.

• Range of psychological or behavioural effects including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggression (particularly in children).

4.8 - Adverse effects (undesirable effects).

• Psychomotor hyperactivity.
• Sleep disorders.
• Aggression.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Endocrine Effects'. Opioids may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with ABSTRAL should be considered.
• Added new warning under subheading 'Gastrointestinal toxicity/Opioid-induced oesophageal dysfunction'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, ABSTRAL has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under Use in Pregnancy, under subheading'Neonatal Abstinence Syndrome'. Chronic use of fentanyl by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g., hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.

4.6 - Fertility, pregnancy and lactation.

• Added Neonatal Abstinence Syndrome cross-reference.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with SUBOXONE should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as SUBOXONE, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, SUBOXONE has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.6 - Fertility, pregnancy and lactation.

• Updated sumatriptan excreted in breast milk.

4.8 - Adverse effects (undesirable effects).

• Breast pain.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Remifentanil-AFT should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as Remifentanil-AFT, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of remifentanil by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Remifentanil-AFT has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of remifentanil during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.5 - Interactions with other medicines and other forms of interactions.

• Addition of warning regarding concomitant administration with ketoconazole or other potent CYP3A inhibitors.

4.8 - Adverse effects (undesirable effects).

• Cough.
• Bronchitis.
• Influenza.
• Back pain.
• Urinary tract infection.

4.2 - Dose and Method of Administration.

• Updated information under subheading 'Dosage'. Perform baseline hepatic laboratory tests to evaluate for hepatic function and injury [including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum alkaline phosphatase (ALP), and serum bilirubin (total and direct)] before initiating treatment with VEOZA. Do not start VEOZA if ALT or AST is ≥ 2 x ULN or if the total bilirubin is ≥ 2 x ULN for the evaluating laboratory. While using VEOZA, perform follow-up hepatic laboratory tests monthly for the first 3 months at 6 months, and 9 months after initiation of therapy. Advise patients to discontinue VEOZA immediately and seek medical attention including hepatic laboratory tests if they experience signs or symptoms that may suggest liver injury.

4.4 - Special warnings and precautions for use.

• Updated warning under subheading 'Hepatotoxicity and liver function monitoring'. In the post-marketing setting, cases of serious but reversible hepatotoxicity have been reported within 40 days of treatment. Patients have experienced transaminase elevations (greater than 10 times the ULN) with concurrent elevations in bilirubin and/or alkaline phosphatase (ALP), sometimes associated with signs or symptoms such as fatigue, pruritus, jaundice, dark urine, or abdominal pain. Evaluate hepatic function (ALT, AST, ALP, and bilirubin) before initiating therapy. Do not initiate VEOZA if ALT or AST is equal to or exceeds 2 times the ULN or if the total bilirubin is elevated (e.g., equal to or exceeds 2 times the ULN). Patients should discontinue VEOZA immediately and seek medical attention, including hepatic laboratory tests, if they experience signs or symptoms that may suggest hepatotoxicity such as new onset fatigue, decreased appetite, nausea, vomiting, pruritus, jaundice, pale faeces, dark urine, or abdominal pain. Perform follow-up evaluation of hepatic function monthly for the first 3 months, at 6 months, and 9 months after initiating VEOZA and thereafter periodically based on clinical judgement. Discontinue VEOZA if: transaminase elevations are greater than 5 times the ULN, transaminase elevations are greater than 3 times the ULN and the total bilirubin level is greater than 2 times the ULN. Monitoring of liver function tests should continue until they have normalised and the other causes of liver injury should be excluded.

4.8 - Adverse effects (undesirable effects).

• Added aspartate aminotransferase (AST) increased with a frequency of common.
• Added hepatotoxicity with a frequency of not known.
• Added new subheading 'Hepatotoxicity'. Serious cases of drug-induced hepatotoxicity occurred within 40 days of starting VEOZA. Patients experienced elevated transaminases (up to 50 x ULN at peak elevation), elevated alkaline phosphatase (up to 4 x ULN at peak elevation), and bilirubin (up to 5 x ULN at peak elevation) coupled with symptoms of fatigue, nausea, pruritus, jaundice, pale faeces, and dark urine. After discontinuation of VEOZA, these abnormalities gradually resolved.

4.4 - Special warnings and precautions for use:

• Updated wording within subheading 'Depression' to include gonadotropin-releasing hormone receptor antagonist, including RYEQO, have been associated with mood disorders (including depression) and suicidal ideation. Evaluate women with a history of suicidal ideation, depression and mood disorders prior to initiating treatment. Women must be advised to contact their physician in case of mood changes and depressive symptoms, including shortly after initiating the treatment. Discontinue Ryeqo if depression recurs to a serious degree. Advise patients to seek immediate medical attention for suicidal ideation and behaviour.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.'.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Adrenal Insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with ENDONE should be considered.
• Added new warning under subheading 'Endocrine Effects'. Opioids, such as ENDONE, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of oxycodone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.6 - Fertility, Pregnancy and Lactation.

• Updated information under subheading 'Use in Pregnancy'. Neonatal withdrawal syndrome has been reported in newborn infants with chronic maternal use of oxycodone during pregnancy.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea syndrome with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.4 - Special warnings and precautions for use.

• Drug resistance in dermatophytes.

4.2 - Dose and method of administration.

• Added recommendation to consider prophylaxis for patients at increased risk of CMV, herpes, pneumocystis jirovecii pneumonia, and other opportunistic infections.

4.4 - Special warnings and precautions for use.

• Recommendation to administer prophylactic antimicrobials, as appropriate for serious infections.

4.8 - Adverse effects (undesirable effects).

• Addition of information on CMV and pneumocystis jirovecii pneumonia infections and colitis.

4.3 - Contraindications.

• Hypertrophic obstructive cardiomyopathy (HOCM).

4.8 - Adverse effects (undesirable effects).

• Heartburn.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with KAPANOL should be considered.
• Updated warning under subheading 'Hormonal Changes'. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.
• Updated warning under subheading 'Post-operatively'. Prolonged release opioids should not be used for acute post-operative pain owing to the increased risk of persistent post-operative opioid use (PPOU) and opioid-induced ventilatory impairment (OIVI).
• Added new warning under subheading 'Neonatal Withdrawal Syndrome'. Chronic use of morphine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.

4.8 - Adverse effects (undesirable effects).

• Added adrenal insufficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Expanded warning related to use with hepatitis C virus treatment regimes, expanded warning in relation to exogenous estrogens, added warning related to depression.

4.5 - Interactions with other medicines and other forms of interactions.

• Expanded information relating to hepatitis C virus treatment regimes.

4.4 - Special warnings and precautions for use.

• Hypersensitivity reactions including anaphylaxis.

4.8 - Adverse effects (undesirable effects).

• Pneumonia.
• Aspiration pneumonia.

4.3 - Contraindications.

Rare hereditary problems:

• Galactose intolerance.
• Total lactase deficiency.
• Glucose-galactose malabsorption.

4.4 - Special warnings and precautions for use.

• Colchicine has a narrow therapeutic index.

4.8 - Adverse effects (undesirable effects).

• Amenorrhoea.
• Dysmenorrhoea.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of methadone by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, PHYSEPTONE has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.8 - Adverse effects (undesirable effects).

• Added central sleep apnoea with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'High Anion Gap Metabolic Acidosis'. Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Dolased Forte should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids, such as Dolased Forte, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Dolased Forte has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated interaction under subheading 'Flucloxacillin'. Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risk factors of glutathione depletion such as sepsis, malnutrition or chronic alcoholism.

4.8 - Adverse effects (undesirable effects).

• Added High anion gap metabolic acidosis with frequency not known. Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol. Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.
• Added central sleep apnoea with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added under subheading 'Codeine', toxic leukoencephalopathy has been observed with opioid overdose.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'High Anion Gap Metabolic Acidosis'. Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
• Added new warning under subheading'Sleep-related breathing disorders'. Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with Dolased should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids, such as Dolased, may influence the hypothalamic-pituitary-adrenal or –gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of codeine by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, Dolased has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.5 - Interactions with other medicines and other forms of interactions.

• Added new interaction, caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risk factors of glutathione depletion such as sepsis, malnutrition or chronic alcoholism.

4.8 - Adverse effects (undesirable effects).

• Added High anion gap metabolic acidosis with frequency not known. Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol. Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.
• Added central sleep apnoea with a frequency of not known.
• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.

4.9 - Overdose.

• Added toxic leukoencephalopathy has been observed with opioid overdose.

4.2 - Dose and method of administration.

• The dose should be determined only by a physician experienced with paediatric patients.

4.3 - Contraindications.

• Breastfeeding and hypersensitivity.

4.4 - Special warnings and precautions for use.

• Testing, hepatic and renal function, immunosuppression, combination therapies, considerations for discontinuation.

4.5 - Interactions with other medicines and other forms of interactions.

• Further information concerning interactions with other medicines.

4.6 - Fertility, pregnancy and lactation.

• Expanded contraception advice and use in pregnancy and breastfeeding.

4.7 - Effects on ability to drive and use machines.

• Dizziness and somnolence.

4.8 - Adverse effects (undesirable effects).

• Significant addition of adverse events.

4.9 - Overdose.

• Treatment, including activated charcoal.

4.4 - Special warnings and precautions for use.

• Added new warning under subheading 'High Anion Gap Metabolic Acidosis'. Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or patients with malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.
• Added new warning under subheading 'Adrenal insufficiency'. Adrenal insufficiency has been reported with opioid use, more often following long-term use. Symptoms may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, or low blood pressure. If adrenal insufficiency is suspected, appropriate laboratory testing is recommended and discontinuation of treatment with ZALDIAR should be considered.
• Added new warning under subheading 'Endocrine effects'. Opioids, such as ZALDIAR, may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Hormonal disturbances that have been observed include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes. Androgen deficiency may manifest as low libido, importance, erectile dysfunction, amenorrhea or infertility.
• Added new warning under subheading'Neonatal Withdrawal Syndrome'. Chronic use of tramadol by the mother at the end of pregnancy may result in a withdrawal syndrome (e.g. hypertonia, neonatal tremor, neonatal agitation, myoclonus, convulsions, apnoea or bradycardia) in the neonate. In many reported cases the withdrawal was serious and required treatment. The syndrome is generally delayed for several hours to several days after birth.
• Added new warning under subheading 'Hepatobiliary disorders'. Opioids may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Therefore, ZALDIAR has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.
• Added new warning under subheading 'Gastrointestinal Toxicity'. Reports of significant oesophageal dysfunction have been observed via high-resolution manometry in patients taking opioid medicines on a long-term basis. Discontinuation or weaning of opioids should be considered in patients presenting with oesophageal complaints including but not limited to dysphagia, regurgitation, or non-cardiac chest pain.

4.5 - Interactions with other medicines and other forms of interactions.

• Updated isoxazolyl penicillins interaction to include that concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis especially in patients with risk factors and prolonged treatment.

4.8 - Adverse effects (undesirable effects).

• Added pancreatitis with a frequency of not known.
• Added spasm of sphincter of Oddi with a frequency of not known.
• Added adrenal insufficiency and androgen deficiency with a frequency of not known.
• Added under subheading 'Paracetamol', high anion gap metabolic acidosis due to pyroglutamic acidosis (PGA) where reported with frequency not known. PGA may occur as a consequence of low glutathione levels in these patients.

4.9 - Overdose.

• Added toxic leukoencephalopathy under subheading 'Symptoms of overdose from tramadol'.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.'.

4.5 - Interactions with other medicines and other forms of interactions.

• Added interaction under subheading 'Levothyroxine'. Oral ciprofloxacin may decrease the absorption of levothyroxine. An interval of 6 hours between the administration of the two medications is recommended.'.

4.4 - Special warnings and precautions for use.

• COX-2 inhibitors added to cautionary statements regarding concomitant medication use.

4.8 - Adverse effects (undesirable effects).

• Intestinal diaphragm-like strictures to adverse effects with unknown frequency.

4.4 - Special warnings and precautions for use.

• Addition of COX-2 inhibitors to cautionary statements regarding concomitant medication use.

4.8 - Adverse effects (undesirable effects).

• Intestinal diaphragm-like strictures.

4.2 - Dose and method of administration.

• Reminder that HEPCLUDEX and auxiliary supplies are for Single Use Only.

4.3 - Contraindications.

• Severe acute exacerbations of HDV and HBV infection especially in patients with cirrhosis. Monitor clinical and laboratory follow-up for at least six months.

4.4 - Special warnings and precautions for use.

• QTc interval prolongation.

4.8 - Adverse effects (undesirable effects).

• QTc interval prolongation.

4.9 - Overdose.

• Posterior reversible encephalopathy syndrome (PRES).

4.3 - Contraindications.

• Lactation.
• Severe hepatic impairment.

4.4 - Special warnings and precautions for use.

• Potential risk of osteoporosis.
• Thromboembolic events are commonly observed in women with advanced breast cancer.

4.8 - Adverse effects (undesirable effects).

• Venous thromboembolism.
• Back pain.
• Vaginal haemorrhage.
• Neuropathy peripheral sciatica.
• Anaphylactic reactions.
• Vaginal moniliasis.
• Leukorrhea.
• Injection site haemorrhage.
• Injection site haematoma.
• Neuralgia.

4.4 - Special warnings and precautions for use.

• Can interfere with the test results from certain radioactive diagnostic agents.

4.9 - Overdose.

• Posterior reversible encephalopathy syndrome (PRES).

4.4 - Special warnings and precautions for use.

• Hyperammonemic encephalopathy.

4.8 - Adverse effects (undesirable effects).

• Nervous system disorders Hyperammonemic encephalopathy.

4.4 - Special warnings and precautions for use.

Severe skin reactions, such as:

• Exfoliative dermatitis,
• Erythema multiforme.
• Stevens-Johnson syndrome.
• Toxic epidermal necrolysis.
• Drug reaction with eosinophilia and.
• Systemic symptoms (DRESS).

4.8 - Adverse effects (undesirable effects).

• Erythema multiforme.
• Fixed drug eruption.

4.8 - Adverse effects (undesirable effects).

• Added thrombotic microangiopathy (TMA) under 'Post-marketing experience'.

4.5 - Interactions with other medicines and other forms of interactions.

• Cabotegravir.
• Fostemsavir.
• Lenacapavir.

4.8 - Adverse effects (undesirable effects).

• Hyperuricaemia.

4.8 - Adverse effects (undesirable effects).

• Updated with data from DESTINY-Gastric02 more recent Data Cut-Off (DCO) of November 2021.

4.2 - Dose and Method of Administration.

• Added to table 2, polymyalgia rheumatica as a footnote for the adverse drug reaction 'Other immune-mediated ADR'.

4.4 - Special warnings and precautions for use.

• Added polymyalgia rheumatica to the existing warning under subheading'Other immune mediated ADR'.
• Added new warning under subheading'Patients with pre-existing autoimmune disease (AID)'. In patients with pre-existing AID, data from observational studies suggest that the risk of immune-mediated ADR following immune checkpoint inhibitor therapy may be increased as compared with the risk in patients without pre-existing AID. In addition, flares of the underlying AID were frequent, but the majority were mild and manageable.

4.8 - Adverse effects (undesirable effects).

• Added polymyalgia rheumatica with a frequency of rare, into Table 3 'Adverse drug reactions in patients treated with IMFINZI monotherapy'.
• Added new adverse event under subheading 'IMFINZI in combination with chemotherapy'. Musculoskeletal and connective tissue disorders: Polymyalgia rheumatica with a frequency of rare, plus a footnote, not observed in the IMFINZI + chemotherapy pool, but observed in other AstraZeneca-sponsored clinical studies.
• Added new adverse events under subheading ' Immune checkpoint inhibitor class effects' There have been cases of the following ADR reported during treatment with other immune checkpoint inhibitors which might also occur during treatment with durvalumab: pancreatic exocrine insufficiency, haemophagocytic lymphohistiocytosis (HLH), aplastic anaemia. Adverse drug reactions in patients with IMFINZI: As monotherapy coeliac disease, in combination with chemotherapy coeliac disease and in combination with tremelimumab coeliac disease. All had a frequency of rare.

4.4 - Special warnings and precautions for use.

• Duration to withhold live vaccinations after chemotherapy.
• Update to cytotoxic and haematological monitoring.
• Recommended TPMT activity test before starting mercaptopurine.
• Update to warning for patients with NUDT15 variant.
• Cholestasis of pregnancy.