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Australian Adverse Drug Reactions Bulletin, Vol 19, No 1

February 2000

Prepared by the Adverse Drug Reactions Advisory Committee (ADRAC) and the Office of Medicine Safety Monitoring (OMSM) of the TGA.

Contents

Drug-induced nightmares

Nightmares are a relatively common spontaneous occurrence but they can also be induced by drugs. Since 1972, ADRAC has received 891 reports of nightmares suspected to be caused by drugs and Table 1 lists those most commonly reported. There was only one suspected drug in 90% of the cases and in those cases where the outcome was stated, 85% had recovered by the time the report was submitted to ADRAC. This usually followed withdrawal of the suspect drug.

Table 1: Reports of Drug-induced Nightmares
Drug No. of Reports
Sertraline 41
Propranolol 39
Metoprolol 38
Pindolol 33
Nicotine patches 30
Nitrazepam 24
Paroxetine 23
Atenolol 20
Simvastatin 17
Captopril 16
Methyldopa 15
Prazosin 15

The most commonly reported class of drugs is the β-blockers which are well known to induce nightmares. It is believed that the mechanism is linked to REM sleep suppression.1 Another class of drugs is the SSRIs including sertraline, paroxetine and also fluoxetine (10) and citalopram (4). The benzodiazepines are well represented with temazepam (11 reports), diazepam (10), and oxazepam (9) in addition to nitrazepam. Nicotine patches are also prominent on the list but this effect may be related to nicotine withdrawal. Nightmares may also be a rare class effect of the "statins" because as well as simvastatin, there are reports with pravastatin (10), fluvastatin (8) and atorvastatin (8).

Prescribers should be aware that a variety of drugs, as well as β-blockers, may cause nightmares and the effect is usually reversible on withdrawal of the drug.

Reference

  1. Thompson DF, Pierce DR. Drug-induced nightmares. Ann Pharmacother 1999; 33: 93-8.

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Take care with Vitamin K

ADRAC recently received a report that described an acute anaphylactoid reaction one minute after an 82 year old female received an intravenous injection of Konakion Paediatric Injection (phytomenadione 1 mg/0.5 mL). The outcome was fatal.

Since 1973, ADRAC has received 40 reports of anaphylactoid reactions in association with phytomenadione (vitamin K). In 38 cases, the reaction was associated with the IV use of the vitamin. While most patients recovered with appropriate treatment, there have been 4 fatalities.

Currently, there are two injectable formulations of phytomenadione. Konakion MM (10 mg/mL, mixed micelle preparation) is administered to adult patients by an intravenous bolus injection over at least 30 seconds. Intramuscular injection is contraindicated.

Konakion Paediatric Injection (1 mg/0.5 mL) is for use in neonates and infants. It is administered as an intramuscular injection. It is believed that the risk of anaphylactoid reactions with this product is increased by the presence of polyethoxylated castor oil (Cremophor) in the formulation. The risk of anaphylaxis is greater if given intravenously and this method of administration should not be used. It is anticipated that this formulation will soon be replaced by a mixed micelle preparation, Konakion MM Paediatric (2 mg/0.2 mL), which may be given by the oral, intramuscular or intravenous route.

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Problems with caffeine

ADRAC recently received a report of the death of a 25 year old woman who had ingested an unknown quantity of a guarana-based product, Race 2005 Energy Blast. The deceased had valvular heart disease and took care to minimise her caffeine intake, but the packaging of this product did not indicate its high caffeine content. An effect of the caffeine was considered likely to have contributed to her death.

There are many sources from which people may unwittingly ingest caffeine. Some of the well-known ones include tea, coffee, chocolate, and some popular soft drinks but people need also be aware that a number of prescription and over-the-counter medicines, such as No Doz and Cafergot tablets, can contain high concentrations of caffeine. Some energy drinks and other dietary supplements also contain substantial amounts of caffeine.1

Guarana is a popular complementary medicine that contains caffeine. It is made from the ground seeds of Paullinia cupana which has a natural caffeine content of about 5 %. Therapeutic goods containing guarana will soon require a label statement to indicate that the product contains caffeine and stating the quantity of caffeine per dose unit. However, guarana is being increasingly added to sports drinks and foods, with claims that it increases stamina and endurance.1 These products are deemed to be foods, and thus are not subject to the labelling and regulatory controls of therapeutic goods.

The inclusion of caffeine in such a large number of products, may lead to an intake of substantial, potentially unsafe, quantities of caffeine. Symptoms of this 'caffeinism' can include: nausea, diarrhoea, light-headedness, indigestion, irregular heartbeat and respiration, jitteriness and frequent urination. In addition, acute symptoms of caffeine withdrawal occur during the first 20-48 hours, but can persist for several days. Symptoms may include headache, nausea, nervousness, reduced alertness and depressed mood. Dependence may develop if coffee is taken in order to abate these symptoms.1

Practitioners are reminded to question patients presenting with possible caffeine overdose about their ingestion of these lesser known caffeinated products.

Reference

  1. Medsafe Editorial Team. Too much caffeine. August 1999. Available from URL: http://www.medsafe.govt.nz/hprofs.htm.

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Allopurinol azathioprine interaction - a reminder

Three recent reports to ADRAC of patients who developed anaemia (2) or neutropenia highlight the dangers of the concomitant use of allopurinol and azathioprine. The interaction between these drugs is well documented and has been publicised by ADRAC, but prescribers may need to be reminded of its importance.1,2,3

Allopurinol (Allohexal, Allorin, Capurate, Progout, Zyloprim) decreases the metabolism of mercaptopurine (Purinethol) which is the active metabolite of the more widely used prodrug, azathioprine (Azamun, Imuran, Thioprine) resulting in increased concentrations of mercaptopurine. Since 1980, ADRAC has received 10 reports attributing adverse haematological consequences to this interaction, including one report of a patient who died.

Concomitant use of allopurinol with azathioprine (or mercaptopurine) is best avoided. If it is necessary for the patient to take these drugs together, a large reduction in the normal dose of azathioprine (or mercaptopurine) is essential.

References

  1. ADRAC. Allopurinol and azathioprine. Fatal interaction. Med J Aust 1980; 2: 130.
  2. ADRAC A reminder - the allopurinol azathioprine interaction. Aust Adv Drug React Bull, February, 1985.
  3. Boyd IW. Allopurinol-azathioprine interaction. J Intern Med 1991; 229: 386.

New drug update - serious adverse reactions with leflunomide

Leflunomide (Arava) is a new disease-modifying antirheumatic drug (DMARD) which is indicated for the treatment of patients with rheumatoid arthritis. This drug is registered in Australia but has had limited marketing. Its mechanism of action is different to the other commonly used DMARDs methotrexate and sulfasalazine but it was expected that leflunomide might have a similar safety profile. Recently, the European Medicines Evaluation Agency (EMEA) has issued a Public Statement which described 16 cases of pancytopenia and 9 cases of serious skin reactions in association with leflunomide. In Australia, prescribers have been informed of these concerns and changes made to the product information and the consumer medicine information.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Acamprosate (Campral)
  • Candesartan (Atacand)
  • Carvedilol (Dilatrend, Kredex)
  • Celecoxib (Celebrex)
  • Clopidogrel (Iscover, Plavix)
  • Donepezil (Aricept)
  • Entacapone (Comtan)
  • Gelatin succinylated (Gelofusine)
  • Leflunomide (Arava)
  • Montelukast (Singulair)
  • Naltrexone (ReVia)
  • Naratriptan (Naramig)
  • Raloxifene (Evista)
  • Sildenafil (Viagra)
  • Telmisartan (Micardis/Pritor)
  • Tiludronate (Skelid)
  • Tramadol (Tramal)
  • Zafirlukast (Accolate)
  • Zanamavir (Relenza)
  • Zolmitriptan (Zomig)

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What to report?

(you do not need to be certain, just suspicious!)

ADRAC encourages the reporting of all suspected adverse reactions to medicines, including vaccines, OTC medicines, herbal, traditional or alternative remedies. ADRAC particularly requests reports of:

  • ALL suspected reactions to new drugs (see drugs of current interest)
  • ALL suspected drug interactions
  • Suspected reactions causing
    • Death
    • Admission to hospital or prolongation of hospitalisation
    • Increased investigations or treatment
    • Birth defects

For blue cards

Reports of suspected adverse drug reactions are best made by using a prepaid reporting form ("blue card") which is available from the website or from the Office of Medicines Safety Monitoring (02 6232 8744).

Reports can also be submitted electronically, by clicking on "Report a problem" on this website, by fax: 02 6232 8392, or email: ADR.Reports@tga.gov.au.

ISSN 0812-3837

© Commonwealth of Australia 2000

All correspondence to be addressed to: The Secretary, ADRAC, PO Box 100, Woden ACT 2606

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