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Australian Adverse Drug Reactions Bulletin, Vol 14, No 2

May 1995

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


Amiodarone - a reminder

Amiodarone is a class III antiarrhythmic agent commonly used in the treatment of ventricular and supraventricular arrhythmias. The drug is known to have multiple adverse effects, which can involve most organ systems. ADRAC has received a total of 273 reports of suspected adverse reactions to amiodarone in the period from November 1972 to January 1995 (Table). There have been 13 cases which resulted in a fatal outcome although, in addition to amiodarone, several other drugs or the underlying condition were also possible contributors to the patients' deaths.

A recent case report forwarded to ADRAC illustrates part of the spectrum of amiodarone toxicity. A 74 year old man was on amiodarone 400 mg daily for 18 months to treat paroxysmal atrial tachycardia when he developed a fever, anorexia, weight loss (16 kgs), muscle weakness and a neurological problem (which he noticed early as it caused him to veer to the left while driving). Clinical examination was essentially unremarkable, except for some observed episodes of markedly ataxic gait. His liver function tests were found to be moderately abnormal, while a series of chest X-rays demonstrated a progressive right upper lobe infiltrate. Subsequent bronchoscopy and bronchial biopsy confirmed interstitial fibrosis of the right upper lobe. Following cessation of amiodarone, and despite some persistence of the pulmonary fibrosis, his symptoms slowly resolved over about 7 months. Amiodarone usage statistics derived from community prescription counts indicate that there has been increasing use of amiodarone with more than a doubling during the past five financial years: from 50,807 prescriptions in 1989/90 to 113,512 prescriptions in 1993/94.*

In view of the severity of some adverse reactions, and increasing use, ADRAC wishes to remind prescribers of the need to ensure that amiodarone is only used in patients with serious arrhythmias where there is no safer alternative drug therapy. The very long half-life of amiodarone (from 14 to 110 days) may contribute to the slow resolution of the drug's adverse effects, although this may not be the only determinant once a pathological process is established. Plasma drug concentration monitoring can be of assistance in preventing and diagnosing toxicity in some patients.

* obtained from the Drug Utilisation Subcommittee (DUSC) of the Pharmaceutical Benefits Advisory Committees

Main Organ Systems Affected by Amiodarone
Organ System Number of Reactions
Heart arrhythmia 22
cardiac failure 7
hypotension 7
cardiac arrest 3
Lung pneumonia/pulmonary infiltration/fibrosis 38
dyspnoea/respiratory insufficiency 21
other 10
Nervous system ataxia/dizziness/vertigo 18
neuropathy/sensory disturbance 15
tremor 9
Eye corneal deposits & other abnormalities 25
lens disorders 5
abnormal vision 9
other 4
Thyroid hyperthyroidism 25
hypothyroidism 14
other 5
Liver abnormal liver function tests 19
hepatitis/jaundice 8
other 7
Skin rashes 34
photosensitivity 18

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Fatal lactic acidosis with metformin

In the last 12 months, ADRAC has received six reports of acidosis with a fatal outcome associated with the use of the biguanide hypoglycaemic drug, metformin. The six patients (4F, 2M) were all elderly (68-87, median 78 years) and died from 4 hours to 6 weeks after the illness was diagnosed and treated.

The Committee has received a total of 15 reports of acidosis implicating metformin. All except two were female and ages ranged from 59 to 88 (median 75) years. Daily doses of metformin ranged from 1 to 3 (median 2) grams. All except one patient had been taking metformin for longer than 12 months (range 3 months to 8 years; median 2 years). In 6 of the reports metformin was implicated as the sole suspected drug cause of acidosis. In 9 cases renal failure was noted either as pre-existing or developing in association with the acidosis. Recovery was documented in 6 cases, 6 resulted in a fatal outcome (described above) and the outcome was unknown for the other 3.

Although the cases with fatal outcomes were complex, acidosis was believed by the reporter to be a significant contributory factor.

On the basis of these reports careful attention to the dose of metformin is necessary, particularly in the elderly. In four of the six fatal cases, the dose of metformin was 3 g daily. In addition, all the recently reported fatal cases had one or more of the contraindications to metformin listed in the product information. These include renal impairment in particular, which may first become evident months or years after hypoglycaemic therapy is commenced. Because of the significant mortality associated with lactic acidosis, prescribers should be aware of contraindications to, and precautions with the use of metformin, and the need for frequent reviews of dose.

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Hepatic reactions to ...... roxithromycin

It is well known that erythromycin can cause hepatic reactions. Roxithromycin (Biaxin, Rulide) is another relatively new macrolide antibiotic which has been marketed in Australia since late 1992. To date the Committee has received 29 reports describing hepatic reactions associated with the use of roxithromycin which was the sole suspected drug cause in 13 of the reports.

Eleven of the other reports involved drugs (flucloxacillin, Augmentin, erythromycin, sulfasalazine and allopurinol) known to be associated with jaundice.

Accompanying clinical features included anorexia, nausea, weight loss, abdominal pain, fever, rashes, fatigue, pruritus and mild hepatomegaly, and jaundice was noted in 12 reports.

Liver function tests usually indicated a cholestatic picture. In the only case in which a liver biopsy was performed the portal tracts exhibited an inflammatory infiltrate comprising lymphocytes, histiocytes and numerous eosinophils.

Ages ranged from 14 to 85 (median 58) years and there was no sex predominance.

Duration of exposure ranged from 2 to 17 (median 6) days and latency of onset ranged from 1 to 29 (median 5) days. Most (19) cases documented full recovery, usually within a few weeks.

In the two reports describing fatal outcomes one death was considered to be unrelated to the hepatic reaction and in the other case where fulminant hepatic failure was the cause of death, sulfasalazine was considered a more likely cause.

Prescribers should be aware that roxithromycin may cause jaundice or abnormal hepatic function even with a relatively short course of therapy.

......and to ranitidine

To January 1995 ADRAC has received 103 reports of hepatic dysfunction associated with ranitidine therapy.

Sex distribution was equal and ages ranged from 1 to 96 (median 57) years.

Onset of the reaction occurred 1 to 63 (median 15) days after commencing ranitidine. Symptoms included jaundice (31 reports), anorexia (9), nausea (10), fever, abdominal pain, pruritus (7 of each) and vomiting (6). Hepatomegaly was noted in 6 cases.

Concurrent involvement of other organ systems was noted in some cases viz. renal impairment (2), marrow depression, pulmonary infiltration and cardiac failure (one of each).

Seventy nine of the reports included the results of biochemistry which confirmed the hepatic dysfunction which was of either cholestatic, hepatitic or mixed pattern. No consistent type of histopathology was noted in the 7 reports which included biopsy results. At the time of reporting 53 patients had recovered and for 43 the outcome was unknown. Of the 7 deaths reported, one was unrelated to hepatic dysfunction and in all cases at least one other drug was also implicated.

Prescribers should remember that ranitidine is a possible cause of liver dysfunction (including jaundice) which often becomes evident within the first month or so after commencement. Prompt withdrawal of the drug is usually followed by rapid recovery in such cases.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Amlodipine (Norvasc)
  • Clarithromycin (Klacid)
  • Enoxacin (Enoxin)
  • Finasteride (Proscar)
  • Gabapentin (Neurontin)
  • Gestrinone (Dimetriose)
  • Itraconazole (Sporanox)
  • Ketorolac (Toradol)
  • Lamotrigine (Lamictal)
  • Lansoprazole (Zoton)
  • Leuprorelin (Lucrin)
  • Loratadine (Claratyne)
  • Moclobemide (Aurorix)
  • Nicotine patch (Nicabate, Nicorette, Nicotinell, Prostep)
  • Nizatadine (Tazac)
  • Paroxetine (Aropax 20)
  • Pravastatin (Pravachol)
  • Piperacillin/tazobactam (Tazocin)
  • Roxithromycin (Biaxin, Rulide)
  • Salmeterol (Serevent)
  • Sertraline (Zoloft)
  • Tacrine (Cognex)
  • Terbinafine (Lamisil)
  • Ticlopidine (Ticlid)
  • Vigabatrin (Sabril)
  • Zopiclone (Imovane)

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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:

ISSN 0812-3837

© Commonwealth of Australia 1999

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

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