You are here

Australian Adverse Drug Reactions Bulletin, Vol 14, No 3

August 1995

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


Cefaclor in the young patient: arthritis and arthralgia

Since the first notifications in 1989, ADRAC has received 42 reports of arthritis or arthralgia associated with the use of the second generation cephalosporin drug, cefaclor. In 35 of these cases, cefaclor was the only drug suspected of causing the adverse reaction. The majority of the reports concerned paediatric patients: 36 of the 42 patients were under 16 years of age.

In most cases, cessation of the drug led to a full and prompt recovery (29 cases), although 9 patients had not recovered at the time the report was submitted and, in another 4, the outcome was unknown. Associated symptoms were commonly reported, such as fever and a variety of skin eruptions, including erythema multiforme. This syndrome is highly suggestive of serum sickness, which has been well-documented with the b-lactam antibiotics in general.

The presence of joint pain or frank arthritis in this group of children and adolescents is of clinical importance, and may be overlooked or misinterpreted. While these adverse reactions are appropriately described in the approved product information, the increasing use of cefaclor has prompted ADRAC to remind prescribers of the occurrence of arthritis and arthralgia in young patients taking this drug.

Simvastatin and adverse endocrine effects in men

Simvastatin (Lipex, Zocor), the first of the 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors available in Australia is now well established in the treatment of hypercholesterolaemia. Since its marketing in 1990 ADRAC has received 1142 reports of suspected adverse reactions in association with the drug. A small percentage of these appear to relate to adverse effects on the male endocrine system, namely gynaecomastia and impotence.

ADRAC has received 11 reports of gynaecomastia in association with simvastatin. Ages of the men involved ranged from 52 to 80 (median: 68) years and they had taken the drug for 2 to 10 (median: 5) months before the problem developed. Simvastatin was the only drug implicated in 5 of the reports and the most likely of the suspected drugs, based on temporal and other considerations, in 4 of the other reports. Gynaecomastia is often slow to resolve, and recovery was documented in only one patient at the time the reaction was reported.

There have been 28 reports of impotence in association with simvastatin. The males affected ranged in age from 45 to 72 (median: 57) years and the onset occurred from 48 hours to 27 months (median: about 4 weeks) after the drug was commenced. Simvastatin was the only drug implicated in 24 of the reports and in 4 cases, the problem recurred on rechallenge. Of the 21 reports where recovery was mentioned, 12 patients had recovered after ceasing the drug whereas for the other 9, there had been no recovery at the time the report was submitted.

ADRAC believes it is important for prescribers to be aware that such effects can occur with simvastatin.

Top of page

Lodema and the liver

Coumarin (Lodema) is a benzopyrone which is used for the treatment of high protein oedema (especially lymphoedema). Although it is chemically related to the 4-hydroxycoumarin anticoagulants (including warfarin), it has no anticoagulant activity. In the 14 months to May 1995 the Committee received a total of 10 reports of suspected adverse reactions in connection with the use of coumarin. Six of these described jaundice occurring in women, aged 49 to 73 years, who had taken coumarin 400 mg orally daily for periods ranging from one to four months. In all but one case coumarin was the only suspected drug cause. In one case jaundice recurred on rechallenge, and in another, a liver biopsy indicated periportal and lobular necrosis. One other case had a fatal outcome due to massive hepatic necrosis (demonstrated at autopsy). The other 5 patients recovered after coumarin was withdrawn.

The high proportion of reports describing severe liver injury in association with coumarin use is of major concern. Moreover, since July 1993 when coumarin became generally available, assuming that approximately 1750 patients1 have been treated with the drug, the incidence of hepatotoxicity is at least 34 cases per 10,000 users. This is considerably higher than for other known hepatotoxins such as flucloxacillin (approximately 0.7 cases per 10,000 users).2


  1. Casley-Smith JR, Casley-Smith JR. Frequency of coumarin hepatotoxicity. Med J Aust 1995, 162: 391.
  2. Jick H, Derby LE, Dean AD, Henry DA. Flucloxacillin and cholestatic hepatitis. Med J Aust 1994, 160: 525.

Interaction of warfarin with macrolide antibiotics

Drug interactions with warfarin are of particular importance because they are potentially life threatening. ADRAC has received a number of reports of patients in whom the addition of a macrolide antibiotic to warfarin has led to an increased prothrombin time [or international normalised ratio (INR)] with consequent risk of bleeding. Eleven reports relate to erythromycin (EES, EMU-V, E-Mycin, Eryc, Erythrocin, Ilosone) and 11 to roxithromycin (Biaxin, Rulide). The latter were all reported in the past two years.

In the 11 erythromycin reports, the majority had been stable on warfarin for some time and the interaction usually occurred after a few days treatment with erythromycin. In the 10 cases where the INR was documented, it ranged from 3.6 to 18 (median = 9). The lowest value is within the therapeutic range of 2.0 to 4.0 but well above the value of 1.2 on which this patient had been stable.

For roxithromycin, in the six reports where values were given, the INR ranged from 3.8 to 19.5 (median = 9). Bleeding was observed in 5 cases and blood or plasma transfusion was required in 3 patients.

The underlying mechanisms are not well established. All antibiotics alter gut flora reducing production of vitamin K which may increase the INR in an individual taking warfarin. It is also possible that the macrolides may interact with warfarin at some point in its pharmacokinetic pathway.

Prescribers should take care when prescribing either erythromycin or roxithromycin in patients taking warfarin.

Top of page

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Azithromycin (Zithromax)
  • Clarithromycin (Klacid)
  • Enoxacin (Enoxin)
  • Gabapentin (Neurontin)
  • Goserelin (Zoladex)
  • Lamotrigine (Lamictal)
  • Lansoprazole (Zoton)
  • Leuprorelin (Lucrin)
  • Naferelin (Synarel)
  • Paroxetine (Aropax 20)
  • Piperacillin/tazobactam (Tazocin)
  • Pravastatin (Pravachol)
  • Salmeterol (Serevent)
  • Sertraline (Zoloft)
  • Tacrine (Cognex)
  • Terbinafine (Lamisil)
  • Ticlopidine (Ticlid)
  • Vigabatrin (Sabril)
  • Zopiclone (Imovane)

Top of page

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 1998

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

Top of page