Australian Adverse Drug Reactions Bulletin

Volume 15, Number 2, May 1996

Prepared by the Adverse Drug Reactions Advisory Committee (ADRAC).

Drug-induced liver disease ...

The liver is a major site of metabolism of drugs and is an important site of adverse drug reactions. These effects can range from mild abnormalities in liver function tests to fulminant hepatic failure and death. Table 1 lists the drugs most commonly reported to ADRAC in association with hepatic reactions, up to March, 1996. As with other lists of this type, the numbers are influenced by the duration of marketing, the extent of use, and the clinical setting in which the drug is used.

Table 1 Reports of Adverse Hepatic Reactions

Suspected Drug (Year of First Report)	Number of Reports (with a fatal outcome)
Flucloxacillin (1980)	435 (20)
Amoxycillin/potassium clavulanate (1987)	314 (9)
Erythromycin (1972)	223 (4)
Carbamazepine (1974)	199 (7)
Methyldopa (1972)	174 (9)
Trimethoprim-sulfamethoxazole (1973)	140 (3)
Simvastatin (1990)	139 (5)
Diclofenac (1982)	136 (8)
Ranitidine (1981)	122 (7)
Phenytoin (1975)	112 (8)
Sulindac (1979)	102 (1)
Allopurinol (1975)	95 (15)
Rifampicin (1972)	92 (11)

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... Antibiotics of continuing concern

To the current time, flucloxacillin (Flopen, Floxapen, Flucil, Staphylex) and the combination of amoxycillin with potassium clavulanate (Augmentin, Augmentin Forte, Clavulin) are clearly the most commonly reported causes of drug-induced adverse hepatic reactions. These two associations have been given extensive publicity by ADRAC and others. The two figures show that although the numbers of reports with flucloxacillin have dropped, those with amoxycillin/clavulanate have remained high. It appears from the accompanying utilisation figures¹ that there has been a considerable drop in the usage of flucloxacillin but use of amoxycillin/clavulanate continues to grow and ADRAC remains concerned that it is not always used under appropriate circumstances.

Liver disease in association with amoxycillin/ clavulanate is predominantly cholestatic and usually begins within a few weeks of ceasing a course of the drug. Increasing age has been demonstrated to be a risk factor.² The reaction usually persists for 5-6 weeks and although the disease is generally not as severe or as prolonged as that associated with flucloxacillin, it can cause considerable morbidity, and in 9 of the 309 cases, the outcome was fatal. In 2 of these cases, the death was considered not drug-related, in 2 others the cause of death was not related to the liver but liver disease may have made a contribution, and in the remaining five, the patients died from liver failure.

ADRAC reminds doctors to prescribe this combination drug only when it is clearly indicated and to exercise particular care with the elderly.

References

1. Figures obtained from the Drug Utilisation Subcommittee (DUSC).
2. Thomson TA, Fairley CK, Ugoni AM et al. Risk factors for the development of amoxycillin-clavulanic acid associated jaundice. Med J Aust 1995; 162: 638-640.

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Hepatitis B vaccines - musculoskeletal reactions

ADRAC supports the immunisation program which includes the appropriate use of hepatitis B vaccine and it has been estimated that about two million doses of the vaccine are given annually.^# However, it is important for prescribers to be aware that adverse effects can occasionally occur and from 1988 to March 1996, ADRAC has received 597 reports of suspected adverse reactions in association with recombinant hepatitis B vaccine and the reactions reported most commonly are listed in Table 2. In many cases, symptoms mentioned in the table occurred in combination resembling a 'flu like illness'. Most reports of this type described an intense but short-lived illness which usually responded to rest and analgesics.

Table 2 Most Common Reactions to Hepatitis B Vaccines

Reaction*	Number of reports
Rash and/or itch	181
Anorexia, nausea or vomiting	131
Musculoskeletal pain	106
Fever and/or rigors	99
Headache	96
Injection site reactions	89
Dizziness and/or vertigo	64
*Commonly more than one reaction term was included in each report. #Reference details available on request.

Of interest are the 106 reports (F:M=62:40, age range: 3 to 69 (median 39) years) of musculoskeletal symptoms such as arthritis, arthralgia, and/or myalgia which were not related to the injection site. About half of these cases were part of a flu-like illness and the vaccine was the only suspected causal agent in the majority of them. Of those reports which provided the information, all documented onset of the reaction within the first month with the majority (70%) commencing within the first week after vaccination. Where it was specified, symptoms of this type were reported following first (32 reports), second (40), third (15), and fourth (2) injections. Half of the reports describing reactions after the second injection also documented similar, but less severe, symptoms following the first injection. Reactions recurring on rechallenge tended to be more rapid in onset.

The majority of patients had joint symptoms. In 21 patients these were accompanied by myalgia whereas myalgia alone was experienced in a further 29 patients. The pattern of joint involvement varied greatly including arthralgia in the hands, wrists, elbows, shoulders, neck, knees and/or ankles. A minority of reports described both upper and lower limb involvement. Full recovery was documented in more than half the cases and in those reports which provided the information, the majority (70%) recovered within a month of onset.

Health professionals should be aware that prophylaxis with recombinant hepatitis B vaccines may be associated with joint and/or muscle pains generally commencing in the first month after vaccination and lasting for several weeks.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

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

The Adverse Drug Reactions Advisory Committee (ADRAC) encourages the reporting of all suspected adverse reactions to drugs and other medicinal substances, including herbal, traditional or alternative remedies. The reporting of seemingly insignificant or common adverse reactions may highlight a widespread prescribing problem.

The Committee particularly requests reports of:

• ALL suspected reactions to NEW DRUGS, especially DRUGS OF CURRENT INTEREST
• ALL suspected drug interactions
• Reactions to other drugs which are suspected of significantly affecting a patient's management, including reactions suspected of causing
  • Death
  • Danger to life
  • Admission to hospital
  • Prolongation of hospitalisation
  • Absence from productive activity
  • Increased investigational or treatment costs
  • Birth defects

Reports of suspected adverse drug reactions are best made by using a pre-paid reporting form ("blue card") which accompanies this Bulletin or is available from the Adverse Drug Reactions Section +61 2 6232 8385.

Tear-out blue cards can also be found at the front of all recent editions of the "Schedule of Pharmaceutical Benefits".

(Problems with therapeutic devices should be reported on 1800-809361)

ISSN 0812-3837

All correspondence to be addressed to: The Secretary, Adverse Drug Reactions Advisory Committee, PO Box 100, Woden ACT 2606

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