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Australian Adverse Drug Reactions Bulletin, Vol 15, No 4

November 1996

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

Contents

Minocycline and ......

The usage of minocycline (Minomycin) appears to be increasing and much of its use is in the treatment of acne. Up until September 1996, the Committee has received 425 reports in association with the drug. These reports describe adverse effects in three particular areas: the liver, the CNS, and the skin.

The liver

There have been 27 (M:F = 15:12) reports involving hepatic dysfunction variously described as hepatitis (9 cases), jaundice (6), fatty liver (1) and abnormal hepatic function (11). Minocycline was the only drug suspected in 24 of the reports. Similar reactions have been recently published overseas and in Australia, and an association with the SLE syndrome has been noted.1,2 Of particular interest was the young age of the patients involved, of whom 12 were under 21 ( median = 32) years. At the time of reporting, 16 had recovered, 9 had not yet recovered and the outcome was unknown for another 2 patients. The indication for use of minocycline, documented in 25 of the 27 reports, was acne in 17 and other infections in the remainder.

The CNS

Minocycline also has been associated with a variety of CNS effects, particularly dizziness. In one recent study, dizziness affected 40% of minocycline-treated patients.3 Of the 425 reports to ADRAC, dizziness or the related symptoms of vertigo, labyrinthine disorder or ataxia are described in 146 cases. Minocycline is the drug most commonly reported to ADRAC in this context. Minocycline has also been implicated in 24 cases of benign intracranial hypertension which is about half of the total ADRAC reports of this condition. These have recently been reviewed.4

The skin

Another unusual adverse reaction in association with minocycline is skin discolouration, for which minocycline has been reported to ADRAC as a cause more than any other drug. The 17 reports describe dark or greyish pigmentation which involves the face, legs, arms, gums, scars, nails and sclerae.

These diverse adverse effects involving minocycline should be borne in mind, particularly when prescribing in the younger patient.

References

  1. Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline-induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169-172.
  2. Malcolm A, Heap TR, Eckstein RP, Lunzer ML. Minocycline-induced liver injury. Am J Gastroenterol 1996; 91: 1641-43.
  3. Tilley BC, Alarcón GS, Heyse SP et al. Minocycline in rheumatoid arthritis. A 48 week, double-blind, placebo-controlled trial. Ann Intern Med 1995; 122: 1-4.
  4. Boyd I. Benign intracranial hypertension induced by minocycline. Current Therapeutics 1995; 36: 70-71.

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Vitamin A and birth defects

ADRAC recently reviewed a report of a child born with microcephaly and dystonia whose mother had inadvertently ingested large quantities of vitamin A during the first 4 or 5 weeks of pregnancy. The child subsequently died. While it was not possible to implicate the ingestion of vitamin A as a definite cause of the birth defects in this case, excess amounts of vitamin A are suspected causes of birth defects and its therapeutically used congeners are established causes of birth defects. This report highlights a possible problem.

It is important for prescribers to realise that the recommended adult daily allowance of vitamin A from all sources is 2500 IU. One of the products implicated in the above case was freeze dried liver extract. One tablet was derived from 10 grams of liver, and depending on the source of the liver and the method of preparation, each of these tablets may contain from 6,500 to 48,000 IU vitamin A which is far in excess of the recommended daily allowance. There is no warning label on such products.

Vitamin A preparations which are labelled for a daily amount of 5000 IU or less of vitamin A are freely available provided there is a statement on the label on the recommended daily amount. Furthermore, there should be a warning statement to the following effect: "WARNING - Taking more than 2500 IU a day during pregnancy may cause birth defects". Other vitamin A preparations are available only on prescription. There is no need for additional vitamin A during pregnancy.

ADRAC urges prescribers to advise their patients who are pregnant or are likely to become pregnant not to exceed the recommended daily allowance of vitamin A from all sources, and if possible, not to take any vitamin A containing products.

Angioedema and ACE inhibitors

Slightly less than 1% of all reports to ADRAC describe angioedema as a suspected adverse reaction and the drugs most commonly involved are ACE inhibitors, antibiotics and NSAIDs with ACE inhibitors particularly prominent. Angioedema appears to be a class effect of ACE inhibitors and ADRAC has received reports in association with all members of the class marketed in Australia. These reports describe a total of 270 patients ranging in age from 27 to 92 (median: 65) years. In the majority of cases (84%), the ACE inhibitor was the only drug suspected of causing the reaction. Most prescribers would be aware that ACE inhibitors can occasionally cause angioedema but there are three important points about this reaction which ADRAC wishes to highlight, namely its onset, its recurrence and the existence of visceral angioedema.

It is generally considered that in most cases, drug-induced angioedema occurs soon after the drug is started and it was once thought that ACE inhibitors were no different. However, it has become increasingly clear from reports to ADRAC and elsewhere that a significant proportion of cases have a delayed onset. Of the reports to ADRAC in which onset details were available, the reaction occurred within the first 24 hours in 19% of the cases, but for 27%, the time to onset was 6 months or more. There were a number of instances of delays of years, and in three cases, there was an interval of about 7 years between initiation of ACE inhibitor therapy and the occurrence of angioedema.

Recurrent episodes of angioedema are described in 87 of the reports. These were often mild events where the role of the drug was not realised until a number of episodes occurred or the drug was withdrawn. The interval between the episodes ranged from 1 day to 9 months with a median of 2 weeks where the exact dates were specified, but in other reports, the average time between episodes ranged from 1 day to more than 2 years. Most cases involved 2 or 3 episodes but 14 involved 6 or more episodes with one case documenting more than 36 episodes.

Most cases of angioedema involve swelling of the face, neck or orolaryngeal tissue but visceral angioedema has also been identified. In one recent report1, a 69 year old female with a 5 year history of recurrent nocturnal attacks of abdominal pain, diarrhoea and vomiting was found to have oedema of the bowel in association with enalapril. Excluding those cases involving other organs such as the liver, ADRAC has received 61 other reports of abdominal pain with ACE inhibitors and it is possible that some of these reports may involve abdominal angioedema.

ADRAC reminds prescribers that ACE inhibitors are an important cause of angioedema. There can be an extended period of latency before onset, recurrent episodes can occur, and visceral involvement is possible. Recognition should lead to cessation of therapy with all members of the class.

Reference

  1. Mullins RJ, Shanahan TM, Dobson RT. Visceral angioedema related to treatment with an ACE inhibitor induced. Med J Aust 1996; 165: 319-321.

Moclobemide and hypertension - is it drug-induced?

Although hypertension was not shown to be associated with moclobemide (Aurorix) in premarketing studies, ADRAC has had 12 reports of this association. In at least 5 cases, the reaction occurred in patients with a past history of hypertension, and in the others, hypertension appeared to be a new development. ADRAC is keen to define further this potentially important "signal" and seeks more reports. Such reports should preferably contain blood pressure readings before and during therapy with moclobemide.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Azithromycin (Zithromax)
  • Cabergoline (Dostinex)
  • Cilazapril (Inhibace)
  • Enoxacin (Enoxin)
  • Famciclovir (Famvir)
  • Fluvastatin (Lescol, Vastin)
  • Gestrinone (Dimetriose)
  • Goserelin (Zoladex)
  • Leuprorelin (Lucrin)
  • Losartan Potassium (Cozaar)
  • Nafarelin (Synarel)
  • Pantoprazole (Somac)
  • Salmeterol (Serevent)
  • Sevoflurane (Sevorane)
  • Tacrine (Cognex)
  • Ticlopidine (Ticlid)
  • Valaciclovir (Valtrex)
  • Venlafaxine (Efexor)
  • 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: ADR.Reports@tga.gov.au.

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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