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Australian Adverse Drug Reactions Bulletin, Vol 18, No 2

June 1999

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


Depression with interferon

Interferon alfa (2a - Roferon-A and 2b - Intron A) is used in a variety of conditions including leukaemias, some carcinomas, multiple myeloma, non-Hodgkin's lymphoma, malignant melanoma and more recently, hepatitis B and C. The most commonly reported adverse reactions in association with interferon alfa are flu-like symptoms such as fever, fatigue, myalgia, joint pain, and headache. Serious effects documented include severe hypersensitivity reactions, and haematological, hepatic, cardiovascular and neurological effects, particularly at high dose. Psychiatric effects have been described and include depression and suicidal ideation.1

ADRAC has received 19 reports of depression or suicidal ideation associated with interferon alfa therapy. Eleven patients had depression alone, 4 had depression and suicidal ideation or attempt and there were 4 additional reports of suicide attempts. Three of the reports of suicide attempt were fatal. The onset was as early as the first day of treatment to 10 months after the start of therapy but most of the reports described a time to onset of a few weeks. In the 19 cases, interferon was used for a variety of conditions with hepatitis C (11 cases) and malignant melanoma (3 cases) the most common.

Prescribers should be aware that the adverse effects of interferon alfa may include mood changes, depression or suicidal ideation. If interferon alfa becomes more widely used in the treatment of hepatitis B and C, the occurrence of these problems is likely to increase. Particular care should be taken with the use of the drug in patients with a history of depression.


  1. Renault PF, Hoofnagle JH, Park Y et al. Psychiatric complications of long-term interferon alfa therapy. Arch Intern Med 1987; 147: 1577-80.

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Coumadin and marevan are not interchangeable

Warfarin is available in two brands: Coumadin and Marevan. Coumadin is marketed in 1 mg, 2 mg and 5 mg tablets whereas Marevan is marketed in 1 mg, 3 mg and 5 mg tablets. ADRAC recently received a report describing an increased therapeutic response in association with the Coumadin brand of warfarin. The problem arose when a patient who had been taking Marevan 2 x 1 mg was prescribed 2 mg warfarin. Only Coumadin is available in this strength and after its use the patient's INR rose from its normally stable value of around 2 to over 5. The reporter indicated that this was the third similar case in the previous 18 months.

ADRAC believes that it is important for prescribers to recognise that Coumadin and Marevan have not been demonstrated to be bioequivalent and are therefore not interchangeable. This information is also presented in the Schedule of Pharmaceuticals Benefits booklet and the issue has been the subject of debate in the pages of the Australian Prescriber.1


  1. See for example, Fry FK, PBAC, Boots. Warfarin tablets. Aust Prescr 1997; 20: 33.

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Drug-induced gingival overgrowth

Gingival overgrowth or enlargement has been reported in 114 of the 128,000 reports contained in the ADRAC database. Those 114 cases are dominated by the presence of five drugs which account for 68% of the reports, as shown in Table 1.

Table 1: Reports of Gingival Overgrowth
Drug Number of Reports
Nifedipine 25
Amlodipine 22
Felodipine 14
Phenytoin 13
Cyclosporin 9

In the series of patients reported to ADRAC in association with the dihydropyridine calcium channel blockers (CCBs), phenytoin and cyclosporin, ages ranged from 3 to 77 (median: 55) years. The reaction occurred from a few days to more than 4 years after commencing treatment although more than half of the patients had been treated for at least 6 months. The majority of patients had not recovered when the report was submitted to ADRAC. When recovery was documented, it was slow and ranged from weeks to more than a year after ceasing the drug. These findings are in keeping with a recent report.1

It has been estimated that gingival overgrowth occurs in about 50% of patients taking phenytoin, 25-80% of patients taking cyclosporin, and 15-20% of patients receiving nifedipine, but severe cases with nifedipine occur in less than 1%.2,3 ADRAC has received only 2 reports each with diltiazem and verapamil so it is possible that gingival overgrowth is mainly associated with the dihydropyridine CCBs. It may be that these drugs all affect gingival tissue in the same way as the clinical features and histological characteristics of gingival overgrowth caused by all 3 classes of drug are similar. The pathogenesis of drug-induced gingival overgrowth is unknown with a number of mechanisms proposed.

Although it is an unusual adverse effect, prescribers should be aware of the possibility of gingival overgrowth associated with use of phenytoin, cyclosporin or the dihydropyridine CCBs. It is usually reversible with withdrawal of the offending drug. It is believed the condition can be minimised or even prevented with meticulous plaque control or dosage reduction.


  1. Brunet L, Miranda J, Farré M, Berini L, Mendieta C. Gingival enlargement induced by drugs. Drug Safety 1996; 15: 219-31.
  2. Lawrence DB, Weart W, Laro JJ, Neville BW. Calcium channel blocker-induced gingival hyperplasia: case report and review of this iatrogenic disease. J Fam Practice 1994; 39: 483-8.
  3. Johnson RB. Nifedipine-induced gingival over-growth. Ann Pharmacother 1997; 31: 935.

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A comparison of dicloxacillin with flucloxacillin

Early in 1997 dicloxacillin was introduced onto the Australian market to provide an alternative to flucloxacillin in the treatment of staphylococcal infections. It was hoped that the incidence and severity of hepatic reactions would be less than with flucloxacillin. Table 2 shows the results after the first two calendar years of marketing.

Table 2: Dicloxacillin versus Flucloxacillin in 1997-98
  Dicloxacillin Flucloxacillin
Community prescriptions 493,000 1,182,000
Reports to ADRAC 151 175
Hepatic reactions 24 62
Cholestasis 3 17
Renal reactions 12 4
Interstitial nephritis 5 -

The table shows total reports, reports of hepatic reactions including those of cholestasis, reports of renal reactions and an estimate of community usage.1 It shows a similar level of reporting despite a higher use of flucloxacillin in the community (hospital usage is unknown). However, this might be expected given that dicloxacillin is a new drug and a "Drug of Current Interest". There are fewer reports of hepatic reactions with dicloxacillin but more importantly, there are considerably fewer reports of cholestasis, and at this stage, no reports of a severe prolonged nature as were observed with flucloxacillin,. Also of interest is the fact that there have been 5 reports of interstitial nephritis with dicloxacillin whereas none have been reported for flucloxacillin in this period.


  1. McManus PR. Drug Utilisation Subcommittee, personal communication.

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Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Candesartan (Atacand)
  • Carvedilol (Dilatrend, Kredex)
  • Clopidogrel (Iscover, Plavix)
  • Donepezil (Aricept)
  • Gelatin succinylated (Gelofusine)
  • Montelukast (Singulair)
  • Naltrexone (ReVia)
  • Naratriptan (Naramig)
  • Nefazodone (Serzone)
  • Raloxifene (Evista)
  • Sildenafil (Viagra)
  • Tiludronate (Skelid)
  • Tramadol (Tramal)
  • Trovafloxacin (Trovan)
  • 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:

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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