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Australian Adverse Drug Reactions Bulletin, Vol 25, No 1

February 2006

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

Contents

Deaths with galantamine in mild cognitive impairment studies

Galantamine (Reminyl), donepezil (Aricept) and rivastigmine (Exelon) are approved in Australia for the treatment of mild to moderately severe Alzheimer's dementia. Cardiac arrhythmias with these cholinesterase inhibitors were described in the October 2004 Bulletin.1

Galantamine has also been investigated in patients with mild cognitive impairment, an indication which is not approved in Australia. In two placebo controlled trials (total of 2048 subjects), there was a higher mortality with galantamine (n=13) than placebo (n=1, relative risk 6.19, 95% confidence interval 2.17, 17.68), and galantamine was not effective.2 The deaths were due to various causes which could be expected in an elderly population.

A description of the results of these studies has recently been added to the 'Precautions' section of the Australian Product Information for Reminyl, along with further advice to use with caution in patients with cardiovascular and pulmonary conditions, particularly immediately after myocardial infarction and with new onset atrial fibrillation, second or third degree heart block, unstable angina and pneumonia.

ADRAC advises that galantamine should only be used for the approved indication of mild to moderately severe Alzheimer's dementia. The safety and efficacy in other indications have not been established and the risks may outweigh the benefit.

References

  1. ADRAC. Cholinesterase Inhibitors and Cardiac Arrhythmias. Australian Adverse Drug Reactions Bulletin, 2004; 23:5.
  2. http:// www.clinicalstudyresults.org/drugdetails/? company_id=19&inn_name_id=66&indication_id=821&sort=c.company_name&page=1&drug_id=96

Fluoroquinolone antibiotics...Interactions with warfarin

The potential interaction between warfarin and fluoroquinolones (ciprofloxacin, norfloxacin, moxifloxacin, gatifloxacin)* was reported in a 1993 review.1 ADRAC has received 20 reports of this interaction, implicating ciprofloxacin (9 reports), norfloxacin (11) and moxifloxacin (1). One of the reports involves both ciprofloxacin and norfloxacin. As yet, no reports have been received with gatifloxacin, which has had little use.

Of the 20 ADRAC reports, one patient had vaginal bleeding; for the other patients the coagulation disorder was detected on laboratory testing. In eight cases an INR of greater than 7 was recorded. In one case, the patient's INR rose from a stable baseline of around 2.0 to more than 10, four days after commencing moxifloxacin. Two days after moxifloxacin and warfarin were withdrawn and treatment with vitamin K was given, the INR had fallen to 1.2. No symptomatic event occurred.

Health Canada has reported 57 cases of this interaction up to Jan 2004.2 Gatifloxacin was also implicated in the Canadian series. In 16 of the 57 cases the patient was hospitalised and four patients aged 70-90 years with complex medical conditions died.

Although significant pharmacokinetic interactions have not been demonstrated in interaction studies, the Product Information for each of the fluoroquinolones and for warfarin warn that an increased effect of warfarin is possible, and that the INR should be closely monitored when a fluoroquinolone and warfarin are administered concomitantly.

Possible mechanisms of this interaction include decreased warfarin cytochrome P450-mediated metabolism, and reduction in gut flora that produce vitamin K.

ADRAC advises health professionals to consider the possibility of this interaction and monitor the INR when fluoroquinolones and warfarin are used concomitantly.

References

  1. Marchbanks CR. Drug-drug interactions with fluoroquinolones. Pharmacotherapy 1993;13:23S-28S.
  2. Morawiecka I. Fluoroquinolones and warfarin: suspected interactions. Canadian Adv Reaction Newsletter 2004;14:1-2.

Fluoroquinolone antibiotics...Remember tendon disorders

Since the beginning of 2005, ADRAC has received 16 cases of tendon disorders, predominantly Achilles tendinitis. Eleven of these cases have involved the fluoroquinolones.*

ADRAC reminds prescribers that there is an increased risk of tendinitis or even tendon rupture with all fluoroquinolones.1 Of the 213 cases of tendinitis or tendon rupture reported to ADRAC, over 80% have involved fluoroquinolones. In addition to fluoroquinolone use, increasing age and concomitant corticosteroid use are established risk factors.

Patients should be advised to be alert for pain or discomfort in the Achilles tendon or calf and to inform their doctors and cease taking the medicine if this occurs.

Reference

  1. ADRAC. Fluoroquinolones and tendon disorders. Australian Adverse Drug Reactions Bulletin 2002;21:15

*The fluoroquinolones are: ciprofloxacin (Arflox, C-Flox, Ciloxan, Ciloquin, Ciproxin, Ciprol, Profloxin, Proquin, Procip, Ciprobay, Ciaxone); norfloxacin (Insensye, Norflohexal, Noroxin, Nufloxib, Roxin); gatifloxacin (Tequin); moxifloxacin (Avelox); as well as several other generic versions of ciprofloxacin and norfloxacin.

Ergot derivatives and fibrotic reactions

Ergot derivatives are now the most commonly used dopamine agonists in the treatment of Parkinson's disease in Australia. In 2005, the number of prescriptions dispensed under the PBS was 92,000 for cabergoline (Cabaser) and 36,000 for bromocriptine (Parlodel) and pergolide (Permax) combined.

Important potential adverse reactions associated with ergot derivatives such as cabergoline, bromocriptine and pergolide are fibrotic complications, including pericarditis and retroperitoneal or pleural fibrosis. From marketing in 1997 to December 2005, ADRAC has received 86 reports of suspected adverse reactions in association with cabergoline. Of these, 15 have described pleural or pulmonary fibrosis/effusion or pneumonitis, involving 11 males and 3 females (gender not stated in 1). Time to onset varied but apart from one report which indicated a few days, the onset time was from 1 month to over 3 years (median: 4 months).

Most of the reports described either pleural fibrosis or pleural effusion or both and this was demonstrated by biopsy or chest X-ray in over half of the cases. Eight of the patients had recovered, two were improving but the remaining five had not recovered at the time the report was submitted.

As cabergoline has a long half-life (65 hours), recovery may be slow or the fibrotic changes may progress after drug withdrawal.1

There have been no reports of fibrotic complications in association with low-dose cabergoline (Dostinex) for the treatment of lactation suppression and hyperprolactinaemia.

All ergot derivatives can induce fibrotic changes. For Cabaser the Product Information contains the following precaution, entitled 'respiratory disorders linked to fibrotic tissue degeneration':2

'Fibrotic complications may present as retroperitoneal fibrosis. Pleural effusion/fibrosis has been infrequently reported following long-term administration of Cabaser, and usually when given in patients previously treated with ergolinic dopamine agonists.'

There is no information in the ADRAC reports about previous use of ergolinic dopamine agonists.

Prescribers should be aware of the possibility of fibrotic changes associated with long-term administration of ergot derivatives such as cabergoline, bromocriptine and pergolide, and should instruct the patient to report dyspnoea or cough.

References

  1. Frans E, Dom R, Demedts M. Pleuropulmonary changes during treatment of Parkinson's disease with a long-acting ergot derivative, cabergoline. Eur Respir J 1992; 5: 263-265.
  2. Cabaser Product Information, Pfizer Australia Pty Ltd, 10 June 2004.

Drugs of current interest

Please report all suspected reactions to these Drugs of Current Interest

  • Aripiprazole (Abilify)
  • Atomoxetine (Strattera)
  • Ezetimibe (Ezetrol)
  • Fenofibrate (Lipidil)
  • Iron sucrose (Venofer)
  • Levetiracetam (Keppra)
  • Pimecrolimus (Elidel)
  • Pregabalin (Lyrica)
  • Reboxetine (Edronax)
  • Teriparatide (Fortéo)

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 2006

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