Archived – New Safety Information Regarding PERMAX and Occurrence of Cardiac Valvulopathy / Fibrosis – Shire BioChem Inc.

Starting date:

October 12, 2004

Posting date:

October 26, 2004

Type of communication:

Dear Healthcare Professional Letter

Subcategory:

Drugs

Source of recall:

Health Canada

Issue:

Important Safety Information

Audience:

Healthcare Professionals

Identification number:

RA-17000825

This is duplicated text of a letter from Shire BioChem Inc.
Contact the company for a copy of any references, attachments or enclosures.

Notice about Health Canada advisories

Health Canada Endorsed Important Safety Information on PERMAX^® (pergolide mesylate)

October 12, 2004

Subject: NEW SAFETY INFORMATION REGARDING PERMAX AND OCCURRENCE OF CARDIAC VALVULOPATHY / FIBROSIS

UPDATE ON THE USE OF PERMAX (pergolide mesylate)

Dear HealthCare Professional:

Shire BioChem Inc., following discussions with Health Canada, is alerting you to important new WARNINGS concerning the risk of cardiac valvulopathy associated with use of PERMAX (pergolide mesylate). The Product Monograph for PERMAX is being revised to reflect the following additions:

Background Information:

PERMAX^® (pergolide mesylate) is indicated in the treatment of the signs and symptoms of idiopathic Parkinson's disease (PD). Pergolide may be used both as early therapy, without concomitant levodopa, and as an adjunct to levodopa (usually with a peripheral decarboxylase inhibitor).

Since PERMAX was first launched in Canada in 1991, retroperitoneal, pleural, and pericardial fibrosis have been recognized as adverse events reported with PERMAX albeit rarely.

In April 2003, a Dear HealthCare Professional Letter (DHPL) was sent to Canadian physicians stating that during the post-marketing surveillance for PERMAX, a small number of individuals as developing cardiac valvulopathy involving one or more valves during PERMAX therapy had been identified. Given the nature of the lesions and known similar effects of other ergot-derived medications, the Warnings section of the Canadian Product Monograph for PERMAX was modified to reflect these reports.

Post-marketing Reports

There have been a number of case reports, both published and unpublished, suggesting an association between the use of PERMAX and occurrence of valvulopathy.

Based on the global postmarketing surveillance database for PERMAX and considering that approximately 1,493,000 patients have been treated with PERMAX worldwide since its first launch in 1989, the reporting rate of valvulopathy-related events with pergolide as of March 2003 is "rare"(CIOMS III Reporting rate criteria where rare is considered between >1/10,000 and greater than 1/1000). More than 1/3 of treatment-emergent post-marketing cases of valvulopathy were associated with doses that, at the time of diagnosis, exceeded the maximum recommended. Note that reporting rates determined on the basis of spontaneously reported health product related adverse events are generally presumed to underestimate the risks associated with drug treatments. In the case of PERMAX, additional factors that may contribute to underreporting are the prevalence of cardiac disease in the elderly, as well as the occult nature of valvulopathy in early stages.

Case-referent Studies

In addition, the results of two case-referent studies^{Footnote 1,Footnote 2} (non-prospective, non-randomized) have recently been published. Although there are substantive confounding factors in both trial designs, cardiac valvulopathy, with characteristics consistent with ergot causality, was found to occur in those studies at an incidence of "very common" (CIOMS III Reporting rate criteria where "very common" is considered greater than 1/10). Data from one of these studies further indicates that these effects occur with greater frequency in PD patients treated with PERMAX than in PD patients who had never been treated with an ergot-derived dopamine agonist¹. From one of the case-referent studies² there appears to be some evidence of a correlation between lifetime doses of PERMAX and the severity of valvulopathy. In some cases, symptoms or manifestations of cardiac valvulopathy have improved after discontinuation of PERMAX.

Recommendations

While the information available from these reports does not clearly establish a causal relationship and does not establish the actual incidence or the temporal association of valvulopathy with PERMAX use, given the potentially serious nature of these events and the known similar effects of other ergot derivatives, the PERMAX Product Monograph is being revised, including but not limited to the following sections: WARNINGS; DOSAGE AND ADMINISTRATION; ADVERSE EVENTS, Post-Marketing; Consumer Information. This information will facilitate better risk-benefit assessment, particularly with regard to comparison with non-ergot dopamine agonists that have not been reported to date in the scientific literature to be associated with valvulopathy.

Given the high background incidence of asymptomatic valvulopathy in the elderly, and that many patients with advanced PD are elderly, assessment for the potential presence of occult valvular disease at baseline and during treatment would enable a more accurate risk assessment. It is therefore recommended that patients undergo a cardiovascular evaluation, including an echocardiogram, before initiating treatment, with periodic clinical diagnostic monitoring for all patients for the duration of treatment with PERMAX. Use of PERMAX at doses above 5 mg/day is not recommended. For any dose increase, potential benefits should be weighed against potential risks.

If a patient develops a fibrotic condition or cardiac valvulopathy disease while on PERMAX, this drug should be discontinued. Abrupt discontinuation is not recommended as it might exacerbate Parkinsonism, precipitate the onset of hallucinations and confusion, or result in a symptom complex resembling neuroleptic malignant syndrome.

Shire BioChem Inc. will continue to monitor pharmacovigilance reports. The safety of patients remains our first priority. The identification, characterization, and management of marketed health product-related adverse reactions are dependent on the active participation of health care professionals in adverse reaction reporting programmes. Any occurrences of cardiac valvulopathy / fibrosis or other serious and/or unexpected adverse reactions in patients receiving PERMAX should be reported to Shire BioChem Inc. or Health Canada at the following addresses:

Your professional commitment in this regard has an important role in protecting the well-being of your patients by contributing to early signal detection and informed use of drugs.

If you have additional questions about PERMAX, please call Shire BioChem Inc. Medical Information at 1-800-268-2772.

Sincerely,

original signed by

Bonnie Cockill
Director, Scientific Affairs
Shire BioChem Inc.

References