New CONTRAINDICATION regarding ergotamine- and dihydroergotamine-containing drugs: Risk of Cerebral and/or Peripheral Ischemia - Novartis Pharmaceuticals Canada Inc

Date: 2003-01-30

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The Marketed Health Products Directorate (MHPD), Therapeutic Products Directorate (TPD) and Biologics and Genetic Therapies Directorate (BGTD) post safety alerts, public health advisories, press releases and other notices from industry as a service to health professionals, consumers, and other interested parties. Although MHPD, TPD and BGTD approve therapeutic products, MHPD, TPD and BGTD do not endorse either the product or the company. Any questions regarding product information should be discussed with your health professional.

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

January 2003

SUBJECT: New CONTRAINDICATION regarding ergotamine- and dihydroergotamine-containing drugs: Risk of Cerebral and/or Peripheral Ischemia

Dear Healthcare Provider:

Novartis Pharmaceuticals Canada Inc, following discussions with Health Canada, would like to inform you of a new contraindication related to concomitant use of potent CYP3A4 inhibitors with the following products that contain ergotamine or dihydroergotamine:

BELLERGAL® Spacetabs® (belladonna alkaloids, ergotamine tartrate and phenobarbital) tablets

CAFERGOT® (ergotamine tartrate and caffeine) suppositories and tablets

CAFERGOT-PB® (ergotamine tartrate, caffeine, belladona alkaloids and pentobarbital) suppositories

DHE (dihydroergotamine mesylate injection USP) injectable

MIGRANAL® (dihydroergotamine mesylate) nasal spray

Following discussions with Health Canada, we understand that the labelling for generic ergotamine and ergotamine-containing products will be updated to reflect the revised Novartis labelling.

NEW CONTRAINDICATION FOR CONCOMITANT USE WITH POTENT CYP-3A4 INHIBITORS:

Concomitant use of potent CYP 3A4 inhibitors with ergotamine- or dihydroergotamine-containing products is contraindicated. Serious and/or life-threatening ischemia, including fatalities and cases of gangrene, has resulted from such concomitant use. Examples of potent CYP 3A4 inhibitors include: protease inhibitors, macrolide antibiotics and antifungal agents.

Because CYP 3A4 inhibition elevates the serum levels of ergotamine or dihydroergotamine, the risk for acute ergot toxicity (ergotism) is increased. Ergotism is characterized by vasospasm leading to cerebral ischemia and/or ischemia of the extremities, with some cases in the global database resulting in death or amputation.

Potent CYP 3A4 inhibitors include:

• Protease inhibitors such as ritonavir, nelfinavir, indinavir,
• Macrolide antibiotics such as erythromycin, clarithromycin, troleandomycin
• Antifungal agents such as ketoconazole, itraconazole

While these reactions have not been reported with less potent CYP 3A4 inhibitors, there is a potential risk for serious toxicity including vasospasm when these drugs are used with ergotamine or dihydroergotamine products. Examples of less potent CYP 3A4 inhibitors include:

• saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole.

These lists are not exhaustive, and the prescriber should consider the effects on CYP3A4 of other agents being considered for concomitant use with ergotamine or dihydroergotamine.

Chronic Daily Use Not Recommended

Chronic daily use of ergotamine- or dihydroergotamine-containing products is not recommended. Risk of ergotism is increased with chronic daily use, and rare fibrotic complications are associated with prolonged chronic use. Physicians are also reminded that, as per current Canadian labelling, prophylactic use is not recommended. There is no evidence that the drug is effective in preventing migraines.

The sections CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, CLINICAL PHARMACOLOGY and PATIENT PACKAGE INSERT of the Product Monographs are being updated accordingly. A copy of the revised Prescribing Information will be sent to you for insertion into your CPS, as soon as it becomes available.

Novartis is committed to providing you with the most current product information available for the management of patients receiving products containing ergotamine or dihydroergotamine. You can further our understanding of adverse events by reporting them.

The identification, characterization, and management of drug-related adverse events are dependent on the active participation of health care professionals in adverse drug reaction reporting programmes. Health care professionals are asked to report any suspected adverse reactions in patients receiving Bellergal® Spacetabs®, CAFERGOT®, CAFERGOT-PB®, DHE and MIGRANAL® directly to Novartis Pharmaceuticals Canada Inc. at the following address:

Novartis Pharmaceuticals Canada Inc.
385 Bouchard Blvd.
Dorval, Quebec
H9S 1A9
Tel: (800) 363-8883 or by fax at (514) 633-7054

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

If you have any questions regarding BELLERGAL® Spacetabs®, CAFERGOT®, CAFERGOT-PB®, DHE or MIGRANAL®, please contact Novartis at 1.800.363-8883

Sincerely,

original signed by

Pier-Giorgio Fontana, PhD
Vice-President, Drug Regulatory Affairs

original signed by

Jean-Marie Leclerc, M.D., F.R.C.P. (c)
Vice-President, Medical Affairs

* BELLERGAL® Spacetabs® are registered trademarks of Novartis Pharmaceuticals Canada inc.
* CAFERGOT® is a registered trademark of Novartis Pharmaceuticals Canada inc.
* CAFERGOT-PB® is a registered trademark of Novartis Pharmaceuticals Canada inc.
* MIGRANAL® is a registered trademark of Novartis Pharmaceuticals Canada inc.

Any suspected adverse drug reactions can also be reported to:
Canadian Adverse Drug Reaction Monitoring Program (CADRMP)
Marketed Health Products Directorate
HEALTH CANADA
Address Locator: 0201C2
OTTAWA, Ontario, K1A 1B9
Tel: (613) 957-0337 or Fax: (613) 957-0335
Toll free for consumers and health professionals:
Tel: 866 234-2345, Fax: 866 678-6789
cadrmp@hc-sc.gc.ca

The ADR Reporting Form and the ADR Guidelines can be found on the TPD web site or in The Canadian Compendium of Pharmaceuticals and Specialties.