Germany. Further to the worldwide withdrawal by the US manufacturer of the calcium channel blocker, mibefradil (Posicor: Roche), the Federal Institute for Drugs and Medical Devices has suspended the marketing authorization for mibefradil (Cerate 50: Asta Medica), until 30 November 1998 because it considers that mibefradil has a negative benefit/risk ratio. In particular, it has a life-threatening potential to induce cardiac arrhythmias (including torsades de pointes) especially when taken concomitantly with other medications.

[See also DRS Information Exchange System Alert No. 70, 9 June 1998]

Reference: Communication from the Federal Institute for Drugs and Medical Devices, 21 August 1998.

Mibefradil - therapy substitution and drug interactions

Roche, United States of America. Following the alert about adverse reactions associated with the calcium channel blocker, mibefradil (Posicor: Roche), the manufacturer has sent a “Dear Doctor” letter concerning drug interactions that patients have experienced with substitute therapy. Mibefradil was withdrawn from all markets by the manufacturer following reports of interactions with a large number of other products. The manufacturer subsequently received reports of adverse reactions in patients who were switched too quickly to alternative medications, and has provided the following advice to doctors:

If amlodipine or atenolol are chosen as substitutes, they should preferably be started two to three days after mibefradil is discontinued.

If other calcium channel blockers are chosen (except felodipine) or other ß-adrenoreceptor antagonists (except timolol), they should preferably be started 7 days after mibefradil is discontinued.

No special precaution regarding the timing for the switch is necessary for other antihypertensive or anti-anginal medications (e.g. ACE inhibitors, angiotension II antagonists, diuretics, nitrates).

Any drugs metabolized by the cytochrome P450 3A4 or 2D6 isoenzymes may interact with mibefradil. Doctors are reminded that co-administration of mibefradil with drugs metabolized by these isoenzymes may result in increased plasma levels of those drugs, therefore dose adjustments may be necessary as mibefradil is withdrawn.

It takes an average of 7 to 14 days for sufficient elimination of the metabolites of mibefradil to minimize the inhibition of the CYP 450 system. This should be taken into consideration together with the patient’s medical history and current status when initiating drugs metabolized by the CYP 450 system.

[See also DRS Information Exchange System Alert No. 70, 9 June 1998]

Reference: “Dear Doctor” letter dated 12 June 1998. [http://www.fda.gov/medwatch/safety/1998/posico2.htm]