Letter - Posicor

This is the retyped text of a letter from Roche Laboratories.

June 12, 1998

Dear Doctor:

Re: IMPORTANT INFORMATION ON DRUG INTERACTION AND THERAPY SUBSTITUTION FOR POSICOR

We wish to thank you for your support during the first few days following the withdrawal of POSICOR, as well as your questions and comments which have reached us. This recent feedback indicated that a few patients have experienced drug interactions upon substituting certain alternate therapy for Posicor. We wish to immediately share the following information with you and suggest it be taken into consideration if you choose to prescribe either calcium channel blockers or beta blockers as alternate therapy:

If you choose to substitute amlodipine or atenolol, they should preferably be started two to three days after Posicor discontinuation.
If you choose to substitute other calcium channel blockers (except felodipine) or other beta blockers (except timolol), they should preferably be started seven days after Posicor discontinuation.
If you choose to substitute felodipine or timolol, they should preferably be started fourteen days after Posicor discontinuation.
No special precaution regarding the timing for switching is necessary for other antihypertensive or anti-anginal medications (e.g., ACE inhibitors, angiotensin II antagonists, diuretics, nitrates).

Any drugs metabolized by the cytochrome P450 3A4 or 2D6 isoenzymes may interact with Posicor. Therefore, as a reminder, the co-administration of mibefradil with drugs metabolized by the 3A4 or 2D6 isoenzymes of the cytochrome P450 system may result in increased plasma levels of those drugs, so dose adjustments may be necessary as mibefradil is withdrawn.

The consequences of clinically relevant interactions depend on the side effect profile of the individual drug to be used. Posicor's inhibition of the CYP 450 3A4 and 2D6 isoenzymes may increase the side effects of the drugs metabolized by these enzymes or prevent the formation of active metabolites. It takes an average of 7 days, but can take up to 14 days, for sufficient elimination of the metabolites of Posicor to minimize the inhibition of CYP 450 system. You should consider this pharmacokinetic information along with the patient's medical history and current status when initiating drugs metabolized by the CYP 450 system, including those identified on the attached table.

If you have any questions, please call Roche Laboratories at 1-800-205-4611.

Sincerely,

Russell H. Ellison, MD
Vice President
Medical Affairs
Roche Laboratories Inc.
340 Kingsland Street
Nutley, New Jersey 07110-1199

DRUGS THAT MAY INTERACT WITH MIBEFRADIL

GENERIC NAME: TRADE NAME

amiodarone: Cordarone
astemizole: Hismanal
bepridil: Vascor
cisapride: Propulsid
cyclosporine: Neoral, Sandimmune
cyclophosphamide: Cytoxan
desipramine: Norpramin
erythromycin: Erythrocin, Ilosone, others
etoposide: VePesid
flecainide: Tambocor
flutamide: Eulexin
halofantrine: Halfan
ifosfamide: Ifex
imipramine: Tofranil
lovastatin: Mevacor
mexiletine: Mexitil
pimozide: Orap
propafenone: Rythmol
quinidine: Cardioquin, Quinaglute, Quinidex, others
simvastatin: Zocor
tacrolimus: Prograf
tamoxifen: Nolvadex
terfenadine: Seldane
thioridazine: Mellaril
vinblastine: Velban
vincristine: Oncovin

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