December 1997

Dear Doctor:

We would like to inform you of important new warning information concerning the use of POSICOR (mibefradil dihydrochloride), a treatment for hypertension and chronic stable angina pectoris. This concerns:

1. a warning related to suppression of sinoatrial activity and severe bradycardia occurring with POSICOR, and

2. a warning and contraindication concerning drug interactions and statin-induced rhabdomyolysis with POSICOR and certain HMG-CoA reductase inhibitors.

This letter emphasizes the importance of patient selection, patient montoring, and attention to concomitant drug therapy to ensure that POSICOR is used appropriately. Please see enclosed complete product information.

I. Decreased Sinus Node Activity and Severe Bradycardia

The use of POSICOR has been associated with the appearance of symptomatic slow junctional rhythm. Ventricular rates have been as low as 30 to 40 bpm and many patients have been symptomatic. To date there have been about three dozen such reports arising from an exposure of 75,000 patients. This adverse effect has occurred mainly in elderly patients who were on concomitant beta-blocker therapy. Similar findings of symptomatic slow junctional rhythm have also been reported with other heart rate lowering compounds such as beta-blockers, digoxin, diltiazem and verapamil, especially when more than one of these agents are used at the same time.

In order to assist you in the appropriate use of POSICOR, please review the following package insert revision:

WARNINGS: Supression of Sinoatrial Node Activity: Use of mibefradil has been associated with slowing or complete suppression of sinoatrial node activity. The supervening junctional rhythms have often been slow (as slow as 30 to 40 bpm). Many of the reports have incorrectly identified the adverse event as complete AV block. The reports have been most common in the elderly, mainly in association with the concomitant use of beta-blockers. Care should be taken when combining POSICOR with beta-blockers, particularly when pretreatment sinus rate is below 55 bpm, and this combination should be avoided in the elderly when pretreatment sinus rate is below 55 bpm (see PRECAUTIONS). In patients with low heart rates, use of any combination of agents that can slow the sinus node or affect the AV node (eg, beta-blockers, digitalis, and the calcium channel blockers mibefradil, diltiazem, and verpamil) should in general be undertaken only after careful consideration, as such combinations can unmask underlying sick sinus syndrome. Use of POSICOR in patients with sick sinus syndrome without a pacemaker is contraindicated (see CONTRAINDICATIONS).

POSICOR is associated with a dose related decrease in heart rate. This effect is achieved whether POSICOR is given as monotherapy or in combination with beta-blockers. In susceptible patients, as described in the revised warnings section, the decrease in sinus node activity may result in severe sinus bradycardia or sinus arrest. In reported cases, cardiac pacing has been taken over by the AV node, but sometimes at low rates that were poorly tolerated.

II. Interaction of POSICOR (mibefradil dihydrochloride) with certain HMG-CoA Reductase Inhibitors

Roche has received 7 domestic reports of statin-induced rhabdomyolysis in patients receiving simvastatin and POSICOR (4 of the cases were also receiving cyclosporine), presumably due to inhibition by POSICOR of the metabolism of simvastatin, markedly increasing simvastatin's plasma concentration. POSICOR is a strong inhibitor of cytochrome P450 3A4, the enzyme responsible for metabolizing several of the HMG-CoA reductase inhibitors. POSICOR also inhibits metabolism of cyclosporin, increasing its blood levels; cyclosporine itself decreases excretion of all HMG-CoA reductase inhibitors and substantially increases their blood levels.

POSICOR would be expected to have effects on blood levels of certain other HMG-CoA reductase inhibitors. Based on the similarity of lovastatin and simvastin metabolism, coadministration of POSICOR and lovastatin would also be expected to result in markedly increased plasma concentrations of lovastatin. Atorvastatin and cerivastatin are also metabolized by CYP450 3A4, but the metabolites are active, so the overall effect of POSICOR on their HMG-CoA reductase activity may not be large. Studies of atorvastatin and cervastatin with erythromycin, a moderate inhibitor of CYP450 3A4, have not shown marked increases in the blood levels of these HMG-CoA reductase inhibitors, but at present there are no studies with stronger inhibitors, such as mibefradil, ketoconazole, or itraconazole.

Since fluvastatin and pravastatin are not significantly metabolized by CYP450 3A4, POSICOR would not be expected to have a significant effect on their blood levels. Please see enclosed complete product information.

In order to assist you in the appropriate use of POSICOR, please review the following package insert revisions:

CONTRAINDICATIONS: POSICOR is contraindicated in patients who:

Are concurrently receiving terfenadine, astemizole, cisapride, lovastatin or simvastatin (see WARNINGS and PRECAUTIONS).

WARNINGS: Interaction Resulting in HMG-CoA Reductase Inhibitor-Induced Rhabdomyolysis: Mibefradil inhibits the action of CYP450 3A4. When this enzyme is inhibited, plasma concentrations of those drugs that are metabolized by CYP450 3A4 may become elevated, sometimes by more than an order of magnitude (see PRECAUTIONS).

Rhabdomyolysis is a known rare adverse effect of all of the HMG-CoA reductase inhibitors (the "statin" cholesterol-lowering agents).

The statins are not identically metabolized:

• Lovastatin and simvastatin are dependent on CYP450 3A4 for their metabolic clearance. Among patients receiving simvastatin and mibefradil there have been reported cases of rhabdomyolysis. These events appear to reflect an incidence of rhabdomyolysis higher than that seen during treatment with simvastatin alone. Because of the metabolic similarities of lovastatin and simvastatin, coadministration of POSICOR with either of these two drugs is contraindicated.

• Atorvastatin and cerivastatin are biotransformed by CYP450 3A4 to active and inactive metabolites. Also, only small changes in HMG-CoA reductase inhibitor activity have been seen in studies where atorvastatin and cerivastatin were combined with erythromycin (a less potent CYP450 3A4 inhibitor than mibefradil). Nevertheless, until there is more information on the coadministration of CYP450 3A4 inhibitors (including mibefradil) with atorvastatin and cerivastatin, coadministration of either of these two drugs with POSICOR should generally be avoided.

• Fluvastatin and pravastatin are not significantly metabolized by CYP450 3A4; no clinically important interaction with mibefradil is anticipated. Therefore, no specific dose adjustment of fluvastatin or pravastatin is recommended with coadministration of POSICOR (mibefradil dihydrochloride).

  Drug Interactions - Cyclosporine/Tacrolimus and HMG-CoA Reductase Inhibitors: The calcineurin immunosuppressants tacrolimus (FK-506) and cyclosporine are metabolized by CYP450 3A4, so their blood levels rise (in the case of cyclosporine, about twofold) when POSICOR is coadministered; dose adjustment may be necessary. Because the immunosuppressants themselves inhibit a drug-transport system that participates in the excretion of HMG-CoA reductase inhibitors, elevated levels of the immunosuppressants can cause additional elevations in the blood levels of any of the HMG-CoA reductase inhibitors. Use of POSICOR should be avoided in patients also receiving both a calcineurin immunosuppressant and an HMG-CoA reductase inhibitor.

We trust this information will assist you in using POSICOR to manage your hypertensive and angina patients appropriately. Please see enclosed complete product information.

If you have any questions about POSICOR, we encourage you to call the toll-free number for Roche Medical Services at 1-800-526-6367. Also, if you are aware of any serious adverse events potentially associated with the use of POSICOR, please report such information to Roche at the above number or the Food and Drug Administration MedWatch program at 1-800-FDA-1088.

Sincerely,

Russell H. Ellison, MD
Vice President
Medical Affairs

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Roche Laboratories Inc.
340 Kingsland Street
Nutley, NJ 07110-1199

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