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:
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:
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:
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:
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