FDA is requesting long-term safety information on the 80 mg and 160 mg strengths of Bristol-Myers Squibb's Pravachol (pravastatin) as a postmarketing commitment associated with the agency's approval of Pravachol 80 mg.

FDA approved Bristol's sNDA (10-898/S-046) for 80 mg pravastatin Dec. 18. Bristol plans to launch the 80 mg strength in late January. Pravachol 160 mg is an unapproved dose.

In its approval letter, FDA requests "submission by April 30, 2002, of the final study report for Period C (long-term extension) of study CV123-321, which will provide additional safety information on daily administration of 80 mg and 160 mg of Pravachol."

"Revisions to the Pravachol label may be needed after review of these data," the letter says.

The approval adds 80 mg Pravachol to Bristol's existing 10 mg, 20 mg and 40 mg pravastatin product line, and also increases the recommended starting dose for Pravachol.

Updated labeling recommends that patients begin Pravachol therapy at 40 mg. Previously, the recommended starting dose for pravastatin was 10 mg, 20 mg or 40 mg. Both old and new versions of labeling suggest a starting dose of 10 mg for patients with a history of significant renal or hepatic dysfunction.

Bristol said the 80 mg dose "provides doctors with an effective titration option from the recommended 40 mg starting dose." Labeling instructs that "if a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily dose is recommended."

The approval of the higher Pravachol strength comes during a time of increased concerns over the safety of statins, particularly at higher doses.

Bayer withdrew Baycol (cerivastatin) in August following fatal rhabdomyolysis reports associated with higher doses (¹ Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 August, 2001., p. 4).

The product was originally approved at the lower doses of .2 and .3 mg, but Bayer later added two higher strengths. Growth accelerated sharply after approval of a .8 mg dose in mid-2000.

At the time of Baycol's withdrawal, Bayer said the "vast majority" of fatalities associated with Baycol were in patients initiated at higher cerivastatin doses rather than initiating at a lower dose and titrating upward.

Public Citizen's Health Research Group has asked FDA to add a black box warning on rhabdomyolysis for the entire statin class (² Also see "Statin Consumer Medication Guides Requested By HRG In Wake Of Baycol" - Pink Sheet, 27 August, 2001., p. 20). In its "Talk Paper" on the Baycol withdrawal, FDA acknowledged that all statins have been associated with very rare reports of rhabdomyolysis but said that fatal cases associated with Baycol use was reported significantly more frequently.

FDA did not strengthen the rhabdomyolysis warning for Pravachol in connection with the 80 mg approval.

The agency's approval of the higher Pravachol dose may bode well for AstraZeneca's pending NDA for Crestor (rosuvastatin). The application was submitted June 26 and discussions with FDA are focusing on the potential for the highest dose to cause rhabdomyolysis, AstraZeneca told analysts in December (³ Also see "AstraZeneca Crestor NDA Includes Rhabdomyolysis Reports At Highest Dose" - Pink Sheet, 10 December, 2001., 2001, p. 21).

Baycol's withdrawal has had a positive impact on Pravachol sales. The company has been aggressively highlighting the safety profile of the 40 mg dose of pravastatin (⁴ Also see "Bristol Pravachol New Rx Up 22% Since Baycol Withdrawal, Company Says" - Pink Sheet, 1 October, 2001., p. 20).

New Pravachol labeling says that the safety profile of Pravachol 80 mg appeared "similar to that of Pravachol at lower doses" in two controlled trials with a mean exposure of 8.2 months, "except that four out of 464 patients taking 80 mg of pravastatin had a single elevation" of creatine kinase greater than 10 times the upper limits of normal "compared to zero of 115 patients taking 40 mg of pravastatin."

Bristol conducted two studies enrolling 277 patients for the 80 mg sNDA. At six weeks, patients experienced a 37% mean decrease in LDL cholesterol (vs. 1% for placebo) and a 3% mean increase in HDL cholesterol (vs. -1% for placebo). In clinical trials of the 40 mg dose, patients showed a 34% mean decrease in LDL cholesterol and a 12% mean increase in HDL.

Bristol has an application for co-packaged Pravachol and aspirin pending at FDA. The product is scheduled for review by FDA's Cardiovascular & Renal Drugs Advisory Committee Jan. 18.

Bristol Pravachol 80 Mg Long-Term Safety Data Is Phase IV Commitment

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