Bristol-Myers Squibb's Pravachol is gaining share in the retail market in the early days following the withdrawal of Bayer's Baycol, prescription tracking data from ArcLight indicate.

Pravachol (pravastatin) held just over 11% of the statin market before the Aug. 8 announcement of the withdrawal of cerivastatin due to reports of rhabdomyolysis. As of Aug. 10, its share had moved up about five percentage points, ArcLight data show.

Merck's Zocor (simvastatin) also gained disproportionately from the Baycol withdrawal, with its share increasing more than two points to 24.5%.

The market leader, Pfizer's Lipitor (atorvastatin), had a smaller increase of about 1.5 points to 53.5%. Novartis' Lescol (fluvastatin) gained slightly to 4.4%, while Merck's Mevacor (lovastatin) continued to lose share to 1.5%.

The shift toward Pravachol could be an early indication that the Baycol withdrawal may make prescribers take a more cautious approach to potency in the statin class.

Public Citizen's Health Research Group intends to argue that FDA should take steps to encourage greater awareness of rhabdomyolysis associated with all statins. The consumer group plans a citizen's petition calling for a black box warning for the class.

HRG believes a more prominent warning is necessary to ensure that patients are attentive to potential symptoms of rhabdomyolysis, including muscle weakness or pain. The group was already preparing the petition when Baycol was withdrawn.

A bolded warning already included in statin labeling states that rhabdomyolysis has been reported with statin use in rare cases, especially with concomitant use of fibrates, including gemfibrozil. FDA said it does not currently plan any labeling changes in the class.

The European Union is conducting its own safety assessment of all the statin products.

"While all statins have been associated with very rare reports of rhabdomyolysis, cases of fatal rhabdomyolysis in association with the use of Baycol have been reported significantly more frequently," FDA states in an Aug. 8 "Talk Paper."

"Fatal rhabdomyolysis reports with Baycol have been reported most frequently when used at higher doses, when used in elderly patients, and particularly, when used in combination with gemfibrozil (Lopid and generics)," the "Talk Paper" says.

Baycol was associated with 31 fatalities reported to FDA and nine additional international reports. The European Union estimates that there have been as many as 480 fatal and non-fatal rhabdomyolysis cases worldwide. FDA said it knew of 1,000 worldwide reports, but cautioned that the total included a significant amount of double-counting.

According to HRG, all of the other statins combined have been associated with approximately 50 reports of death and 100 reports of non-fatal cases.

The timing of the Baycol withdrawal could prove particularly challenging for AstraZeneca, which has an NDA pending for the "superstatin" Crestor (rosuvastatin).

FDA may be prompted to take a more cautious approach in light of the Baycol experience. AstraZeneca may also have a more difficult time rolling Crestor out if physicians become more conservative about trying newer, higher potency agents.

The withdrawal could have an impact beyond the statin class if it increases the focus on drug safety and the quality of FDA reviews heading into the Prescription Drug User Fee Act reauthorization process.

Baycol is the fifth drug approved in 1997 to be withdrawn from the market due to side effects (along with Warner-Lambert's Rezulin, Wyeth-Ayerst's Duract, Roche's Posicor and Glaxo's Raxar). A sixth 1997 NDA, Pfizer's antibiotic Trovan, was withdrawn from the outpatient market. Baycol is also the 12th drug to be pulled from the market since Jan. 1, 1997.

Cerivastatin is by far the most significant drug in terms of sales to be pulled from the class of 1997, with sales this year expected to approach $1 bil. The next largest, Rezulin, was expected to generate about $400 mil. in 2000, the year it was withdrawn.

HRG argues that the recent product withdrawals illustrate the flaws with the user fee system. The consumer group has highlighted the 1997 drugs as evidence that FDA was acting with less caution in the context of the FDA Modernization Act debate.

The concentration of the Baycol adverse events around the higher doses may draw attention in the post mortems of Baycol's regulatory history.

FDA originally approved Baycol only in the .2 mg and .3 mg strengths. However, Bayer and copromotion partner SmithKline Beecham (now GlaxoSmithKline) decided to gain approval for higher strengths to position Baycol better against Lipitor.

During a 1997 investor conference, GSK CEO J.P. Garnier highlighted the importance of higher doses of Baycol. "We think there is more to the story than the .3 mg dose, which showed you have a very potent drug," Garnier said. "The question is, if you push the dose what happens?"

"We know we have a linear dose relationship in efficacy. That is excellent news. That is not the case for all HMG-CoAs, so that means that if you push the dose you get more efficacy. The question is, do you also get more side effects? Well, we're studying all this."

Garnier's comments about the commercial importance of the higher doses were apparently borne out in the marketplace. Baycol was launched after a .4 mg strength was approved in 1998, but it got off to a slow start in the crowded statin class. Growth accelerated sharply after approval of a .8 mg dose in mid-2000.

The number of fatality reports also accelerated: FDA said that 24 of the 31 U.S. deaths were reported after the higher dose was approved. Fifteen of the deaths were associated with use of the .8 mg strength and 14 with the .4 mg. The other two cases did not have a reported dose.

"The vast majority of fatalities involve patients being started directly on the highest dose, rather than the usual medical practice of starting patients on the lower dose, evaluating their response and then only increasing the dose...in patients that really need [it]," Bayer VP-Medical Affairs Paul MacCarthy, MD, said during an Aug. 7 media conference call.

Bayer has revised Baycol's label on two occasions in the past 18 months, most recently in May to recommend initiating therapy on the .4 mg dose rather than the .8 mg dose. The company also ceased physician sampling of the .8 mg dose in May (¹ Also see "Bayer Baycol Label Revised To Emphasize Risk Of Starting With .8 mg Dose" - Pink Sheet, 2 July, 2001.).

Bayer modified Baycol's label to include a contraindication for the antihyperlipidemic gemfibrozil in November 2000.

Twelve of the deaths reported to FDA involved concomitant use of gemfibrozil, with the first fatality reported in January 2000. Bayer highlighted the gemfibrozil warning on First Data Bank a "few months ago," VP-Cardiovascular Marketing Tig Conger noted.

"The message was transmitted to healthcare professionals in the last couple of months, but the experience is that these labeling changes have really not achieved the desired effect," MacCarthy explained.

Bayer does not have "definitive information at this stage" as to whether there is a unique characteristic of Baycol that causes rhabdomyolysis more than other statins, MacCarthy said. About 1.5% of all statin prescriptions in the U.S. also include a gemfibrozil Rx, versus .03% in Europe, Conger added.

The company said it has no plans to reintroduce Baycol in the U.S. and will most likely halt all ongoing clinical trials, including studies in diabetics and longer-term cardiovascular trials.

Baycol is being pulled from all markets except Japan, where Bayer co-markets the drug with Takeda. Since gemfibrozil is not available in Japan and cerivastatin's dose is lower than the high dose in the U.S., Bayer considers the drug safe and effective in the Japanese market, MacCarthy said.

HRG plans to write to Japanese health authorities questioning that position.

The product was emerging as one of Bayer's key franchises, and the withdrawal may prompt the company to rethink its strategic presence in the Rx sector (² Also see "Bayer Baycol Kansas City Facility Construction Halted Following Withdrawal" - Pink Sheet, 13 August, 2001.).

As with other recent product withdrawals, Bayer is likely to face a number of product liability suits with Baycol. Trial lawyers are already advertising for business: the Google internet search engine returns five "sponsored links" to law firms in response to a search of the term "Baycol."

Bayer's competitors are also moving quickly: Merck ran a direct-to-consumer print ad for Zocor in the Washington Post Aug. 10 which included an advisory suggesting that Baycol users ask their doctor about the Merck drug.

Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?

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