AstraZeneca Agrees To Limit Distribution, Promotion Of Crestor 40 Mg

AstraZeneca has agreed to an unusual distribution system for Crestor to limit use of the 40 mg dose of the statin.

"At the time of the launch of Crestor and after, AstraZeneca will not stock the 40 mg tablet bottles directly with retailers," FDA's Aug. 12 approval letter for rosuvastatin states. "Retail pharmacies will need to go through a wholesaler to obtain the 40 mg tablets."

"This will result in a one-day lag time to obtain this rosuvastatin dose," FDA noted. "These steps will help ensure that the 40 mg dose is available only to patients who truly need this dose."

In addition, Crestor 40 mg will be supplied only in 30-count unit-of-use bottles, while the other doses will be supplied in 90-count bottles. AstraZeneca has also agreed not to sample the 40 mg dose.

The approval letter notes that AstraZeneca has "voluntarily undertaken" the limited distribution measures for the 40 mg dose.

Higher doses of Crestor were associated with increased rates of renal-related adverse events, such as proteinuria and hematuria, in clinical trials.

FDA approved Crestor (rosuvastatin) for the treatment of various lipid disorders, including primary hypercholesterolemia, mixed dyslipidemia and isolated hypertriglyceridemia.

Crestor is approved in four doses: 5 mg, 10 mg, 20 mg and 40 mg. The approved start dose for the general population is 10 mg, with the 20 mg dose reserved for patients with "marked hypercholesterolemia (LDL-C> 190 LDL mg/dL) and aggressive lipid targets," labeling states.

"Initiation of therapy with 5 mg once daily may be considered for patients requiring less aggressive LDL-C reductions or who have predisposing factors for myopathy," labeling notes.

AstraZeneca is expected to focus on the efficacy and convenience of the 10 mg dose in launching Crestor (see ¹ (Also see "AstraZeneca Crestor 10 Mg Starting Dose Priced At 12% Discount To Lipitor" - Pink Sheet, 18 Aug, 2003.)).

However, FDA's approval letter also discloses AstraZeneca's last-minute agreement, on the same day as the Crestor approval, "to make 5 mg professional samples available for distribution within six months after approval of this NDA."

The timing of the agreement and formality of its disclosure indicates that AstraZeneca may not have been planning to sample the 5 mg dose.

The agreement also marks a rare instance where FDA would be involved in a discussion to make product samples available as part of a risk management plan.

The agency is presumably encouraging the production and distribution of the 5 mg samples as a means of increasing awareness of the lower dose.

AstraZeneca proposed a general fixed start dose of 10 mg, reserving the 20 mg dose for patients with severe hypercholesterolemia (>190 LDL mg/dL) and the 5 mg start dose for patients on cyclosporine.

However, FDA asked the advisory committee to consider whether a range of start doses, 5 mg to 20 mg, "should be considered which would allow prescribers to select a dose based on [coronary heart disease] risk factors present, baseline LDL levels and degree of total LDL-lowering needed" (² (Also see "AstraZeneca Crestor 10 mg Fixed Starting Dose Supported By Committee" - Pink Sheet, 14 Jul, 2003.), p. 3).

AstraZeneca is distinguishing the Crestor 5 mg dose from the other dosage strengths by its color: the 5 mg tablets are yellow while the 10 mg, 20 mg and 40 mg tablets are pink.

Some doses of rosuvastatin in controlled clinical trials were associated with more reports of proteinuria.

The proportion of patients who developed a dipstick urine protein level of 2+ or greater on 5 mg, 10 mg, 20 mg, 40 mg and 80 mg of the drug was .5%, .8%, .5%, 2.8% and 11%, respectively. The incidence of 2+ proteinuria for placebo patients was .6%.

For other statins in the analysis, proteinuria reports were generally fewer.

Bristol-Myers Squibb's Pravachol at 20 mg had a 1.1% incidence of proteinuria 2+ and 0% for 40 mg. Pfizer's Lipitor doses of 10 mg, 20 mg, 40 mg and 80 mg had incidences of proteinuria 2+ of .6%, .8%, .4% and .3%, respectively. The incidences for Merck's Zocor 20 mg, 40 mg and 80 mg doses were 1.1%, .6%, and .3%, respectively.

FDA's Endocrinologic & Metabolic Drugs Advisory Committee recommended that renal function monitoring be required for patients taking Crestor 40 mg (³ , p. 5).

However, AstraZeneca and FDA appear to have addressed the safety concerns with the 40 mg dose through the limited distribution plan rather than through restrictive labeling.

Crestor labeling does not require renal function monitoring despite an increased incidence of renal-related adverse events and the advisory committee's monitoring recommendation. The risk of renal-related adverse events is described in the "precautions" section, rather than the "warnings" section.

The "precautions" section of labeling notes that "dipstick-positive proteinuria and microscopic hematuria were observed among rosuvastatin treated patients, predominantly in patients dosed above the recommended dose range, i.e., 80 mg."

"However, this finding was more frequent in patients taking rosuvastatin 40 mg, when compared to lower doses of rosuvastatin or comparator statins, though it was generally transient and not associated with renal function," labeling adds.

"Although the clinical significance of this finding is unknown, a dose reduction should be considered for patients on rosuvastatin 40 mg therapy with unexplained persistent proteinuria during routine urinalysis testing."

Patients with severe renal impairment not on hemodialysis should be started at 5 mg and should not exceed 10 mg, labeling states. No dose modification is necessary for patients with mild to moderate renal insufficiency.

Crestor labeling also carries warnings related to elevated liver enzymes and myopathy/rhabdomyolysis, which appear in labeling for all statins. As with other members of the class, baseline and intermittent liver function monitoring is recommended.

Similarly, labeling notes that rosuvastatin "should be prescribed with caution in patients with predisposing factors for myopathy, such as renal impairment, advanced age and hypothyroidism."

In Crestor clinical trials, one case of rhabdomyolysis occurred at the 10 mg dose and seven cases at the 80 mg dose. AstraZeneca was originally developing an 80 mg dose of the statin, but development was halted following reports of rhabdomyolysis and renal impairment (⁴ (Also see "AstraZeneca Crestor Plan: Drop 80 Mg, Submit Lower-Dose Data In Q1" - Pink Sheet, 12 Aug, 2002.), p. 27).

By comparison, no cases of rhabdomyolysis occurred during development for the other statins. Several incidences of rhabdomyolysis have been reported with Zocor and lovastatin (Merck's Mevacor and generics) since approval.

Concerns about serious adverse events with statins have risen since the withdrawal of Bayer's Baycol (cerivastatin) in August 2001. While all statins have been associated with muscle weakness, Baycol was connected to a significantly higher incidence of the adverse event (⁵ (Also see "Baycol Withdrawal Gives Boost To Pravachol; Will Crestor NDA Be Affected?" - Pink Sheet, 13 Aug, 2001.), p. 4).

Eleven cases of myopathy not related to exercise or injury were observed in Crestor clinical trials on the 80 mg dose. One case was observed in each of the 10 mg, 20 mg and 40 mg arms while, no cases were observed in patients taking the 5 mg dose.

Results from an FDA review of myopathy occurrence in pre-approval clinical studies and Phase IV trials indicated that the incidence for the Crestor 5 mg, 10 mg, 20 mg and 40 mg doses is similar to that of currently marketed statins, at .2%, .1%, .1% and .2% respectively.

The FDA analysis showed ranges of 0%-.4% for Pravachol, .04% to .5% for Zocor, 0% for Lipitor and 0% to 2.1% for Baycol.

The company has committed to one Crestor post-marketing study: "to perform an appropriately conducted pharmacokinetic study of Asians residing in the U.S. to further explore the pharmacokinetic differences that were previously found in Japanese residing in Japan and Chinese residing in Singapore."

Pharmacokinetic studies of Crestor showed "an approximate two-fold elevation in median exposure in Japanese subjects residing in Japan and in Chinese subjects residing in Singapore when compared with Caucasians residing in North America and Europe."