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IVAX' GENERIC SUSTAINED-RELEASE VERAPAMIL APPROVED ON JULY 31; LAUNCH DATE DELAYED UNTIL FDA COMPLETES INSPECTIONS; SEARLE FILES CITIZEN’s PETITION ON AUG. 5

Executive Summary

Ivax's sustained-release verapamil 240 mg was approved on July 31 as a first generic substitute for Searle's Calan SR and Knoll's Isoptin SR in the treatment of hypertension. The Ivax generic is not substitutable for Lederle/Wyeth-Ayerst's Verelan sustained release verapamil. The drug will be marketed by Ivax' Miami-based subsidiary Baker Norton (formerly Baker Cummins Pharmaceuticals). The firm said the introduction of its verapamil HCL ER must wait until FDA has "completed a pre-marketing inspection of [the product's] production process." Searle filed a citizen's petition with FDA on Aug. 5, requesting a "meeting as soon as possible" to discuss the agency's approval of Baker Norton's verapamil. Searle also requested that "FDA stay any contemplated AB therapeutic equivalent rating for the Ivax verapamil sustained-release product." In an Aug. 5 letter to FDA Commissioner Kessler, Searle maintained that the Ivax approval "was granted despite the fact that the generic product failed significant traditional bioequivalence measures." Searle contends that the agency should have required that sustained-release verapamil bioequivalence studies include "stereochemistry parameters" that were outlined in a recent FDA guideline for new chemical entity batch scale-ups ("The Pink Sheet" June 1, T&G-10). The company apparently does not intend to challenge the actual approval of the Ivax ANDA for sustained-release verapamil. Searle points out in the letter to Kessler that its petitions "require a recommendation of the Ivax ANDA." The company plans to dispute the Ivax products "AB" therapeutic equivalence rating based on an argument that stereochemistry must be taken into account in generic bio studies. However, FDA is unlikely to reconsider a therapeutic rating for an already approved drug since the agency's position is that all ANDA approvals -- with the two exceptions of potassium chloride and theophylline line extensions -- are by definition therapeutically equivalent. The latest citizen's petition is Searle's second on the subject of sustained-release verapamil bioequivalence testing. The company filed its original petition on Nov. 27, 1989, asking FDA to "issue a guideline setting forth the testing and other requirements necessary to establish bioequivalence and therapeutic equivalence of sustained-release verapamil HCL ('verapamil SR') drug products," ("The Pink Sheet" Jan. 1, 1990, T&G-2). The company said that its research demonstrated that stereochemistry, especially chirality, is an important factor in assessing the bioequivalence of sustained-release verapamil. Searle's latest petition resurrects the company's earlier arguments on verapamil bioequivalence and requests that FDA schedule a meeting of the agency's Generic Drugs Advisory Committee to "consider the importance and interrelationship of the stereochemistry and bioequivalence issues" associated with sustained-release verapamil as well as other sustained products. FDA "has historically recognized that extreme care must be given before approving ANDA's for controlled-release products and for then granting products and "AB" therapeutic rating," the petition notes. "Extreme care in this [Ivax verapamil] situation justifies advisory committee attention." In addition, Searle's petition asks the agency to allow the company to participate in the therapeutic rating deliberations for all verapamil sustained release products. Searle suggests this could be accomplished by giving the company an opportunity to comment on proposed ratings prior to FDA's formal decision. Searle representatives will meet with Office of Generic Drugs Director Roger Williams, MD, on Aug. 26. Searle said the meeting is to discuss the relationship of stereochemistry and bioequivalence as it relates to verapamil. FDA reportedly is open to the idea of addressing the issue in an upcoming advisory committee meeting; however, the next meeting of the Generic Drugs Advisory Committee may not be soon enough for Searle. The next meeting of the committee has not yet been announced. Searle outlined its scientific position in a June 2 letter to the New Jersey Department of Health opposing the addition of the Ivax sustained-release verapamil to the New Jersey formulary. "Specific verapamil enantiomer concentrations should be measured to determine bioequivalency," the letter states. Searle's argument to both New Jersey and to FDA is that verapamil is essentially "a combination drug" containing racemic verapamil -- a 50:50 mixture of the two stereoisomers (+) R- verapamil and (-) S-verapamil -- and that bio studies should be required to show that generic verapamil products have equal concentrations of the two stereoisomers. Since the pharmacological effect of one isomer is stronger than the other, a difference in the ratio of the two isomers could affect a generic product's efficacy or side effects profile, Searle maintains. "A formulation that results in a total verapamil Cmax of 264 ng/ml (160 ng/ml of R and 104 ng/ml of S) could be deemed bioequivalent to a formulation resulting in a total verapamil Cmax of 264 ng/ml (188 ng/ml of R and 76 ng/ml of S)," Searle explained in its letter to New Jersey. Therefore, Searle maintained, "the concentrations of the 'active molecules' (enantiomers) of verapamil need to be measured to determine bioequivalency of modified-release verapamil formulations." Searle also contends that Ivax bio studies comparing the generic to Knoll's Isoptin SR do not necessarily guarantee that it is bioequivalent to Calan SR. "Ivax has conducted some studies," Searle's petition states, "although not the necessary stereochemistry and chiral studies, that purport to show that its product" is "bioequivalent" to Isoptin SR. Searle noted that it has "conducted extensive studies, including chiral studies," to show that Calan SR is bioequivalent to Isoptin SR. "What is missing, however," Searle maintained, "are any data" demonstrating that Ivax' verapamil is bioequivalent to Calan SR. In addition, Searle is arguing that the Ivax submission "included only a single-dose study under fed conditions and no multiple-dose study under fed conditions." Labeling for Calan SR and Isoptin SR notes that the products "should be administered with food." Searle maintains that when the bioavailability data under fed conditions are compared between Ivax' verapamil and Isoptin SR, that Cmax is not equivalent, "even under the range of differences usually deemed acceptable." Searle's petition asks FDA to issue a guideline that mandates: "(1) testing to establish that the proposed formulation will have the same pharmacodynamic effects in hypertensive patients as the reference formulation; (2) testing that compares the pharmacokinetics of the proposed and reference formulations at steady state; (3) testing according to a crossover, replicate design; (4) testing for food effect at a steady state, comparing the proposed and reference formulations with and without high-fat meal; (5) testing that is specific for the active mioeties -- i.e. the S and the R enantiomers of verapamil sustained release and of norverapamil, verapamil sustained release's active metabolite (of these, the S isomer of verapamil sustained release has the predominant pharmacological effect); and (6) testing that demonstrates that AUC, Cmax, Tmax, and fluctuation index for the proposed and reference drugs meet a more stringent standard than the traditional 20% requirement, based on the two one-sided t- test."
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