IVAX BEGINS SHIPMENTS OF GENERIC ALBUTEROL MDI IMMEDIATELY FOLLOWING DEC. 28 ANDA APPROVAL; BIOEQUIVALENCE TO VENTOLIN SHOWN IN IN VIVO TESTS, FDA SAYS

Ivax began shipping its generic version of Glaxo's Ventolin metered-dose inhaler on Dec. 29, less than 24 hours following FDA approval of the ANDA for the albuterol product. The company will market the product approved Dec. 28 through its Zenith Goldine subsidiary. Ivax is understood to have 2 mil. cannisters ready for shipping.

The asthma product is manufactured at Ivax' Norton subsidiary's Waterford, Ireland plant. The firm reports that it has sold over 28 mil. albuterol inhalers in over 30 countries worldwide. The albuterol approval gives Ivax a total of 18 ANDA approvals in 1995 for 12 different chemical compounds.

The FDA approval for the much debated generic drug during the late 1995 holiday season ends an almost seven-year effort by brand name manufacturers to block clearance of the nonsystemically absorbed product.

In a Dec. 29 "Talk Paper," FDA declared the Ivax product "safe and effective as the brand name product" based on "a series of laboratory analyses and in vivo tests in humans." Showing bioequivalence has been difficult since albuterol MDIs, including innovator products, have great variability in the amount of drug delivered to the lung and do not easily fall within the 80%-125% biointerval required for generic bioequivalence.

FDA lays out the bioequivalence tests that supported the approval of the generic albuterol MDI, including in vitro particle and plume tests, bronchoprovocation studies in asthmatics, and cardiovascular and metabolic tests in healthy volunteers.

In vitro performance tests for aerosol products "determined the equivalence or similarity of the generic and brand name products for the delivered amount of albuterol, the particle size and the shape of the aerosol cloud produced by both products," FDA said. The agency conducted its own tests for physical characteristics of the product to see if its results were similar to those of the firm.

In the bronchoprovocation study, "the equivalence of the pharmacological action of albuterol MDIs was established by comparing the generic version and the brand name product's capacity to protect the airways from constriction induced by histamine," the agency noted. FDA added that "the bioequivalence of the generic albuterol MDI and Ventolin MDI was also confirmed by comparing the cardiovascular and metabolic effects of these products in healthy people at exposure levels substantially exceeding the recommended therapeutic doses."

Albuterol MDI manufacturer Schering-Plough (Proventil) first challenged FDA's bioequivalence requirements for generic albuterol MDIs in 1989. Schering, Glaxo and then 3M Pharmaceuticals, which has an NDA pending for an albuterol MDI with a CFC-free propellant, launched a second round of petitions following FDA's January 1994 issuance of its "Interim Guidance for Documentation of In Vivo Bioequivalence of Albuterol Inhalation Aerosols (Metered-Dose Inhalers)" ("The Pink Sheet" Feb. 7, 1994, p. 4).

Over the last few months Ivax garnered political support from congressional representatives, including Rep. Waxman (D-Calif.), who urged FDA to approve the generic product expeditiously. Hearing that the Ivax approval might be near, 3M wrote to Center for Drug Evaluation & Research Director Janet Woodcock, MD, on Dec. 7 reasserting its contention with expert testimony that the product should not be approved without further study, especially in patients with severe asthma ("The Pink Sheet" Dec. 11, 1995, T&G-15). The company requested an advisory committee meeting be held prior to any generic albuterol MDI approval. 3M also assembled some congressional backers for its position largely among the Minnesota delegation.