Solvay is asking FDA to prevent generic companies from using the "little eight" carve-out in their ANDAs for Marinol (dronabinol).

The firm is concerned that generic applications may seek approval for one of Marinol's indications, the treatment of refractory nausea and vomiting associated with chemotherapy-induced nausea and vomiting, but would file a section viii statement to exclude from labeling the indication for treatment of weight and appetite loss in patients with AIDS.

The chemotherapy-related indication was approved in 1985 and no longer enjoys any patent or exclusivity protection. The AIDS-related indication, approved in 1992, is covered by a patent that expires in 2011.

Solvay argues that allowing ANDAs to carve out the AIDS-related claim - using the relatively common procedure under which generics are approved with still-protected elements omitted from the label - presents a safety risk.

The firm "does not challenge FDA's general authority to approve a generic drug with 'carved out' labeling." However, the circumstances of Marinol's indications "in particular" dictate that carve-outs not be permitted.

Because dosing regimens for the two indications are vastly different, carving out AIDS indication and safety information, Solvay claims, is misleading. For AIDS patients, Marinol is typically prescribed for a longer period of time and taken at lower dose levels less frequently. In the case of cancer patients, Marinol is used in short periods of time at relatively high doses many times during the day. The daily dose for a cancer-related indication could be up to 16 times higher than for the AIDS indication, Solvay said.

Also important is that AIDS patients account for two-thirds of the patients who are prescribed Marinol, Solvay noted. In addition, any generic version will likely be dispensed by pharmacists for AIDS-related indication, regardless of labeling, Solvay said.

FDA will likely face a similar dilemma with an ANDA for AstraZeneca's Crestor (rosuvastatin). Cobalt is proposing to market a generic that carves out the statin's principle indication for treatment of primary hypercholesterolemia (¹ Also see "AstraZeneca Aims To Grow Seroquel XR With Added Indications, Not Switches" - Pink Sheet, 5 November, 2007., p. 3).

Solvay's petition argues that FDA's imperative to prevent carved-out Marinol generics derives from sections 352(a) and 321(n) of the Food, Drug and Cosmetics Act. Section 352(a) states that a drug is misbranded if its labeling is "false or misleading in any particular." Circumstances that can lead to misbranding under section 321(n) include misleading advertising as well as labeling that "fails to reveal facts material" under "conditions of use as are customary or usual."

This line of reasoning was not addressed in the court cases (Sigma-Tau Pharmaceuticals, Inc v. Schwetz and Bristol-Myers Squibb Co. v. Shalala) which affirmed FDA's authority to allow carve outs, Solvay said.

The issue in those suits was "whether FDA's approval of a generic product with exclusivity-protected labeling 'carved out' was consistent with the ANDA approval provisions of the FD&C Act in 21 U.S.C. In both cases, there was no discussion of false and misleading labeling or FD&C Act sections 352(a) and 321(n)."

Solvay's petition was submitted Oct. 25 by VP of U.S. Regulatory Affairs Victor Raczkowski, former director of FDA's Office of Drug Safety, and appears to be the first citizen petition affected by the provisions of the Food and Drug Administration Amendments Act of 2007 designed to curb petitions that are merely designed to delay generic approvals (² Also see "FDARA Citizen Petition Provisions No “Silver Bullet,” Bradshaw Tells GPhA" - Pink Sheet, 10 September, 2007., p. 12).

The petition is a resubmission of one made Sept. 27, the day FDAAA was enacted. That one, which did not include the certifications of completeness and timeliness that are required under the new law, was rejected by FDA.

FDA is not the only federal agency looking ahead to the release of generic Marinol. The Drug Enforcement Administration published a notice of proposed rulemaking in September that would expand the classification of dronabinol as a Schedule III controlled substance under the Controlled Substance Act.

Currently, it is a federally-controlled Schedule I controlled substance, and only Marinol is regulated as a Schedule III controlled substance. Its lower classification is based on the fact that the formulation (synthetic formulation of dronabinol in sesame oil and encapsulated in a soft gelatin capsule) greatly diminishes potential for THC abuse. The proposed rule would expand the classification of dronabinol products in Schedule III to include tablets and capsules, not just soft gel capsules. The rule would also allow for classification of both synthetic and natural dronabinol products.

- Lauren Smith (lauren.smith@elsevier.com)

Generic Labeling “Carve-Outs” For Marinol Challenged On Safety Grounds

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