A review of the safety of generic drugs.

Generic drugs have been around for many years. The Drug Price Competition and Patent Term Restoration Act 1984 makes the abbreviated new drug application process available to drugs approved after 1962. It does not lower any standards for generic drugs. FDA's comprehensive drug approval process evaluates information concerning (1) chemistry, manufacturing, and controls, (2) in vivo bioequivalence, (3) labeling, (4) in vitro dissolution data where applicable, and (5) inspection and auditing of all facilities. This stringent and comprehensive approval process ensures the quality of generic drug products marketed in the US and assures the health professionals and patients of the safety and efficacy of generic drug products.

Bioequivalence of racemic drugs.

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

Bioequivalence of generic thioridazine drug products--the FDA viewpoint.

The phenothiazines are among the most widely used drugs to treat symptoms commonly associated with acute and chronic psychoses. One of the commonly prescribed compounds within this class of drugs is thioridazine, available both as a generic product as well as the innovator product, Mellaril. Each of these products is coded as bioequivalent and consequently therapeutically equivalent by the Food and Drug Administration (FDA). A recent issue of this journal contained an article that raised a number of questions concerning the bioequivalence of the generic versions of thioridazine that have been approved by the FDA. Their article was based in part on information obtained from the FDA as well as information supplied to the authors by Sandoz, Inc., the manufacturer of the original thioridazine drug product Mellaril. The FDA has reviewed its original decision of bioequivalence. Based on this reassessment, the FDA strongly rejects the assertion by the authors that several of the approved generic thioridazine products are not bioequivalent. The rationale behind the FDA decisions and the FDA's viewpoint on the bioequivalence of generic thioridazine drug products is discussed in detail.

Bioavailability of regular and controlled-release chlorpheniramine products.

The bioavailability of chlorpheniramine regular-release versus controlled-release products was compared using 15 human subjects. The dosage forms evaluated were an 8-mg barrier coated-bead capsule, an 8-mg repeat action tablet, two 4-mg tablets, and 4- and 8-mg syrups. Single doses of each product were administered orally in a 5-way crossover study, plasma samples were collected at specific time intervals, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The average plasma elimination half-life of chlorpheniramine was calculated to be approximately 18.3 hr. The controlled-release products gave a higher Cmax than the 4-mg syrup, but less than two 4-mg tablets. The controlled-release products also extended the time necessary to attain peak drug levels compared to the 4- and 8-mg syrups. The area under the curve (AUC) data for the controlled-release products was not equivalent to equal amounts of the regular-release products. The study indicated that while the controlled-release chlorpheniramine products were successful in prolonging the time course of absorption, this was at the expense of incomplete bioavailability of the drug.

Blood levels following multiple oral dosing of chlorpheniramine conventional and controlled release preparations.

An examination of steady-state performance of chlorpheniramine conventional versus controlled release products was conducted using 15 male subjects in a 3-way crossover study with a 2-week washout period between studies. The study was designed to determine if chlorpheniramine formulations provide consistent pharmacokinetic performance between individual units upon going from single dose to multiple dose therapy. In addition, the validity of predicting steady-state levels for these kinds of products using only single oral dose data was examined. The dosage forms evaluated were a conventional 4 mg tablet, and 8 mg barrier coated-bead capsule, and an 8 mg repeat action tablet. Multiple doses of each product were orally administered to each subject for 6 days prior to the study day to achieve steady-state levels and on the actual study day. Serum samples were collected at specific time intervals on the study day, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The mean plasma elimination half-lives of the various dosage forms were in the range 24.5-25.4 h. There was no rapid release of drug from the controlled release products nor did they have drug release problems during the dosing interval. Good agreement was obtained between predicted average drug concentration at steady-state and drug concentration actually present for all the formulations studied. Based upon comparative examination of AUC, Cmax, and fraction of dose absorbed data, the controlled release products administered every 12 h were comparable in performance to a conventional release tablet administered every 6 h. Since the half-life of chlorpheniramine is approximately 1 day, therapeutic management may possibly be gained with dosing the patient once daily with a controlled release product or twice daily with a conventional tablet.