Finasteride 5mg was approved by the U.S. Food and Drug Administration (FDA) in 1992 for the treatment of benign prostatic hyperplasia, and in 1997 for male pattern hair loss (MPHL) in the 1mg dose. For many years, because of cost and availability issues of finasteride 1mg, physicians, especially outside of North America, have suggested that patients divide brand or generic 5mg finasteride into quarters. Recently, numerous hair transplant physicians have commented on anecdotal reports by their patients of increased shedding and progressive hair loss noted after changing from brand to generic finasteride 1mg. This raises several questions about generic medications: how does the efficacy compare to brand, how are generic drugs regulated, are there variations among generic manufacturers, and is the active ingredient evenly distributed in the tablet?
Using bioequivalence as the basis for approving generic copies of drug products was established by the “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Hatch-Waxman Act. This Act expedites the availability of less costly generic drugs by permitting the FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials. At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through the FDA’s approval process. Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation.
According to the FDA website, a generic drug is identical or bioequivalent to a brand-name drug, and must follow the same standards as the innovator drug:
• Contain the same active ingredients as the innovator drug (inactive ingredients may vary).
• Be identical in strength, dosage form, and route of administration.
• Have the same use indications.
• Be bioequivalent.
• Meet the same batch requirements for identity, strength, purity, and quality.
• Be manufactured under the same strict standards of FDA’s good manufacturing practice regulations required for innovator products.
In order to obtain FDA approval to market a generic drug, companies must submit an abbreviated new drug application (ANDA). The ANDA process does not require the drug sponsored to repeat preclinical (animal) and clinical (human) research on ingredients or dosage forms already approved for safety and effectiveness. Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug). Bioequivalence is often demonstrated by studies measuring the time it takes the generic drug to reach the bloodstream in 24-36 healthy volunteers. This determines the rate of absorption, or bioavailability, of the generic drug, which is then compared to that of the innovator drug. The generic version must deliver the same amount of active ingredients into a patient’s bloodstream in the same amount of time as the innovator drug. Bioavailability is usually assessed by measuring the area under the plasma concentration–time curve (AUC).1
For FDA approval, a generic manufacturer must demonstrate that the 90% confidence interval for the ratio of the mean responses (usually of AUC and the maximum concentration, Cmax) of its product to that of the brand-name drug is within the limits of 80% to 125%. While AUC refers to the extent of bioavailability, Cmax refers to the rate of bioavailability.2
The 80-125% criterion is used to compare two treatments to evaluate bioequivalence. The bioequivalence test states that we can conclude that two treatments are not different from one another if the 90% confidence interval falls completely within the range 80-125%. The 80-125% criterion cannot conclude that the drugs are the “same,” only that they are not “different.” For drugs with a narrow therapeutic index range, small differences in dose or serum concentration may have therapeutic failures or adverse events, and the acceptance range of 80-125% may need to be smaller.3
The Federal Food, Drug and Cosmetic Act (FFDCA) established the “180-day exclusivity” period, during which the FDA will not approve other ANDAs for the same product. Dr. Reddy’s, an international generic pharmaceutical company based in India, was awarded a 180-day period of marketing exclusivity for finasteride 1mg on January 2, 2013, which expired on July 1, 2013. Since then, the following generic manufacturers also produce finasteride 1mg and 5mg: Accord Healthcare Inc., Actavis, Aurobindo, Camber, Hetero Labs, Mylan, Sun Pharma, Teva, and Zydus (5mg).
Increasingly, generic pharmaceutical active ingredients are made outside of the United States. This has raised concerns about drug quality and regulation in various countries, and the potential for counterfeit drugs. The FDA reported that 40% of finished generic drugs, and 80% of active ingredients, are coming into the United States from overseas sources.4 In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). In summary, it allows the FDA to inspect foreign facilities, to increase penalties for adulterated or counterfeit products, and to collect user fees from industry to fund the reviews of innovator and generic drugs, medical devices, and bio-similar products, and to expedite the development, review, and approval of “breakthrough therapies.” On February 14, 2014, The New York Times published an article titled “Medicines Made in India Set Off Safety Worries,” which noted that “India is the second-largest exporter of generic and OTC drugs to the U.S., supplying 40% of the US market.” They reported that the FDA has increased inspection of Indian plants, with new penalties and warning letters, and expressed concerns about potential counterfeit operations in China, and frustration with their efforts to increase inspections.
Counterfeiting occurs throughout the world, but it is most common in countries where there are few or no rules about making drugs. An estimated 10-30% of medicines sold in developing countries are counterfeit. In the industrialized world (countries such as the United States,
Australia, Japan, Canada, New Zealand, and those in the European Union), estimates suggest that less than 1% of medicines sold are counterfeit.5 The only way to know if a drug is counterfeit is through chemical analysis done in a laboratory. Counterfeit drugs may look strange or be in poor-quality packaging, but they often seem identical to the real thing. In March 2013, the FDA formed a new Cyber Crimes Investigation Unit, a special team within their Office of Criminal Investigations (OCI), devoted to combating rogue Internet pharmacies. This unit works with other domestic and international agencies to track down the operators and suppliers of websites that illegally sell prescription drugs.
Tablet splitting is a widespread practice to allow for dose flexibility and cost advantages for consumers. On July 21, 2009, the FDA posted “Tablet Splitting: A Risky Business” on its consumer site (www.FDA.gov), which noted: “FDA does not encourage the practice of tablet splitting unless it’s specified in the drug’s professional prescribing information. If a patient is considering splitting a tablet, FDA recommends that the patient gets advice directly from his or her doctor or pharmacist to determine whether it is appropriate or not for a particular drug.” Possible risks to consumers include confusion over the dose, as people may forget to split them, and tablets may be difficult to split evenly due to size, shape, and technique. Several studies have shown weight variability of unscored split tablets, even those split by pharmacists.6 These concerns are especially relevant in drugs with a narrow therapeutic index.
Concerning the practice of splitting finasteride 5mg, two issues come into question: How evenly distributed is the drug in half or quarter fragments, and does splitting affect the clinical outcome? The U.S. Pharmacopeial Convention (USP) sets the standards for identity, strength, quality, and purity of medications, which are enforced by the FDA. The amount of active drug is never 100% evenly distributed in any tablet. One study looking at the uniformity of distribution of finasteride in 5mg halves and quarters showed a high mean average content in both (2.88, 1.33).7 Another study concluded that drug content variation in half-tablets appeared to be attributable primarily to weight variation during the splitting process, highly determined by the ability of patients to split tablets perfectly in half.8 A Veterans Affairs study noted that 4/12 products that failed the weight-uniformity test when split in halves, varied in tablet shape and hardness.9 Splitting devices also vary in quality and design. Among various manufacturers, finasteride 5mg tablets vary in size and shape; thus fragmentation, powdering, and fragment loss may occur with splitting. In addition, patients should be advised not to split more than one pill at a time to be stored for later use as exposure to heat, moisture, humidity, and other factors could affect drug efficacy.
A review of the clinical pharmacology of finasteride is relevant to its therapeutic index range. Finasteride is a competitive and specific inhibitor of Type II 5α-reductase with preferential inhibition of the Type II isozyme, and is 100. selective for the Type II 5α-reductase over Type I isozyme. For both isozymes, the inhibition by finasteride is accompanied by a reduction of the inhibitor to dihydrofinasteride and adduct formation with NADP+. The turnover for the enzyme complex is slow (t1/2 approximately 30 days for the Type II enzyme complex and 14 days for the Type I complex). This may explain its long relative clinical effect on hair loss. In terms of absorption, Merck’s original study in 15 healthy young male subjects, the mean bioavailability of finasteride 1mg tablets was 65% (range 26-170%), based on the ratio of area under the curve (AUC) relative to an intravenous (IV) reference dose. Relative to an intravenous reference dose, the oral bioavailability of finasteride is approximately 80%. The bioavailability is not affected by food. Maximum finasteride plasma concentrations are reached approximately two hours after dosing and the absorption is complete after 6-8 hours. The mean terminal half-life is approximately 5-6 hours in men 18-60 years of age and 8 hours in men more than 70 years of age.10
The concerns of adverse events and post-finasteride syndrome have initiated discussions among physicians in terms of titration of dose to potentially reduce symptoms, or patient concerns over potential side effects, yet still maintain efficacy for hair loss. In the original dose ranging study with finasteride for male pattern hair loss,11 efficacy was demonstrated at 0.2mg for all end points including hair count, investigator and patient self-assessment of hair growth, and global photography. Efficacy results were similar at 1mg and 5mg doses, which were superior to the 0.2mg dose. Some suggested regimens are . tablet every other day, . three times per week, and a “titration” program of 1mg per week for 1 month, 1mg twice a week for 1 month, then 1mg every other day. Fewer side effects and better patient compliance, without reduced efficacy, have been observed.12 However, controlled clinical trials using 1mg, 5mg, and placebo arms have not shown a dose-dependency relationship for sexual side effects in both androgentic alopecia and benign prostatic hyperplasia age groups.13,14
Several hair transplant surgeons anecdotally report comments from patients that shedding occurred after switching from brand to generic finasteride, or the generic seemed less effective. Explanations for this might include placebo effect, counterfeit drug, or quality control differences in batches or processing. Based on my research of FDA requirements for generic approval, and the relative long effective half-life of finasteride Type II isozyme complex, the splitting of generic finasteride 5mg should be an equally effective alternative to the 1mg generic, or to the brand-name drug, despite the potential for fragment loss during splitting.
The many different pill shapes and sizes.
5. “Counterfeit Drugs: Fighting Illegal Supply Chains.” Howard Sklamberg testimony before Congressional Committee of Energy and Commerce, February 27, 2014.
6. Rosenberg, J.M., J.P. Nathan, and F. Plakogiannis. Weight variability of pharmacist dispensed split tablets. J Am Pharm Assoc. 2002; 42:200-205. doi: 10.1331/108658002763508498.
7. Al-Haddab, M. Drug content and uniformity in commonly split tablets in dermatology. J Am Acad Dermatol. 2014(May); 70(5): Supplement 1, AB151.
8. Hill, S.W., et al. Analysis of drug content and weight uniformity for half-tablets of 6 commonly split medications. J Manag Care Pharm. 2009(Apr); 15(3):253-261.
9. Polli, J.E., S. Kim, and B.R. Martin. Weight uniformity of split tablets required by a Veterans Affairs policy. J Managed Care Pharm. 2003; 9(5):401-407.
10. Merck & CO., INC.
11. Roberts, J., et al. Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss. J Am
Acad Dermatol. 1999; 555-563.
12. Email communication with Drs. Michael Beehner, Ron Shapiro, and Russell Knudsen.
13. Gormley, G., et al. The effect of finasteride in men with benign prostatic hyperplasia. N Eng J Med. 1992; 327:1185-1191.
14. Roberts, J., et al. Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss. J Am Acad Dermatol. 1999; 555-563.