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2002 Selected Articles

Therapeutic Substitution of Low-Dose OCs
Public Health Concerns

Rudi Ansbacher, MD; Mitchell D. Creinin, MD; John M. Thorpe, Jr, MD;
Thomas E. Nolan, MD, MBA; Ian H. Thorneycroft, MD, PhD

Low-dose oral contraceptives (OCs) have been growing in popularity because of their more favorable side-effect and long-term risk profiles (when compared with higher-dose OCs). However, some physicians have expressed concern that differences in hormone bioavailability between brand-name OCs and their “therapeutically equivalent” generic counterparts may increase rates of breakthrough bleeding (BB) and compromise contraceptive efficacy. BB is the most common reason cited for discontinuing OC use among US women.¹ Because many of these women switch to a less effective birth-control method or stop using any method after OC cessation, BB may indirectly contribute to a higher rate of unintended pregnancy. Thus, substituting a therapeutically equivalent generic OC for a brand-name OC may save money in the short run but could be more costly in the long run.

The availability of therapeutically equivalent generic drugs of all types has increased dramatically since 1984. All 50 states permit or require pharmacists to substitute such products for brand-name drugs whenever possible.² However, substituting generic low-dose OCs for brand-name products may have major clinical and economic consequences. This is especially true when OCs containing 20 mg of ethinyl estradiol (EE), the lowest estrogen dose available in OC combinations in the United States, are prescribed. More than a decade ago, it was suggested that OCs should be placed in the “critical drug” category, in which generic substitution and interchangeability of products are not advised.^2,3

ALLOWABLE VARIATIONS

The US Food and Drug Administration (FDA) requires that so-called therapeutically equivalent generic drugs be tested for bioequivalence, but not for efficacy or safety, before they are approved.⁴ This raises three concerns about allowable variations:

• Typical studies measuring bioequivalence enroll only 20 to 25 subjects, which does not constitute a representative sample.

• A generic drug is considered therapeutically equivalent to a brand-name drug—and therefore acceptable—if its mean extent of absorption, as measured by a bioequivalence study, differs by less than 20% from that of the brand-name drug.⁵

• The US Pharmacopeia has established an official standard allowing drugs to differ from their stated potency by up to 10%.⁵

Thus, the potency of brand-name OCs and their generic equivalents could differ by up to 28%. However, as mentioned above, the FDA does not mandate that these generic low-dose OCs be tested for contraceptive efficacy and BB profiles in large clinical trials. In fact, one study showed that BB was almost twice as great with an OC containing levonorgestrel 75 mg/EE 15 mg as with a formulation containing levonorgestrel 100 mg/EE 20 mg.^6,7

IMPLICATIONS

As mentioned above, BB is the most common adverse effect prompting OC discontinuation. Women who do not experience BB until their pharmacy switches them to a therapeutically equivalent low-dose generic OC may be particularly likely to stop using the Pill. Among women who discontinue OCs, 69% switch to a less effective method of contraception, and 19% use no method at all.¹ It has been estimated that more than 1 million unintended pregnancies in the United States per year are related to OC misuse or cessation with the latter accounting for 61%.⁸ Thus, if low-dose generic OCs are, in fact, linked to higher BB rates and higher OC cessation rates—resulting in a greater risk of unplanned pregnancy—then use of these agents instead of brand-name products may have serious implications.

OC efficacy may also be compromised by indiscriminate switching among therapeutically equivalent versions of brand-name drugs, which could result in a 40% to 60% difference in the rate or extent of absorption.² For drugs that require careful titration to ensure efficacy—including low-dose OCs—such variability can have major consequences.² Once women find the OC formulation that works best for them—that is, one that they tolerate well—they should continue to use that product.³ After all, OC efficacy depends on proper use.⁹ Also, as OC products vary in terms of both packaging and pill colors, which serves to designate proper pill sequence, switching from one product to another might be confusing. The narrow therapeutic range of action with therapeutically equivalent low-dose OCs may not allow for typical margins of error in bioavailability, missed tablets, and improper pill sequences.³

Variations in the manufacturing process of OCs may also contribute to differences in their efficacy and tolerability. For example, variations in the excipients used by different manufacturers may affect the bioavailability and release profile of the active hormonal ingredients,³ which may ultimately modify absorption and potentially change efficacy and/or tolerability.

Finally, OC compliance among adolescent users is of particular concern.¹⁰ Unintended pregnancy in this population leads to major psychological, financial, and social problems, along with serious physical risks.¹¹ For these girls, taking the Pill should be as simple as possible and the efficacy of the Pill should be as reliable as possible. And, physicians should bear in mind that adolescents are not the only age group that has difficulty using OCs as directed. One study showed that even in the third month of OC use, approximately 50% of women missed at least three pills.¹²

CONCLUSION

Prescribing low-dose generic OCs that are not identical to the brand-name OCs for which they are intended as substitutes may compromise both individual and public health. To help prevent potential problems with contraceptive efficacy and BB, the authors propose that, at the very least, these generic formulations undergo efficacy and safety testing similar to that required by the FDA for brand-name drugs. Also, they advise that, once an optimal OC formulation and brand is found for a particular woman, that she continue to take that product (to maximize efficacy and minimize adverse effects). Cost-saving from using generic products is misleading and temporary if use of these products results in an increase in unplanned pregnancies.

Rudi Ansbacher, MD, is a professor of obstetrics and gynecology, University of Michigan Medical Center, Ann Arbor. Mitchell D. Creinin, MD, is an associate professor, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pa. John M. Thorpe, Jr, MD, is a professor, Department of Obstetrics and Gynecology, University of North Carolina School of Medicine, Chapel Hill. Thomas E. Nolan, MD, MBA, is a professor of obstetrics and gynecology, and head of the section of general obstetrics and gynecology, Louisiana State University Medical Center, New Orleans. Ian H. Thorneycroft, MD, PhD, is professor and chairman, Department of Obstetrics and Gynecology, University of South Alabama Medical Center, Mobile.

REFERENCES

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2. Colaizzi JL, Lowenthal DT. Critical therapeutic categories: a contraindication to generic substitution? Clin Ther. 1986;8:370-379.
3. Ansbacher R. Interchangeability of low-dose oral contraceptives: are current bioequivalent testing measures adequate to ensure therapeutic equivalency? Contraception. 1991; 43:139-147.
4. Mangione RA. Understanding generic drug equivalence. US Pharmacist. 1998;23:51-60.
5. Nightingale SL, Morrison JC. Generic drugs and the prescribing physician. JAMA. 1987;258:1200-1204.
6. Wyeth-Ayerst Laboratories. Data on file. 1999.
7. Del Conte A, Loffer F, Grubb GS. Cycle control with oral contraceptives containing 20 mg of ethinyl estradiol: a multicenter, randomized comparison of levonorgestrel/ethinyl estradiol (100 mg/20 mg) and norethindrone/ethinyl estradiol (1000 mg/20 mg). Contraception. 1999;59:187-193.
8. Rosenberg MJ, Waugh MS, Long S. Unintended pregnancies and use, misuse and discontinuation of oral contraceptives. J Reprod Med. 1995;40:355-360.
9. Rosenberg MJ, Waugh MS, Meehan TE. Use and misuse of oral contraceptives: risk indicators for poor pill taking and discontinuation. Contraception. 1995;51:283-288.
10. Jay MS, Bridges CE, Gottlieb AA, DuRant RH. Adolescent contraception: an overview. Adolesc Pediatr Gynecol. 1988;1:83-95.
11. Forrest JD, Singh S. Public-sector savings resulting from expenditures for contraceptives services. Fam Plann Perspect. 1990;22:6-10.
12. Potter L, Oakley D, de Leon-Wong E, Cañamar R. Measuring compliance among oral contraceptive users. Fam Plann Perspect. 1996;28:154-158.

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