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Contraception Corner

Combination OCs and Prescribed Antibiotics

Miriam Zieman, MD; Anita Nelson, MD

The response to Contraception Corner is very positive. The following is a question that arises on a daily basis and one that needs addressing. Any concerns about this or any other contraceptive subject, please contact us at contraception@qhc.com. We welcome any comments and questions.

Do I need to prescribe a back-up method of contraception for women on combined oral contraceptives who are prescribed antibiotics?
This is an area of clinical practice where there is conflicting advice. To answer this question, we will review the science behind the advice and then review different recommendations regarding this topic.

First, let's review how combination oral contraceptives (COCs) work and how they are metabolized, so we can understand how other medications may influence efficacy.

The mechanism of action of COCs is primarily suppression of ovulation by inhibiting gonadotropin secretion. Of primary importance, the progestin component suppresses the luteinizing hormone (LH) surge, and thus prevents ovulation. The estrogen component plays a role by suppressing the follicle-stimulating hormone (FSH) thereby preventing the development of a dominant follicle. The progestin contributes to contraception by other means, too: decidualized endometrium not receptive to implantation, thick cervical mucus that inhibits sperm, and possibly inhibition of fallopian tube peristalsis.^1,2

Enterohepatic metabolism of COCs
Metabolism of ethinyl estradiol and the various progestins is complicated, but a limited description follows. After absorption in the small intestine, the steroids are carried in the hepatic portal vein to the liver. A portion is directly absorbed into the bloodstream, but much is metabolized in conjugated forms that are released through the gallbladder back into the intestines. Liver metabolism (either at the first pass or later after the steroids have been transported around the body) creates conjugated metabolites of both the estrogen and progestins. These conjugates are mostly sulfates and glucuronides. When these metabolites re-enter the lumen of the bowel, they can be excreted or the bowel flora can deconjugate the metabolites, which are reabsorbed causing an increase in circulating ethinyl estradiol (entero-hepatic circulation).^3,4

Variability of metabolism
Serum levels of ethinyl estradiol and the progestins vary enormously (up to tenfold) among women taking the same doses of pills.^3,5 There is individual variation in absorption, liver and gut metabolism, binding to transport proteins, and the efficiency with which ethinyl estradiol is re-formed by the bowel flora.

Furthermore, oral ingestion results in a peak and trough pattern of serum levels, which in has a fivefold to tenfold variation in blood levels.³

The effectiveness of COC or other low-dose hormonal contraceptive may be lowered by administration of other medications, such as those that induce liver enzymes. Medications that are considered "enzyme inducers" increase the activity of liver enzymes that metabolize the steroids as they pass through the liver, thereby reducing serum steroid levels. These may reduce efficacy of COCs. Other medications may increase plasma sex hormone binding globulin (SHBG) levels, thereby decreasing the amount of biologically active-free steroid. There are other medications that may decrease the amount of hormone absorbed initially or reabsorbed after passing through the liver. This is the concern with use of broad-spectrum antibiotics. The question is if antibiotics kill the bacteria responsible for deconjugation in the colon, could this result in decreased hormone levels and reduced contraceptive efficacy.^3,4 Side effects of medication may cause vomiting or diarrhea, or induce drowsiness, which could lead to lost or missed pills.¹

What do pharmacokinetic studies show?

• Medications that induce hepatic enzymes do reduce serum levels of steroids. This can compromise efficacy. These include the antibiotics rifampin and griseofulvin and other medications such as phenytoin, carbamazepine, phenobarbital, primidone, carbamazepine, felbamate, topiramate, vigabatrin.
• Pharmacokinetic studies of antibiotics other than rifampin have not shown any systematic interaction between antibiotics and oral contraception (OC) steroid levels.^4,5,7,8 Studies of serum levels in the face of amoxicillin and tetracycline found that such a large intrasubject and intersubject variability in steroid levels at baseline, a small number of women might be vulnerable when exposed to an antibiotic.^5,6

What are the current recommendations?
Here is a summary of the current information or recommendations.

COC product labeling.—The COC product labeling for prescribers states "reduced efficacy and increased incidence of breakthrough bleeding and menstrual irregularities have been associated with concomitant use of rifampin. A similar association, though less marked, has been suggested with barbiturates, phenylbutazone, and possibly with griseofulvin, ampicillin, and tetracyclines." The product labeling for patients states "Certain drugs may interact with birth control pills to make them less effective...Such drugs include... and possibly certain antibiotics."⁹

ACOG Practice Bulletin.—"Because OC steroids are strikingly reduced in women concomitantly taking rifampin, such women should not rely on COCs, progestin-only OCs, or implants for contraceptive protection. Pharmacokinetic studies have not demonstrated lower OC steroid levels with concomitant use of tetracycline, doxycyline, ampicillin or metronidazole or quinolone antibiotics."⁷

Modern Oral Contraception.—Updates from The Contraception Report conclusion of their evidence based review: "No sound evidence suggests that other (besides enzyme inducers) antibiotics decrease the efficacy of OCs...Extra precautions are probably not warranted but have been suggested."⁴

Council for Scientific Affairs of the American Medical Association:—"Women prescribed rifampin concomitantly with OCs faced a significant risk of OC failure and should be counseled about the additional use of nonhormonal contraceptive methods during the course of rifampin therapy.

Women using COCs should be informed about the small risk of interactions with antibiotics and that it is not possible to identify in advance the women who may be at risk of contraception failure... Women who have breakthrough bleeding during concomitant use of antibiotics and OCs should be counseled about alternate methods of contraception if they engage in intercourse during the period of concomitant use, as they may be part of the subset of women at high risk of contraceptive failure."⁶

Regarding the recommendations cited above, one notes a lack of consensus and a fair amount of hedging. When a woman is prescribed an enzyme-inducing medication, you can either recommend use of an alternate contraceptive, concomitant use of a back-up contraceptive, or as some experts recommend, you can switch to a higher dose pill such as a 50-mcg ethinyl estradiol combination pill. When it comes to recommendations for when a patient is prescribed a broad-spectrum antibiotic, you can either follow the ACOG or the AMA approach cited above. From a review of the literature, there is not enough evidence to support the need for back-up contraception when broad-spectrum antibiotics are prescribed to COC users.

REFERENCES

1. Hatcher RA, Trussel J, Stewart F, et al. Contraceptive Technology. 17th ed. New York, NY: Ardent Media Inc;1998.
2. Speroff L, Daney P. A Clinical Guide for Contraception. Baltimore, Md: Williams & Wilkins;1996.
3. Guillebaud J. Contraception: Your Questions Answered. 3rd ed. New York, NY: Churchill Livingstone;1999.
4. Wallach M, Grimes DA. Modern oral contraception. The Contraception Report. June 2000.
5. Neeley JL, Abate M, Swinker M, D'Angio R. The effect of doxycycline on serum levels of ethinyl estradiol, norethindrone, and endogenous progesterone. Obstet Gynecol. 1991;77:416.
6. Dickinson BD, Altman RD, Nielsen NH, Sterling ML. Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol. 2001;98:853-860.
7. ACOG Practice Bulletin. The use of hormonal contraception in women with coexisting medical conditions. 2000;18.
8. Murphy AA, Zacur HA, Charache P, Burkman RT. The effect of tetracycline on levels of oral contraceptives. Am J Obstet Gynecol. 1991;164:28-33.
9. Physicians' Drug Reference. Montvale, NJ: Medical Economics Company Inc; 2001.

About ARHP
ARHP is a nonprofit, national medical organization that has been educating front line providers and their patients since 1963. The organization and members are dedicated to educating physicians and health care providers, and the public about important reproductive health issues including contraception, sexually transmitted diseases, menopause, abortion, sexuality, and infertility. ARHP contact information: 2401 Pennsylvania Ave, N.W., Suite 350, Washington DC 20037-1718; ph: (202) 466-3825; fax: (202) 466-3826; e-mail: arhp@arhp.org; Web: www.arhp.org.

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