Executive Summary
To evaluate possible drug-drug interactions with combined pills, clinicians need to understand how the estrogen and progestin in pills are absorbed, distributed, metabolized, and eliminated.
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When ethinyl estradiol is in contact with the liver, it induces changes in hepatic enzyme and protein synthesis. It increases hepatic production of carrier proteins, and it also activates cytochrome P-450 enzymes, boosting the rate at which many drugs are cleared by the liver from the bloodstream.
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The only antibiotics that profoundly affect combined oral contraceptive potency are drugs that contain hepatic enzyme inducers: rifampin, used alone or with other drugs in treatment of tuberculosis, and griseofulvin.
The next patient in your office is a 32-year-old mother of two who is using oral contraceptives (OCs) for family planning. She tells you she also is using ampicillin for bronchitis. Should she be concerned about the antibiotic’s impact on her Pill’s efficacy?
Hormone levels in women using combined pills are not lowered by broad-spectrum antibiotics such as ampicillin, amoxicillin metronidazole, or doxycycline, says Anita Nelson, MD, professor in the Obstetrics and Gynecology Department at the David Geffen School of Medicine at the University of California in Los Angeles. Nelson recently presented on the subject of drug interactions with hormonal contraceptives at the Contraceptive Technology Atlanta 2014 conference.1
"Don’t worry about it, and advise patients not to worry," Nelson says of broad-spectrum antibiotics and estrogen-containing contraceptives. "There is no need for backup method, unless there are other problems with oral contraceptives."
To evaluate possible drug-drug interactions with combined pills, clinicians need to understand how the estrogen and progestin in pills are absorbed, distributed, metabolized, and eliminated. According to Contraceptive Technology, people used to worry about "enterohepatic circulation," but today we understand this process has only a slight impact on pill efficacy. The story goes like this: Sex steroids in combined OCs are absorbed by the small intestine and shunted primarily through the liver, known as first pass. About 60% of the absorbed ethinyl estradiol is conjugated to form glucoronic and sulfate conjugates, which are excreted through the gallbladder and back into the small intestine without entering the bloodstream. Bacteria in the large intestine unconjugate the estrogen compounds, which are then absorbed from the colon. They are then delivered to the liver through the enterohepatic circulation for additional hepatic passes for absorption into the bloodstream or for reconjugation and re-excretion back into the intestine. They are then eliminated in the feces. The sex steroids that enter circulation ultimately are conjugated hepatically and excreted in the urine. This is no longer considered a problem because the re-circulation contributes only slightly to serum levels.2
The real story, even for rifampin and griseofulvin, happens within the liver.2 When ethinyl estradiol is in contact with the liver, it induces changes in hepatic enzyme and protein synthesis. It increases hepatic production of carrier proteins, and it also activates cytochrome P-450 enzymes. They boost the rate at which many drugs are cleared by the liver from the bloodstream.2 Drugs that are metabolized more rapidly cannot work as thoroughly.
What drugs to flag?
Remember that rifampin also is widely used in treatment of skin infections associated with methicillin-resistant Staphylococcus aureus, notes Nelson.
Women with seizure disorders face special challenges when it comes to use of combined OCs, says Nelson. Enzyme-inducing anti-epileptic drugs (AEDs) increase clearance and decrease systemic levels of contraceptive hormones, as well as increase contraceptive failures and up the risk of teratogenicity. On the other hand, the estrogen in combined OCs increases the clearance and decreases systemic levels of anticonvulsives, and it boosts seizure frequency.
Use of carbamazepine, phenobarbital, phenytoin, primidone, eslicarbazepine, oxcarbazepine, and topiramate will decrease serum concentrations of estrogen, while felbamate and rufinamide will increase serum concentrations of estrogen, explains Nelson. On the other hand, combined OC use results in reduced levels of lamotrigine and valproic acid (oxcarbazepine). Remember that many AEDs also are used in other applications, such as to reduce drug dependency and to treat depression.2
What are contraceptive management options for women using AEDs and combined hormonal contraception? Clinicians can look at either voiding systemic combined hormonal methods and progestin-only pills or can consider using 50 mcg ethinyl estradiol combined pills or adding barrier method usage to combined pills, advises Nelson. The contraceptive implant, injection, and intrauterine contraception all represent effective options for women who use AEDs.
Antiretrovirals and OCs?
What does the U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) say about use of combined pills in women with HIV/AIDS? According to the U.S. MEC, all combined hormonal methods (the Pill, patch, and ring) are listed as "Category 1" (no restrictions on use) for women using nucleoside reverse transcriptase inhibitors for antiretroviral therapy.3 However, for women using non-nucleoside reverse transcriptase inhibitors, the U.S. MEC classes combined hormonal method use as "Category 2" (advantages of using the method generally outweigh the theoretical or proven risks). For women who use ritonavir-boosted protease inhibitors, combined hormonal method use is classed as Category 3 (a condition for which the theoretical or proven risks usually outweigh the advantages of using the method).
For women undergoing antiretroviral therapy, "pill burden" is real, notes Nelson. Non-daily delivery systems might reduce that burden and also avoid first pass metabolism issues, she states.
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Nelson AL. Drug interactions with hormonal contraceptives: What are the real problems? Presented at the Contraceptive Technology Atlanta 2014 conference. Atlanta; October 2014.
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Nelson AL, Cwiak C. Combined oral contraceptives. In: Hatcher RA, Trussell J, Nelson AL, et al. Contraceptive Technology: 20th revised edition. New York: Ardent Media; 2011.
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Centers for Disease Control and Prevention. U.S. medical eligibility criteria for contraceptive use. MMWR 2010; 59(RR04):1-6.
