Latebreakers

We call it contraceptive failure when someone uses a method correctly and consistently but gets pregnant nonetheless. We have come to understand that a medication someone takes for a medical condition can alter the effectiveness of hormonal contraceptives in many ways.

Some contraceptive methods have been studied extensively to determine the interactions that diminish effectiveness, but other methods have had little study. For example, Interactions between POPs and other drugs have not been well studied. In the absence of a high degree of evidence, it is reasonable to suspect that they may be similar to interactions with COCs, which have been well studied, state Shaalini Ramanadhan, MD, MCR, and Alison Edelman, MD, MPH. (1)

Since POPs produce relatively low progestin levels even in the absence of other drugs, POPs may not be a good contraceptive option for people who are taking certain drugs on a chronic basis. These drugs include rifampicin, certain anticonvulsants, and some antiretroviral drugs, which affect the metabolism of ingested steroid hormones and lower serum levels of the contraceptive hormone. (2)

People on these drugs can increase the effectiveness of their contraceptive use by adding a second contraceptive that is nonhormonal like a barrier method, spermicide, or withdrawal. Advise POP users who want to maintain effectiveness while temporarily taking a potentially interacting drug to use a backup method while on the medication, and possibly for some period of time after stopping it. Although some providers have proposed that POP users should increase the dose of POPs while taking a potentially interacting drug, no data are available on the efficacy or advisability of this idea.

Cytochrome P450 Enzyme

The most important way a medication can interact with some hormonal contraceptives is through the liver’s cytochrome P450 enzyme activation. (3,4)  This is relevant for combined hormonal contraceptives, including combined oral contraceptives (COCs), rings, and patches as metabolism occurs in the liver after systemic absorption via transdermal or vaginal routes. Implant efficacy relies on adequate systemic levels of ENG, which makes this method susceptible to interactions with drugs metabolized through the liver.

Induction of cytochrome P450 will cause more rapid clearance of medications, including contraceptives, that are metabolized by this pathway. Medication development is ongoing, thus the knowledge regarding whether a new medication interacts with a hormonal contraceptive often lags. However, most medication labeling will contain information on its metabolism pathway—if it is a cytochrome P450 inducer, then it is possible that it could decrease contraceptive effectiveness.

Combined Oral Contraceptives (COCs)

Most studies looking at drug–drug interactions involve COCs. The major class of medications that often decrease COC’s effectiveness is anticonvulsants such as carbamazepine, phenytoin, and topiramate. Lamotrigine (Lamictal®) is a special case, as the COC is not affected by concurrent use but the lamotrigine level is. Lamotrigine levels drop by almost half when COCs are started because increases in cytochrome P450 start rapidly after COC initiation, and they are slow to normalize after COC cessation. (5) Involving the provider who prescribes lamotrigine in the decision about COC use is critical.

For the most up-to-date list, please refer to the CDC MEC CDC: contraceptive drug interactions). Antiretrovirals (ARVs) and COCs appear to have varying impacts: they may have no impact on each other, or the COCs may impact the ARVs, or the ARVs may impact the COC. Medication development and treatment regimens for human immunodefciency virus (HIV) are rapidly changing; for the most up-to-date list of potential interactions, please refer to the CDC MEC CDC: contraceptive ARV interactions).

Most antibiotics have no impact on the effectiveness of COCs. A systematic review of nearly 200 articles found that only rifampin impaired the effectiveness of COCs.80 Specific studies of tetracycline, doxycycline, ampicillin, metronidazole, and quinolones demonstrated no impact on medication levels. (6,7,8,9,10) St. John’s Wort is an over-the-counter herbal product that is used to treat depression; evidence is limited, but it may decrease the effectiveness of COCs. (11)  Other psychotropic medications do not appear to be of concern. (12) 

Implant

The most significant threat to implant contraceptive efficacy comes from drugs that increase activity of the hepatic cytochrome P-450 enzyme system that promotes metabolic clearance of ENG, explain Melissa J. Chen, MD, MPH, and Melissa C. Matulich, MS, MAS. (13) Anticonvulsants are important because they are used as treatment for a broad array of clinical indications in addition to epilepsy, such as several nonepileptic neurologic and psychiatric conditions. (14) One small study found that the median ENG concentrations before and after carbamazepine coadministration were 158.1 pg/mL and 50.9 pg/mL, respectively (p=.005), and in 8 of 10 participants the ENG concentration was below the threshold for ovulatory suppression. (2) These findings call into question the effectiveness of this method when using carbamazepine or other drugs with similar pharmacologic effects.

Herbal remedies such as St. John’s Wort may have similar effects as well. For up to 30 days after the user has taken the last dose of St. John’s Wort, hepatic enzyme activity can remain increased. Studies of St. John’s Wort with implants are not directly available, but St. John’s Wort showed a pattern of small to moderate induction of metabolism of contraceptive steroids, including progestin. (10)

Ritonavir-boosted protease inhibitors can suppress circulating ENG after 2 years of implant use, so implant replacement at that time might be prudent to avoid an ENG drop below therapeutic levels. Case reports of pregnancies in people with human immunodeficiency virus (HIV) using efavirenz have raised issues about this antiretroviral agent as well. (15) However, in combination with lopinavir, neither ritonavir nor efavirenz impaired the efficacy of the implant. (16) Discuss medications—both prescription and nonprescription supplements—with patients considering the implant and remind them of the potential for deleterious drug–drug interactions when they rely on the implant for pregnancy prevention.

Injectables

For patients on a medication that can reduce the serum level of concomitant hormonal contraception, the relatively high progestin dose in depot-medroxyprogesterone acetate (DMPA) alleviates concerns for potential decreased effectiveness due to drug–drug interactions, according to Megan Lawley, MD, MPH, and Carrie Cwiak, MD, MPH. (17) DMPA is metabolized by the liver and avoids the first-pass metabolism that occurs in the gastrointestinal tract. Therefore, the higher progestin dose is not decreased by the concomitant use of medications that induce cytochrome P450 metabolism. (18) 

References

1. Ramanadhan S, Edelman A. Combined hormonal contraceptives. In: Cason P, Cwiak C, Edelman A, et al. (Eds) Contraceptive technology, 22nd edition. Burlington, MA: Jones-Bartlett Learning, 2023.
2. Dutton C, Kim R, Janiak E. Prevalence of contraindications to progestin-only contraceptive pills in a multi-institution patient database. Contraceptive. 2021;103(5):367-70.
3. Stanczyk FZ, Archer DF, Bhavnani BR. Ethinyl estradiol and 17beta-estradiol in combined oral contraceptives: pharmacokinetics, pharmacodynamics and risk assessment. Contraception. 2013;87:706-27.
4. Stanczyk FZ. All progestins are not created equal. Steroids. 2003;68:879-90.
5. Sabers A, Buchholt JM, Uldall P, Hansen EL. Lamotrigine plasma levels reduced by oral contraceptives. Epilepsy Res. 2001;47:151-4.
6. 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.
7. Neely 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;77:416-20.
8. Joshi JV, Joshi UM, Sankholi GM, et al. A study of interaction of low-dose combination oral contraceptive with ampicillin and metronidazole. Contraception. 1980;22:643-52.
9. Maggiolo F, Puricelli G, Dottorini M, Caprioli S, Bianchi W, Suter F. The effect of ciprofloxacin on oral contraceptive steroid treatments. Drugs Exp Clin Res. 1991;17:451-4.
10. Friedman CI, Huneke AL, Kim MH, Powell J. The effect of ampicillin on oral contraceptive effectiveness. Obstet Gynecol. 1980;55:33-7.
11. Berry-Bibee EN, Kim MJ, Tepper NK, Riley HE, Curtis KM. Co-administration of St. John’s wort and hormonal contraceptives: a systematic review. Contraception. 2016;94:668-77.
12. Berry-Bibee EN, Kim MJ, Simmons KB, et al. Drug interactions between hormonal contraceptives and psychotropic drugs: a systematic review. Contraception. 2016;94:650-67.
13. Chen MJ, Matulich MC. Contraceptive implant. In: Cason P, Cwiak C, Edelman A, et al. (Eds) Contraceptive technology, 22 nd edition. Burlington, MA: Jones-Bartlett Learning, 2023.
14. Lazorwitz A, Davis A, Swartz M, Guiahi M. The effect of carbamazepine on etonogestrel concentrations in contraceptive implant users. Contraception. 2017;95(6)
15. Leticee N, Viard JP, Yamgnane A, Karmochkine M, Benachi A. Contraceptive failure of etonogestrel implant in patients treated with antiretrovirals including efavirenz. Contraception. 2012;85(4):425-7.
16. Vieira CS, Bahamondes MV, de Souza RM, et al. Effect of antiretroviral therapy including lopinavir/ritonavir or efavirenz on etonogestrel-releasing implant pharmacokinetics in HIV-positive women. J Acquir Immune Defic Syndr. 2014;66(4):378-85.
17. Lawley M, Cwiak C. Injectable contracetpives. In: Cason P, Cwiak C, Edelman A, et al. (Eds) Contraceptive technology, 22nd edition. Burlington, MA: Jones-Bartlett Learning, 2023.
18. Curtis KM, Tepper NK, Jatlaoui TC, et al. U.S. medical eligibility criteria for contraceptive use, 2016. MMWR Recomm Rep. 2016;65(3):1-103.):571-7.