Oral Contraceptives Are Susceptible to Several Interactions

Oral contraceptives (OCs) are the most common method of birth control used by US women aged 15 to 44 years to suppress ovulation and prevent pregnancies.^1,2

OCs are absorbed in the gastrointestinal (GI) mucosa, which can be altered when OCs are taken with sequestrants and medications that slow motility. After absorption, ethinyl estradiol (EE) undergoes first-pass metabolism in the liver by cytochrome P450 (CYP) 3A4.3 CYP3A4 is responsible for most drug interactions, as it metabolizes more than 80% of all drugs affected by CYP.³ CYP3A4 inhibition occurs within 48 hours and can increase drug concentrations of CYP3A4 substrates. This is critical because of the significance of vascular complications with increased EE levels. Inducers of CYP3A4 may take up to 3 weeks, resulting in decreased substrate concentrations.^4,5 Consequently, short-term use of CYP3A4 inducers generally will not have clinical significance. After the discontinuation of a CYP inducer, the induction may take several weeks to subside.⁶ Pharmacists are in a great position to suggest alternative therapies when presented with a patient receiving OCs who requires medications that may pose a drug interaction risk.

Many anticonvulsants can pose clinically significant interactions. Carbamazepine, oxcarbazepine, phenobarbital, and phenytoin, when taken with OCs, can decrease the efficacy of contraceptives through 2 mechanisms: first via the induction of EE serum concentrations that reduce CYP3A4 by about 50% for up to 4 weeks after discontinuation and second by potentially increasing sex hormone—binding globulin (SHBG) concentration.⁷ SHBG binds to progestin, decreasing free progestin concentration in plasma.⁷ Lamotrigine is not a CYP inducer. However, it has a dose-dependent effect on hormone plasma concentrations (see Table 1. Oral Contraceptives and Cyp Interactions).

Topiramate, a weak CYP inducer, reduces EE at higher doses. Although lamotrigine does not decrease the efficacy of OCs, its concentrations decrease when taken with OCs.^7,8 Fortunately, patients can take other anticonvulsants and gabapentinoids with OCs safely with appropriate lab monitoring (see Table 1. Suggested Alternatives).

Antimicrobials may interact with OCs, but not all interactions are clinically significant. Macrolides, except for azithromycin, are CYP inhibitors. Unlike CYP inducers, CYP inhibitors potentially increase the risk of adverse effects (AEs) of EE, such as vascular disease complications within 48 hours, because of increased EE plasma concentration.⁹ This may be detrimental to women who already carry an increased risk of deep vein thrombosis or pulmonary embolism. In addition, the subclass azoles of the antifungals are known to be CYP inhibitors. Most reported cases reflect increased concentrations of EE. However, the clinical significance of these increased concentrations is questionable.⁹ Drug databases do not identify a clear contraindication, nor do they suggest an increased risk of AEs of EE.

Some antimycobacterials, including rifabutin, rifampin, and rifapentine, are strong CYP inducers. Rifampin’s induction can be prolonged. Therefore, women need a backup method of contraception for 6 weeks after discontinuing rifampin.¹⁰

HIV requires lifelong treatment with antiretrovirals, such as efavirenz, nevirapine, and ritonavir, which are CYP inducers that decrease the efficacy of contraceptives. Uniquely, ritonavir reduces contraceptive efficacy through a dual mechanism by decreasing plasma concentrations of EE through induction of the CYP enzyme and by glucuronidation in phase 2 metabolism, which decreases progestogen’s plasma concentration. Female patients on ritonavir boosted should use an additional method of contraception because of decreased concentrations of EE.¹¹ Cobicistat is used to enhance antivirals, such as atazanavir and darunavir, by inhibiting CYP3A enzymes, which are known to concordantly alter concentrations of EE and progestin from OCs.^12,13

Despite their lack of effect on CYP enzymes, colesevelam and exenatide interact with OCs by interfering with absorption. Colesevelam binds EE in the GI tract and inactivates it, so when taken, it should be separated from EE-containing OCs (see Table 1. Oral Contraceptives and Cyp Interactions).¹⁴ Although OCs should be separated from exenatide by 1 hour because of decreased gastric emptying, exenatide is affected by multiple culprits, including food.¹⁵ Drospirenone, in OCs such as Yaz, has antimineralocorticoid activity, such that 3 mg of drospirenone is equivalent to 25 mg of spironolactone.¹⁶ Use caution, even in healthy women, when using drospirenone with potassium-sparing medications.^15,16

OCs containing EE should not be used with cyclosporine because of increased trough concentrations and should also not be used when treating hepatitis because of an increased risk of hepatoxicity.¹⁷ It is important to note that paritaprevir/ritonavir/ ombitasvir (Technivie) and paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekira Pak) are major substrates and strong inhibitors of CYP3A4, which can increase EE concentrations, exposing patients to increased vascular AEs in addition to an increased risk of elevated alanine aminotransferase and aspartate aminotransferase. Women should restart EE 2 weeks after discontinuing Technivie or Viekira Pak.^18,19

Herbals and nutraceuticals commonly interact with medications. Clinicians should therefore advise caution in patients taking herbals while receiving OCs. St John’s wort is a common offender of drug interactions, as it has been associated with an increased risk of breakthrough bleeding because of an approximately 50% decreased half-life of EE (see Table 1. Oral Contraceptives and Cyp Interactions).²⁰

CONCLUSION

OCs are the most common form of contraceptive used. Most OCs are metabolized by CYP3A enzymes and are subject to several drug interactions. Fortunately, not all drug interactions with OCs are deemed clinically significant, and not all forms of contraceptives exhibit the same extent of drug interactions, such as progestin-only injectables and intrauterine system contraceptives (see Table 2).²¹ Pharmacists play a crucial role in assessing drug—drug interactions for clinical significance and severity and, when appropriate, recommending alternative therapy for concurrent conditions (Table 1. Suggested Alternatives).

Verina Mansour is a 2019 PharmD candidate at the Albany College of Pharmacy and Health Sciences (ACPHS) in New York.Amy T. Murdico, PharmD, BCPS, is the associate chief of pharmacy services, the PGY-1 pharmacy residency director, and the PGY-2 pain and palliative care pharmacy residency coordinator at Albany Stratton VA Medical Center in New York. She coordinates and precepts in the VA Learning Opportunities Residency intern program and is an adjunct advanced pharmacy practice experience preceptor for ACPHS and Western New England University in Springfield, Massachusetts.Jeffrey Fudin, PharmD, DAIPM, FCCP, FASHP, FFSMB, is CEO and chief medical officer of Remitigate LLC and the owner and managing editor of paindr.com. He is also an adjunct associate professor at Western New England University College of Pharmacy and Health Sciences, an adjunct associate professor of pharmacy practice and pain management at ACPHS, and the director of the PGY-2 pain residency at Albany Stratton VA Medical Center.

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