Antiepileptic Drugs and Contraception

US Pharm. 2014;39(1):39-42.

ABSTRACT: Certain antiepileptic drugs (AEDs) can interact with hormonal contraceptives and decrease their effectiveness, leading to unplanned pregnancy. In addition, hormonal contraception can have a bidirectional interaction with some AEDs, which can result in loss of seizure control or toxicity. Several contraceptive options that do not interact with AEDs, such as barrier and long-acting forms, are available. High dosages of emergency contraception and oral regimens also may be considered. Intervention by the pharmacist can include making recommendations about contraceptive options, advising on therapeutic drug concentration monitoring, and increasing awareness among patients and prescribers.

Hormonal contraception can have a bidirectional interaction with some antiepileptic drugs (AEDs), which can lead to loss of seizure control or toxicity.^1-5 This article will review the interaction between AEDs and hormonal contraception. Alternative contraception recommendations are addressed so that more effective forms of birth control can be discussed with patients and providers.

Introduction

The interaction of AEDs with serum hormone concentrations came to light in the 1970s, when the ethinyl estradiol (EE) component of combined oral contraceptives (COCs) was reduced from 100 mcg to <50 mcg because of thromboembolic risks and because increased rates of breakthrough bleeding and contraceptive failure were observed among epileptic women.^6,7 Many COCs used today contain just 20 to 35 mcg EE, along with a progestin.^4,7 AEDs are widely prescribed on- and off-label for treatment of seizures, pain syndromes, bipolar disorder, and anxiety, as well as for migraine prophylaxis. Patients are likely to be prescribed these medications by providers in different disciplines, further increasing the risk of interactions. Pharmacists are in a unique position to identify and counsel patients who may be affected by these interactions and to provide patients and healthcare providers with information on alternative options, when indicated.

Contraceptive failure may be responsible for up to one in four unplanned pregnancies in women with epilepsy.⁸ Most epileptic women taking interacting AEDs are unaware of their effect on oral contraceptives (OCs).⁹ Practitioners not only may be unaware of concurrent medications from another provider, they may not be cognizant of the interaction or may fail to make therapy adjustments. In a survey of neurologists and obstetricians, only 41% and 43%, respectively, reported making changes in OC dosage when prescribed concurrently with an interacting AED.¹⁰ Therefore, women of childbearing age who are prescribed AEDs should be counseled about potential teratogenicity, interaction with hormonal contraceptives, and effects on folate, vitamin K, calcium, and vitamin D metabolism.¹¹

Interaction With Hormonal Contraception

Pharmacokinetic interactions can lead to decreased serum concentrations of hormonal contraceptives. The metabolism of EE, the most common estrogen component of COCs, is susceptible to induction of CYP450 and increased glucuronidation, which leads to reduced serum concentrations.⁵ Several progestins that are included in COCs and used in progesterone-only preparations also may be affected by enzyme induction.⁵ Induction of CYP3A4 by enzyme-inducing AEDs (EIAEDs) increases metabolism of EE and progestins.^3,5,6,8 Serum concentrations of these hormones are subject to interindividual variation and may be reduced by 50% or more, possibly resulting in contraceptive failure.¹ Induction continues for up to 4 weeks after the offending AED is discontinued, necessitating continued use of alternative or backup contraceptive methods during this time.^1,5 Another possible mechanism involving an increase in sex hormone–binding globulin (SHBG) occurs with phenobarbital, phenytoin, and carbamazepine. The elevation in SHBG increases this glycoprotein’s capacity to bind progestins and reduce their free plasma concentrations.^3,6,8

Lamotrigine, although not an EIAED, has been shown to decrease levonorgestrel concentrations at higher dosages (300 mg/day), and breakthrough bleeding has been reported.^5,12 Topiramate also has been demonstrated to cause a dose-dependent reduction in EE serum concentrations at dosages greater than 200 mg/day.¹³ Because of these effects, alternative methods of contraception should be considered in women taking higher dosages of these AEDs.^2,11,13,14 TABLE 1 lists AEDs that do not alter hormonal contraceptive effectiveness and those that reduce it.

The interactions described above can diminish the effectiveness of combined hormonal contraceptives (CHCs), including COCs, the combined contraceptive patch (Ortho Evra), and the vaginal ring (NuvaRing), as well as progesterone-only preparations such as progesterone pills, implants, and emergency contraception (Plan B, My Way, Next Choice).¹¹ TABLE 2 lists contraceptive choices not affected by these interactions. TABLE 3 describes alternative contraceptive methods for women who are taking AEDs that decrease contraceptive effectiveness.

 

Combined Hormonal Contraceptives

CHCs typically contain EE 20 to 35 mcg plus a progestin. In EE-only products, 100 mcg is required to inhibit ovulation; in CHCs, the progestin is responsible for inhibiting ovulation, whereas the estrogen component reinforces this effect and provides menstrual-cycle control.^1,2 CHCs are available in pill, topical patch, and vaginal ring formulations.

EIAEDs reduce serum concentrations of EE and progestins by inducing hepatic metabolism. This interaction is also anticipated with the EE prodrug mestranol (a component of Necon 1/50 and Norinyl 1+50). Mestranol 50 mcg produces plasma concentrations similar to those of EE 35 mcg, which could result in contraceptive failure when coadministered with an EIAED.¹ One way to overcome this induction is to use a COC with at least 50 mcg of EE plus a progestin.^{1,5,6,10,14,15} Zovia 1/50 and Ogestrel are the only products containing this amount of EE that are available in the United States. Alternatives may be to use an off-label combination of COC tablets containing EE 30 mcg and 20 mcg or to use two 30-mcg tablets, as long as the progestin type is the same.^1,5 The EE dosage may be further increased to 75 to 100 mcg if breakthrough bleeding occurs.^6,14 A maximum increase to EE 70 mcg (two 35-mcg tablets) has also been recommended.⁵ Side effects from these high-dose regimens are not expected to increase, since the induction from an interacting AED will reduce EE plasma concentrations.¹ The use of two topical patches or two vaginal rings concurrently is not recommended; therefore, these formulations are best avoided in women taking EIAEDs.¹

The use of a high-dose COC regimen with an EIAED still carries the risk of contraceptive failure,¹⁰ although failure rates are lower than for barrier methods alone (~7% vs. 15%-20%).⁶ Additional backup methods (e.g., condoms and spermicidal gel), along with a high-dose COC, are recommended to improve contraceptive effectiveness.^5,6 Another method of improving effectiveness is tricycling, in which a high-dose COC is taken for three to four cycles, followed by a shorter pill-free interval.^1,14 The extended-cycle regimen, in which the high-dose COC is taken continuously to suppress menstruation, is another option.¹ Although these practices have been recommended in the literature, they are not supported by evidence that they improve contraceptive efficacy in women taking EIAEDs.⁵

Progesterone-Only Preparations

Progesterone-Only Pill: The only available progesterone-only pill in the U.S. is norethindrone (or “minipill”). This contraceptive is not recommended for use in women taking EIAEDs.¹ The progesterone-only pill has a time-sensitive 3-hour window of compliance to support serum concentrations for contraceptive efficacy. This form of contraception is especially likely to be further affected by induced metabolism. Patients should be encouraged to use an alternative method of contraception that is unaffected by EIAEDs (TABLE 3).

Emergency Contraception: Women taking interacting EIAEDs may experience reduced efficacy of the emergency contraceptive pill⁵ and should be referred to a physician for evaluation. The copper-containing intrauterine device (IUD; ParaGard), which is recommended as the most effective method of emergency contraception for patients taking EIAEDs, may be inserted within 120 hours of unprotected sex or within 5 days of expected ovulation.⁵ If the levonorgestrel emergency contraceptive pill (Plan B, My Way, Next Choice) is used, the dosage should be doubled and administered as a single 3-mg dose within 120 hours of unprotected sex.⁵ The use of this higher dose and the time frame beyond the recommended 72 hours are outside of the product labeling, and therefore this option may not be dispensed without a prescription.

Depot Medroxyprogesterone Acetate (DMPA): DMPA (Depo-Provera) is recommended for contraceptive use because its efficacy is unaffected by EIAEDs. Its metabolism is dependent upon hepatic blood flow, with a first-pass effect of nearly 100%, and additional enzyme induction does not affect blood concentrations.^1,5 Even with this apparent lack of interaction, some researchers have recommended that the dosing interval be decreased in the presence of EIAEDs, from every 3 months (13 weeks) to every 10 weeks.^6,14 This may be due to irregular menstrual bleeding and spotting, which commonly occurs upon initiation of DMPA, even in the absence of EIAEDs, and may be misinterpreted as a sign of contraceptive failure.¹⁶ Clinical trials proving this strategy are lacking, and adjustment of the dosing interval is unnecessary.^1,5

Progesterone Implants: There have been reports of high failure rates with progesterone implants and EIAEDs, including the etonogestrel (Implanon, Nexplanon) and levonorgestrel implants (Norplant, off market); therefore, the use of these implants is not recommended in patients taking EIAEDs.^1-3,6,8 Patients with an implant who are started on an EIAED should be advised to use barrier methods, and alternative contraceptive methods should be offered upon implant removal (TABLE 3).¹ Implants may still be preferred for women taking lamotrigine.

IUDs: The levonorgestrel IUD (Mirena) produces high progesterone concentrations locally. Although levonorgestrel is a progestin, the IUD’s effectiveness does not appear to be significantly decreased by EIAEDs.^1-3,5,6,14 The copper IUD (ParaGard) has nonhormonal local spermicidal effects and is not affected by metabolism. Therefore, both types of IUD are recommended for contraception in patients taking EIAEDs.^1,5

Effects of Hormonal Contraceptives on AEDs

Lamotrigine: EE has been shown to induce glucuronidation of lamotrigine, resulting in decreased serum concentrations and increasing the risk of breakthrough seizures in women using a COC, contraceptive patch, or vaginal ring.^1,2,14 However, if lamotrigine is already coadministered with an EIAED, estrogens do not significantly reduce its serum concentrations further.¹ Another concern is an increase in side effects during the hormone-free interval, when lamotrigine concentrations can double; this can occur with any CHC formulation.^1,2 DMPA, the levonorgestrel and copper IUDs, and the etonogestrel implant are all effective contraceptive options with lamotrigine and do not affect its serum concentrations.^1,2 If CHCs are used, lamotrigine concentrations and possible breakthrough seizures should be monitored upon initiation and discontinuation.⁴ The use of extended-cycle or tricycling regimens with COCs is recommended in order to limit hormone-free intervals and fluctuations in serum lamotrigine concentrations.¹

Valproic Acid: As with lamotrigine, EE has been shown to increase glucuronidation of total and free valproate. A significant increase in mean total and unbound valproic acid clearance of 21.5% and 45.2%, respectively, has been shown in women using very-low-dose COCs, low-dose COCs, or the contraceptive patch during the active-hormone period, compared with the hormone-free interval.^3,4 In a pharmacokinetic study, serum valproate concentrations declined 23.4% during COC coadministration.³ Additionally, there is a case report of one patient with an increase in seizure frequency associated with decreased valproic acid concentrations during the active-pill versus pill-free interval of an OC regimen.^3,4 Therefore, valproic acid concentrations should be monitored upon initiation and discontinuation of CHC therapy, and possibly during the hormone-free interval.^4,11

Benzodiazepines: Coadministration of COCs with clonazepam, clorazepate, or diazepam may decrease the oxidative metabolism of the affected benzodiazepines, resulting in increased sedation, prolonged central nervous system depression, or psychomotor impairment.⁴ Women who have been taking or are initiating COCs may require lower dosages of these benzodiazepines and should be monitored for increased side effects.^4,11 The glucuronidation of lorazepam may be increased by COCs, leading to an increase in its clearance. The extent and significance of this increased clearance may vary considerably. Women should be monitored for decreased lorazepam effectiveness during coadministration with COCs.^4,11 If this occurs, a higher dosage may be indicated.

Phenytoin: The use of OCs with phenytoin has been reported to increase steady-state serum concentrations and may lead to toxicity; injectable contraceptives could potentially have the same effect.⁴ Limited information is available on the significance of this interaction. Management should include monitoring of phenytoin concentrations whenever CHC therapy is initiated or discontinued.^4,11

Conclusion

The widespread use of AEDs for various indications exposes many women of childbearing age to potentially clinically significant drug interactions with hormonal contraception. These interactions include reduced effectiveness of either drug and increased side effects and toxicity of the AED. Intervention by the pharmacist can help prevent contraceptive failure and ensure safe and effective use of AEDs through education and increased patient and prescriber awareness.

REFERENCES

1. O’Brien MD, Guillebaud J. Contraception for women taking antiepileptic drugs. J Fam Plann Reprod Health Care. 2010;36:239-242.
2. Schwenkhagen AM, Stodieck SR. Which contraception for women with epilepsy? Seizure. 2008;17:145-150.
3. Gaffield ME, Culwell KR, Lee CR. The use of hormonal contraception among women taking anticonvulsant therapy. Contraception. 2011;83:16-29.
4. Hormonal contraception. Drug Facts and Comparisons. Facts & Comparisons [database]. St. Louis, MO: Wolters Kluwer Health, Inc; March 2005. www.factsandcomparisons.com. Accessed August 17, 2013.
5. Faculty of Sexual and Reproductive Health Care Clinical Guidance. Drug interactions with hormonal contraception. www.fsrh.org/pdfs/CEUguidancedruginteractionshormonal.pdf. Accessed August 17, 2013.
6. Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263-272.
7. Sabers A. Pharmacokinetic interactions between contraceptives and antiepileptic drugs. Seizure. 2008;17:141-144.
8. Reddy DS. Clinical pharmacokinetic interactions between antiepileptic drugs and hormonal contraceptives. Expert Rev Clin Pharmacol. 2010;3:183-192.
9. Pack AM, Davis AR, Kritzer J, et al. Antiepileptic drugs: are women aware of interactions with oral contraceptives and potential teratogenicity? Epilepsy Behav. 2009;14:640-644.
10. Krauss GL, Brandt J, Campbell M, et al. Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians. Neurology. 1996;46:1534-1539.
11. Williams D. Contraception and prenatal vitamin supplementation for women on antiepileptic medications. Ment Health Clin. 2013;3:100.
12. Sidhu J, Job S, Singh S, Philipson R. The pharmacokinetic and pharmacodynamic consequences of the co-administration of lamotrigine and a combined oral contraceptive in healthy female subjects. Br J Clin Pharmacol. 2006;61:191-199.
13. Rosenfeld WE, Doose DR, Walker SA, Nayak RK. Effect of topiramate on the pharmacokinetics of an oral contraceptive containing norethindrone and ethinyl estradiol in patients with epilepsy. Epilepsia. 1997;38:317-323.
14. Crawford P. Best practice guidelines for the management of women with epilepsy. Epilepsia. 2005;46(suppl 9):117-124.
15. Practice parameter: management issues for women with epilepsy (summary statement). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 1998;51:944-948.
16. Kaunitz AM. Injectable depot medroxyprogesterone acetate contraception: an update for U.S. clinicians. Int J Fertil Womens Med. 1998;43(2):73-83.
17. How well does the Today Sponge prevent pregnancy? http://web.archive.org/web/20060717204734/http:/www.todaysponge.com/howwell.htm. Accessed August 17, 2013.

To comment on this article, contact rdavidson@uspharmacist.com.