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.
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
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 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
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
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.
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Accessed August 17, 2013.
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