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Oral Contraceptives

ABSTRACT

TOP ABSTRACT Oral Contraceptives Conclusion REFERENCES

 
Nearly 50 years ago, the introduction of Enovid^© (norethynodrel 10 µg and mestranol 150 µg), which provided convenient and reliable contraception, revolutionized birth control. Reports of interactions between oral contraceptives (OCs) and other drugs began to trickle into the literature. At first, these drug interactions appeared to be random and unrelated. Increased understanding of P450 enzymes and phase II reactions of sulfation and glucuronidation has permitted preliminary categorization and assessment of the clinical relevance of these drug interactions.

Oral Contraceptives

TOP ABSTRACT Oral Contraceptives Conclusion REFERENCES

 
Most oral contraceptives (OCs) contain both estrogen and progestin. The estrogen suppresses ovulation, and the progestin suppresses luteinizing hormone, to create an environment unreceptive to sperm. Also, progestins limit endometrial hyperplasia and decrease the likelihood of endometrial carcinoma. There has been a strong trend in recent years toward using lower-dose estrogen preparations, to reduce the likelihood of estrogen-related complications (e.g., headache and thromboembolic disorders). Most OCs contain between 35 µg and 50 µg of estrogen, usually in the form of ethinylestradiol. Low-dose OCs (e.g., Alesse^©, Levlite^©, Loestrin 1/20^©, and Mircette^©) contain only 20 µg of ethinylestradiol (EE). Only a few OCs contain the original estrogen, mestranol, the 3-methyl ether pro-drug of EE (e.g., Genora 1/50^©, Nelova 1/50M^©, Norinyl 1+50^©, and Ortho-Novum 1/50^©).

Many formulations of OCs are now available. Monophasic preparations contain the same amount of EE and progestin and are taken for 21 days of each 28-day cycle. Biphasic and triphasic preparations take the form of two or three types of pills, with varying amounts of active ingredients. Biphasic and triphasic OCs have been formulated so that the amount of progestin is reduced and the effects correspond more closely to hormonal influences during natural menstrual cycles. Recently, several formulations of continuous daily regimens of ethinylestradiol (10 µg and 30 µg) and a progestin have entered the market. These formulations allow withdrawal-bleeding periods only 4 times a year. A yearly, no-cycling version of levonorgestrel and EE (Lybrel^©) received FDA approval in May 2007. There are a limited number of progestin-only contraceptives. These contraceptives are the mini-pill containing norethindrone, norgestrel, or levonorgestrel; a subdermal implant of norgestrel (Norplant II^©); intramuscular and subcutaneous preparations of medroxyprogesterone acetate and norethindrone enanthate, administered every 3 months; and intrauterine devices that release progesterone and levonorgestrel.

Metabolism of Oral Contraceptives
The metabolism of OCs, which is very complicated, is incompletely understood (see Table 1). Mestranol is first metabolized by 2C9 to EE.¹ After first-pass metabolism, about half of EE reaches the systemic circulation unchanged; the remainder is metabolized in the liver and gut wall. Although a variety of metabolic pathways exist, the major route of inactivation of EE is via 3A4, probably largely hepatic, and through 2C9, as a minor pathway.^2,3 An enterohepatic recirculation is also postulated for conjugated EE. but it is not important for progestins. EE is hydrolyzed by gut bacteria (principally clostridia) back to free EE. Further metabolic steps include formation of estrone, estradiol, and catechol estrogens. Each estrogen is glucuronidated and sulfated via unique or overlapping conjugates (see Raftogianis et al., 2000⁴ for an excellent review of estrogen metabolism). Sulfated estrone, the major circulating form of estrogen, is desulfated, metabolized, and transported to free EE to act at estrogen receptors.⁵ SULT1E1 plays a major role.³ Transformation of EE and estrone to catechol estrogens and to quinones can result in DNA adducts that are genotoxins and that may be very important in the development of breast and other cancers.⁶ EE is conjugated principally by UGT1A1 and perhaps by UGT1A8 and 1A9.³ The possible genetic polymorphisms at each "node" of this complex metabolic "web" may account for the enormous interindividual variations of each estrogen moeity.

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TABLE 1. Some Drugs, Herbs, and Foods That Affect Oral Contraceptives

Progestins are also metabolized via 3A4, including progestins containing desogestrel, a pro-drug that must be metabolized via 3A4 to the active form of progestin.⁷

3A4 and UGT Induction of Oral Contraceptives
Induction of 3A4 or uridine-diphosphate glucuronosyltransferase (UGT) 1A1, and others, may lead to increased clearance of EE and/or progestins and loss of clinical efficacy (Table 2). Drug interactions resulting in spotting, breakthrough bleeding, or unwanted pregnancy have occurred in women taking OCs and griseofulvin,⁸ rifampin,⁹ rifabutin,¹⁰ troglitazone,¹¹ or the enzyme-inducing anticonvulsants: phenobarbital, primidone, pheny-toin,¹² or oxcarbazepine.¹³ Carbamazepine can both render OCs ineffective and cause fetal neural tube defects.^14,15 Topiramate (above 200 mg/day)¹⁶ and felbamate may also induce 3A4, and these two drugs increase clearance of EE and may also cause contraceptive failure.^17,18

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TABLE 2. Some Drugs Whose Clearance Is Changed by Oral Contraceptives

Chronic use of ritonavir and ritonavir-boosted protease inhibitors may induce the metabolism of EE.¹⁹ The combination lopinavir and ritonavir carries a manufacturer’s warning about its ability to induce the metabolism of EE, and tipranavir/ritonavir can reduce ethinylestradiol area under the curve (AUC) by 50% (http://www.aidsetc.org/aetc/aetc?page=cm-307_women; accessed May 15, 2007). Nevirapine and nelfinavir have been shown to affect EE similarly²⁰ (Viracept product insert; accessed May 15, 2007). Although it is commonly listed in the literature as a 3A4 inducer and prohibited with EE, efavirenz may actually increase the plasma concentration of EE through an unknown mechanism (Sustiva,^© 2007; accessed May 15, 2007). St. John’s wort has been shown to induce 3A4.^21,22 Despite the possibility that this herbal preparation is likely to cause contraceptive failure, it has been shown in studies that in drugstores and health-food stores, consumers are rarely told about this interaction.²³ Clinicians should ask their patients about use of St. John’s wort. Modafinil has also been shown to decrease the maximum observed plasma concentration of EE.²⁴ Some anticonvulsants/mood stabilizers, including valproate,²⁵ gabapentin,²⁶ lamotrigine,^27,28 zonisamide,²⁹ vigabatrin,³⁰ levetiracetam, tiagabine, and pregabalin¹⁴ have been shown in studies not to increase OC clearance. (However, lamotrigine and valproic acid concentrations are reduced by OC induction.^31,32)

Aprepitant is a dose-related 3A-inhibitor, short-term, and a 3A-inducer, long-term, so that, when combined with EE, an 18% AUC decrease in EE ensues (Emend^© package insert, accessed May 15, 2007). Co-administration of bosentan and EE leads to decreases in EE AUC.³³ There is a small decrease in the AUC of EE (9%) when isotretinoin is co-administered with OCs, and co-administration of the two is unlikely to lead to contraceptive failure.³⁴

Because EE is believed to be largely metabolized by hepatic 3A4, agents that are known to be specific intestinal 3A-inducers do not affect EE. Rifaximin, known to induce intestinal 3A, has been shown not to change the clearance of EE.³⁵

3A4- or UGT-inducers also increase clearance of progestin-only contraceptives, since they are substrates of 3A4. Although not as well documented as interactions involving EE, contraceptive failure of levonorgestrel has been reported in women given phenobarbital³⁶ or phenytoin.^37,38 It is likely that the same perpetrating inducers that affect EE will also affect progestin-only contraceptives.

There are reports of women becoming pregnant while taking both EE or progestin-only preparations and other drugs, but it is not known how common such pregnancies are. Pharmacokinetic interactions between OCs and 3A4- or UGT-inducers do occur, but how often do clinically significant pharmacodynamic outcomes result? Given the wide interindividual variation of 3A4 and UGTs, some women may be vulnerable to these drug interactions. A recent small clinical study of rifampin, rifabutin, and OCs substantiated the ability of rifampin and rifabutin to increase clearance of OCs, although none of the 12 women in the study ovulated.¹⁰ Currently, lower dosing of EE is being used, and women who take OCs with only 20 mg of EE may be especially vulnerable. It is recommended that until clinicians can identify women at risk, patients taking enzyme-inducing anticonvulsants (see section "1A2, 2B6, 2C19, and 3A4 Inhibition by Oral Contraceptives") with OCs take 50 µg to 100 µg of EE. Women taking enzyme-inducing drugs along with OCs should also be instructed to use barrier contraceptives midcycle to prevent pregnancy.³⁹ Another option is to substitute depo-medroxyprogesterone acetate as a contraceptive, since it does not seem to be affected by enzyme-inducing anticonvulsants.⁴⁰ Replacement of 3A4-inducing anticonvulsants with non-inducing alternatives can also be considered.⁴¹ An enzyme-inducer’s effects can continue for a few weeks after administration of the inducer has ceased. As has been recommended with rifampin use,⁴² after short-term treatment with 3A4- or UGT-inducers is discontinued, patients taking OCs need to take extra contraceptive precautions for up to 4 weeks.

3A4 Inhibition of Oral Contraceptives
Because EE is a 3A4 substrate, potent inhibitors of 3A4 can increase or prolong estrogenic activity. Although not likely to impair contraceptive efficacy, potent 3A4-inhibitors can be expected to increase estrogen-related side effects (e.g., migraine headaches or thromboembolic events) in susceptible women. Drugs known to increase EE levels include the antifungals ketoconazole, itraconazole, and fluconazole,^43,44 and potent 3A4-inhibiting macrolides.^45–47 Dapsone has been shown to increase peak EE concentration.⁴ Atorvastatin increases ethinyl estradiol by 20% (Lipitor^© product insert, accessed May 15, 2007). Even grapefruit juice is known to increase EE levels.⁴⁹ Although gestodene has been shown to increase EE in vitro,⁵⁰ this interaction may not be clinically significant.⁵¹ It is likely that nefazodone, known to potently inhibit 3A4, will also be shown to affect EE clearance. If these 3A4 inhibitors are added to OCs that contain only 20 µg of EE, the low-dose OC may be converted functionally to a higher-dose OC and cause adverse events (e.g., breast tenderness, bloating, weight gain). In one case, these symptoms occurred when nefazodone was added to Mircette.^©52

OCs containing desogestrel (e.g., Mircette^©, Ortho-Cept^©) are also vulnerable to 3A inhibitors because such OCs are metabolized to their active forms by 3A.⁷ Long-term use of OCs that do not contain progestin may have deleterious effects.⁵²

Although the mechanism of action is not clear, several HIV drugs have been shown to increase the AUC of EE: atazanavir, fosamprenavir, and amprenavir, indinavir, and efavirenz (http://www.aidsetc.org/aetc/aetc?page=cm-307_women; accessed May 15, 2007).

2C9 Inhibition of Oral Contraceptives
Mestranol is demethylated to EE by 2C9, so potent inhibitors of 2C9 may lessen the likelihood of adequate EE levels in OCs such as Genora 1/50^©, Nelova 1/50M^©, Norinyl 1+ 50^©, and Ortho-Novum 1/50^©. Examples of 2C9-inhibitors are sulfaphenazole and other sulfonamide antibiotics (such as sulphamethoxazole),^1,53,54 valproate,⁵⁵ and fluconazole.⁵⁶

1A2, 2B6, 2C19, and 3A4 Inhibition by Oral Contraceptives
Not only is the clearance of OCs affected by other agents, but OCs can affect the clearance of other drugs. Current evidence suggests that OCs are moderate inhibitors of 1A2 and 2C19 and mild inhibitors of 2B6 and 3A4. OCs decrease the clearance of caffeine and theophylline, well-known substrates of 1A2.^57–61 Because a 30% decrease in theophylline clearance occurs with OC use,⁶² clinicians should reduce theophylline doses. The side-chain oxidation of propranolol is catalyzed by 1A2, and this process is inhibited by OCs.^63,64 However, any increase in propranolol levels from this process is effectively nullified by the ability of OCs to induce the glucuronidation of propranolol. These offsetting interactions allow the combination of OCs and propranolol to be tolerated without difficulty.^64,65 Two cases of interactions between OCs and psychotropic 1A2 substrates have been reported. Clozapine levels were significantly increased with the addition of an OC,⁶⁶ and chlorpromazine levels increased sixfold when an OC was added.⁶⁷ No reports of drug interactions between olanzapine and tacrine with OCs have been found in the literature, although these drug interactions are possible. Plasma concentrations of tacrine are increased by hormone-replacement therapy (which contains very low amounts of estrogen);⁶⁸ therefore, OCs likely increase tacrine levels. A combination of EE and gestodene was shown to increase levels of tizanidine (a known 1A2 substrate) at clinically significant levels.⁶⁹

An OC containing 30 µg of EE and 150 mg of desogestrel coadministered with bupropion was shown to decrease the AUC of bupropion’s metabolite (a measure of 2B6 activity) and hormone-replacement therapy, with larger amounts of estrogen, 2 mg estradiol valerate, showed a more marked inhibition of 2B6.⁷⁰

Support for OC inhibition of 2C19 has been provided by three population studies.^71–73 The activity of 2C19 in women who used OCs was decreased by 68%, as compared with that in women who did not use OCs.⁷³ Although the focus of interest in the interaction between OCs and phenytoin has been on phenytoin’s induction of OC metabolism (because of reduced efficacy of OCs), OCs have also been found to decrease the clearance of phenytoin.⁷⁴ Thus, increasing OC dosing to overcome phenytoin induction of EE can result in phenytoin toxicity, and this drug combination is best avoided. The concentration of selegiline (a substrate of 2C19 and 2B6) is increased more than 10 times when OCs are added.⁷⁵ The AUC of carisoprodol was increased 60% when OCs were added.⁷⁶ Omeprazole AUC was increased 38% by ethinylestradiol in a clinical study, but this interaction is unlikely to have clinical significance because of the wide margin of therapeutic index of omeprazole.⁷⁷ Proguanil, a pro-drug via 2C19, is increased by 34% with OCs, and it is recommended that its dosage be boosted by 50% to increase the concentration of the active metabolite.⁷⁸

Results of in-vitro studies of EE effects are conflicting,⁵⁰ but there is evidence to support the finding of very modest in-vivo inhibition of 3A4 by EE.^79,80 The concentrations of EE are higher in women who take OCs for more than 6 months, and clearance of EE in these women is reduced.⁶⁰ Other inferential evidence comes from several interactions between OCs and drugs known to be substrates of 3A4: cyclosporine,⁸¹ midazolam,⁸⁰ prednisolone,⁸² and levonorgestrel.⁸³

Inhibition by OCs of both 3A4 and 2C19 is likely responsible for several well-documented OC–drug interactions. Clearances of imipramine, amitriptyline, and diazepam are decreased by OCs.^84–86 2C19 is a principal pathway for demethylation of these drugs; 3A4 is also involved.^31,87,88 Clearance of chlordiazepoxide may also be reduced by OCs.⁸⁹ Chlordiazepoxide’s intermediate metabolite, nordiazepam, is known to be metabolized by 3A4 and 2C19.⁹⁰ Whether other benzodiazepines that are metabolized via this intermediate metabolite are also affected has not yet been investigated.

Most of the studies above used OCs with EE and various progestins. Whether the progestin portion of the OC is also a CYP- or UGT-inhibitor or inducer is not clear. There is only fragmentary information on the contribution of individual progestins to CYP inhibition or induction. There is in-vivo evidence that parenteral progestins (medroxyprogesterone acetate) can induce CYP3A, in contrast to oral progestins, which do not induce CYP3A.³² There is in-vitro evidence that several progestins are 2C9- and 2C19-inhibitors,⁹¹ but their in-vivo effects have yet to be determined.

CYP2A6 and Phase 2 Induction Of and By Oral Contraceptives
OCs have been shown to be associated with higher rates of nicotine clearance—an index of 2A6 activity.⁹² This may account for the finding that women smokers have higher rates of lung cancer than their male counterparts.

Although the specific UGTs remain to be identified, OCs increase glucuronidation clearance of the following drugs: clofibrate,^93,94 propranolol,⁶⁴ phenprocoumon,⁹⁵ diflunisal,⁹⁶ and lamotrigine (1A4).⁹⁷ It has been shown that during the "wash-out week," the week off ethinylestradiol, lamotrigine plasma levels were 84% higher.^98,99 A similar finding was made for valproic acid.¹⁰⁰ In order to avoid fluctuating levels of lamotrigine and valproic acid when they are combined with these traditional OCs, it may be advantageous to keep women on a continuous daily regimen of OC therapy after monitoring and adjusting levels of the anticonvulsants/mood stabilizers.

Data are conflicting with regard to changes in lorazepam, oxazepam, and temazepam concentrations^89,101,102 when combined with OCs. Acetaminophen is conjugated by UGT1A1, UGT1A6, and UGT1A9,¹⁰³ and OCs are known to increase glucuronidation of acetaminophen.¹⁰⁴

EE clearance decreases when vitamin C or acetaminophen is added. This interaction occurs because vitamin C and acetaminophen compete with EE in the gut wall¹⁰⁵ for sulfation via sulfotransferase SULT1A1.¹⁰⁶

Transporters and Oral Contraceptives
It is known that EE inhibits P-glycoproteins (ABCB1) and may have effects on other transporters. However, there is no information on their clinical effects.³

Conclusion

TOP ABSTRACT Oral Contraceptives Conclusion REFERENCES

 
When obtaining a woman’s medication history, the clinician should inquire whether the patient is taking OCs. Clinicians often neglect to ask this question,¹⁰⁷ despite the fact that OCs are so commonly used by women in their reproductive years. Clinicians need to be knowledgeable and vigilant about drug interactions involving OCs, and they should be particularly alert when adding or terminating other drugs in women taking OCs.

ACKNOWLEDGMENTS

 
Reminder: This article is dedicated primarily to metabolic interactions. Interactions due to displaced protein-binding, alterations in absorption or excretion, and pharmacodynamics are not covered.

Jessica R. Oesterheld, M.D., is Acting Director, Spurwink, Dept. of Psychiatry of Maine Medical Center, and Clinical Associate Professor, Dept. of Psychiatry, University of Vermont College of Medicine.

Kelly L. Cozza, M.D., F.A.P.M. is Associate Professor of Psychiatry at the Uniformed Services University in Bethesda, MD, and psychiatric consultant to the Dept. of Psychiatry at Walter Reed Army Medical Center in Washington, DC, and is a co-author of The Concise Guide to Drug Interaction Principles for Medical Practice (American Psychiatric Publishing, Inc.).

Neil B. Sandson, M.D., is a psychiatrist working within the Veterans Affairs Maryland Health Care System, and is a Clinical Assistant Professor in the Department of Psychiatry at the University of Maryland School of Medicine. Dr. Sandson is also Column Editor for the Psychosomatics Med.–Psych. Drug–Drug Interaction series.

REFERENCES

TOP ABSTRACT Oral Contraceptives Conclusion REFERENCES

 

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