Interactions between hormonal contraception and antiepileptic drugs: Clinical and mechanistic considerations.

Antiepileptic drugs (AEDs) and hormonal contraceptives may affect each other's metabolism and clinical efficacy. Loss of seizure control and unplanned pregnancy may occur when these compounds are used concomitantly. Although a large number of available preparations yield a plethora of possible drug combinations, most of these drug interactions are predictable and, thus, avoidable. Unfortunately, there is a substantial lack of data regarding the newer AEDs. Detailed understanding of these issues is necessary for those who prescribe AEDs and/or hormonal contraception to women with epilepsy, as well as for those who provide comprehensive care, education and counseling to them, in order to reduce the unacceptably high number of unplanned pregnancies among women with epilepsy.

Contraception for women with epilepsy.

The choice of a contraceptive drug can be challenging for women with epilepsy due to possible interactions between antiepileptic drugs (AEDs) and hormonal contraception. Enzyme-inducing AEDs can cause hormonal contraception to fail and can increase the risk of teratogenicity. Higher doses of oral contraceptives can overcome pharmacologic failure but may create additional risks. The effects of reproductive hormones on individual AEDs have recently been clarified, providing helpful guidelines for physicians and patients. Studies show that lamotrigine has a significantly increased clearance (> 50%) when used with combined oral contraceptives, which results in an increased seizure frequency in most patients. Useful alternatives to oral contraceptives include depot injections and intrauterine devices. Subdermal implants may increase the risk of pregnancy in women with epilepsy on enzyme-inducing AEDs. Depot medroxyprogesterone acetate is effective but can increase side effects. Intrauterine devices are an alternative to pharmacologic approaches because they lack drug-drug interactions and side effects.

Antiepileptic medication and oral contraceptive interactions: a national survey of neurologists and obstetricians.

Hepatic enzyme-inducing antiepileptic drugs (AEDs) lower oral contraceptive (OC) sex hormone levels approximately 40% and increase the risk of unplanned pregnancies in women with epilepsy. AEDs also increase the risk of birth defects in offspring of women with epilepsy. We performed a national survey to determine obstetricians' and neurologists' knowledge of OC and AED interactions and the risk of birth defects for women with epilepsy taking AEDs. We received responses to a mailed questionnaire from 160 of 1,000 neurologists (16%) and 147 of 1,000 obstetricians (15%) from 47 states. Practice demographics and ages of responders were typical for U.S. neurologists and obstetricians. Ninety-one percent of neurologists and 75% of obstetricians said they treat women with epilepsy of child-bearing age. Only 4% of the neurologists and none of the obstetricians, however, knew the effects of the six most common AEDs on OCs, even though 27% of neurologists and 21% of obstetricians reported OC failures in their patients taking AEDs. Although increasing OC doses can compensate for insufficient OC sex hormone levels due to AEDs, most physicians do not increase the doses. Even though the risk of birth defects for the offspring of women with epilepsy is 4 to 6%, up from the background level of 2%, 44% of neurologists thought the risk was lower (0 to 3%), and some of the respondents guessed that it was as high as 50%. Many neurologists and obstetricians do not have accurate information to counsel women with epilepsy properly about their contraceptive and pregnancy choices.

PIP: Responses from 160 of 1000 neurologists (16%) and 147 of 1000 obstetricians (15%), selected from an American Medical Association listing to receive a mailed questionnaire, revealed a disturbing lack of knowledge about the interactions between antiepileptic medications and oral contraceptives (OCs). Hepatic enzyme-inducing antiepileptic drugs lower OC estradiol levels by about 40% and may reduce free progestin levels, thereby increasing the risk of unplanned pregnancy; moreover, antiepileptics increase the risk of birth defects in their epileptic users, who already have a 4-6% increased risk of such defects. Physicians can reduce, but not prevent, the risk of unwanted pregnancy by increasing the OC estradiol dose to at least 50 mcg and prescribing valproic acid and gabapentin (non-enzyme-inducing antiepileptics). 91% of neurologists and 75% of obstetricians reported that they treated epileptic women of childbearing age, and 27% of the former and 21% of the latter physicians acknowledged cases of OC failure in these patients. Only 4% of the neurologists and none of the obstetricians knew the effects of the 6 most common antiepileptic drugs on OCs. Just 41% of neurologists and 43% of obstetricians routinely had patients adjust their OC doses if they were taking antiepileptics. Such adjustment was more likely among physicians who had an epileptic patient with an unintended pregnancy and those who had accurate knowledge of OC-antiepileptic drug interactions. 44% of neurologists and 23% of obstetricians underestimated the birth defects risk as 0-3%. Since the physicians who chose to respond to this survey were presumably more concerned and knowledgeable about the reproductive effects of antiepileptic drugs than those who chose not to respond, continuing education efforts are urged to enable health care providers to counsel epileptic women about contraception.

GnRH analogues for contraception.

The production of chemical analogues of GnRH permits direct suppression of the pituitary-gonadal axis at the level of the gonadotroph. Continuous administration of GnRH agonists desensitizes the gonadotroph and ovulation is uniformly prevented, forming the practical basis for use in contraception. However, long-term treatment is constrained by variable effects on oestrogen secretion, which cause irregular bleeding patterns on the one hand and risks of hypo-oestrogenism on the other. Their use as a post-partum contraceptive has attractions because any analogue in milk should be without biological activity in the infant. GnRH antagonists have the advantage of immediate inhibitory action. They have potential application in circumstances in which agonists have been employed and, in addition, can interrupt any stage of the menstrual cycle. Clinical trials to utilise their potential antifertility action have not been performed. Use of GnRH analogues for contraception in women may require combination with low dose oestrogen and progestin and it has been proposed that such development may yield important benefits in health. When combined with testosterone, GnRH antagonists may form the basis for a male contraceptive.

PIP: Use of gonadotropin releasing hormone (GnRH) analogues for contraception in women may require combination with low-dose estrogen and progestin. When combined with testosterone, GnRH antagonists may form the basis for a male contraceptive. Once-daily administration of GnRH agonist throughout the menstrual cycle prevents ovulation, even at low doses. Administration of buserelin intranasally at a dose of 300 mcg daily, starting at 6 weeks postpartum for the duration of breast feeding, prevented ovulation in a group of 9 women. During the study period, 7 of 9 control mothers ovulated. The use of GnRH agonists in treatment of sex-hormone-dependent tumors of the breast and uterus has become established by suppression of estrogen secretion by increasing the dose of agonist or, more effectively, by using a depot preparation. The development of GnRH antagonists involved a stepwise introduction of hydrophobic residues which block proteolysis, increase GnRH receptor affinity, and prolong the pharmacokinetics of the molecule. The GnRH antagonists have to be administered by injection every 24-48 hours, and high doses (3-5 mg per day) are required to obtain adequate suppression of the GnRH receptor. Longterm trials with GnRH antagonists in men are currently being conducted in a number of centers. In a recent report, 8 subjects received daily subcutaneous injections of 10 mg Nal-Glu antagonist for 20 weeks. Supplemental androgen therapy with testosterone enanthate was commenced at 2 weeks to provide low-normal replacement levels. Azoospermia was reached with 6-12 weeks in 6 of the 8 subjects, and doubling the dose of antagonist resulted in azoospermia in the remaining men. No significant changes in libido occurred. These preliminary clinical trials together with findings from longer-term studies in macaques, suggest that the GnRH/androgen combination may prove to be an effective and reversible system of male contraception.

[2 patients with brain metastases who became pregnant during phenytoin administration]. / Twee patiënten met hersenmetastasen die zwanger werden tijdens fenytoïnegebruik.

Two young women taking phenytoin because of symptomatic brain metastases are described. Both patients, one with end-stage lung cancer and the other in complete remission after intensive chemotherapeutic treatment of a choriocarcinoma, became pregnant while using oral contraceptives in combination with phenytoin. One patient had the child, but died a year after the metastases became apparent, in the other the pregnancy was terminated. When prescribing phenytoin, attention should be paid to fertility--even in patients with end-stage cancer or after intensive, possibly sterilising, chemotherapeutic treatment.

Effect of antibiotics on oral contraceptive efficacy.

It is estimated that there are currently 10 million women in the United States who are taking oral contraceptives on a daily basis. Although the actual number is not known, it is also estimated that a large number of these same women are on concomitant drug therapy. In recent years, there has been a number of published reports linking a loss of contraceptive efficacy with the concurrent administration of other drugs, including antibiotics. Because of the common practice of prescribing antibiotics in dentistry, oral healthcare providers should be aware of the possibility of oral contraceptive failure with antibiotic treatment. Since it is often the dental hygienist who interviews patients and assists them in completing their health questionnaire, she or he can play an important role in educating and counseling these patients in possible drug interactions. This article reviews the published incidence of oral contraceptive/antibiotic interaction, along with a discussion of the possible mechanisms by which this interaction occurs. Recommendations are also presented for the oral health management of women taking oral contraceptives and other prescribed drugs.

[Inefficacy of oral contraception during use of minocycline]. / Ineffectiviteit van orale anticonceptie tijdens gebruik van minocycline.

A healthy woman aged 21 years who used the oral contraceptive Trigynon became pregnant while being treated with Minocin (minocycline; 100 mg per day) for acne conglobata. While the risk of use of antibiotics such as this one reducing the efficacy of oral contraceptives is small, patients should nevertheless be informed that the risk exists.

PIP: A 21-year old woman using an oral contraceptive, the combination preparation Trigynon containing levonorgestrel (LNG) and ethinyl estradiol (EE), since June 1987 had experienced pain in the groin. In September 1988 she had a single occurrence of bleeding, a sign of lessened effectiveness of the OC. She was treated with 50 mg of minocycline/day as of April 1989, and for inguinal acne conglobata with locally applied clindamycine (10 mg/ml of clindamycine hydrochloride lotion). She switched to another OC, and the next month timely, normal menstruation ensued. A few days later the dose of minocycline was raised to 100 mg/day. Subsequently she had a regular breakthrough bleeding followed by a missed cycle and a positive pregnancy test. There have been several recent reports about the interaction between antibiotics and OCs (breakthrough bleeding and contraceptive failure). Rifampicin and griseofulvin are known to reduce the activity of OCs via induction of liver enzymes. Between 1968-84 there was a total of 62 failures of OCs (15 using OCs with 50 mcg of EE) reported in the UK. The suspected cause was the combined use with antibiotics (70% penicillin and tetracycline). In the Netherlands 6 cases of possible interactions were reported during 1980-86: 2 cases caused by nitrofurantoin and/or trimethoprim, and 1 case by sulfamethoxazol with trimethoprim. The interference of minocycline with the intestinal flora can occur as 34% of it is excreted in feces, and its antibacterial spectrum corresponds to that of tetracycline hydrochloride (reduction of beta-glucuronidase in the feces). The failure of Trigynon cannot be irrefutable ascribed to minocycline as unintended pregnancy also occurs while using OCs without antibiotics. Clindamycine could have also influenced the intestinal flora percutaneously.

Use of oral contraceptives by women with epilepsy.

Oral contraceptives have not been associated with exacerbation of epilepsy despite warnings in package inserts. No clinical study has provided scientific evidence of worsening of seizures in epileptic women who use oral contraceptives, and improvement in seizure control has occurred in some cases. The main concern about use of oral contraceptives in this population is their effectiveness in preventing conception. Failure rates are higher in groups of women taking enzyme-inducing antiepileptic drugs. The degree of increased metabolism of estrogen and progestin components is highly variable and unpredictable among individuals. Use of higher doses increases protection against conception but also increases the risk of side effects, particularly in patients in whom no enzyme induction occurs. The strength of hormones in the pill should be selected individually when initiating use. Some women may require higher doses for full contraceptive effect.

Cicloxilic acid and the bile lipids in oral contraceptive users.

Cholesterol supersaturation of gallbladder bile induced by oral contraceptives is significantly reduced by the administration of cis-2-hydroxy-2-phenyl-cyclohexane-carboxilic acid (cicloxilic acid), a choleretic substance which has been demonstrated to exert an antilithogenic effect in the rat and in man.

Drug stimulated biotransformation of hormonal steroid contraceptives: clinical implications.

On the basis of well documented biochemical and pharmacological data about the influence of drug mediated enzyme induction on the biotransformation of natural and synthetic sex steroids, practical consequences for hormonal steroid contraception are described and discussed. Clinical reports dealing with this problem are still sparse. The clinical symptoms of drug stimulated biotransformation of hormonal steroid contraceptives are characteristic. Spotting or breakthrough bleeding are observed and in the extreme case conception may occur despite the regular intake of the contraceptive. The appearance of these symptoms differs from one individual to another. With a strong enzyme inducer, bleeding disorders can be provoked artifically in 50 to 60% of the women receiving hormonal contraceptive treatment. The range of drugs which stimulate biotransformation of hormonal contraceptives with consequent loss of their biological effectiveness is not completely known. For practical purposes, it is recommended that bleeding disturbances under hormonal steroid contraception in a previously regular cycle be regarded as loss of reliability; they should be remedied and taken as a sign to search for uncontrolled drug taking.