Ethinyl Estradiol; Desogestrel Apri�, Desogen�, Mircette�, Ortho-Cept� | Apri� [ Indications/Dosage ] [ Administration ] [ Contraindications ] [ Interactions ] [ Adverse Reactions ] [ Patient Education ] [ Costs ] [ Product Info ] [ Classification ] [ Manufacturer Links ] [ Chemical Structures] Description: Ethinyl estradiol/desogestrel are used together as an oral contraceptive agent. At this time, desogestrel containing products have not been evaluated for postcoital contraception. Ethinyl estradiol is one of two estrogens currently used in oral contraceptive pills. The other, mestranol, is converted to ethinyl estradiol before it is biologically active. Desogestrel is a progestin with high progestational selectivity, lowered affinity for androgenic receptors, and no estrogenic action. Thus desogestrel may have less adverse influence on carbohydrate and lipid metabolism, weight gain, acne, and other side effects than older progestins. Desogestrel appears to have favorable effects on lipoproteins by slightly elevating HDL cholesterol. The clinical significance of these findings is unknown. Initial observations of minimal effects on hemostasis with desogestrel have not resulted in lowered rates of thromboembolic events. In fact, evaluations of recent clinical trials have noted an increased risk of non-fatal venous thromboembolism with desogestrel versus levonorgestrel containing contraceptives.[1178] Desogen� and Ortho-Cept� are fixed dose combination products. Special product formulations have been developed. Mircette� consists of 21 combination tablets; followed by 2 days of non-active tablets, and then 5 days of low dose ethinyl estradiol alone. The unique dosing regimen was developed to provide a reduced hormone-free interval, which may be advantageous for patients experiencing migraines, dysmenorrhea or other symptoms the week they do not take the oral contraceptive. The clinical significance or advantage of reduced hormone intervals has not been established. Mircette� was approved in April 1998. Products containing desogestrel were initially FDA approved in 1992. Mechanism of Action: The primary action of the combination of an estrogen with a progestin is to suppress the hypothalamic-pituitary system, decreasing the secretion of gonadotropin-releasing hormone (GnRH). Progestins blunt luteinizing hormone (LH) release, and estrogens suppress follicle-stimulating hormone (FSH) from the anterior pituitary. Both estrogen and progestin ultimately inhibit maturation and release of the dominant ovule. In addition, viscosity of the cervical mucus increases with hormonal contraceptive use, preventing penetration of sperm. Alteration in endometrial tissues also occurs. When traditional regimens of oral contraception are discontinued, ovulation usually returns within three menstrual cycles but can take up to 6 months in some women. Pituitary function and ovarian functions recover more quickly than endometrial activity, which can take up to 3 months to regain normal histology. Both estrogens and progestins are responsible for a number of other metabolic changes. The summary of these changes is dependent on the net actions of the estrogen and progestin combinations. Such total effects may only be clinically significant for some predisposed individuals. At the cellular level, estrogens and progestins diffuse into their target cells and interact with a protein receptor. Metabolic responses to estrogens and progestins require an interaction between DNA and the hormone-receptor complex. Target cells include the female reproductive tract, the mammary gland, the hypothalamus, and the pituitary. Estrogens increase the hepatic synthesis of sex hormone binding globulin (SHBG), thyroid-binding globulin (TBG), and other serum proteins. Estrogens generally have a favorable effect on blood lipids, and lack of estrogen is now recognized as a risk factor for myocardial infarction. Estrogens reduce LDL and increase HDL cholesterol concentrations. Serum triglycerides increase with estrogen administration. Folate metabolism and excretion is increased by estrogens and may lead to slight serum folate deficiency. Estrogens also enhance sodium and fluid retention. Progestins are classified according to their progestational, estrogenic and androgenic properties. Progestins can alter hepatic carbohydrate metabolism, increase insulin resistance, and have either little to slightly favorable effects on serum lipoproteins. Less androgenic progestins have only slight effects on carbohydrate metabolism. More androgenic progestins can aggravate sebaceous gland hyperresponsiveness to androgens and lead to acne. Serious adverse events, like thrombosis, have long been associated with the estrogen component of oral contraceptives but may be the result of both estrogen and progestin components. The mechanism for thrombosis may be associated with increased clotting factor production and/or decreases in anti-thrombin III. Minor side effects can be addressed by choosing formulations that take advantage of relative estrogen, progestin, and androgenic potencies. Pharmacokinetics: Following oral administration in the third cycle of use, roughly 84% of desogestrel and 83% of ethinyl estradiol survive absorption and first pass through the liver. Both drugs are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Estrogens are metabolized in the GI mucosa during absorption and in the liver. The major 1st-pass metabolite of ethinyl estradiol is its sulfate conjugate. Ethinyl estradiol is primarily metabolized in the liver to 2-hydroxy-ethinylestradiol, which is thought to contribute to some of the adverse cardiovascular effects of the drug. Both ethinyl estradiol and its metabolites undergo glucuronide and sulfate conjugation. All conjugates can be hydrolyzed back to the active drug in the GI tract and undergo entero-hepatic recycling. The progestin desogestrel is rapidly and completely metabolized by hydroxylation and first-pass through the liver to 3-keto-desogestrel, the active metabolite responsible for the pharmacologic actions. Some minor, non-active metabolites have been identified. These occur via conjugation to the sulfate and glucuronate salts. Excretion of the oral contraceptive steroids as inactive metabolites occurs via the urine and feces. Elimination half-life is approximately 38 hours for 3-keto-desogestrel and about 26 hours for ethinyl estradiol at steady state. It is the prolonged biologic effects of the hormones that allows for once-daily administration.

Indications...Dosage For routine contraception: Oral dosage (all formulations except Mircette�): Adult and adolescent females: When a 21-day preparation is used, the dosage regimen is 1 tablet (containing 0.15 mg desogestrel and 30 �g of ethinyl estradiol) PO once daily for 21 days, followed by a period of 7 days without drug. When a 28-day preparation is used, the dosage regimen is 1 tablet PO once daily for 28 days (i.e., active tablets for 21 days, followed by 7 inert tablets). Repeat dosage cycles begin on the eighth day after taking the last hormonally active tablet. Administration of most monophasic fixed-combination oral contraceptives (OCs) begins on day 5 of the menstrual cycle or on the first Sunday after or on which bleeding has started. However, some clinicians and manufacturers suggest that administration begin on day 1 of the menstrual cycle to decrease the risk of early ovulation. If administration begins on day 1, spotting and breakthrough bleeding may be more common during the initial dosage cycle. Oral dosage (Mircette� only): Adult and adolescent females: 1 tablet PO once daily for 28 days (as white tablets for 21 days containing ethinyl estradiol-desogestrel, then 2 green inert tablets, followed by 5 yellow tablets containing ethinyl estradiol only). Administration should begin on the first Sunday after or on which bleeding has started, or on day 1 of menstruation. For all subsequent cycles, the patient then begins a new 28-day regimen on the next day after taking the last yellow tablet from the previous cycle. For the treatment of severe acne vulgaris� related to sebum overproduction in females who have no known contraindications to oral contraceptives, desire contraception, have achieved menarche, and are unresponsive to topical anti-acne medications: Oral dosage (all formulations except Mircette�): Adult and adolescent females: Follow dose regimens as for contraception. Improvement in acne may not be noticeable for 2�4 months of treatment. Prolonged treatment may be needed to control condition. For the treatment or adjuvant treatment of amenorrhea�, dysfunctional uterine bleeding�, hirsutism�, hypermenorrhea�, or polycystic ovary syndrome� related to hypoestrogenic or hyperandrogenic conditions in females who have no known contraindications to oral contraceptives, desire contraception, have achieved menarche, and have been evaluated for causes of the condition: Oral dosage (all formulations except Mircette�): Adult and adolescent females: Follow dose regimens as for contraception. Treatment for 6 months to 1 year may be required before effects are apparent. Oral contraceptives have limited utility when the underlying cause of the condition is not related to a hypoestrogenic or hyperandrogenic state. For the treatment of endometriosis� to induce endometrial involution to a "resting" phase and reduce the size and growth of endometrial tissue in females with no contraindications to oral contraceptives, have achieved menarche and who desire contraception: Oral dosage (all formulations except Mircette�): Adult and adolescent females: Follow dose regimens as for contraception. Alternatively, the active tablets can be given continuously. Treatment for 6�9 months may be needed to induce endometrial atrophy and reduce symptoms. Patients with hepatic impairment: Hormonal contraceptives are contraindicated for use in the presence of markedly impaired liver function of any type. Patients with renal impairment: Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. �non-FDA-approved indication

Administration NOTE: Products containing 50 �g estrogen should be used only when medically indicated. Examples of potential medical indications for products containing 50 �g of estrogen include a history of known contraceptive failure on the 50 �g products, or increased hepatic metabolism of OCs, such as occurs with some anticonvulsant medications. NOTE: Some contraceptive packs contain 28 tablets. For most of these (exeption: Mircette�), 21 tablets contain active hormone and 7 contain either iron or inert ingredients, so that the daily dosage cycle can be continuous. This reduces the chance of missed doses. The 7 extra tablets are taken at the end of the cycle. NOTE: Products vary in the type and amount of estrogen and/or progestin; formulations of different hormonal content are not interchangeable. NOTE: If oral contraceptives are first taken postpartum or later than the fifth day of the menstrual cycle, the contraceptive effect should not be relied on until after 7 consecutive days of drug administration. Oral Administration �To minimize nausea, administer with or after the evening meal or at bedtime. Take at the same time each day to ensure maximum contraceptive efficacy. �Instruct patient on risks and warnings associated with hormonal contraceptives (see Patient Information).

Contraindications Estrogens are generally contraindicated in patients with pre-existing breast cancer. The relationship between oral contraceptive use and various cancers, however, is controversial. The information from any long-term study must be balanced with the knowledge that virtually all epidemiologic data on cancer risks and oral contraceptive use pertain to women younger than 60 years of age because oral contraceptives (OCs) were first available for general use in the early 1960's. In 1996, the results of a meta-analysis of 54 studies specifically looking at the effects of oral contraceptives in more than 150,000 women were published. A small, statistically significant risk for breast carcinoma existed for women taking OCs and for up to 10 years after they stop taking OCs, although the increased risk was very slight.[1350] Another meta-analysis of 25 studies of breast cancer in women younger than 60 reported a slight increase in risk in development of early-occurring breast cancer in women under the age of 45 years old. This risk may increase with increasing duration of OC use. Summary relative risk for women with OC use greater than 4 years was 1.18. However, there may be little effect on overall lifetime risk of breast cancer.[1825] Whether OC's may promote earlier clinical manifestation of breast cancer in some women is unclear. The issue of prescribing OCs to women with a family history of breast cancer is controversial. Individual risk versus benefit must be performed. Oral contraceptives are contraindicated in patients with pre-existing cervical cancer. An association between oral contraceptive use and cervical cancer has been demonstrated. Generally, the risk of invasive cervical cancer in women who use oral contraceptives is greatest in women who take OCs for more than 5 years. (see Adverse Reactions.) Evaluation of patients via cervical cytology screening should be performed prior to OC use. Since 1970, at least 35 epidemiological studies have examined the association of exogenous estrogen and an increased incidence of cancer of the endometrium. A recent meta-analysis of 10 studies indicates a significant trend in decreasing endometrial and ovarian carcinoma risk with increasing duration of combined OC use.[1825] The beneficial effects of the OCs in this regard may persist for 15 years after OC use ceases. However, in those women with known endometrial cancer or other estrogen-dependent tumors (e.g., vaginal cancer), estrogen containing OCs are contraindicated, as administration of exogenous estrogen may worsen the condition. Hormonal contraceptive agents are relatively contraindicated in women with undiagnosed menstrual irregularity including undiagnosed vaginal bleeding, or incomplete abortion. Relative contraindication exists also for uterine leiomyomata (fibroids) because the drug can cause the fibroids to increase in size. Oral contraceptives are contraindicated during pregnancy and are labeled FDA pregnancy risk category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens or synthetic progestins alone in pregnant women. With the exception of effects on sexual development, the majority of recent studies do not indicate a teratogenic effect of oral contraceptives when taken inadvertently during early pregnancy. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing oral contraceptive use. In addition, oral contraceptive use may change folate metabolism, and women who discontinue oral contraceptives to pursue pregnancy should preferably wait 3 months for folate concentrations to normalize if possible. Folate supplementation should be be given once pregnant to reduce the incidence of neural tube defects. Recent studies have found no increased risks of birth defects among women who have inadvertently continued to take birth control pills after they unknowingly became pregnant. Because of an increased risk of thromboembolism in the immediate post-partum period, combination hormonal OCs should be used no earlier than 4 weeks following obstetric delivery. Because estrogens and progestin do distribute to breast milk in small quantities, and may interfere with the quality and quantity of lactation, combination OC's should be used with caution in breast-feeding. While occasionally a few acute adverse events in infants have been reported, long-term follow-up of infants whose mothers used combined hormonal contraceptives during lactation has shown no deleterious effects. In general, other forms of contraception are preferred until the infant has been weaned. Although the effects appear to be minimal in most non-diabetic patients receiving hormone therapy with estrogen-progestin combinations; altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing therapy. Estrogens generally have a favorable effect on blood lipids, and reduce LDL and increase HDL cholesterol concentrations. Progestins, however, may attenuate some of these effects by raising LDL and may make control of pre-existing hyperlipidemia more difficult. Serum triglycerides increase with estrogen administration. A small proportion of women may have persistent hypertriglyceridemia while using combined hormonal contraceptives. Hormonal contraceptive agents have been associated with thromboembolic disease such as deep venous thrombosis (DVT). A positive relationship between estrogen dosage and thromboembolic disease has been demonstrated. Products containing 50 �g estrogen should not be used unless medically indicated. In addition, certain progestins may increase thromboembolic risk. (see Adverse Reactions.) Because tobacco smoking increases the risk of DVT, myocardial infarction, stroke and other thromboembolic disease, estrogen-progestin contraceptives should be used cautiously, if at all, in smokers. Risk is especially high for female smokers 35 years of age or older or those who smoke >= 15 cigarettes per day. Women receiving OCs should be advised not to smoke. Pre-existing high blood pressure, renal disease, hypercholesterolemia, hyperlipidemia, morbid obesity or diabetes may increase risks. Hormonal contraceptive agents are contraindicated in patients with a history of stroke, cerebrovascular disease, coronary thrombosis, thrombophlebitis, or thromboembolic disease. Because of their association with elevations in blood pressure, hormonal contraceptive agents should be used cautiously in patients with hypertension, renal disease, or coronary artery disease. Desogestrel has minimal androgenic activity and there is some evidence that the risk of myocardial infarction associated with oral contraceptives is lower when the progestogen has minimal androgenic activity than when the activity is greater. Products containing 50 �g estrogen should not be used unless medically indicated. Blood pressure should be monitored closely in these individuals. Any significant increase in blood pressure while on OCs may require discontinuation of the medication. The onset or exacerbation of migraine or the development of headache with a new pattern which is recurrent, persistent or severe requires evaluation of the cause. Do not use hormonal contraceptives in those patients with headaches which include focal neurologic symptoms. Estrogen-progestin agents are relatively contraindicated in gallbladder disease and acute or intermittent porphyria. Because of their association with the development of cholestatic jaundice and hepatic neoplasms, hormonal contraceptive agents should be used cautiously in patients with any pre-existing hepatic disease. Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in markedly impaired liver function (e.g., uncompensated cirrhosis) of any type; also, those patient with a history of cholestatic jaundice/pruritus of pregnancy or jaundice due to prior hormonal contraceptive use should not use this drug. Estrogen-progestin combinations are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. Mood disorders, like depression, may be aggravated in women taking exogenous hormones. Women with a history of depression may need special monitoring. Low-dose oral contraceptive products may have minimal effect on depressive symptoms. If significant depression occurs, the oral contraceptive should be discontinued. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. There have been clinical case reports of retinal thrombosis. Any change in vision or visual acuity should be examined by an ophthalmologist. Hormonal contraceptive agents should be discontinued in patients developing any unexplained visual disturbance or ocular disease. The safety and efficacy of hormonal contraceptive products have only been established in females of reproductive age. Safety and efficacy of hormonal birth control is expected to be the same for postpubertal children under the age of 16 and for users 16 years of age and older. Use of hormonal contraceptive products in female children before menarche is not indicated.

nteractions Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs. Estrogens are metabolized by CYP3A4. Anticonvulsants that stimulate the activity of this enzyme include: barbiturates, carbamazepine, fosphenytoin, oxcarbazepine, phenytoin, primidone, and topiramate. The anticonvulsants mentioned may cause oral contraceptive failure, especially when low-dose estrogen regimens are used. Epileptic women taking both anticonvulsants and OC's may be at higher risk of folate deficiency secondary to additive effects on folate metabolism. During oral contraceptive failure, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Women on OC's and enzyme-inducing anticonvulsant medications concurrently should report breakthrough bleeding to their prescribers. Oral contraceptive formulations containing higher dosages of ethinyl estradiol (i.e., 50 �g ethinyl estradiol) may be needed to increase contraceptive efficacy. It may be prudent for some women who receive OCs concurrently with enzyme-inducing anticonvulsants to use an additional contraceptive method to protect against unwanted pregnancy. Medications that stimulate CYP3A4 and that may increase OC metabolism include griseofulvin, rifabutin, rifampin, and rifapentine. Rifampin, a potent hepatic enzyme inducer, increases the elimination of both estrogens and progestins. In addition, free estrogen-hormone concentrations are decreased because rifampin increases estrogenic protein binding ability. It is estimated that 70% of women taking estrogen-containing oral contraceptives and rifampin experience menstrual abnormalities, and 6% become pregnant. Like other anti-infectives, rifampin indirectly inhibits the enterohepatic recirculation of estrogen through disruption of GI flora growth and this may also contribute to the interaction with oral contraceptives. Griseofulvin use is also associated with well documented therapeutic failures with OCs. The use of an alternative method of contraception is recommended during rifamycin or griseofulvin use and should be continued for at least one OC cycle (i.e., one month) after the interacting medication is finished. Anti-retroviral protease inhibitors used in the treatment of HIV increase OC metabolism by stimulation of CYP3A4 metabolism. For example, ritonavir decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women on OC's and anti-retroviral protease inhibitors concurrently should report breakthrough bleeding to their prescribers. It may be prudent for women who receive OCs concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy. Oral contraceptive formulations containing higher dosages of ethinyl estradiol (i.e. 50 �g ethinyl estradiol) may be needed to increase contraceptive efficacy. While food does not appear to interfere with OCs, grapefruit juice has been reported to decrease estradiol metabolism. Grapefruit juice contains a furano-coumarin compound, 6,7�dihydroxybergamottin that inhibits CYP3A4 in enterocytes.[1806] Estrogen levels may increase by up to 30%. The clinical significance of the interaction is unknown. It is possible that estrogen induced side effects could be increased in some individuals. Ascorbic acid, vitamin C acts as a competitive inhibitor of the sulfation of ethinyl estradiol in the gastrointestinal tract wall and may increase the bioavailability by 50%. Patients who ingest ascorbic acid supplements may experience an increase in estrogen related side effects. Anti-infectives which disrupt the normal GI flora, including amoxicillin, ampicillin, chloramphenicol, neomycin, nitrofurantoin, penicillin V, sulfonamides, and tetracyclines, may potentially decrease the effectiveness of estrogen-containing oral contraceptives. Normally, GI bacteria hydrolyze estrogen conjugates that are eliminated via the bile. This hydrolyzation allows enterohepatic recirculation of the active estrogenic component to occur. A decrease in enterohepatic recirculation could compromise the effectiveness of estrogen-containing oral contraceptives. In addition, significant antibiotic-induced diarrhea may impair the oral bioavailability of oral contraceptives in some patients. Although several case reports suggested amoxicillin and ampicillin reduced the efficacy of estrogen-progestin oral contraceptives, subsequent studies of this drug-drug interaction have not substantiated a pharmacokinetic interaction. The incidence of the interaction of anti-infective agents with OCs is unpredictable; cases of antibiotic-associated contraceptive failure have been reported, but are not well-documented. Patients should be made aware of this potential interaction. The use of an alternative method of contraception may be recommended during use of these antibiotics, especially ampicillin or amoxicillin. Depending on the length of antibiotic therapy, an additional contraceptive method may be needed for at least one OC cycle after the antibiotic is finished. Some macrolide anti-infectives may increase estrogen metabolism. Dirithromycin, for example, has increased the metabolism of ethinyl estradiol containing oral contraceptives, but has not been associated with breakthrough ovulation or contraceptive failure. However, practitioners should be alert to the possibility that breakthrough bleeding or contraceptive failure may occur with either dirithromcin, erythromycin or clarithromycin. The incidence of an interaction bewteen anti-infective agents and OCs is unpredictable; cases of antibiotic-associated contraceptive failure have been reported, but are not well-documented. Patients should be made aware of this potential interaction. The use of an alternative method of contraception may be recommended during use of antibiotics. Depending on the length of antibiotic therapy, an additional contraceptive method may be needed for at least one OC cycle after the antibiotic is finished. Modafinil may cause failure of oral contraceptives or hormonal contraceptive-containing implants or devices due to induction of CYP3A4 isoenzyme metabolism of ethinyl estradiol and/or the progestins in these products. Female patients of child-bearing potential should be advised to discuss contraceptive options with their health care provider to prevent unintended pregnancies. An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation. Mineral oil can reduce absorption of oral contraceptives from the GI tract producing lower plasma levels of progestin and estrogen. This interaction is the result of simultaneous administration. Estrogens can increase the hepatic synthesis of proteins and vitamin K-dependent clotting factors. The effects of warfarin are generally decreased during concurrent use with estrogens because estrogens increase the production of clotting factors VII, VIII, IX, and X. Furthermore, estrogens promote platelet aggregation. Because of this, patients receiving warfarin should be monitored for loss of anticoagulant effect if an estrogen is added. Dosage adjustment of warfarin should be based on the prothrombin time or INR value. Ethinyl estradiol and other estrogens can decrease the hypoglycemic effects of antidiabetic agents by impairing glucose tolerance. Changes in glucose tolerance occur more commonly in patients receiving > 50 �g of ethinyl estradiol per day. The presence or abscence of concomitant progestin use may influence the significance of this effect. Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control when therapy with any of these agents is instituted. In addition, patients receiving antidiabetic agents should be closely monitored for signs of hypoglycemia when estrogen therapy is discontinued. Troglitazone or pioglitazone may decrease OC effectiveness by increasing metabolism of the estrogens. OC concentrations have been reduced by up to 30% with troglitazone co-administration. Higher-dosage oral contraceptive formulations may be needed to increase contraceptive efficacy. Alternatively, the use of an alternative or additional method of contraception is recommended during troglitazone or pioglitazone use. Estrogen-containing oral contraceptives appear to decrease the effectiveness of clofibrate by increasing the glucuronide conjugation of the active form of clofibrate. Atorvastatin can increase the plasma concentrations of oral contraceptives when the drugs are coadministered. The mechanism is probably competition for the CYP3A4 substrate. Area-under-the-curve values for ethinyl estradiol were increased by approximately 20% when atorvastatin was given concurrently. These increases should be considered when administering atorvastatin and ethinyl estradiol concomitantly. It is unclear if patients on both medications concurrently experience an increase in estrogen related side effects. Ethinyl estradiol may inhibit the clearance of benzodiazepines which undergo oxidation such as diazepam and chlordiazepoxide. Other benzodiazepines which undergo oxidation and could potentially interact include alprazolam, clorazepate, clonazepam, estazolam, flurazepam, halazepam, prazepam, quazepam, and triazolam. Conversely, ethinyl estradiol may enhance the metabolism of lorazepam, oxazepam and temazepam; it appears glucuronide conjugation of these medications is increased in the presence of combined hormonal oral contraceptives. Serum concentrations of theophylline or caffeine may be increased during concurrent administration with ethinyl estradiol. This interaction occurs from the inhibition of methylxanthine oxidation in the liver. The resulting increased half-life and decreased clearance may necessitate a decrease in theophylline dosage. Patients may need to be informed about increased caffeine-like side effects; patients taking theophylline should report these side effects to their health care professional. The oxidative metabolism of tricyclic antidepressants may be decreased by ethinyl estradiol. Increased antidepressant serum concentrations may occur. Ethinyl estradiol has been reported to intensify side effects from imipramine. Patients should be monitored for increased tricyclic antidepressant side effects if an estrogen is added. Current evidence indicates that this interaction may be related to the estrogen dosage, with larger doses (i.e., >= 50 �g ethinyl estradiol/day) causing a more significant interaction. Estrogens may inhibit the metabolism of cyclosporine. A few reports of increased cyclosporine levels and cyclosporine toxicity have been documented following concurrent administration of oral contraceptives. Patients taking these medications concurrently should have cyclosporine levels evaluated regularly. Estrogens have been postulated to increase the risk of liver toxicity when combined with medications that are associated with hepatotoxicity (e.g., dantrolene, isoniazid, INH, methotrexate). In the liver, estrogens may alter the chemical and physical properties of hepatocyte membranes, leading to impaired activity of cellular function, and increasing susceptibility to hepatotoxicity due to other agents. Concurrent administration of troleandomycin and estrogen-containing oral contraceptives may decrease the metabolism of the latter, causing alterations in bilirubin and bile acid secretion. Cholestatic jaundice has occurred in some patients. Although both agents have caused jaundice independently, concurrent use is not recommended. Concurrent use of ethinyl estradiol in oral contraceptives reduced naratripatan clearance by 32% and volume of distribution by 22% during clinical trials. The decrease in clearance resulted in slightly higher plasma levels of naratriptan. Similar changes in clearance have been reported with other serotonin-receptor agonists (5-HT agonists) when administered with ethinyl estradiol. The clinical implication of these interactions is unknown. Ethinyl estradiol has been associated in rare cases with pseudocholinesterase deficiency (i.e., reduced plasma cholinesterase). Since non-depolarizing neuromuscular blockers are metabolized by cholinesterase, prolonged neuromuscular blockade may occur in individuals on concurrent therapy with ethinyl estradiol or combination hormonal oral contraceptives. The administration of estrogens with aminocaproic acid may lead to additive hypercoagulability. The mechanism is pharmacodynamic in nature. Estrogens increase clotting factor production and platelet aggregation; aminocaproic acid inhibits fibrinolysis and the activity of plasminogen. Estrogens have caused abnormal thyroid function test results. Estrogens and oral contraceptives containing estrogens increase serum thyroxine binding globulin (TBG). This is not usually a problem for euthyroid patients. However, hypothyroid patients who are on exogenous thyroid hormones for replacement therapy may have decreased clinical response to their dose as a result of decreased free thyroxine levels induced by increased TBG. Dose adjustments in thyroid therapy may be needed in some patients. Estrogen-induced changes in TBG concentration should be taken into consideration when reviewing T4 and T3 laboratory values. Unbound (free) T3 should be measured, rather than total T3 (TT3). The incidence of estrogen-thyroid hormone interactions is not well documented. Chronic ingestion of ethinyl estradiol may result in reduced serum concentrations of folic acid, vitamin B9 and RBC folate concentrations. The clinical significance of this interaction is uncertain, especially with ethinyl estradiol doses of < 50 �g/day. Hematologic abnormalities due to this interaction are rarely noted. Women taking estrogens should maintain adequate folic acid intake in the diet as recommended by guidelines for daily allowances (RDAs). Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone and delayed the clearance of prednisolone. Studies involving other corticosteroids (i.e., dexamethasone, methylprednisolone, and prednisone) have failed to show an interaction. Estrogens may decrease corticosteroid metabolism secondary to enzyme inhibition, compete at metabolism sites, or alter the protein binding of corticosteroids. Patients should be monitored for increased corticosteroid effects when estrogens are used in patients receiving either hydrocortisone or prednisolone. Estrogens can increase calcium absorption. In general, the interaction between calcium salts and estrogen is beneficial. However, this interaction may not be advantageous in patients predisposed to hypercalcemia or nephrolithiasis. Cimetidine has been reported to reduce the hepatic clearance of estradiol. While the clinical significance of cimetidine's action on exogenous estrogens is uncertain, this interaction may partially explain the association between cimetidine therapy and gynecomastia. Patients who ingest cimetidine might experience an increase in estrogen related side effects. Estrogen containing oral contraceptives can induce fluid retention and may increase blood pressure in some patients; patients who are receiving antihypertensive agents concurrently with OCs should be monitored to confirm that the desired antihypertensive effect is being obtained. Estrogens may interact with growth hormone (somatropin and somatrem) during prepuberty by accelerating epiphysial maturation. Tamoxifen and raloxifene exert their effects by blocking selective estrogen receptors. Since tamoxifen or raloxifene and estrogens are pharmacological opposites, it would be illogical to coadminister them. A multiple-dose, placebo-controlled, randomized two-way crossover study investigated the use of lansoprazole with a low-dose oral contraceptive containing ethinyl estradiol and levonorgestrel. The bioavailability of oral contraceptives was not affected by lansoprazole.[763] Selegiline concentrations may be increased by the co-administration of oral contraceptives containing estrogens and progestins. In one pharmacokinetic study, it was reported that both peak and total selegiline concentrations were increased 10- and 20-fold, respectively, in users of oral contraceptives versus non-users. The metabolism of selegiline appears to be decreased by the presence of oral contraceptives. Dose reductions in selegiline may be necessary in patients on ethinyl estradiol or oral contraceptive agents in order to limit the risk of increased MAO type B inhibition. Exemestane should not be given concurrently with any estrogen-containing products including oral contraceptives, as these could interfere with the pharmacologic action of exemestane. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. One report noted intermenstrual bleeding after the concurrent use of St. John's wort in 8 premenstrual women who had been on oral contraceptives for long durations of time. Intermenstrual bleeding implies that there may be a loss of contraceptive or hormonal-replacement efficacy. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. The interaction occurred within 1 week of beginning St. John's wort in five of the cases. In 3 patients for whom follow-up was available, the discontinuation of St. John's wort resolved the bleeding abnormalities.[2717] It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of progestin-only contraceptives (e.g., levonorgestrel, medroxyprogesterone, and norgestrel). Women should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of these combinations is recommended. The coadministration of mycophenolate mofetil and oral contraceptives containing ethinyl estradiol and levonorgestrel, desogestrel, or gestodene resulted in similar AUC values for ethinyl estradiol and 3-keto desogestrel; however, the mean levonorgestrel AUC was significantly decreased by about 15%. There was large interpatient variability in the data, especially for ethinyl estradiol. Mycophenolate mofetil may not have any influence on the ovulation-suppressing action of the studied oral contraceptives. However, it is recommended that oral contraceptives be given to women receiving mycophenolate and additional birth control methods be considered.

Ethinyl Estradiol; Desogestrel Apri�, Desogen�, Mircette�, Ortho-Cept� | Apri�

1178. Jick H, Jick SS, Gurewich V et al. Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral contraceptives with differing progestagen components. Lancet 1995;346:1589�93.

1825. Schlesselman J. Net effect of oral contraceptive use on the risk of cancer in women in the United States. Obstet Gynecol 1995;85:793�801.

1350. Collaborative Group of Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713�27.

1806. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 1998;18:84�112.