Ortho Tri-Cyclen Interactions
- Aminocaproic Acid
- Amoxicillin
- Ampicillin
- Amprenavir
Antidiabetic Agents
Antihypertensive Agents
- Aprepitant
Aromatase Inhibitors
- Ascorbic Acid, Vitamin C
- Atazanavir
- Atorvastatin
Barbiturates
Benzodiazepines
- Bexarotene
- Bosentan
- Caffeine
- Calcium Salts
- Carbamazepine
- Charcoal
- Chloramphenicol
- Cimetidine
- Clarithromycin
- Clindamycin
- Clofibrate
- Cyclosporine
- Dantrolene
- Delavirdine
- Dirithromycin
- Doxercalciferol
- Echinacea
- Erythromycin
- Ethotoin
- Felbamate
- Folic Acid, Vitamin B9
- food
- Fosamprenavir
- Fosphenytoin
- grapefruit juice
- Green Tea
- Griseofulvin
- Guarana
- Hydrocortisone
- Indinavir
- Isoniazid, INH
- Lincomycin
- Lopinavir; Ritonavir
- Methotrexate
- Mineral Oil
- Modafinil
- Mycophenolate
- Nefazodone
- Nelfinavir
- Neomycin
Neuromuscular blockers
- Nitrofurantoin
- Oxcarbazepine
- Penicillin V
- Phenytoin
- Prednisolone
- Raloxifene
- Rifabutin
- Rifampin
- Rifapentine
- Ritonavir
- Rosuvastatin
- Saquinavir
- Selegiline
Serotonin-Receptor Agonists
- Somatropin, rh-GH
- Soy Isoflavones
- St. John’s Wort, Hypericum perforatum
Sulfonamides
- Tamoxifen
Tetracyclines
- Theophylline, Aminophylline
Thyroid hormones
- Tipranavir
- Tizanidine
- tobacco
- Topiramate
Tricyclic antidepressants
- Troleandomycin
- Ursodeoxycholic Acid, Ursodiol
- Warfarin
Ortho TriCyclen Interactions
Females receiving combined hormonal contraceptives should be advised not to smoke tobacco. Tobacco smoking appears to enhance the procoagulant effect of estrogens. Tobacco smoking and combined hormonal contraceptives may interact synergistically via a pharmacodynamic interaction to increase the risk of DVT, myocardial infarction, stroke and other thromboembolic disease. Risk is especially high for female smokers 35 years of age or older or those who smoke >= 15 cigarettes per day.
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 (including primidone), carbamazepine, felbamate, oxcarbazepine, phenytoin or fosphenytoin (and possibly ethotoin), and topiramate. The anticonvulsants mentioned may cause oral contraceptive failure, especially when low-dose estrogen regimens (e.g., ethinyl estradiol is < 50 mcg/day) are used. Epileptic women taking both anticonvulsants and OCs may be at higher risk of folate deficiency secondary to additive effects on folate metabolism and the higher risk for oral contraceptive failure. During oral contraceptive failure, the additive effects could potentially heighten the risk of neural tube defects in pregnancy. Women on OCs 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 mcg 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. Higher dosages of oral contraceptives (e.g., ethinyl estradiol >= 50 mcg/day) or a second contraceptive method are typically suggested if women use an enzyme-inducing anti-epileptic drug or a barbiturate. Proper intake of folic acid should also be ensured.
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. In one review, the authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available.
Hormonal contraceptives may decrease the serum concentrations of amprenavir and fosamprenavir, which could lead to loss of virologic response and possible viral resistance. Hormonal contraceptives should not be administered with amprenavir or fosamprenavir. Data on the effects that other protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, saquinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. For example, ritonavir decreases ethinyl estradiol AUC by 40% and Cmax by 32%. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms.
The concentration of ethinyl estradiol may increase during concurrent administration of delavirdine. However, the clinical significance of this interaction is unknown.
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. 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, clindamycin, lincomycin, 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. One retrospective study reviewed the literature to determine the effects of oral antibiotics on the pharmacokinetics of contraceptive estrogens and progestins, and also examined clinical studies in which the incidence of pregnancy with oral contraceptives (OCs) and antibiotics was reported; antituberculous drugs (e.g., rifampin) were the only agents clearly associated with OC failure and pregnancy. It was concluded other antibiotics studied did not alter plasma levels of OCs. Based on the results, these authors recommended that back-up contraception may not be necessary if OCs are used reliably during oral antibiotic use. Another review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available.
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 dirithromycin, erythromycin or clarithromycin. The incidence of an interaction between 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. One review of the subject concurred with these data, but noted that individual patients have been identified who experienced significant decreases in plasma concentrations of combined OC components and who appeared to ovulate; the agents most often associated with these changes were rifampin, tetracyclines and penicillin derivatives. These authors concluded that because females most at risk for OC failure or noncompliance may not be easily identified and the true incidence of such events may be under recognized or under-reported, and given the serious consequence of unwanted pregnancy, that recommending an additional method of contraception during short-term antibiotic use may be justified. During long-term antibiotic administration, alternative or additional contraception may be advisable in selected circumstances. Data regarding progestin-only contraceptives or newer combined contraceptive deliveries (e.g., patches, rings) are not available.
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.
While information on this interaction is limited, it appears that the simultaneous administration of estrogens and mineral oil, as a laxative, may decrease the absorption of the estrogens, resulting in lower estrogen plasma concentrations. This interaction may be more likely with the chronic administration of mineral oil, as opposed to a single dose of mineral oil used for occasional constipation. In order to avoid an interaction, it would be prudent to separate administration times, giving estrogens 1 hour before or 2 hours after the administration of mineral oil.
Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability. A positive relationship between combination oral contraceptives (OCs) and thromboembolic disease has been demonstrated; the US FDA has suggested class labeling of combined OCs in accordance with this data. OC products containing >= 50-mcg ethinyl estradiol are associated with the greatest risk of thromboembolic complications. Combined oral contraceptive agents are contraindicated in patients with a current or past history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis, thromboembolic disease or valvular heart disease with complications. Because of these contraindications and the potential for pharmacodynamic interaction, concurrent use of estrogens or OCs in female patients receiving anticoagulation therapy with warfarin is generally avoided, even though the dose of ethinyl estradiol is < 50 mcg/day in many modern combined hormonal oral contraceptives. If concurrent use of an estrogen or OC cannot be avoided in a patient taking warfarin, the patient should be carefully monitored for alterations in anticoagulant effectiveness and signs and symptoms of thromboembolic complications or bleeding. 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 mcg of ethinyl estradiol per day. The presence or absence 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 coadministration. 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. Exenatide may slow gastric emptying which may reduce the rate and/or extent of absorption of orally administered drugs, such as oral contraceptives. Patients should take oral contraceptives at least 1 hour prior to exenatide injection.
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 that undergo oxidation., thereby increasing serum concentrations of concomitantly administered benzodiazepines. Benzodiazepines that undergo oxidation and could potentially interact include alprazolam, chlordiazepoxide, clorazepate, clonazepam, diazepam, estazolam, flurazepam, halazepam, prazepam, quazepam, and triazolam. Patients receiving oral contraceptive therapy should be observed for evidence of increased response to such benzodiazepines. Low-dose estrogen-containing oral contraceptives have not been shown to significantly influence the metabolic clearance of alprazolam in a pharmacokinetic study. 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; the clinical significance of these interactions is not determined.
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 side effects; patients taking theophylline should report these side effects to their health care professional. In addition, patients may desire to limit products that contain high amounts of caffeine (e.g., coffee, green tea, other teas, colas, chocolate, guarana) in an effort to minimize caffeine-related side effects such as nausea or tremors.
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 mcg ethinyl estradiol/day) causing a more significant interaction.
There have been reports indicating the estrogens and/or progestins in oral contraceptives may inhibit the metabolism of cyclosporine. Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to nephrotoxicity and/or hepatotoxicity. If oral contraceptives, estrogens, or progestins are initiated or discontinued in patients receiving cyclosporine, the patient’s cyclosporine concentrations should be monitored closely.
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 naratriptan 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.
Early clinical data indicated that the chronic ingestion of higher doses (>= 50 mcg/day PO) of ethinyl estradiol (or estrogen equivalent) may result in reduced serum concentrations of folic acid, vitamin B9 and diminished folate status. Hematologic abnormalities due to this interaction are rarely noted; epidemiologic data do not indicate a clinically significant effect of combined oral contraceptives (OCs) or non-oral combination contraceptives on folate status, especially with lower estrogen doses per day and with controlled adequate dietary intake of folate. Women taking combined hormonal contraceptives should maintain adequate folic acid intake in the diet as recommended by guidelines for daily allowances (RDAs). Depressed serum folate levels may be clinically significant if a woman becomes pregnant; as low serum folate is associated with a higher incidence of fetal neural tube defects.
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.
The use of estrogens, including oral contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances. The use of estrogens may aggravate conditions for which tamoxifen is prescribed. Tamoxifen exerts its effects by blocking estrogen receptors. Since tamoxifen and estrogens are pharmacological opposites, they are not usually given concurrently.
Raloxifene exerts its effects by blocking estrogen receptors. Since raloxifene and estrogens are pharmacological opposites, it would be illogical to coadminister them.
Selegiline concentrations may be increased by the coadministration 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 hormonal combined contraceptive agents in order to limit the risk of increased MAO type B inhibition.
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. 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.
Estrogens and combination hormonal oral contraceptives increase hepatic cholesterol secretion, and encourage cholesterol gallstone formation and hence may theoretically counteract the effectiveness of ursodeoxycholic acid, ursodiol.
Theoretically, the soy isoflavones may compete with drugs that have estrogenic activity or which selectively modulate estrogen receptors. Soy isoflavones should be used with caution in patients taking estrogens or combination hormonal oral contraceptives.
Estrogens, including hormonal contraceptives, could interfere competitively with the pharmacologic action of the aromatase inhibitors. The goal of aromatase inhibitor therapy is to decrease circulating estrogen concentrations and inhibit the growth of hormonally-responsive cancers. Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions. Aromatase inhibitors (e.g., aminoglutethimide, anastrozole, exemestane, letrozole, testolactone, vorozole) exhibit their antiestrogenic effects by reducing the peripheral conversion of adrenally synthesized androgens (e.g., androstenedione) to estrogens through inhibition of the aromatase enzyme.
Concomitant administration of bexarotene capsules and tamoxifen in women with breast cancer resulted in a modest decrease in plasma concentrations of tamoxifen, possibly due to an induction of cytochrome P450 (CYP) 3A4. Based on this interaction, bexarotene capsules may theoretically increase the rate of metabolism and reduce plasma concentrations of other substrates metabolized by CYP3A4, including oral contraceptives. It is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method, during oral bexarotene therapy. Because of the potential interaction with hormonal contraceptives (e.g., estrogens or progestins), it is strongly recommended that one of the forms of contraception be non-hormonal.
A retrospective analysis of population pharmacokinetic data indicates that the clearance of tizanidine may be 50% lower in women who take oral contraceptives concurrently with tizanidine.
Note that charcoal exerts a nonspecific effect, and many medications can be adsorbed by activated charcoal; repeat doses may decrease the enterohepatic recycling of some drugs. Patients who ingest activated charcoal in non-overdose situations for flatulence or other purposes should be aware that the effectiveness of other regularly taken medications (e.g., oral contraceptives) might be decreased. However, pharmacokinetic or pharmacodynamic data clearly demonstrating this interaction are not available. Ovulatory potential was studied during the use of two monophasic oral contraceptive pill preparations, after repeated mid-cycle administration of activated charcoal to treat diarrhea in women. None of eleven women ovulated. Repeated charcoal treatment, when administered 3 hours after but at least 12 hours before pill intake, did not alter oral contraceptive efficacy.
Bosentan is a significant inducer of CYP3A hepatic enzymes. Hormonal contraceptives, including oral contraceptives, injectable, transdermal, and implantable contraceptives may not be reliably effective in the presence of bosentan, since many contraceptive drugs are metabolized by CYP3A4 isoenzymes. There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. An interaction study has demonstrated that coadministration of bosentan and an oral contraceptive product (ethinyl estradiol; norethindrone) produced average decreases in norethindrone and ethinyl estradiol serum concentrations of 14% and 31%, respectively; however, decreases in drug exposure were are as high as 56% and 66%, respectively, in individual subjects.
Nefazodone inhibits the hepatic CYP3A4 isoenzyme. Estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when nefazodone is coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives. An interaction has been reported clinically, but more study is needed to determine the clinical significance of this interaction in the general population.
When coadministered with oral contraceptives, rosuvastatin reportedly increases the plasma concentration of ethinyl estradiol and norgestrel by 26% and 34%, respectively (manufacturer data). The mechanism and clinical significance for this potential interaction is unclear.
Upon coadministration with aprepitant, the efficacy of hormonal contraceptives during and for 28 days following the last dose of aprepitant may be reduced. Alternative or back-up methods of contraception should be used during treatment with aprepitant and for 1 month following the last dose of aprepitant. The exact mechanism for this interaction has not been described. Ethinyl estradiol is a CYP3A4 substrate and theoretically may be subject to induced CYP3A4 metabolism by aprepitant, although aprepitant has been shown to moderately inhibit CYP3A4 metabolism of several other CYP3A4 substrates. In a pharmacokinetic study, a daily dose of oral contraceptives containing ethinyl estradiol and norethindrone was administered on Days 1 through 21. Aprepitant was given as a 3-day regimen of 125 mg on Day 8 and 80 mg/day on Days 9 and 10. Ondansetron 32 mg IV on Day 8 and dexamethasone 12 mg PO on Day 8 and 8 mg/day on Days 9, 10, and 11 were also administered. In the study, the AUC of ethinyl estradiol decreased by 19% on Day 10 and there was as much as a 64% decrease in ethinyl estradiol trough concentrations during Days 9 through 21. While there was no effect of aprepitant on the AUC of norethindrone on Day 10, there was as much as a 60% decrease in norethindrone trough concentrations during Days 9 through 21. Since specific studies have not been done with other hormonal contraceptives (e.g., progestins, non-oral combination contraceptives), an alternative or additional non-hormonal method of birth control during treatment and for 28 days after treatment is prudent to avoid potential for contraceptive failure.
Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors including ethinyl estradiol may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if ethinyl estradiol is coadministered with doxercalciferol.
Ethinyl estradiol is metabolized by CYP3A4. The effects of echinacea on CYP3A4 are complex. In vitro data suggest that echinacea can inhibit the CYP3A4 isoenzyme; however, the clinical significance of these data are not yet known, as some authors have reported the in vivo activity in humans to be minor. Other limited in vivo data indicate that echinacea inhibits intestinal CYP3A4, but induces hepatic CYP3A4. In 6 subjects administered echinacea plus intravenous midazolam a probe for CYP3A4), the systemic clearance of midazolam increased by 34% and the AUC decreased to 75%. However, when oral midazolam was administered, the oral availability increased leading to no change in the overall clearance of oral midazolam. The overall effects on drugs metabolized by CYP3A4 are unknown and may be negligible. It may be prudent to closely monitor for changes in efficacy or toxicity when echinacea is coadministered with drugs that are metabolized by CYP3A4, including contraceptives containing ethinyl estradiol, until more data are available.
[ Last revised: 5/1/2006 4:41:00 PM ]
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