Phenytoin with oral contraceptives

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

Carbamazepine levels are increased by CYP3A4 inhibitors (cimetidine, macrolides, diltiazem, fluoxetine, ketoconazole, verapamil, valproate) levels are decreased by CYP3A4 inducers (cisplatin, doxorubicin, felbamate, phenobarbital, phenytoin, primidone, rifampin, theophylline). Carbamazepine may increase levels of clomipramine, phenytoin, and primidone and lithium toxicity may decrease levels of phenytoin, warfarin, oral contraceptives, doxycycline, theophylline, haloperidol, alprazolam, clozapine, ethosuximide, and valproate may interfere with other anticonvulsants. 

Theophylline is a narrow therapeutic index drug with significant difference in bioavailability following oral administration. The half-life of the drug is increased by heart failure, cirrhosis and viral infections, in elderly patients, and by certain drugs, such as cimetidine, ciprofloxacin, oral contraceptives and fluvoxamine. The half-life is decreased in smokers, chronic alcoholism, and by certain drugs, such as phenytoin, rifampicin and carbamazepine. 

Drugs that may be affected by HMG-CoA reductase inhibitors include oral contraceptives, diclofenac, digoxin, glyburide, phenytoin, and warfarin. Atorvastatin, lovastatin, and simvastatin are primarily metabolized by CYP3A4 they may interact with CYP3A4 inhibitors. 

Stopping oral contraceptives - For women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin, the maintenance dose of lamotrigine may need to be decreased by as much as 50% of the maintenance dose with concurrent oral contraceptives. 

Folate deficiency can be dietary, especially in the eiderly, due to increased demand like in pregnancy, or due to maiabsorption syndromes. Agents which can cause folic acid deficiency with long-term use include phenytoin, oral contraceptives, isoniazid and glucocorticosteroids. In rare instances the use of dihydrofolate reductase inhibitors like trimethoprim, methotrexate or pyrimethamine can contribute to the occurrence of folate deficiency. Folinic acid can circumvent the need for the inhibited dihydrofolate reductase. 

Certain concomitantly administered drugs may interfere with the effectiveness of the oral contraceptives or lead to an increased incidence of breakthrough bleeding. These include rifampin, isoniazid, ampiciUin, neomycin, penicillin V, chloramphenicol, sulfonamides, nitrofurantoin, phenytoin, barbiturates, primidone, analgesics, and phenothiazines. 

Levodopa or dopamine agonists produce diverse dyskinesias as a dose-related phenomenon in patients with Parkinson s disease dose reduction reverses them. Chorea may also develop in patients receiving phenytoin, carbamazepine, amphetamines, lithium, and oral contraceptives, and it resolves with discontinuance of the offending medication. Dystonia has resulted from administration of dopaminergic agents, lithium, serotonin reuptake inhibitors, carbamazepine, and metoclopramide and postural tremor from theophylline, caffeine, lithium, valproic acid, thyroid hormone, tricyclic antidepressants, and isoproterenol. 

Crawford P, Chadwick DJ, Martin C, Tjia J, Back DJ, Orme M. The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids. Br J Clin Pharmacol 1990 30(6) 892-6. 

Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. 

UGT1A6 is a high-affinity (Km = 2.2 mM), low-capacity enzyme. UGT1A1 has intermediate affinity (9 mM) with high capacity, and UGT1A9 is a low-affinity, high-capacity enzyme (21 mM) (59). With a kinetic model, Court et al. estimated that at typical therapeutic concentrations (0.05-5 mM), UGT1A9 was the most important enzyme (>55% of total activity). Consequently, the mechanism of induction by oral contraceptives, phenytoin, and rifampin is unclear and may involve multiple enzymes. 

Fluconazole Fluconazole may increase the plasma concentration of phenytoin, sulfonylurea (hypoglycemic), cyclosporin, zidovudine, cisapride, and terfenadine. Coadministration of fluconazole with rifampicin results in the reduced plasma concentration of fluconazole. Griseofulvin may reduce the plasma concentration of salicylates, coumarin, anticoagulants, and oral contraceptives. 

Clinically important, potentially hazardous interactions with alprazolam, astemizole, carbamazepine, cisapride, clarithromycin, dexamethasone, diltiazem, docetaxel, ifosfamide, imatinib, irinotecan, itraconazole, ketoconazole, methylprednisolone, midazolam, nefazodone, oral contraceptives, paroxetine, phenytoin, pimozide, rifampin, ritonavir, terfenadine, tolbutamide, trabectedin, troleandomycin, vinblastine, vincristine, warfarin... 

Clinically important, potentially hazardous interactions with diuretics, estrogens, ketoconazole, live vaccines, oral contraceptives, phenytoin, rifampin, warfarin... 

Clinically important, potentially hazardous interactions with benzodiazepines, carbamazepine, chlordiazepoxide, ciclesonide, clonazepam, clorazepate, dasatinib, diazepam, dihydroergotamine, ergot alkaloids, eszopiclone, eucalyptus, fentanyl, fesoterodine, flurazepam, ivabradine, lapatinib, lorazepam, methysergide, midazolam, oral contraceptives, oxazepam, phenytoin, pimozide, quazepam, rifampin, sildenafil, solifenacin, St John s wort, temazepam, temsirolimus, tolvaptan... 

Clinically important, potentially hazardous interactions with aluminum, aminophylline, carbamazepine, carbimazole, cyclosporine, daclizumab, diuretics, etoposide, etretinate, grapefruit juice, indomethacin, isoniazid, itraconazole, ketoconazole, licorice, live vaccines, methotrexate, naproxen, oral contraceptives, pancuronium, phenobarbital, phenytoin, rifampicin, troleandomycin... 

Clinically important, potentially hazardous interactions with alfentanil, alfuzosin, alprazolam, amiodarone, amprenavir, aprepitant, astemizole, atazanavir, bepridil, buprenorphine, bupropion, carbamazepine, chlordiazepoxide, ciclesonide, clozapine, conivaptan, cyclosporine, cyproterone, dasatinib, diazepam, dihydroergotamine, ergot alkaloids, estazolam, eszopidone, etravirine, ezetimibe, fentanyl, fesoterodine, flecainide, flurazepam, fluticasone, halazepam, ivabradine, ixabepilone, ketoconazole, lapatinib, levothyroxine, meperidine, meptazinol, methysergide, midazolam, nifedipine, nilotinib, oral contraceptives, phenytoin, pimozide, piroxicam, propafenone, propoxyphene, quazepam, quinidine, ranolazine, rifabutin, rifampin, rifapentine, rimonabant, rivaroxaban, saquinavir, sildenafil, silodosin, simvastatin, solifenacin, St John s wort, tadalafil, temsirolimus, trabectedin, triazolam, vardenafil, voriconazole, zolpidem... 

The following drugs have been commonly associated with inducing, aggravating or unmasking SLE beta-blockers, carbamazepine, chlorpromazine, estrogens, griseofulvin, hydralazine, isoniazid (INH), lithium, methyldopa, minoxidil, oral contraceptives, penicillamine, phenytoin (diphenylhydantoin), procainamide, propylthiouracil, quinidine, and testosterone. 

Interpretation In normal subjects, serum cortisol concentration is suppressed to 2 pg/dL or less after administration of 1 mg of dexamethasone. Most patients with Cushing s syndrome do not show adequate suppression, and 0800 hours cortisol concentrations are usually >10pg/dL. Serum cortisol >2pg/dL may also be seen in cases of stress, obesity, infection, acute or chronic illness, alcohol abuse, severe depression, oral contraceptive use, pregnancy, estrogen therapy, failure to take the dexamethasone, or treatment with phenytoin or phenobarbital (enhancement of dexamethasone metabolism). 

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