The effectiveness of oral contraceptives (OC) can be reduced to produce a contraceptive failure when administered with drugs that increase the metabolism of the active ingredients it contains. Examples are rifampicin, rifabutin, barbiturates, primidone, phenylbutazone, phenytoin, dexamethasone, carbamazepine, felbamate, oxcarbazepine, topiramate, griseofulvin and modafinil. In these cases, in general, it is preferable to use a non-hormonal contraceptive method.

The most widely used active ingredient as estrogen in oral contraceptives is ethinyl estradiol. Most contraceptive failures are probably related to interactions of this estrogen. The substrate undergoes binding intestinal sulfates, hydroxylation and conjugation with glucuronic acid in the liver and is recirculated in the enterohepatic cycle. The progestin only undergo metabolism in the liver.

Ethinyl estradiol may inhibit several isoenzymes (CYP2C19, CYP3A4, CYP2B6 and possibly others), which would explain the numerous observations of drug interactions that are involved in oral contraceptives. Numerous studies indicate that ethinyl estradiol is extensively metabolized in the intestine and liver, being the most important step hydroxylation by CYP3A4. Therefore, inducers of this isoenzyme, such as rifampin or rifabutin, may produce a contraceptive failure, by reducing plasma levels of the hormone by increased metabolism. In contrast, inhibitors of this isoenzyme may raise the level of ethinyl estradiol in plasma.

Oral contraceptives inhibit the metabolism of many drugs and can increase its plasma concentration, but only in some cases have reached clinical significance, as in the case of benzodiazepines.

There have been a number of observations about contraceptive failure in relation to taking antibiotics, especially for penicillins, but also with other antibiotics. However, in general, the studies to determine interactions between oral contraceptives and antibiotics have not led to conclusive results.

Amoxicillin

Several studies agree in attributing a decrease of contraceptive effect to amoxicillin. This interaction does not have a mechanism known as it failed to identify the antibiotic pharmacokinetic influence on oral contraceptives. For many authors, the action of amoxicillin is controversial since the pregnancy rate is similar in patients taking and those not taking the antibiotic (1%).

Is is recommended to use an additional contraceptive method when a patient receiving oral contraceptives should take amoxicillin.

Other antibiotics

A review of the possible interactions between OCs and antibiotics showed three categories: At first, including rifampin and, perhaps, rifabutin, the antibiotic would reduce estrogen levels by inducing its metabolism by CYP3A4. The second category would include those antibiotics which have been reported more contraceptive failures (ampicillin, amoxicillin, metronidazole and tetracycline) and the latter category includes drugs with at least one case of contraceptive failure (cephalexin, clindamycin, dapsone, erythromycin, griseofulvin, isoniazid, penicillin V, telampicillin and trimethoprim).

The elevation of the plasma concentration of ethinyl estradiol during treatment with cotrimoxazole is attributable to inhibition of metabolism of estrogen, as with other drugs. However, short-term treatment with cotrimoxazole is not likely to negatively affect contraceptive treatment.

Contraceptive failure by antibiotics include absorption failures provoking diarrhea, impaired intestinal bacterial flora and enterohepatic recycling decrease of estrogenic metabolites. It is not known why the progesterone-based contraceptives alone may fail, but is considered likely not related to drug interactions. Alteration of the intestinal flora can be produced by penicillins, cephalosporins, tetracyclines, sulfonamides, neomycin and erythromycin.

Since the second half of the 70 have been reported almost a hundred cases of cholestatic syndromes with jaundice, pruritus and elevated serum enzymes induced by coadministration of oral contraceptives and TAO. A few days after starting treatment with antibiotics, patients show clinical symptoms, usually mild to moderate sagging in about 4 weeks after removal of the TAO, the mechanism of this interaction has not been established.

OC administration along with the anticoagulant warfarin or acenocoumarol produces INR decreased by an increase in conjugation with glucuronic acid and subsequent increase in anticoagulant elimination.

The recommended action is to adjust the INR within the therapeutic range, in addition to using an alternative contraceptive method.

Several anticonvulsant drugs, including phenobarbital, phenytoin, carbamazepine, oxcarbazepine, felbamate and topiramate have been shown to increase the metabolism of ethinyl estradiol and progestin. Many experts believe that if a woman taking AEDs want take oral contraceptives, should do so with a specialty having at least 50 mcg of ethinyl estradiol.

Phenytoin

This medicine is the anticonvulsant of which have been published more observations of contraceptive failure. Both ethinyl estradiol and levonorgestrel experience a decrease in their plasma concentration in stationary phase due to the effect of phenytoin.

This substance, like rifampin, increases the concentration of sex hormone binding globulin (SHBG), which reduces the fraction of free hormone in plasma in the case of certain progestogens, thereby increasing the probability of failure of hormonal contraceptive treatments combined.

Oxcarbazepine

This anticonvulsant drug decreases the AUC, peak concentration and elimination half-life of both ethinyl estradiol and levonorgestrel almost 47% compared to placebo. It also decreases the mean serum concentration of both substances. The likely mechanism is hepatic metabolic stimulation and / or intestinal CYP3A.

Some authors recommend the use of high-dose contraceptives and monitor the level of hormones in patients undergoing prolonged treatment with oxcarbazepine.

Lamotrigine

Concurrent administration of oral contraceptives and lamotrigine causes a decrease in the concentration of the anticonvulsant, being the average decrease in Cmax of 39% and 52% for AUC (0-24 h). The interaction also affects levonorgestrel, whose plasma concentration decreases slightly, but not statistically significant nor clinically relevant.

The likely mechanism is an enzyme induction of UDP-glucuronyltransferase system, which would favor the metabolism of lamotrigine.

In the case of administration of this medication with oral contraceptives, it is necessary to adjust the dose of lamotrigine.

Carbamazepine

A similar result occurs when co-administered with carbamazepine, a metabolic inducer of oral contraceptives. The hormone levels can drop to sub-therapeutic concentrations, which may result in contraceptive failure.

Primidone

Concurrent use with contraceptives may decrease the effect of the hormonl pill, due to induction of liver enzymes by primidone, as with other antiepileptic drugs. It is advisable to use a non-hormonal or progestin-based contraceptive.

Barbiturates

Phenobarbital and other similar compounds induce metabolism of ethinylestradiol, decreasing its contraceptive effect.

A study carried out in five women treated with phenobarbital long and oral contraceptives showed a plasma concentration of ethinyl estradiol in the lower limit of the therapeutic range in these patients. Monitoring during two menstrual cycles with phenobarbital and contraceptive, two patients showed a significant decrease in plasma ethinylestradiol with elevated protein bound fraction. It is advisable an alternative contraceptive method.

Estrogens inhibit the metabolism of cyclosporine, increasing its plasma concentration as well as the risk of toxicity for liver and kidney.

Observations have been reported cases of hepatitis in patients treated concurrently with cyclosporine and oral contraceptives. It is recommended to use an alternative contraceptive method.

It is not advisable the combined use of cyclosporine and oral contraceptives. If so, the physician should monitor closely the level of cyclosporine in blood and liver and kidney functions.

This interaction includes prednisolone, methylprednisolone, prednisone and budesonide. Indeed it is a group effect consisting of an increase in concentration of the corticosteroid and its pharmacological action, which lacks clinical significance. Possibly due to inhibition of metabolism of corticosteroids by contraceptive or a change in protein binding.

It is recommended to monitor clinical response to corticosteroid and adjust the dose of this if deemed necessary.

The simultaneous use of ACTH may potentiate the anti-inflammatory effect of endogenous cortisol stimulated by ACTH.

Vitamin B6 requirements are higher in patients receiving oral contraceptives. Subclinical deficiencies of other vitamins have been linked to contraceptives prior to 1974, when the pills low in estrogen were introduced, although in general the oral contraceptives can cause certain nutritional deficiencies, especially folic acid, vitamins B2, B6 and B12.

Vitamin B12

Taking of contraceptives and vitamin B_{12 produces a plasmatic reduction of the vitamin. The mechanism of production has not been established, but the interaction lacks clinical significance. For some authors, it would be rather a redistribution of serum protein binding that an actual decrease, which would not justify prophylactic treatment.}

It seems prudent to monitor levels of folate or vitamin B12 occasionally.

Vitamin C

Co-administration of contraceptives with high-dose of ascorbic acid may increase plasma concentrations of the hormone preparation, by decreasing its metabolism, although more recent studies seem to rule out such an interaction. It seems advisable to reduce the dose of vitamin C to a maximum of 100 mg/day.

Calcium supplements

Estrogens increase calcium absorption and may exacerbate pre-existing renal lithiasis in certain susceptible patients.

Griseofulvin

Concomitant use of griseofulvin may decrease the effectiveness of contraceptive, probably because of enzyme induction, which decreases serum hormone preparation. This may lead to breakthrough bleeding, amenorrhea, or pregnancy. In these patients is recommended an alternative contraceptive method for one month after stopping treatment with griseofulvin.

Ketoconazole

Co-administration of this substance increases by at least 150% of the AUC of ccontraceptive.

Women taking OCs are more sensitive to the psychomotor effects of benzodiazepines.

Plasma concentration of diazepam and other benzodiazepines is raised by contraceptive steroids. The effect of these tranquilizers depends of the metabolism of each compound, either the case of oxidation or nitro reduction. Chlordiazepoxide, alprazolam, diazepam and nitrazepam have decreased clearance while taking the pill.

A study in healthy volunteers with chlordiazepoxide, showed a more prolonged elimination half life and reduced plasma protein binding. However, these data did not reach statistical significance. There have been cases of contraceptive failure, but breakthrough bleeding or spotting is common with chlordiazepoxide.

The apparent elimination half-life of diazepam is significantly longer and clearance of tranquilizers significantly lower in patients taking OCs. The consequence of the interaction with diazepam is a possible alteration of motor and cognitive performance. In contrast, other substances such as lorazepam and oxazepam, to undergo a process of conjugation, suffer no interference with the OCs.

OCs increase the risk of hypertension, but essentially do not interact with most antihypertensive drugs.

Estrogens are the most important group of drugs that can induce hypertension. Some studies report a high incidence of this disease prior to treatment of 1%, a figure that doubles after 5 years of treatment with OCs. The contraceptive discontinuation returns blood pressure to previous values??.

Beta-blockers

In patients receiving low-dose contraceptive containing ethinyl estradiol, are observed higher values of AUC and Cmax when co-administered metoprolol, oxprenolol and propranolol, although only the first shows significant differences. Inversely behaves acebutolol, although without statistically significant values.

Guanethidine

OCs appear to decrease the effect of guanethidine. It is recommended in such cases frequently monitor patient's BP.

Progestogens can increase insulin resistance, which can force to readapt prior antidiabetic treatment. In general, contraceptives may decrease the effects of insulin and oral antidiabetic.

Troglitazone

Concomitant administration of troglitazone with an OCs combined (estrogen + progestin) reduces the plasma concentration of these hormones by 30%, which could reduce contraceptive efficacy. Can be considered to increase the dose of the OCs or use an alternative method.

Both ritonavir and nelfinavir are metabolic inducers of hormonal steroids.

In the case of progestins, significant changes were observed of plasma levels in some cases from coadministration with protease inhibitors or reverse transcriptase inhibitors.

Ritonavir reduces by 40% AUC of ethinylestradiol and also the elimination half-life. A similar result was seen both with other estrogens as other protease inhibitors.

Changes in the pharmacokinetics of ethinyl estradiol are compatible with clearance elevation caused by enzyme induction due to hydroxylation or conjugation of estrogen.

It is advisable to switch to an alternative contraceptive method when administered ritonavir. A similar case happens with darunavir and also is preferable to use an alternative contraception method.

Imipramin

Possible increased toxicity of l antidepressant. It is advisable to switch to an alternative contraceptive method.

MAOIs

Concomitant use of selegiline with oral contraceptives causes a dramatic increase in the bioavailability of antidepressant, to at least 20 times its usual value.

The mechanism of this interaction is the inhibition of demethylation of selegiline. Avoid use of sex steroids together with selegiline or significantly reduce the dose of this.

Hypericum or St. John's wort

Drugs or herbal products containing St. John's wort are CYP450 enzyme and P-glycoprotein inducers , so can reduce the effectiveness of birth control. In some cases can lead to bleeding similar to that produced at the end of cycle control. It is advisable to use an alternative contraceptive method or change by another antidepressant.

Carisoprodol

Contraceptive use increases carisoprodol AUC by 60%. It is recommended to monitor the response of patients to carisoprodol.

Paracetamol

Acetaminophen increased the blood concentration of ethinyl estradiol in a competitive manner during the sulfation process of both substances. This interaction may have clinical significance when the patient takes on a regular basis whether high doses of paracetamol or ethinylestradiol.

On the other hand, patients treated with ACO have a half-life of paracetamol lowest for women who do not receive (2.12 vs 2.71 hours, P <0.005). so that the clearance of paracetamol is greater.

Acetyl salicylic acid

The AUC and plasma half-life of aspirin and salicylate was significantly lower in patients receiving OCs compared to controls.

Dipyrone

Ethinyl estradiol at a dose of 0.05 mg, both alone and in combination with levonorgestrel, slows down the removal metamizol metabolites.

Narcotics

The pill increases clearance of morphine.

The interaction of the OCs with meperidine, cited in an article by Stambaugh and Wainer is controversial, since it is supported by documentation poorly demonstrative. Probably the risk to patients is low and reactions are unlikely.

Alcohol

As in the case of caffeine and theophylline, ethyl alcohol is removed more slowly in patients taking contraceptives. The patient should be warned of this possibility.

Antacids, intestinal adsorbents and antiulcer medicines

Norethisterone acetate, which is part of many commercial specialty of OCs, in the presence of certain gastrointestinal adsorbents or peptic ulcer drugs, suffers a decrease in solubility, so it is not advisable to associate when taking contraceptives.

Atorvastatin

Coadministration of atorvastatin with norethindrone and ethinyl estradiol increases the AUC of both substances 30 and 20% respectively. Some authors recommend in these cases, a low-dose OCs.

Bromocriptine

Estrogens may interfere with the therapeutic effects of bromocriptine. It is recommended to adjust the dose of this drug.

Caffeine

Some data suggest that contraceptive therapy can reduce by 40% the plasma clearance of caffeine. OCs may inhibit the enzyme system that degrades this substance and that drinking three or four cups of coffee a day could lead to accumulation of caffeine in women who are being treated with OCs.

Other observations indicate that taking 0.125 mg of levonorgestrel per day for two weeks reduced slightly the metabolism of caffeine. However, chronic administration (more than 3 months) of OCs with low estrogen dose (less than 50 mcg) in healthy volunteers produced a half-life of caffeine greater than 50% compared to controls as a result of altered clearance of this substance. The peak concentration was also increased in the consumers of caffeine, probably through the CYP448 isoenzyme.

OCs also seem to alter the effects of caffeine on nocturnal melatonin levels.

Clonidine and apomorphine

In normal women induced sedation by IV administration of clonidine was higher after treatment with OCs continued for 3 weeks. However, the response to dopamine agonist apomorphine was lower in the group receiving OCs. These results suggest that estrogen modifies the sensitivity of adrenergic and dopaminergic receptors. These interactions may explain the mood changes of patients receiving estrogens.

Chlorpromazine

Contraceptives increase the plasma concentration of chlorpromazine, which may result in extrapyramidal symptoms (dyskinesia, tremor). An observation found chlorpromazine concentration twenty times higher than expected.

Factor VIII/Factor V leiden

There is an increased risk of deep venous thrombosis in patients with elevated factor VIII or factor V Leiden. These anomalies alone are not thrombogenic, but are thrombogenic associated with other risk factors, such as OCs.

Levothyroxine

It is believed that estrogens may produce changes in the peripheral effects of thyroid hormone, particularly in the amount of thyroxine binding protein, which might produce a compensatory thyroid hyperplasia. If there is a trend to hypothyroidism, it is advisable to consider an adjustment of doses of levothyroxine.

Pancreatitis-inducing drugs

Although physiological doses of estrogen do not cause pancreatitis, those patients taking concomitant medications that induce this disorder should use ACO with many precautions, especially if there are factors that predispose to this disease, as hypertriglyceridemia.

Metronidazole and disulfiram

Metronidazole may delay the elimination of the OCs and, perhaps, increase the potential adverse effects of these substances. This would also be the case of interaction with disulfiram.

Naratriptan

It has been published an observation of a patient who received treatment with OCs and received a dose of migraine abortive medication developing ischemic colitis. Although no causal relationship has been established, the author notes that probably the concomitant use of these medications is not advisable.

Hepatotoxic risk substances

Concurrent use of dantrolene, isoniazid or cyclosporine with OCs may increase the risk of liver toxicity. With the first two drugs severe hepatitis have occurred, especially in women over 35 years or patients with prior history of liver disease.

Smoke

Pharmacodynamic interactions with smoke are particularly significant with combined OCs. Using ACO of any kind in women over age 35 or who smoke more than 15 cigarettes a day is considered contraindicated because of the alarming increase in the risk of severe cardiovascular complications.

There is a relationship between the use of ACO high in estrogen, smoking and increased risk of cardiovascular adverse events, including stroke, thrombophlebitis and pulmonary embolism. This risk increases with age, especially after age 35, and with the degree of tobacco consumption, particularly from 15 cigarettes a day.

The metabolism of estrogens may increase with the consumption of cigarettes, which promotes contraceptive failure.

Theophylline

Oral contraceptives decrease theophylline clearance by an average of 30%.

The clearance of ethinylestradiol registered a decrease of around 30%. It recomedable reduce theophylline dose and monitor blood level.

Tizanidine

OCs containing ethinyl estradiol and gestodene cause increase of plasmatic concentrations and clinical effects of tizanidine .

The probable mechanism of this interaction is the inhibition of CYP1A2 by the contraceptive. It is advisable to closely monitor patients undergoing treatment with OCs when tizanidine are prescribed.