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An increased risk of the following serious adverse reactions has been associated with the use of oral contraceptives (see WARNINGS section):

• Thrombophlebitis
• Arterial thromboembolism
• Pulmonary embolism
• Myocardial infarction
• Cerebral hemorrhage
• Cerebral thrombosis
• Hypertension
• Gallbladder disease
• Hepatic adenomas or benign liver tumors

There is evidence of an association between the following conditions and the use of oral contraceptives:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported in patients receiving oral contraceptives and are believed to be drug related:

• Nausea
• Vomiting
• Gastrointestinal symptoms (such as abdominal cramps and bloating)
• Breakthrough bleeding
• Spotting
• Change in menstrual flow
• Amenorrhea
• Temporary infertility after discontinuation of treatment
• Edema/fluid retention
• Melasma/chloasma which may persist
• Breast changes: tenderness, enlargement, and secretion
• Change in weight or appetite (increase or decrease)
• Change in cervical ectropion and secretion
• Possible diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine headache
• Rash (allergic)
• Mood changes, including depression
• Vaginitis, including candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses
• Decrease in serum folate levels
• Exacerbation of systemic lupus erythematosus
• Exacerbation of porphyria
• Exacerbation of chorea
• Aggravation of varicose veins
• Anaphylactic/anaphylactoid reactions, including urticaria, angioedema, and severe reactions with respiratory and circulatory symptoms

The following adverse reactions have been reported in users of oral contraceptives and the association has been neither confirmed nor refuted:

• Premenstrual syndrome
• Cataracts
• Optic neuritis which may lead to partial or complete loss of vision
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Impaired renal function
• Hemolytic uremic syndrome
• Budd-Chiari syndrome
• Acne
• Changes in libido
• Colitis
• Pancreatitis
• Dysmenorrhea

Changes in contraceptive effectiveness associated with co-administration of other products

Anti-infective agents and anticonvulsants

Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with antibiotics, anticonvulsants, and other drugs that increase the metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include rifampin, barbiturates, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate, and griseofulvin. Several cases of contraceptive failure and breakthrough bleeding have been reported in the literature with concomitant administration of antibiotics such as ampicillin and tetracyclines. However, clinical pharmacology studies investigating drug interaction between combined oral contraceptives and these antibiotics have reported inconsistent results.

Anti-HIV protease inhibitors

Several of the anti-HIV protease inhibitors have been studied with co-administration of oral combination hormonal contraceptives; significant changes (increase and decrease) in the plasma levels of the estrogen and progestin have been noted in some cases. The safety and efficacy of combination oral contraceptive products may be affected with co-administration of anti-HIV protease inhibitors. Healthcare providers should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products

Herbal products containing St. John's Wort (hypericum perforatum) may induce hepatic enzymes (cytochrome P450) and p-glycoprotein transporter and may reduce the effectiveness of contraceptive steroids. This may also result in breakthrough bleeding.

Increase in plasma levels of estradiol associated with co-administered drugs

Co-administration of atorvastatin and certain combination oral contraceptives containing ethinyl estradiol increase AUC values for ethinyl estradiol by approximately 20%. Ascorbic acid and acetaminophen may increase plasma ethinyl estradiol levels, possibly by inhibition of conjugation. CYP 3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone levels.

Changes in plasma levels of co-administered drugs

Combination hormonal contraceptives containing some synthetic estrogens (e.g., ethinyl estradiol) may inhibit the metabolism of other compounds. Increased plasma concentrations of cyclosporin, prednisolone, and theophylline have been reported with concomitant administration of combination oral contraceptives. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid, due to induction of conjugation have been noted when these drugs were administered with combination oral contraceptives.

Interactions with Laboratory Tests

Certain endocrine and liver function tests and blood components may be affected by oral contraceptives:

1. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
2. Increased thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 by column or by radioimmunoassay. Free T3 resin uptake is decreased, reflecting the elevated TBG, free T4 concentration is unaltered.
3. Other binding proteins may be elevated in serum.
4. Sex hormone binding globulins are increased and result in elevated levels of total circulating sex steroids and corticoids; however, free or biologically active levels remain unchanged.
5. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
6. Glucose tolerance may be decreased.
7. Serum folate levels may be depressed by oral contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing oral contraceptives.

Last reviewed on RxList: 11/18/2008
This monograph has been modified to include the generic and brand name in many instances.