The most common adverse events reported by 9 to 22% of women using ORTHO EVRA® in clinical trials (N= 3,330) were the following, in order of decreasing incidence: breast symptoms, headache, application site reaction, nausea, upper respiratory infection, menstrual cramps, and abdominal pain.

The most frequent adverse events leading to discontinuation in 1 to 2.4% of women using ORTHO EVRA® in the trials included the following: nausea and/or vomiting, application site reaction, breast symptoms, headache, and emotional lability.

Listed below are adverse events that have been associated with the use of combination hormonal contraceptives. These are also likely to apply to combination transdermal hormonal contraceptives such as ORTHO EVRA®.

An increased risk of the following serious adverse reactions has been associated with the use of combination hormonal contraceptives (see WARNINGS Section).

• Thrombophlebitis and venous thrombosis with or without embolism
• 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 combination hormonal contraceptives:

• Mesenteric thrombosis
• Retinal thrombosis

The following adverse reactions have been reported in users of combination hormonal 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
• Melasma which may persist
• Breast changes: tenderness, enlargement, secretion
• Change in weight (increase or decrease)
• Change in cervical erosion and secretion
• Diminution in lactation when given immediately postpartum
• Cholestatic jaundice
• Migraine
• Rash (allergic)
• Mental depression
• Reduced tolerance to carbohydrates
• Vaginal candidiasis
• Change in corneal curvature (steepening)
• Intolerance to contact lenses

The following adverse reactions have been reported in users of combination hormonal contraceptives and a cause and effect association has been neither confirmed nor refuted:

• Pre-menstrual syndrome
• Cataracts
• Changes in appetite
• Cystitis-like syndrome
• Headache
• Nervousness
• Dizziness
• Hirsutism
• Loss of scalp hair
• Erythema multiforme
• Erythema nodosum
• Hemorrhagic eruption
• Vaginitis
• Porphyria
• Impaired renal function
• Hemolytic uremic syndrome
• Acne
• Changes in libido
• Colitis
• Budd-Chiari Syndrome

Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Drugs

Contraceptive effectiveness may be reduced when hormonal contraceptives are co-administered with some antibiotics, antifungals, anticonvulsants, and other drugs that increase metabolism of contraceptive steroids. This could result in unintended pregnancy or breakthrough bleeding. Examples include barbiturates, griseofulvin, rifampin, phenylbutazone, phenytoin, carbamazepine, felbamate, oxcarbazepine, topiramate and possibly with ampicillin.

The proposed mechanism of interaction of antibiotics is different from that of liver enzyme-inducing drugs. Literature suggests possible interactions with the concomitant use of hormonal contraceptives and ampicillin or tetracycline. In a pharmacokinetic drug interaction study, oral administration of tetracycline HCl, 500 mg q.i.d. for 3 days prior to and 7 days during wear of ORTHO EVRA® did not significantly affect the pharmacokinetics of norelgestromin or EE.

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 mean AUC of the estrogen and progestin have been noted in some cases. The efficacy and safety of oral contraceptive products may be affected; it is unknown whether this applies to ORTHO EVRA®. Healthcare professionals should refer to the label of the individual anti-HIV protease inhibitors for further drug-drug interaction information.

Herbal products containing St.John'sWort (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 Hormone Levels Associated With Co-Administered Drugs

Co-administration of atorvastatin and certain 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 cyclosporine, prednisolone, and theophylline have been reported with concomitant administration of oral contraceptives. In addition, oral contraceptives may induce the conjugation of other compounds. Decreased plasma concentrations of acetaminophen and increased clearance of temazepam, salicylic acid, morphine and clofibric acid have been noted when these drugs were administered with oral contraceptives.

Although norelgestromin and its metabolites inhibit a variety of P450 enzymes in human liver microsomes, the clinical consequence of such an interaction on the levels of other concomitant medications is likely to be insignificant. Under the recommended dosing regimen, the in vivo concentrations of norelgestromin and its metabolites, even at the peak serum levels, are relatively low compared to the inhibitory constant (Ki) (based on results of in vitro studies).

Health care professionals are advised to also refer to prescribing information of co-administered drugs for recommendations regarding management of concomitant therapy.

Interactions With Laboratory Tests

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

a. Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.

b. 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.

c. Other binding proteins may be elevated in serum.

d. Sex hormone binding globulins are increased and result in elevated levels of total circulating endogenous sex steroids and corticoids; however, free or biologically active levels either decrease or remain unchanged.

e. Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.

f. Glucose tolerance may be decreased.

g. Serum folate levels may be depressed by hormonal contraceptive therapy. This may be of clinical significance if a woman becomes pregnant shortly after discontinuing ORTHO EVRA®.

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