"The U.S. Food and Drug Administration today announced that it has approved an amended application submitted by Teva Women's Health, Inc. to market Plan B One-Step (active ingredient levonorgestrel) for use without a prescription by women 15 years"...
The following serious adverse reactions with the use of combination hormonal contraceptives, including ORTHO EVRA®, are discussed elsewhere in the labeling:
- Serious cardiovascular events and smoking (see WARNINGS)
- Vascular events, including venous and arterial thromboembolic events (see WARNINGS)
- Liver disease (see WARNINGS and PRECAUTIONS)
Adverse reactions commonly reported by users of combination hormonal contraceptives are:
- Irregular uterine bleeding
- Breast tenderness
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The data described below reflect exposure to ORTHO EVRA® in 3330 sexually active women (3322 of whom had safety data) who participated in three Phase 3 clinical trials designed to evaluate contraceptive efficacy and safety. These subjects received six or 13 cycles of contraception (ORTHO EVRA® or an oral contraceptive comparator in 2 of the trials). The women ranged in age from 18 to 45 years and were predominantly white (91%).
The most common adverse reactions reported during clinical trials were breast symptoms, headache, application site disorder, nausea, dysmenorrhea and abdominal pain. The most common events leading to discontinuation were application site reaction, breast symptoms (including breast discomfort, engorgement and pain), nausea and/or vomiting, headache and emotional lability.
Adverse drug reactions reported by ≥2.5% of ORTHO EVRA®-treated subjects in these trials are shown in Table 7.
Table 7: Adverse Drug Reactions Reported by ≥ 2.5%
of ORTHO EVRA®-treated
Subjects in Three Phase 3 Clinical Trials
|System/Organ Class* Adverse reaction||ORTHO EVRA®
|Reproductive system and breast disorders|
|Vaginal bleeding and menstrual disorders†||6.4%|
|Nervous system disorders|
|General disorders and administration site conditions|
|Application site disorder†||17.1%|
|Mood, affect and anxiety disorders†||6.3%|
|Skin and subcutaneous tissue disorders|
|Infections and infestations|
|Vaginal yeast infection†||3.9%|
|* MedDRA version 10.0
† Represents a bundle of similar terms
Additional adverse drug reactions that occurred in < 2.5 % of ORTHO EVRA® treated subjects in the above clinical trials datasets are:
Gastrointestinal disorders: Abdominal distension
General disorders and administration site conditions: Fluid retention1, malaise
Hepatobiliary disorders: Cholecystitis
Investigations: Blood pressure increased, lipid disorders1
Musculoskeletal and connective tissue disorders: Muscle spasms
Psychiatric disorders: Insomnia, libido decreased, libido increased
Respiratory, thoracic and mediastinal disorders: Pulmonary embolism
Skin and subcutaneous tissue disorders: Chloasma, dermatitis contact, erythema, skin irritation
1Represents a bundle of similar terms
The following adverse reactions (Table 8) have been identified during postapproval use of ORTHO EVRA®. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Table 8: Alphabetical List of Adverse Drug Reactions
Identified During Postmarketing Experience with ORTHO EVRA®/EVRA® by System Organ Class*
|System Organ Class||Adverse Drug Reactions|
|Cardiac disorders||Myocardial infarction†|
|Endocrine disorders||Hyperglycemia, insulin resistance|
|Eye disorders||Contact lens intolerance or complication|
|General disorders and administration site conditions||Application site reaction†, edema†|
|Hepatobiliary disorders||Blood cholesterol abnormal, cholelithiasis, cholestasis, hepatic lesion, jaundice cholestatic, low density lipoprotein increased|
|Immune system disorders||Allergic reaction†, urticaria|
|Investigations||Blood glucose abnormal, blood glucose decreased|
|Metabolism and nutrition disorders||Increased appetite|
|Neoplasms benign, malignant and unspecified (Incl cysts and polyps)||Breast cancer†, cervix carcinoma, hepatic adenoma, hepatic neoplasm|
|Nervous system disorders||Dysgeusia, migraine with aura|
|Psychiatric disorders||Anger, emotional disorder, frustration, irritability|
|Reproductive system and breast disorders||Breast mass, cervical dysplasia, fibroadenoma of breast, menstrual disorder†, suppressed lactation, uterine leiomyoma|
|Skin and subcutaneous tissues disorders||Alopecia, eczema, erythema multiforme, erythema nodosum, photosensitivity reaction, pruritus generalized, rash†, seborrheic dermatitis, skin reaction|
|Vascular disorders||Arterial thrombosis†, cerebrovascular accident†, deep vein thrombosis†, hemorrhage intracranial†, hypertension, hypertensive crisis, pulmonary embolism†, thrombosis†|
|* MedDRA version 10.0
† Represents a bundle of similar terms
Read the Ortho Evra (norelgestromin, ethinyl estradiol transdermal) Side Effects Center for a complete guide to possible side effects »
Changes in Contraceptive Effectiveness Associated With Co-Administration of Other Drugs
If a woman on hormonal contraceptives takes a drug or herbal product that induces enzymes, including CYP3A4, that metabolize contraceptive hormones, counsel her to use additional contraception or a different method of contraception. Drugs or herbal products that induce such enzymes may decrease the plasma concentrations of contraceptive hormones, and may decrease the effectiveness of hormonal contraceptives or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include:
- St. John's wort
HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors: Significant changes (increase or decrease) in the plasma levels of the estrogen and progestin have been noted in some cases of co-administration of HIV protease inhibitors and non-nucleoside reverse transcriptase inhibitors.
Antibiotics: There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. 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.
Consult the labeling of the concurrently-used drug to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Increase in Plasma Hormone Levels Associated With Co-Administered Drugs
Some drugs and grapefruit juice may increase the plasma levels of ethinyl estradiol if co-administered. Examples include:
- ascorbic acid
- CYP3A4 inhibitors (including itraconazole, ketoconazole, voriconazole, fluconazole and grapefruit juice)
- HMG-CoA reductase inhibitors (including atorvastatin and rosuvastatin)
Changes in Plasma Levels of Co-Administered Drugs
Data from oral combination hormonal contraceptives indicate that they may also affect the pharmacokinetics of some other drugs if used concomitantly.
Examples of drugs whose plasma levels may be increased (due to CYP inhibition) include:
Examples of drugs whose plasma levels may be decreased (due to induction of glucuronidation) include:
Combined hormonal contraceptives have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary.
Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations.
Interactions with Laboratory Tests
Certain endocrine and liver function tests and blood components may be affected by hormonal contraceptives:
- Increased prothrombin and factors VII, VIII, IX, and X; decreased antithrombin 3; increased norepinephrine-induced platelet aggregability.
- 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.
- Other binding proteins may be elevated in serum.
- 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.
- Triglycerides may be increased and levels of various other lipids and lipoproteins may be affected.
- Glucose tolerance may be decreased.
- 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®.
Last reviewed on RxList: 10/10/2012
This monograph has been modified to include the generic and brand name in many instances.
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