The most common adverse reactions reported during clinical trials (≥2%) were: Norgestimate and ethinyl estradiol tablets: headache/migraine, breast issues (including breast pain, enlargement, and discharge), vaginal infection, abdominal/gastrointestinal pain, mood disorders (including mood alteration and depression), genital discharge, changes in weight (including weight increased or decreased). ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
The following serious adverse reactions with the use of COCs are discussed elsewhere in labeling:
- Serious cardiovascular events and stroke [see BOXED WARNING AND WARNINGS AND PRECAUTIONS ( 5.1 )]
- Vascular events [see WARNINGS AND PRECAUTIONS ( 5.1 )]
- Liver disease [see WARNINGS AND PRECAUTIONS ( 5.2 )]
6.1Clinical Trial 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 clinical practice. The safety of norgestimate and ethinyl estradiol tablets was evaluated in 4,826 healthy women of child-bearing potential who participated in 6 clinical trials and received at least 1 dose of norgestimate and ethinyl estradiol tablets for contraception.
Two trials were randomized active-controlled trials and 4 were uncontrolled open-label trials. In 3 trials, subjects were followed for up to 24 cycles; in 2 trials, subjects were followed for up to 12 cycles; and in 1 trial, subjects were followed for up to 6 cycles. Common Adverse Reactions (≥ 2% of subjects) The most common adverse reactions reported by at least 2% of the 4,826 women were the following in order of decreasing incidence: headache/migraine (33.6%), breast issues (including breast pain, enlargement, and discharge) (8.0%), vaginal infection (7.1%), abdominal/gastrointestinal pain (5.6%), mood disorders (including mood alteration and depression) (3.8%), genital discharge (3.2%), and changes in weight (including weight fluctuation, increased or decreased) (2.5%).
Adverse Reactions Leading to Study Discontinuation Over the trials, between 9 to 27% of subjects discontinued the trial due to an adverse reaction. The most common adverse reactions (≥1%) leading to discontinuation were: metrorrhagia (4.3%), nausea/vomiting (2.8%), headache/migraine (2.4%), mood disorders (including depression and mood altered) (1.1%), and weight increased (1.1%). Serious Adverse Reactions Breast cancer (1 subject), carcinoma of the cervix in situ (1 subject), hypertension (1 subject), and migraine (2 subjects).
6.2Postmarketing Experience
Five studies that compared breast cancer risk between ever-users (current or past use) of COCs and never-users of COCs reported no association between ever use of COCs and breast cancer risk, with effect estimates ranging from 0.90 - 1.12 (Figure 1). Three studies compared breast cancer risk between current or recent COC users (<6 months since last use) and never users of COCs (Figure 1). One of these studies reported no association between breast cancer risk and COC use.
The other two studies found an increased relative risk of 1.19 - 1.33 with current or recent use. Both of these studies found an increased risk of breast cancer with current use of longer duration, with relative risks ranging from 1.03 with less than one year of COC use to approximately 1.4 with more than 8-10 years of COC use. Figure 1: Relevant Studies of Risk of Breast Cancer with Combined Oral Contraceptives RR = relative risk; OR = odds ratio; HR = hazard ratio. "ever COC" are females with current or past COC use; "never COC use" are females that never used COCs.
The following additional adverse reactions have been reported from worldwide postmarketing experience with norgestimate/ethinyl estradiol. 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. Infections and Infestations Urinary tract infection; Neoplasms Benign, Malignant and Unspecified (Incl.
Cysts and Polyps) Breast cancer, benign breast neoplasm, hepatic adenoma, focal nodular hyperplasia, breast cyst; Immune System Disorders Anaphylactic reaction, Hypersensitivity; Metabolism and Nutrition Disorders Dyslipidemia; Psychiatric Disorders Anxiety, insomnia; Nervous System Disorders Syncope, convulsion, paresthesia, dizziness; Eye Disorders Visual impairment, dry eye, contact lens intolerance; Ear and Labyrinth Disorders Vertigo; Cardiac Disorders Tachycardia, palpitations; Vascular Events Deep vein thrombosis, pulmonary embolism, retinal vascular thrombosis, hot flush, venous thrombosis (including Budd Chiari Syndrome and hepatic vein thrombosis); Arterial Events Arterial thromboembolism, myocardial infarction, cerebrovascular accident; Respiratory, Thoracic and Mediastinal Disorders Dyspnea; Gastrointestinal Disorders Pancreatitis, abdominal distension, diarrhea, constipation; Hepatobiliary Disorders Hepatitis; Skin and Subcutaneous Tissue Disorders Angioedema, erythema nodosum, hirsutism, night sweats, hyperhidrosis, photosensitivity reaction, urticaria, pruritus, acne; Musculoskeletal, Connective Tissue, and Bone Disorders Muscle spasms, pain in extremity, myalgia, back pain; Reproductive System and Breast Disorders Ovarian cyst, suppressed lactation, vulvovaginal dryness; General Disorders and Administration Site Conditions Chest pain, asthenic conditions.
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