Estradiolside effects

The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders Malignant Neoplasms The most common adverse reactions (≥10%) with DOTTI are: headache, breast tenderness, nasopharyngitis, sinusitis, sinus headache, upper respiratory tract infection, back pain, depression, and irregular vaginal bleeding or spotting. To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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. There were no clinical trials conducted with DOTTI. DOTTI is bioequivalent to the original formulation of estradiol transdermal system. The following adverse reactions have been reported with the original formulation of estradiol transdermal system therapy: Table 1. Summary of Most Frequently Reported Adverse Reactions Regardless of Relationship Reported at a Frequency ≥5 Percent Estradiol 0.025 mg/day † (N=47) N (%) Estradiol 0.0375 mg/day † (N=130) N (%) Estradiol 0.05 mg/day † (N=103) N (%) Estradiol 0.075 mg/day † (N=46) N (%) Estradiol 0.1 mg/day † (N=132) N (%) Placebo (N=157) N (%) Gastrointestinal disorders Constipation 2 5 4 3 2 4 Dyspepsia 4 12 3 2 0 10 Nausea 2 8 4 0 7 5 General disorders and administration site conditions*** Influenza-like illness 3 6 8 0 3 10 Pain NOS* 0 8 0 2 7 7 Infections and infestations Influenza 4 4 6 0 10 14 Nasopharyngitis 3 16 10 9 11 24 Sinusitis NOS* 4 17 13 3 7 16 Upper respiratory tract infection NOS* 3 8 11 4 6 9 Investigations Weight increased 4 5 2 2 0 3 Musculoskeletal and connective tissue disorders Arthralgia 0 11 4 2 5 9 Back pain 4 10 9 4 14 10 Neck pain 3 4 4 0 6 2 Pain in limb 0 10 7 2 6 9 Nervous system disorders Headache NOS* 7 35 32 23 34 37 Sinus headache 0 12 5 5 2 8 Psychiatric disorders Anxiety NEC** 3 5 0 0 2 4 Depression 5 4 7 0 4 6 Insomnia 3 6 4 2 2 9 Reproductive system and breast disorders Breast tenderness 8 10 8 3 17 0 Dysmenorrhea 0 0 0 3 0 0 Intermenstrual bleeding 3 9 6 0 14 7 Respiratory, thoracic and mediastinal disorders Sinus congestion 0 4 3 3 6 7 Vascular disorders Hot flushes NOS* 3 0 3 0 0 6 Hypertension NOS* 2 0 3 0 0 2 † Represents milligrams of estradiol delivered daily by each system. * NOS represents not otherwise specified. ** NEC represents not elsewhere classified. *** Application site erythema and application site irritation were observed in a small number of patients (3.2% or less of patients across treatment groups).

6.2 Post-marketing

Experience The following additional adverse reactions have been identified during post-approval use of DOTTI. 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. Genitourinary System Vaginal hemorrhage and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, uterine leiomyomata, vaginitis, vaginal discharge, ovarian cancer, endometrial hyperplasia, dysmenorrhea. Breast Enlargement, pain, nipple discharge, fibrocystic breast changes, breast cancer. Cardiovascular Deep venous thrombosis, pulmonary embolism, thrombophlebitis. Gastrointestinal Nausea, vomiting, abdominal cramps, bloating, cholelithiasis, liver function tests abnormal, diarrhea. Skin Application site reactions include localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, erythema multiforme, erythema nodosum, inflammation, irritation, pain, papules and vesicles. Other skin reactions include paresthesia, skin discoloration, skin pigmentation, urticaria, swelling, loss of scalp hair, hirsutism, pruritus, and rash. Eyes Intolerance to contact lenses. Central Nervous System Migraine, dizziness, chorea, nervousness, affect liability, irritability. Miscellaneous Decrease in weight, reduced carbohydrate tolerance, edema, arthralgias, leg cramps, changes in libido, purpura, hypersensitivity, anaphylactic reaction, anaphylactoid reaction, angioedema.