Estradiolside effects

The following serious adverse reactions are discussed elsewhere in labeling: Cardiovascular Disorders Malignant Neoplasms The most common adverse reactions (greater than or equal to 5 percent) with LYLLANA are: headache, breast tenderness, back pain, pain in limb, nasopharyngitis, dyspepsia, nausea, sinusitis, and intermenstrual bleeding 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 LYLLANA. LYLLANA is bioequivalent to Vivelle ®. The following adverse reactions are reported with Vivelle therapy: Table 1: Summary of Most Frequently Reported Adverse Reactions (Vivelle versus Placebo) Regardless of Relationship Reported at a Frequency ≥5 Percent Vivelle 0.025 mg/day † (N=47) N (%) Vivelle 0.0375 mg/day † (N=130) N (%) Vivelle 0.05 mg/day † (N=103) N (%) Vivelle 0.075 mg/day † (N=46) N (%) Vivelle 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 3.2% or less of patients across treatment groups. During the clinical pharmacology studies with LYLLANA, 35 percent or less of subjects experienced barely perceptible erythema. No transdermal systems were removed due to irritation. Three subjects (2.2 percent) reported mild discomfort while wearing LYLLANA (N=136).

6.2 Postmarketing

Experience The following adverse reactions have been identified during post-approval use of LYLLANA. 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. Breast Breast enlargement Cardiovascular Palpitations, angina unstable Gastrointestinal Hemorrhage, diarrhea Skin Application site reactions, erythema, rash, hyperhidrosis, pruritus, urticaria Central Nervous System Dizziness, paresthesia, migraine, mood swings, emotional disorder, irritability, nervousness Miscellaneous Portal vein thrombosis, dyspnea, malaise, fatigue, peripheral edema, muscle spasms, paresthesia oral, swollen tongue, lip swelling, pharyngeal edema