Combipatch (estradiol/norethindrone Acetate Transdermal System) Side Effects

ADVERSE REACTIONS See BOXED WARNING , WARNINGS , and PRECAUTIONS .

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.

All Adverse Reactions Regardless of Relationship Reported at a Frequency of Greater than or Equal to 5 percent with CombiPatch VASOMOTOR SYMPTOM STUDIES CombiPatch 0.05/0.14 mg per day† CombiPatch 0.05/0.25 mg per day† Placebo n=113 n=112 n=107 Body as a Whole 46% 48% 41% Abdominal Pain 7% 6% 4% Accidental Injury 4% 5% 8% Asthenia 8% 12% 4% Back Pain 11% 9% 5% Flu Syndrome 9% 5% 7% Headache 18% 20% 20% Pain 6% 4% 9% Digestive 19% 23% 24% Diarrhea 4% 5% 7% Dyspepsia 1% 5% 5% Flatulence 4% 5% 4% Nausea 11% 8% 7% Nervous 16% 28% 28% Depression 3% 5% 9% Insomnia 3% 6% 7% Nervousness 3% 5% 1% Respiratory 24% 38% 26% Pharyngitis 4% 10% 2% Respiratory Disorder 7% 12% 7% Rhinitis 7% 13% 9% Sinusitis 4% 9% 9% Skin and Appendages 8% 17% 16% Application Site Reaction* 2% 6% 4% Urogenital 54% 63% 28% Breast Pain 25% 31% 7% Dysmenorrhea 20% 21% 5% Leukorrhea 5% 5% 3% Menstrual Disorder 6% 12% 2% Papanicolaou Smear Suspicious 8% 4% 5% Vaginitis 6% 13% 5% †Represents milligrams of estradiol/NETA delivered daily by each system.

*Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, skin discoloration, skin pigmentation, swelling, urticaria, and vesicles.

All Adverse Reactions Regardless of Relationship Reported at a Frequency of Greater than or Equal to 5 percent with CombiPatch ENDOMETRIAL HYPERPLASIA STUDIES CombiPatch 0.05/0.14 mg per day† n=325 CombiPatch 0.05/0.25 mg per day† n=312 Vivelle 0.05 mg per day n=318 Body as a Whole 61% 60% 59% Abdominal Pain 12% 14% 16% Accidental Injury 10% 11% 8% Asthenia 10% 13% 11% Back Pain 15% 14% 13% Flu Syndrome 14% 10% 7% Headache 25% 17% 21% Infection 5% 3% 3% Pain 19% 15% 13% Digestive 42% 32% 31% Constipation 2% 5% 3% Diarrhea 14% 9% 7% Dyspepsia 8% 6% 5% Flatulence 7% 5% 6% Nausea 8% 12% 11% Tooth Disorder 6% 4% 1% Metabolic and Nutritional Disorders 12% 13% 11% Peripheral Edema 6% 6% 5% Musculoskeletal 17% 17% 15% Arthralgia 6% 6% 5% Nervous 33% 30% 28% Depression 8% 9% 8% Dizziness 6% 7% 5% Insomnia 8% 6% 4% Nervousness 5% 6% 3% Respiratory 45% 43% 40% Bronchitis 5% 3% 4% Pharyngitis 9% 9% 8% Respiratory Disorder 13% 9% 13% Rhinitis 19% 22% 17% Sinusitis 10% 12% 12% Skin and Appendages 38% 37% 31% Acne 4% 5% 4% Application Site Reaction* 20% 23% 17% Rash 6% 5% 3% Urogenital 71% 79% 74% Breast Enlargement 2% 7% 2% Breast Pain 34% 48% 40% Dysmenorrhea 30% 31% 19% Leukorrhea 10% 8% 9% Menorrhagia 2% 5% 9% Menstrual Disorder 17% 19% 14% Vaginal Hemorrhage 3% 6% 12% Vaginitis 9% 13% 13% †Represents milligrams of estradiol/NETA delivered daily by each system.

*Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema, edema, erythema, inflammation, irritation, pain, papules, paresthesia, pruritus, rash, skin discoloration, skin pigmentation, swelling, urticaria, and vesicles.

Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of CombiPatch.

Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Genitourinary System Endometrial hyperplasia, endocervical polyp, uterine leiomyomata, fallopian tube cyst, uterine spasms.

Breast Breast cancer.