CombiPatch (estradiol/norethindrone acetate transdermal system) .05 mg/d; .14 mg/d Patch, Extended Release, 8 patches — NDC 68968-0514-8 (Billing 68968-0514-08)

WARNINGS See BOXED WARNING . 1. Cardiovascular Disorders An increased risk of PE, DVT, stroke and MI has been reported with estrogen plus progestin therapy.

An increased risk of stroke and DVT has been reported with estrogen-alone therapy. Should any of these occur or be suspected, estrogen with or without progestin therapy should be discontinued immediately. Risk factors for arterial vascular disease (for example, hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) (for example, personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately. a.

Stroke In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women in the same age group receiving placebo (33 versus 25 per 10,000 women-years). (See CLINICAL STUDIES ) The increase in risk was demonstrated after the first year and persisted. 1 Should a stroke occur or be suspected, estrogen plus progestin therapy should be discontinued immediately.

In the WHI estrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg)-alone compared to women in the same age group receiving placebo (45 versus 33 per 10,000 women-years). (See CLINICAL STUDIES ) The increase in risk was demonstrated in year 1 and persisted. Should a stroke occur or be suspected, estrogen-alone therapy should be discontinued immediately.

Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg)-alone versus those receiving placebo (18 versus 21 per 10,000 women-years). 1 b. Coronary Heart Disease In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events (defined as nonfatal MI, silent MI, or CHD death) reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to women receiving placebo (41 versus 34 per 10,000 women years).

1 An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5 (See CLINICAL STUDIES ). In the WHI estrogen-alone substudy, no overall effect on CHD events was reported in women receiving estrogen-alone compared to placebo. 2 (See CLINICAL STUDIES ) Subgroup analyses of women 50 to 59 years of age suggest a statistically nonsignificant reduction in CHD events (CE [0.625 mg]-alone compared to placebo) in women less than 10 years since menopause (8 versus 16 per 10,000 women-years).

1 In postmenopausal women with documented heart disease (n=2,763, average 66.7 years of age), in a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/Progestin Replacement Study; HERS), treatment with daily CE (0.625 mg) plus MPA (2.5 mg) demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established CHD. There were more CHD events in the CE plus MPA-treated group than in the placebo group in year 1, but not during the subsequent years.

Two thousand three hundred twenty-one (2,321) women from the original HERS trial agreed to participate in an open-label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the CE plus MPA group and the placebo group in the HERS, the HERS II, and overall. c.

Venous Thromboembolism In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE (DVT and PE) was reported in women receiving daily CE (0.625 mg) plus MPA (2.5 mg) compared to placebo (35 versus 17 per 10,000 women-years). Statistically signi… [Excerpted — this section continues on DailyMed.]

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. Table 9.

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.

Table 10. 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. Cardiovascular Hypertension, varicose veins. Gastrointestinal Jaundice cholestatic, cholelithiasis, gall bladder disorder, transaminases increased.

Skin Skin discoloration. Central Nervous System Affect lability, libido disorder, migraine, vertig… [Excerpted — this section continues on DailyMed.]

Drug Interactions No drug interaction studies have been conducted with CombiPatch. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism.

Inducers of CYP3A4 such as St. John’s wort ( Hypericum perforatum ) preparations, anticonvulsants (e.g., phenobarbital, phenytoin and carbamazepine), phenylbutazone, and anti-infectives (e.g., rifampin, rifabutin, nevirapine and efavirenz) may reduce plasma concentrations of estrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4 such as erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

Adhesion Averaging across 6 clinical trials lasting 3 months to 1 year, of 1,287 patients treated, CombiPatch transdermal systems completely adhered to the skin nearly 90 percent of the time over the 3- to 4-day wear period. Less than 2 percent of the patients required reapplication or replacement of systems due to lifting or detachment. Two patients (0.2 percent) discontinued therapy during clinical trials due to adhesion failure.

D. Drug-Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased antithrombin III activity; increased levels of fibrinogen and fibrinogen activity; increased plasminogen antigen and activity.

2. Increased TBG leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T 4 levels (by column or by radioimmunoassay) or T 3 levels by radioimmunoassay. T 3 resin uptake is decreased, reflecting the elevated TBG.

Free T 4 and free T 3 concentrations are unaltered. Women on thyroid replacement therapy may require higher doses of thyroid hormone. 3.

Other binding proteins may be elevated in serum (i.e., corticosteroid binding globulin [CBG], SHBG), leading to increased circulating corticosteroids and sex steroids, respectively. Free hormone concentrations, such as testosterone and estradiol, may be decreased. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

4. Increased plasma high density lipoprotein (HDL) and HDL-2 subfraction concentrations, reduced low density lipoprotein (LDL) cholesterol concentration, increased triglycerides levels. 5.

Impaired glucose tolerance.

PRECAUTIONS A. General 1. Addition of a Progestin when a Woman has not had a Hysterectomy Studies of the addition of a progestin for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone.

Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestins with estrogens compared to estrogen-alone regimens. These include an increased risk of breast cancer.

2. Elevated Blood Pressure In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogen therapy on blood pressure was not seen.

3. Hypertriglyceridemia In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of treatment if pancreatitis occurs.

4. Hepatic Impairment and/or Past History of Cholestatic Jaundice Although transdermally administered estrogen therapy avoids first-pass hepatic metabolism, estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

5. Hypothyroidism Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Women with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T 4 and T 3 serum concentrations in the normal range.

Women dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range. 6.

Fluid Retention Estrogens plus progestins may cause some degree of fluid retention. Women with conditions which might be influenced by this factor, such as cardiac or renal impairment warrant careful observation when estrogens plus progestins are prescribed. 7.

Hypocalcemia Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur. 8. Exacerbation of Endometriosis A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy.

For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered. 9. Exacerbation of Other Conditions Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or porphyria, systemic lupus erythematosus, and hepatic hemangiomas and should be used with caution in women with these conditions.

B. Patient Information Physicians are advised to discuss the content of the PATIENT INFORMATION leaflet and INSTRUCTIONS FOR USE with patients for whom they prescribe CombiPatch. C.

Laboratory Tests Serum FSH and estradiol levels have not been shown to be useful in the management of moderate to severe vasomotor symptoms and moderate to severe symptoms of vulvar and vaginal atrophy. Laboratory parameters may be useful in guiding dosage for the treatment of hypoestrogenism due to hypogonadism, castration and primary ovarian failure. D.

Drug-Laboratory Test Interactions 1. Accelerated prothrombin time, partial thromboplastin time, and platelet aggregation time; increased platelet count; increased factors II, VII antigen, VIII antigen, VIII coagulant activity, IX, X, XII, VII-X complex, II-VII-X complex; and beta-thromboglobulin; decreased levels of anti-factor Xa and antithrombin III; decreased ant… [Excerpted — this section continues on DailyMed.]