Data from FDA (Food and Drug Administration, USA) - Curated by EPG Health - Last updated 30 January 2017

Indication(s)

INDICATIONS AND USAGE CombiPatch is indicated in a woman with a uterus for: Treatment of moderate to severe vasomotor symptoms due to menopause.

Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause.

When prescribing solely for the treatment of symptoms of vulvar and vaginal atrophy, topical vaginal products should be considered.

Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.

Learning Zones

An epgonline.org Learning Zone (LZ) is an area of the site dedicated to providing detailed self-directed medical education about a disease, condition or procedure.

Cushing's Syndrome

Cushing's Syndrome

Cushing’s syndrome shares symptoms such as hypertension, glucose intolerance and obesity with other common conditions – how can you confidently diagnose this rare disorder?

+ 2 more

Cardiovascular Metabolism Knowledge Centre

Cardiovascular Metabolism Knowledge Centre

The Cardiovascular Metabolism Knowledge Centre is an information hub providing expert insight into the management of hypertension and type 2 diabetes. This Knowledge Centre contains a wealth of scientific video content offering insights and opinion from some of the leading experts in the field.

EADV 2018 Highlights

EADV 2018 Highlights

EADV Congress 2018: Bringing you the latest news and insights from 27th EADV Congress, 12-16 September 2018 Paris, France.

Load more

Related Content

Advisory information

contraindications

CONTRAINDICATIONS CombiPatch is contraindicated in women with any of the following conditions: Undiagnosed abnormal genital bleeding.

Known, suspected, or history of breast cancer.

Known or suspected estrogen-dependent neoplasia.

Active DVT, PE, or history of these conditions.

Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions.

Known anaphylactic reaction or angioedema or hypersensitivity to CombiPatch.

Known liver impairment or disease.

Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders Known or suspected pregnancy.

Special warnings and precautions

PRECAUTIONS A. General 1.

Addition of a P rogestin w hen a W oman h as n ot h ad a H ysterectomy 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 B lood P ressure 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 I mpairment and/or P ast H istory of C holestatic J aundice 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 T4 and T3 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 R etention 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 E ndometriosis 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 O ther C onditions 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 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 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), T4 levels (by column or by radioimmunoassay) or T3 levels by radioimmunoassay.

T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 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.

E. Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

NETA was not mutagenic in a battery of in_vitro or in_vivo genetic toxicity assays.

F. Pregnancy CombiPatch should not be used during pregnancy.

(See CONTRAINDICATIONS) There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins as an oral contraceptive inadvertently during early pregnancy.

G. Nursing Mothers CombiPatch should not be used during lactation.

Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk.

Detectable amounts of estrogens and progestins have been identified in the breast milk of women receiving these drugs.

Caution should be exercised when CombiPatch is administered to a nursing woman.

H. Pediatric Use CombiPatch is not indicated in children.

Clinical studies have not been conducted in the pediatric population.

I. Geriatric Use There have not been sufficient numbers of geriatric women involved in studies utilizing CombiPatch to determine whether those over 65 years of age differ from younger subjects in their response to CombiPatch.

The Women 's Health Initiative Stud ies In the WHI estrogen plus progestin substudy (daily CE [0.625 mg] plus MPA [2.5 mg] versus placebo), there was a higher relative risk of nonfatal stroke and invasive breast cancer in women greater than 65 years of age.

(See CLINICAL STUDIES) In the WHI estrogen-alone substudy (daily CE [0.625 mg] -alone versus placebo), there was a higher relative risk of stroke in women greater than 65 years of age.

(See CLINICAL STUDIES) The Women 's Health Initiative Memory Study In the WHIMS ancillary studies of postmenopausal women 65 to 79 years of age, there was an increased risk of developing probable dementia in women receiving estrogen plus progestin or estrogen-alone when compared to placebo.

(See CLINICAL STUDIES and WARNINGS, Probable Dementia) Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.

(See CLINICAL STUDIES and WARNINGS, Probable Dementia)

Adverse reactions

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 can not 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 CombiPatch Placebo 0.05/0.14 mg per day 1 n=113 0.05/0.25 mg per day 1 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 % 1Represents milligrams of estradiol/NETA delivered daily by each system.

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 CombiPatch Vivelle 0.05/0.14 mg per day 1 n=325 0.05/0.25 mg per day 1 n=312 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 % 1Represents milligrams of estradiol/NETA delivered daily by each system.

Postmarketing Experience The following additional adverse reactions have been identified during postapproval 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, vertigo, paraesthesia.

Miscellaneous Angioedema, hypersensitivity, weight increased.

Additional postmarketing adverse reactions have been reported in patients receiving other forms of hormone therapy.

Usage information

Dosing and administration

DOSAGE AND ADMINISTRATION When estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be initiated to reduce the risk of endometrial cancer.

A woman without a uterus does not need progestin.

Use of estrogen-alone or in combination with a progestin, should be with the lowest effective dose and for the shortest duration consistent with treatment goals and risks for the individual woman.

Patients should be reevaluated periodically as clinically appropriate (for example at 3-month to 6-month intervals) to determine whether treatment is still necessary.

Adequate diagnostic measures, such as directed or random endometrial sampling, when indicated, should be undertaken to rule out malignancy in a postmenopausal woman with a uterus with undiagnosed persistent or recurring abnormal genital bleeding.

Initiation of Therapy Patients should be started at the lowest dose.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

The lowest effective dose of CombiPatch has not been determined in clinical trials.

Women not currently using continuous estrogen or combination estrogen plus progestin therapy may start therapy with CombiPatch at any time.

However, women currently using continuous estrogen or combination estrogen plus progestin therapy should complete the current cycle of therapy, before initiating CombiPatch therapy.

Women often experience withdrawal bleeding at the completion of the cycle.

The first day of this bleeding would be an appropriate time to begin CombiPatch therapy.

Therapeutic Regimens Combination estrogen plus progestin regimens are indicated for women with an intact uterus.

Two CombiPatch (estradiol/NETA) transdermal delivery systems are available: 0.05 mg estradiol with 0.14 mg NETA per day (9 cm2) and 0.05 mg estradiol with 0.25 mg NETA per day (16 cm2).

The lowest effective dose should be used.

For all regimens, women should be reevaluated at 3- to 6-month intervals to determine if changes in hormone therapy or if continued hormone therapy is appropriate.

Continuous Combined Regimen A CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm2) matrix transdermal system is worn continuously on the lower abdomen.

Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm2 system) is available if a greater progestin dose is desired.

A new system should be applied twice weekly during a 28-day cycle.

Irregular bleeding may occur particularly in the first six months, but generally decreases with time, and often to an amenorrheic state.

Continuous Sequential Regimen CombiPatch can be applied as a sequential regimen in combination with an estradiol-only transdermal delivery system.

In this treatment regimen, a 0.05 mg per day (nominal delivery rate) estradiol transdermal system (Vivelle) is worn for the first 14 days of a 28-day cycle, replacing the system twice weekly according to product directions.

For the remaining 14 days of the 28-day cycle, CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm2) transdermal system should be applied to the lower abdomen.

Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm2 system) is available if a greater progestin dose is desired.

The CombiPatch system should be replaced twice weekly during this period in the cycle.

Women should be advised that monthly withdrawal bleeding often occurs.

Application of the System Site Selection CombiPatch should be placed on a smooth (fold-free), clean, dry area of the skin on the lower abdomen.

CombiPatch should not be applied to or near the breasts.

The area selected should not be oily (which can impair adherence of the system), damaged, or irritated.

The waistline should be avoided, since tight clothing may rub the system off or modify drug delivery.

The sites of application must be rotated, with an interval of at least one week allowed between applications to the same site.

Application After opening the pouch, remove 1 side of the protective liner, taking care not to touch the adhesive part of the transdermal delivery system with the fingers.

Immediately apply the transdermal delivery system to a smooth (fold-free) area of skin on the lower abdomen.

Remove the second side of the protective liner and press the system firmly in place with the hand for at least 10 seconds, making sure there is good contact, especially around the edges.

Care should be taken that the system does not become dislodged during bathing and other activities.

If a system should fall off, the same system may be reapplied to another area of the lower abdomen.

If necessary, a new transdermal system may be applied, in which case, the original treatment schedule should be continued.

Only 1 system should be worn at any 1 time during the 3 - to 4 -day dosing interval.

Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.

Removal of the System Removal of the system should be done carefully and slowly to avoid irritation of the skin.

Should any adhesive remain on the skin after removal of the system, allow the area to dry for 15 minutes.

Then gently rub the area with an oil-based cream or lotion to remove the adhesive residue.

Interactions

Drug Interactions 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, phenobarbital, carbamazepine and rifampin 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 and grapefruit juice may increase plasma concentrations of estrogens and may result in side effects.

More information

Category Value
Authorisation number NDA020870
Agency product number 4TI98Z838E
Orphan designation No
Product NDC 0078-0377,0078-0378
Date Last Revised 25-04-2014
Type HUMAN PRESCRIPTION DRUG
RXCUI 1251495
Marketing authorisation holder Novartis Pharmaceuticals Corporation
Warnings

WARN ING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER, AND PROBABLE DEMENTIA Estrogen Plus Progestin Therapy Cardiovascular Disorders and Probable Dementia Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders and Probable Dementia) The Women 's Health Initiative (WHI) estrogen plus progestin sub study reported increased risks of deep vein thrombosis (DVT), pulmonary embolism (PE), stroke and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (CE) [0.625 mg] combined with medroxyprogesterone acetate (MPA) [2.5 mg], relative to placebo.

(S ee CLINICAL STUDIES and WARNINGS, Cardiovascular Disorders) The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women.

(See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use) Breast Cancer The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.

(See CLINICAL STUDIES and WARNINGS, Malignant N e o plasms, Breast C ancer) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and MPA, and other combinations and dosage forms of estrogens and progestins.

Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.

Estrogen-Alone Therapy Endometrial Cancer There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.

Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer.

Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.

(See WARNINGS, Malignant N eoplasms, Endometrial C ancer) Cardiovascular Disorders and Probable Dementia Estrogen-alone therapy should not be used for the prevention of cardiovascular disease or dementia.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular D isorders and Probable Dementia) Th e WHI estrogen-alone substudy reported increased risks of stroke and DVT in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral CE (0.625 mg) -alone, relative to placebo.

(See CLINICAL STUDIES and WARNINGS, Cardiovascular D isorders) The WHIMS estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 5.2 years of treatment with daily CE (0.625 mg) -alone, relative to placebo.

It is unknown whether this finding applies to younger postmenopausal women.

(See CLINICAL STUDIES and WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use) In the absence of comparable data, these risks should be assumed to be similar for other doses of CE and other dosage forms of estrogens.

E strogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.