combipatch
Pharmaranks rates Combipatch 3.3/5 for recall safety — an independent score from its FDA recall history and its manufacturer's record. Combipatch is a combination medicine containing Estradiol and Norethindrone Acetate.
Estradiol and Norethindrone Acetate · by Noven Pharms Inc
Based on 1 source · Recall-safety score from FDA recall history — this product's own recalls and its manufacturer's record. Not an efficacy or quality rating. methodology →
Key facts
- Active ingredient
- Estradiol and Norethindrone Acetate
- Form
- Patch, extended release
- Strength
- Estradiol 0.05MG/24HR; Norethindrone Acetate 0.14MG/24HR · Estradiol 0.05MG/24HR; Norethindrone Acetate 0.25MG/24HR
- Type
- Prescription (Rx)
- Brand or generic
- Brand-name
- Manufacturer
- Noven Pharms Inc
- Half-life
- about 8 hours (how long it stays in your system)
- What the pharmacy pays
- ~$6.64 per gm — not your price
- FDA application
- NDA020870
- FDA boxed warning
- Yes — see the boxed warning
What is Combipatch?
From the FDA label:CombiPatch ® (estradiol/norethindrone acetate transdermal system) is an adhesive-based matrix transdermal patch designed to release both estradiol, an estrogen, and norethindrone acetate (NETA), a progestational agent, continuously upon application to intact skin. Two systems are available, providing the following in vivo delivery rates of estradiol and NETA. 1 NETA=norethindrone acetate. 2 Based on in vivo/in vitro flux data, delivery of both components per day via skin of average permeability (interindividual variation in skin permeability is approximately 20 percent). System Size Estradiol (mg) NETA 1 (mg) Nominal Delivery Rate 2 (mg per day) Estradiol / NETA 9 cm 2 round 0.62 2.7 0.05/0.14 16 cm 2 round 0.51 4.8 0.05/0.25 Estradiol USP (estradiol) is a white to creamy white, odorless, crystalline powder, chemically described as estra-1,3,5(10)-triene-3,17 β -diol. The molecular weight of estradiol is 272.39 and the molecular formula is C 18 H 24 O 2 . NETA USP is a white to creamy white, odorless, crystalline powder, chemically described as 17-hydroxy-19-nor-17α-pregn-4-en-20-yn-3-one acetate. The molecular weight of NETA is 340.47 and the molecular formula is C 22 H 28 O 3 . The structural formulas for estradiol and NETA are: CombiPatch is comprised of 3 layers. Proceeding from the visible surface toward the surface attached to the skin, these layers are (1) a translucent…
How to use
Generally, when estrogen therapy is prescribed for a postmenopausal woman with a uterus, a progestin should be considered to reduce the risk of endometrial cancer. A woman without a uterus generally does not need a progestin. In some cases, however, hysterectomized women with a history of endometriosis may need a 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. Postmenopausal women should be reevaluated periodically as clinically appropriate 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…
Side effects
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…
FDA Boxed Warning (the FDA’s most serious warning)
Boxed (black-box) warning — from the FDA label
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 substudy reported an increased risk 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. (See CLINICAL STUDIES and WARNINGS , Cardiovascular Disorders ). The WHI Memory Study (WHIMS) estrogen plus progestin ancillary study of the WHI reported an 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 demonstrated an increased risk of invasive breast cancer. (See CLINICAL STUDIES and WARNINGS , Malignant Neoplasms , Breast Cancer ). 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 Neoplasms , Endometrial Cancer ). 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 Disorders and Probable Dementia ). The 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 Disorders ). 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. 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.
Warnings
Important safety information
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 significant increases in risk for both DVT (26 versus 13 per 10,000 women-years) and PE (18 versus 8 per 10,000 women years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted. 3 (See CLINICAL STUDIES ) Should a VTE occur or be suspected, estrogen plus progestin therapy should be discontinued immediately. In the WHI estrogen-alone substudy, the risk of VTE was reported to be increased for women receiving daily CE (0.625 mg)-alone compared to women receiving placebo (30 versus 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 versus 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. 4 (See CLINICAL STUDIES ) Should a VTE occur or be suspected, estrogen-alone therapy should be discontinued immediately. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. 2. Malignant Neoplasms a. Breast Cancer The WHI substudy of daily CE (0.625 mg)-alone provided information about breast cancer in estrogen-alone users. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily CE-alone was not associated with an increased risk of invasive breast cancer (relative risk [RR] 0.80) 5 [see CLINICAL STUDIES ]. After a mean follow-up of 5.6 years, the WHI substudy of daily CE (0.625 mg) plus MPA (2.5 mg) reported an increased risk of invasive breast cancer in women who took daily CE plus MPA compared to placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 versus 25 cases per 10,000 women-years, for CE plus MPA compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 versus 36 cases per 10,000 women-years for CE plus MPA compared with placebo. In the same substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the CE (0.625 mg) plus MPA (2.5 mg) group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the two groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the groups [see CLINICAL STUDIES ]. Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. One large meta-analysis of prospective cohort studies reported increased risks that were dependent upon duration of use and could last up to >10 years after discontinuation of estrogen plus progestin therapy and estrogen-alone therapy. Extension of the WHI trials also demonstrated increased breast cancer risk associated with estrogen plus progestin therapy. Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with estrogen plus progestin therapy as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast…
Who should not take Combipatch
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 with CombiPatch. Known liver impairment or disease. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy.
Overdose — what happens if you take too much
Overdosage of estrogen or estrogen plus progestin may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness and fatigue, and withdrawal bleeding may occur in women. Treatment of overdose consists of discontinuation of CombiPatch therapy with institution of appropriate symptomatic care.
U.S. Poison Control: call or text 1-800-222-1222 (free, 24/7). In an emergency call 911. From the FDA label; not medical advice.
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.
How long does Estradiol and Norethindrone Acetate stay in your body?
The elimination half-life of estradiol and norethindrone acetate is about 8 hours — the time it takes the body to clear about half of it. As a rule of thumb, a medicine is mostly gone after roughly 4 to 5 half-lives, though this varies from person to person with age and kidney or liver function. This is the terminal (elimination) half-life, not a distribution phase: the label states "the mean terminal elimination half-life of norethindrone following single dose administration ... is approximately 8 hours," and its single-dose PK table gives t½ = 7.7 ± 0.5 hours (12 healthy women, 0.35 mg, fasting). Norethindrone itself is the active drug, and the label names no active metabolite that outlasts it — it is extensively reduced and then sulfate/glucuronide conjugated, with less than 5% excreted unchanged. Related point for anyone reading a different label: norethindrone ACETATE is a prodrug that is rapidly converted to norethindrone, so norethindrone is the active moiety in those products too. This label does not characterize how the half-life changes in older adults or in kidney or liver impairment — no such pharmacokinetic data is given, so no number can be quoted for those groups (the label does contraindicate use in women with significant liver disease, but that is a safety statement, not a half-life adjustment).
This is general information, not medical advice. It doesn’t tell you when a drug test would read negative (tests detect substances for different, often longer, windows) or when it’s safe to take another dose — ask your pharmacist or prescriber. Source: CAMILA (norethindrone) 0.35 mg tablets — DailyMed label, Clinical Pharmacology / Pharmacokinetics.
Dosage forms
Patch, extended release
The forms currently marketed in the U.S., per the FDA National Drug Code Directory.
Ways to save
Ask for the generic
Same active ingredient, far cheaper. Is there a generic? →
Request a 90-day supply
Bulk fills usually lower the per-dose price vs monthly refills.
Use copay cards
Manufacturer copay cards & patient-assistance programs — especially for brand drugs.
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Frequently asked questions
- How is Combipatch rated?
- pharmaranks gives Combipatch a composite score of 3.3 out of 5, currently based on 1 weighted source (FDA regulatory recall-safety data weighted highest). See our methodology at /how-we-rate.
- How much does Combipatch cost?
- Nobody can tell you what you will pay — your price is set by your insurer's formulary, your deductible and the pharmacy's markup, and none of those are published. What IS published is what the pharmacy paid to acquire it: about $6.64 per gm, per the CMS NADAC survey. Treat that as the floor, not the quote — ask the pharmacist for the cash price as well as your copay, because for cheap generics the cash price often wins.
- Is there a coupon or discount for Combipatch?
- pharmaranks is an independent ratings site, not a pharmacy — we don't issue coupons or sell Combipatch. To pay less, ask your prescriber or pharmacist whether a generic equivalent exists, check the manufacturer's copay/savings card and patient-assistance program, and compare a pharmacy discount card against your insurance copay. Prices vary by pharmacy, insurance, and location, so always confirm at the counter. This is general reference, not medical or financial advice.
- Who makes Combipatch?
- Combipatch is marketed by Noven Pharms Inc. You can see Noven Pharms Inc's full profile, rating, and other products on pharmaranks.
- Is Combipatch a brand-name or generic drug?
- Combipatch is a brand-name product with the active ingredient Estradiol and Norethindrone Acetate.
- Is Combipatch available over the counter?
- No. Combipatch is a prescription (Rx) medication in the US — you need a prescription from a licensed clinician (in person or via telehealth); it isn't sold over the counter. For some conditions there are OTC alternatives — ask your pharmacist.
- What forms does Combipatch come in?
- Combipatch is currently marketed as patch, extended release, per the FDA's National Drug Code Directory.
- Is Combipatch FDA-registered?
- Combipatch is on record with the U.S. FDA under application number NDA020870. You can verify this on its official FDA label.
- Has Combipatch been recalled by the FDA?
- Yes. Combipatch has 1 recorded FDA recall event in the openFDA enforcement database. A recall removes specific lots from the market — usually for manufacturing, contamination, potency, or labeling issues — and does not mean the drug is unsafe to take; your specific lot was almost certainly never affected. This recall history is factored into its safety score above. Always check the FDA recall database or your pharmacist for current alerts.
- Is Combipatch safe?
- There's no single safe-or-not verdict. pharmaranks gives Combipatch a recall-safety score of 66/100, based on its FDA recall history (1 recorded recall event) — not an efficacy or side-effect rating. Review its FDA-label side effects and warnings before use, and always consult a licensed professional.
- What are the side effects of Combipatch?
- Combipatch's side effects are taken directly from its FDA label. From the label: 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… Both common and serious reactions are documented in full on this page. This is general reference from the FDA, not medical advice — always consult a professional.
Clinical content sourced from the FDA label via openFDA (U.S. FDA). View the FDA label on DailyMed → Provided for general reference only — not medical advice. Always consult a licensed professional and the current prescribing information.
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