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.

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 C18H24O2.

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 C22H28O3.

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 polyolefin film backing, (2) an adhesive layer containing estradiol, NETA, acrylic adhesive, silicone adhesive, oleic acid NF, povidone USP and dipropylene glycol, and (3) a polyester release protective liner, which is attached to the adhesive surface and must be removed before the system can be used.

The active components of the system are estradiol USP and NETA USP. The remaining components of the system are pharmacologically inactive.

Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol at the receptor level.

The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone in the peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women.

Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, 2 estrogen receptors have been identified. These vary in proportion from tissue to tissue.

Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women.

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.

Effects on Vasomotor Symptoms

In 2 clinical trials designed to assess the degree of relief of moderate to severe vasomotor symptoms in postmenopausal women (n=332), CombiPatch was administered for 3 28-day cycles in Continuous Combined or Continuous Sequential treatment regimens versus placebo. In the Continuous Combined regimen, CombiPatch was applied throughout the 3 cycles, replacing the system twice weekly. In the Continuous Sequential regimen, an estradiol-only transdermal system (Vivelle® 0.05 mg) was applied twice weekly during the first 14 days of a 28-day cycle; CombiPatch was applied for the remaining 14 days of the cycle and replaced twice weekly, as well. The mean number of hot flushes at baseline were 10 to 11 per day and 11 to 12 per day in the Continuous Combined and Continuous Sequential regimen trials, respectively. The mean number and intensity of daily hot flushes (intent-to-treat population) was significantly reduced from baseline to endpoint with either the Continuous Combined or Continuous Sequential administration of CombiPatch at all doses as compared to placebo (intent-to-treat population). (See Tables 3 and 4)

Effects on the Endometrium

The use of unopposed estrogen therapy has been associated with an increased risk of endometrial hyperplasia, a possible precursor of endometrial adenocarcinoma. Progestins counter the estrogenic effects by decreasing the number of nuclear estradiol receptors and suppressing epithelial DNA synthesis in endometrial tissue.

Clinical studies indicate that the addition of a progestin to an estrogen regimen at least 12 days per cycle reduces the incidence of endometrial hyperplasia and the potential risk of adenocarcinoma in women with intact uteri. The addition of a progestin to an estrogen regimen has not been shown to interfere with the efficacy of estrogen therapy for its approved indications.

CombiPatch was effective in reducing the incidence of estrogen-induced endometrial hyperplasia after 1 year of therapy in two clinical trials. Nine hundred fifty-five (955) postmenopausal women (with intact uteri) were treated with (i) a continuous regimen of CombiPatch alone ( Continuous Combined regimen), (ii) a sequential regimen with an estradiol-only (Vivelle 0.05 mg) transdermal system followed by a CombiPatch transdermal system ( Continuous Sequential regimen), or (iii) continuous regimen with an estradiol-only transdermal system (Vivelle 0.05 mg). The incidence of endometrial hyperplasia (primary endpoint) was significantly less after 1 year of therapy with either CombiPatch regimen than with the estradiol-only transdermal system. Tables 5 and 6 summarize these results (intent-to-treat populations).

Effects on Uterine Bleeding or Spotting

With the Continuous Combined regimen, of the women treated with CombiPatch and who completed the 1-year study, the incidence of cumulative amenorrhea (the absence of bleeding or spotting during a 28-day cycle and sustained to the end of the study) increased over time. The incidence of amenorrhea from cycle 10 through 12 was 53 percent and 39 percent for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. Women who experienced bleeding usually characterized it as light (intensity of 1.3 on a scale of 1 to 4) with a duration of 4 and 6 days for the CombiPatch 0.05/0.14 mg per day and CombiPatch 0.05/0.25 mg per day treatment groups, respectively. (See Figure 1)

Figure 1. Incidence of Cumulative Amenorrhea* in CombiPatch Continuous Combined Transdermal Therapy by Cycle Over a 1-Year Period (Intent-to-Treat Population)

*Cumulative amenorrhea is defined as the absence of bleeding for the duration of a 28-day cycle and sustained to the end of the study.

Women’s Health Initiative Studies

The WHI enrolled approximately 27,000 predominantly healthy postmenopausal women in two substudies to assess the risks and benefits of daily oral CE (0.625 mg)-alone or in combination with MPA (2.5 mg) compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) [defined as nonfatal MI, silent MI and CHD death], with invasive breast cancer as the primary adverse outcome. A “global index” included the earliest occurrence of CHD, invasive breast cancer, stroke, PE, endometrial cancer (only in the CE plus MPA substudy), colorectal cancer, hip fracture, or death due to other cause. These substudies did not evaluate the effects of CE plus MPA or CE-alone on menopausal symptoms.

WHI Estrogen Plus Progestin Substudy

The WHI estrogen plus progestin substudy was stopped early. According to the predefined stopping rule, after an average follow-up of 5.6 years of treatment, the increased risk of invasive breast cancer and cardiovascular events exceeded the specified benefits included in the “global index.” The absolute excess risk of events included in the “global index” was 19 per 10,000 women-years.

For those outcomes included in the WHI “global index” that reached statistical significance after 5.6 years of follow-up, the absolute excess risks per 10,000 women years in the group treated with CE plus MPA were 7 more CHD events, 8 more strokes, 10 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures.

Results of the estrogen plus progestin substudy, which included 16,608 women (average 63 years of age, range 50 to 79 years; 83.9 percent white, 6.8 percent black, 5.4 percent Hispanic, 3.9 percent Other), are presented in Table 7. These results reflect centrally adjudicated data after an average follow-up of 5.6 years.

Timing of the initiation of estrogen plus progestin therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen plus progestin substudy stratified by age showed in women 50 to 59 years of age a nonsignificant trend toward reduced risk for overall mortality [hazard ratio (HR) 0.69 (95 percent CI 0.44 to 1.07)].

WHI Estrogen-Alone Substudy

The WHI estrogen-alone substudy was stopped early because an increased risk of stroke was observed, and it was deemed that no further information would be obtained regarding the risks and benefits of estrogen-alone in predetermined primary endpoints.

Results of the estrogen-alone substudy, which included 10,739 women (average 63 years of age, range 50 to 79 years; 75.3 percent white, 15.1 percent black, 6.1 percent Hispanic, 3.6 percent Other) after an average follow-up of 7.1 years, are presented in Table 8.

For those outcomes included in the WHI “global index” that reached statistical significance, the absolute excess risk per 10,000 women-years in the group treated with CE-alone was 12 more strokes, while the absolute risk reduction per 10,000 women-years was 7 fewer hip fractures.9 The absolute excess risk of events included in the “global index” was a nonsignificant 5 events per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.

No overall difference for primary CHD events (nonfatal MI, silent MI and CHD death) and invasive breast cancer incidence in women receiving CE-alone compared with placebo was reported in final centrally adjudicated results from the estrogen-alone substudy, after an average follow-up of 7.1 years (see Table 8).

Centrally adjudicated results for stroke events from the estrogen-alone substudy, after an average follow-up of 7.1 years, reported no significant difference in distribution of stroke subtype or severity, including fatal strokes, in women receiving CE-alone compared to placebo. Estrogen-alone increased the risk for ischemic stroke, and this excess was present in all subgroups of women examined.10 (see Table 8).

Timing of the initiation of estrogen therapy relative to the start of menopause may affect the overall risk benefit profile. The WHI estrogen-alone substudy stratified by age showed in women 50 to 59 years of age, a nonsignificant trend toward reduced risk for CHD [HR 0.63 (95 percent, CI 0.36 to 1.09)] and overall mortality [HR 0.71 (95 percent CI, 0.46 to 1.11)].

Women’s Health Initiative Memory Study

The WHIMS estrogen plus progestin ancillary study of WHI enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47 percent were 65 to 69 years of age; 35 percent were 70 to 74 years of age; 18 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg) plus MPA (2.5 mg) on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 4 years, the relative risk of probable dementia for CE plus MPA versus placebo was 2.05 (95 percent CI, 1.21 to 3.48). The absolute risk of probable dementia for CE plus MPA versus placebo was 45 versus 22 cases per 10,000 women-years. Probable dementia as defined in this study included Alzheimer disease (AD), vascular dementia (VaD) and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use)

The WHIMS estrogen-alone ancillary study of WHI enrolled 2,947 predominantly healthy hysterectomized postmenopausal women 65 to 79 years of age (45 percent were 65 to 69 years of age; 36 percent were 70 to 74 years of age; 19 percent were 75 years of age and older) to evaluate the effects of daily CE (0.625 mg)-alone on the incidence of probable dementia (primary outcome) compared to placebo.

After an average follow-up of 5.2 years, the relative risk of probable dementia for CE-alone versus placebo was 1.49 (95 percent CI, 0.83 to 2.66). The absolute risk of probable dementia for CE-alone versus placebo was 37 versus 25 cases per 10,000 women-years. Probable dementia as defined in this study included AD, VaD and mixed type (having features of both AD and VaD). The most common classification of probable dementia in the treatment group and the placebo group was AD. Since the ancillary study was conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use)

When data from the two populations were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95 percent CI, 1.19 to 2.60). Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See WARNINGS, Probable Dementia and PRECAUTIONS, Geriatric Use)

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.

CombiPatch is contraindicated in women with any of the following conditions:

1. Undiagnosed abnormal genital bleeding.
2. Known, suspected, or history of breast cancer.
3. Known or suspected estrogen-dependent neoplasia.
4. Active DVT, PE, or history of these conditions.
5. Active arterial thromboembolic disease (for example, stroke and MI), or a history of these conditions.
6. Known anaphylactic reaction or angioedema or hypersensitivity with CombiPatch.
7. Known liver impairment or disease.
8. Known protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders.
9. Known or suspected pregnancy.

See BOXED WARNING.

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.

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, vertigo, paresthesia.

Miscellaneous

Angioedema, hypersensitivity, weight increased.

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.

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 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

CombiPatch 0.05 mg estradiol/0.14 mg NETA per day (9 cm2) matrix transdermal system is used for continuous uninterrupted treatment applied twice weekly on the lower abdomen. A new system should be applied to the skin every 3 to 4 days (twice weekly) during a 28-day cycle.

Additionally, a dose of 0.05 mg estradiol/0.25 mg NETA (16 cm2 system) is available if a greater progestin dose is desired. 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-Dot®) is worn for the first 14 days of a 28-day cycle, replacing the system every 3 to 4 days (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 worn continuously on the lower abdomen. The CombiPatch system should be replaced every 3 to 4 days (twice weekly) during this 14-day period in the 28-day cycle.

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

CombiPatch estradiol/NETA transdermal delivery system is available in:

Storage Conditions

Store CombiPatch in the refrigerator at 36℉ to 46℉ (2℃ to 8℃).

Store the systems in the sealed foil pouch.

Do not store the system in areas where extreme temperatures can occur.

Keep this and all medicines out of the reach of children.

Vivelle® is a registered trademark of Novartis Corporation. & Vivelle-Dot ® is a registered trademark of Novartis AG.

1. Rossouw JE, et al. Postmenopausal Hormone Therapy and Risk of Cardiovascular Disease by Age and Years Since Menopause. JAMA. 2007;297:1465-1477.
2. Hsia J, et al. Conjugated Equine Estrogens and Coronary Heart Disease. Arch Int Med. 2006;166:357-365.
3. Cushman M, et al. Estrogen Plus Progestin and Risk of Venous Thrombosis. JAMA. 2004;292:1573-1580.
4. Curb JD, et al. Venous Thrombosis and Conjugated Equine Estrogen in Women Without a Uterus. Arch Int Med. 2006;166:772-780.
5. Chlebowski RT, et al. Influence of Estrogen Plus Progestin on Breast Cancer and Mammography in Healthy Postmenopausal Women. JAMA. 2003;289:3234-3253.
6. Stefanick ML, et al. Effects of Conjugated Equine Estrogens on Breast Cancer and Mammography Screening in Postmenopausal Women With Hysterectomy. JAMA. 2006;295:1647-1657.
7. Anderson GL, et al. Effects of Estrogen Plus Progestin on Gynecologic Cancers and Associated Diagnostic Procedures. JAMA. 2003;290:1739-1748.
8. Shumaker SA, et al. Conjugated Equine Estrogens and Incidence of Probable Dementia and Mild Cognitive Impairment in Postmenopausal Women. JAMA. 2004;291:2947-2958.
9. Jackson RD, et al. Effects of Conjugated Equine Estrogen on Risk of Fractures and BMD in Postmenopausal Women With Hysterectomy: Results From the Women's Health Initiative Randomized Trial. J Bone Miner Res. 2006;21:817-828.
10. Hendrix SL, et al. Effects of Conjugated Equine Estrogen on Stroke in the Women's Health Initiative. Circulation. 2006;113:2425-2434.

CombiPatch® is a registered trademark of Noven Pharmaceuticals, Inc.

Manufactured by:
Noven Pharmaceuticals Inc.
Miami, FL 33186

Distributed by:
Noven Therapeutics, LLC
Miami, FL 33186

© 2024 Noven Pharmaceuticals, Inc.

For more information call 1-800-455-8070 or visit www.combipatch.com.

102538-5

CombiPatch
(käm-bē `pach)
(estradiol/norethindrone acetate transdermal system)

Read this Patient Information before you start using CombiPatch and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your menopausal symptoms or your treatment.

What is CombiPatch?

CombiPatch is a prescription medicine patch (Transdermal System) that contains 2 kinds of hormones, estrogen and progestin.

What is CombiPatch used for?

CombiPatch is used after menopause to:

• Reduce moderate to severe hot flashes
  Estrogens are hormones made by a woman’s ovaries. The ovaries normally stop making estrogens when a woman is between 45 and 55 years old. This drop in body estrogen levels causes the “change of life” or menopause (the end of monthly menstrual periods). Sometimes, both ovaries are removed during an operation before natural menopause takes place. The sudden drop in estrogen levels causes “surgical menopause.” When estrogen levels begin dropping, some women get very uncomfortable symptoms, such as feelings of warmth in the face, neck, and chest or sudden strong feelings of heat and sweating (“hot flashes” or “hot flushes”). In some women, the symptoms are mild, and they will not need to use estrogens. In other women, symptoms can be more severe.
• Treat moderate to severe menopausal changes in and around your vagina
  You and your healthcare provider should talk regularly about whether you still need treatment with CombiPatch to control these problems. If you use CombiPatch only to treat menopausal changes in and around your vagina, talk with your healthcare provider about whether a topical vaginal product would be better for you.
• Treat certain conditions in women before menopause if their ovaries do not make enough estrogens naturally.
  You and your healthcare provider should talk regularly about whether you still need treatment with CombiPatch.

Who should not use CombiPatch?

Do not use CombiPatch if you have had your uterus (womb) removed (hysterectomy).

CombiPatch contains a progestin to decrease the chance of getting cancer of the uterus. If you do not have a uterus, you do not need a progestin and you should not use CombiPatch.

Do not start using CombiPatch if you:

• have unusual vaginal bleeding
  Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• currently have or have had certain cancers
  Estrogens may increase the chance of getting certain types of cancers, including cancer of the breast or uterus. If you have or have had cancer, talk with your health care provider about whether you should use CombiPatch.
• had a stroke or heart attack
• currently have or have had blood clots
• currently have or have had liver problems
• have been diagnosed with a bleeding disorder
• are allergic to CombiPatch or any of its ingredients
  See the list of ingredients in CombiPatch at the end of this leaflet.
• think you may be pregnant
  CombiPatch is not for pregnant women. If you think you may be pregnant, you should have a pregnancy test and know the results. Do not use CombiPatch if the test result is positive and talk to your healthcare provider.

What should I tell my healthcare provider before I use CombiPatch?

Before you use CombiPatch, tell your healthcare provider if you:

• have any unusual vaginal bleeding
  Vaginal bleeding after menopause may be a warning sign of cancer of the uterus (womb). Your healthcare provider should check any unusual vaginal bleeding to find out the cause.
• have any other medical conditions
• Your healthcare provider may need to check you more carefully if you have certain conditions such as asthma (wheezing), epilepsy (seizures), diabetes, migraine, endometriosis, lupus, angioedema (swelling of face and tongue), or problems with your heart, liver, thyroid, kidneys, or have high calcium levels in your blood.
• are going to have surgery or will be on bed rest
  Your healthcare provider will let you know if you need to stop using CombiPatch.
• are breastfeeding
  The hormones in CombiPatch can pass into your breast milk.

Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Some medicines may affect how CombiPatch works. CombiPatch may also affect how other medicines work. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.

How should I use CombiPatch?

• For detailed instructions, see the step-by-step instructions for using CombiPatch at the end of this Patient Information.
• Use CombiPatch exactly as your healthcare provider tells you to use it.
• CombiPatch is for skin use only.
• Change your CombiPatch 2 times each week or every 3 to 4 days.
• Apply your CombiPatch to a clean, dry area on your lower abdomen. This area must be clean, dry, and free of powder, oil or lotion for your CombiPatch to stick to your skin.
• Apply your CombiPatch to a different area of your lower abdomen each time. Do not use the same application site 2 times in the same week.
• Do not apply CombiPatch to or near your breasts.
• If you forget to apply a new CombiPatch, you should apply a new CombiPatch as soon as possible.
• Once in place, the transdermal system should not be exposed to the sun for prolonged periods of time.
• You and your healthcare provider should talk regularly (every 3 to 6 months) about your dose and whether you still need treatment with CombiPatch.

How do I change CombiPatch?

• When changing CombiPatch, slowly peel away the used CombiPatch from your skin.
• After you remove CombiPatch, you may have a small amount of stickiness (adhesive) left on your skin. If you have any adhesive left on your skin after you remove CombiPatch, allow the area to dry for 15 minutes. Gently rub the sticky area of your skin with oil or lotion to remove the adhesive.
• The new CombiPatch must be applied to a different area of your lower abdomen. This area must be clean, dry, cool and free of powder, oil or lotion. The same site should not be used again for at least 1 week after removal of CombiPatch.

What are the possible side effects of CombiPatch?

Side effects are grouped by how serious they are and how often they happen when you are treated.

Serious, but less common side effects include:

• heart attack
• stroke
• blood clots
• dementia
• breast cancer
• cancer of the lining of the uterus (womb)
• cancer of the ovary
• high blood pressure
• high blood sugar
• gallbladder disease
• liver problems
• changes in your thyroid hormone levels
• enlargement of benign tumors of the uterus (“fibroids”)
• depression

Call your healthcare provider right away if you get any of the following warning signs or any other unusual symptoms that concern you:

• new breast lumps
• unusual vaginal bleeding
• changes in vision or speech
• sudden new severe headaches
• severe pains in your chest or legs with or without shortness of breath, weakness and fatigue

Less serious, but common side effects include:

• headache
• breast pain
• irregular vaginal bleeding or spotting
• stomach or abdominal cramps, bloating
• nausea and vomiting
• hair loss
• fluid retention
• vaginal yeast infection
• redness or irritation at patch placement site

These are not all the possible side effects of CombiPatch. For more information, ask your healthcare provider or pharmacist. Tell your healthcare provider if you have any side effects that bother you or does not go away.

You may report side effects to Noven at 1-800-455-8070 or to FDA at 1-800-FDA-1088.

What can I do to lower my chances of getting a serious side effect with CombiPatch?

• Talk with your healthcare provider regularly about whether you should continue using CombiPatch.
• See your healthcare provider right away if you get vaginal bleeding while using CombiPatch.
• Have a pelvic exam, breast exam and mammogram (breast X-ray) every year unless your healthcare provider tells you something else.
• If members of your family have had breast cancer or if you have ever had breast lumps or an abnormal mammogram, you may need to have breast exams more often.
• If you have high blood pressure, high cholesterol (fat in the blood), diabetes, are overweight, or if you use tobacco, you may have higher chances for getting heart disease.
• Ask your healthcare provider for ways to lower your chances for getting heart disease.

How should I store and throw away used CombiPatch?

• Store CombiPatch in the refrigerator at 36℉ to 46℉ (2℃ to 8℃). Allow patch to reach room temperature before application.
• Do not store CombiPatch outside of its pouch.
• Used patches still contain estrogen and progestin. To throw away the patch, fold the sticky side of the patch together, place in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.

Keep CombiPatch and all medicines out of the reach of children.

General information about the safe and effective use of CombiPatch.

Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use CombiPatch for conditions for which it was not prescribed. Do not give CombiPatch to other people, even if they have the same symptoms you have. It may harm them.

This leaflet provides a summary of the most important information about CombiPatch. If you would like more information, talk with your healthcare provider or pharmacist. You can ask for information about CombiPatch that is written for health professionals. You can get more information by calling 1-800-455-8070

What are the ingredients in CombiPatch?

Active Ingredients: estradiol and norethindrone acetate

Inactive Ingredients: acrylic adhesive, silicone adhesive, oleic acid NF, povidone USP, dipropylene glycol, polyester release protective liner

102538-5

CombiPatch
(käm-bē `pach)
(estradiol/norethindrone acetate transdermal system)

Step 1. Pick the days you will change your CombiPatch.

• You will need to change your patch every 3 to 4 days (twice weekly).

Step 2. Remove CombiPatch from the pouch.

• Tear open the protective pouch at the slit (do not use scissors) and remove the patch. See Figure A.
• The pouch should not be opened until you are ready to put the patch on.

Step 3. Remove the adhesive liner.

• Peel off one side of the protective liner. See Figure B.
• Do not touch the sticky part of the patch with your fingers. See Figure B.

Step 4. Placing the CombiPatch on your skin.

• Put the sticky side of the patch on the lower abdomen (below the panty line). See Figure C.
• Peel off the second side of the protective liner. See Figure C.
• Press the patch firmly in place with your hand for about 10 seconds. See Figure D.

Note:

• Avoid the waistline, since clothing and belts may cause the CombiPatch to be rubbed off.
• Do not apply the CombiPatch to or near your breasts.
• Only apply the CombiPatch to skin that is clean, dry, and free of any powder, oil, or lotion.
• You should not apply the CombiPatch to injured, burned, or irritated skin, or areas with skin conditions (such as birth marks, tattoos, or that is very hairy).

Step 5. Press the CombiPatch firmly onto your skin.

• Rub the edges of the CombiPatch with your fingers to make sure that it will stick to your skin. See Figure E.

Note:

• Bathing, swimming, or showering will not affect the CombiPatch.
• Once in place, the patch should not be exposed to the sun for prolonged periods of time.
• If your CombiPatch falls off reapply it. If you cannot reapply the CombiPatch, apply a new CombiPatch to another area (See Figures C, D and E) and continue to follow your original placement schedule.
• If you stop using your CombiPatch or forget to apply a new CombiPatch as scheduled you may have spotting, or bleeding, and your symptoms may come back.

Step 6. Throwing away your used CombiPatch.

• When it is time to change your CombiPatch, remove the old CombiPatch before you apply a new one.
• To throw away the patch, fold the sticky side of the patch together, place it in a sturdy child-proof container, and place this container in the trash. Used patches should not be flushed in the toilet.

This Patient Information and Instructions for Use have been approved by the U.S. Food and Drug Administration.

Manufactured by:
Noven Pharmaceuticals Inc.
Miami, FL 33186

Distributed by:
Noven Therapeutics, LLC
Miami, FL 33186

For more information call 1-800-455-8070 or visit www.combipatch.com.

© 2024 Noven Pharmaceuticals, Inc.

102538-5

02/2024

PRINCIPAL DISPLAY PANEL - NDC - 68968-0514-8 CombiPatch Count - 50/140

NDC 68968-0514-8
Includes 8 Systems

See New Storage Requirements

Combipatch® 50/140

(estradiol/norethindrone acetate transdermal system)

0.05/0.14 mg per day

Noven

www.combipatch.com

Twice-Weekly Rx Only

Combipatch® 50/140

(estradiol/norethindrone acetate transdermal system)

0.05/0.14 mg per day

Twice-Weekly Rx Only

Contains 0.62 mg estradiol USP and 2.7 mg norethindrone acetate (NETA) USP to provide 0.05/0.14 mg of estradiol/NETA per day.

Inactive components: a silicone and acrylic-based multi-polymeric adhesive, povidone USP, oleic acid NF, polyolefin laminate backing, polyester release liner and dipropylene glycol.

Dosage and Administration: For transdermal use only. See package insert. Allow patch to reach room temperature before application. DO NOT STORE UNPOUCHED.

Keep out of the reach of children.

Store Combipatch® refrigerated at 36°F to 46°F (2°C to 8°C)

See side panel for lot number and expiration date. www.combipatch.com

N3 68968-0514-8 0 302391-4

Noven

PLEASE READ THIS BEFORE APPLYING PATCH.

Allow patch to reach room temperature before application.

See reverse side for patient instructions.

pull To open here

LOT/EXP GTIN 00368968051480

969864

Mfd. By: Noven Pharmaceuticals, Inc.

Miami, Florida 33186

Dist. By Noven Therapeutics, LLC

Miami, Florida 33186

PRINCIPAL DISPLAY PANEL - NDC - 68968-0525-8 CombiPatch Count - 50/250

NDC 68968-0525-8

Includes 8 Systems

See New Storage Requirements

Combipatch® 50/250

(estradiol/norethindrone acetate transdermal system)

0.05/0.25 mg per day

Noven

www.combipatch.com

Twice-Weekly Rx Only

Combipatch® 50/250

(estradiol/norethindrone acetate transdermal system)

0.05/0.25 mg per day

Twice-Weekly Rx Only

Contains 0.51 mg estradiol USP and 4.8 mg norethindrone acetate (NETA) USP to provide 0.05/0.25 mg of estradiol/NETA per day.

Inactive components: a silicone and acrylic-based multi-polymeric adhesive, povidone USP, oleic acid NF, polyolefin laminate backing, polyester release liner and dipropylene glycol.

Dosage and Administration: For transdermal use only. See package insert. Allow patch to reach room temperature before application. DO NOT STORE UNPOUCHED.

Keep out of the reach of children.

Store Combipatch® refrigerated at 36°F to 46°F (2°C to 8°C)

See side panel for lot number and expiration date. www.combipatch.com

N3 68968-0525-8 0 302390-4

Noven

PLEASE READ THIS BEFORE APPLYING PATCH.

Allow patch to reach room temperature before application.

See reverse side for patient instructions.

pull To open here

LOT/EXP GTIN 00368968052586

969864

Mfd. By: Noven Pharmaceuticals, Inc.

Miami, Florida 33186

Dist. By Noven Therapeutics, LLC

Miami, Florida 33186