Short answer: In the label's placebo-controlled hot flash studies, the most common CombiPatch side effects were breast pain (25% on 0.05/0.14 mg and 31% on 0.05/0.25 mg vs 7% on placebo), dysmenorrhea (20% and 21% vs 5%), headache and back pain. CombiPatch carries a boxed warning on blood clots, stroke, heart attack, breast cancer, probable dementia and endometrial cancer.
What CombiPatch is approved for: CombiPatch is a patch that releases both estradiol, an estrogen, and norethindrone acetate (NETA), a progestin. It is approved for a woman with a uterus to treat moderate to severe hot flashes due to menopause, moderate to severe symptoms of vulvar and vaginal atrophy due to menopause, and low estrogen due to hypogonadism, castration or primary ovarian failure (Indications and Usage). For vaginal symptoms alone, the label says topical vaginal products should be considered.
Source
COMBIPATCH (estradiol/norethindrone acetate transdermal system), prescribing information, Patient Information and Instructions for Use. Noven Pharmaceuticals. DailyMed, version published February 27, 2024. DailyMed setid 83198ef1-11c4-11e4-9191-0800200c9a66
WARNING: CARDIOVASCULAR DISORDERS, BREAST CANCER, ENDOMETRIAL CANCER, AND PROBABLE DEMENTIA
Estrogen plus progestin therapy: in the Women's Health Initiative (WHI), daily oral conjugated estrogens (CE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg raised the risk of deep vein thrombosis, pulmonary embolism, stroke and heart attack in women 50 to 79 over 5.6 years, and of invasive breast cancer. The WHI Memory Study found a higher risk of probable dementia in women 65 and older over 4 years. Estrogen-alone therapy: a woman with a uterus who uses estrogen without a progestin has a higher risk of endometrial cancer, and CE alone raised the risk of stroke, DVT and probable dementia. Neither is to be used to prevent heart disease or dementia. Without comparable data, the label says these risks should be assumed to be similar for other doses and forms. Estrogens, with or without progestins, are prescribed at the lowest effective dose for the shortest duration consistent with treatment goals and risks.
These are the label's own numbers from the Adverse Reactions section. Where the label compares with placebo (a dummy treatment), both columns are shown, so you can see how much more often a reaction happened on CombiPatch.
| Adverse reaction | CombiPatch 0.05/0.14 (n=113) | CombiPatch 0.05/0.25 (n=112) | Placebo (n=107) |
|---|---|---|---|
| Breast pain | 25% | 31% | 7% |
| Dysmenorrhea | 20% | 21% | 5% |
| Headache | 18% | 20% | 20% |
| Back pain | 11% | 9% | 5% |
| Nausea | 11% | 8% | 7% |
| Asthenia | 8% | 12% | 4% |
| Flu syndrome | 9% | 5% | 7% |
| Papanicolaou smear suspicious | 8% | 4% | 5% |
| Abdominal pain | 7% | 6% | 4% |
| Respiratory disorder | 7% | 12% | 7% |
| Rhinitis | 7% | 13% | 9% |
| Menstrual disorder | 6% | 12% | 2% |
| Vaginitis | 6% | 13% | 5% |
| Leukorrhea | 5% | 5% | 3% |
| Pharyngitis | 4% | 10% | 2% |
| Sinusitis | 4% | 9% | 9% |
| Application site reaction | 2% | 6% | 4% |
| Depression | 3% | 5% | 9% |
| Insomnia | 3% | 6% | 7% |
Two placebo-controlled studies of moderate to severe hot flashes, three 28-day cycles. Doses are mg of estradiol/NETA delivered per day. Values are percent of women. Application site reactions include bleeding, bruising, burning, redness, itching, rash, swelling and other skin changes where the patch was worn.
| Adverse reaction | CombiPatch 0.05/0.14 (n=325) | CombiPatch 0.05/0.25 (n=312) | Vivelle 0.05 mg (n=318) |
|---|---|---|---|
| Breast pain | 34% | 48% | 40% |
| Dysmenorrhea | 30% | 31% | 19% |
| Headache | 25% | 17% | 21% |
| Application site reaction | 20% | 23% | 17% |
| Rhinitis | 19% | 22% | 17% |
| Pain | 19% | 15% | 13% |
| Menstrual disorder | 17% | 19% | 14% |
| Back pain | 15% | 14% | 13% |
| Diarrhea | 14% | 9% | 7% |
| Flu syndrome | 14% | 10% | 7% |
| Abdominal pain | 12% | 14% | 16% |
| Nausea | 8% | 12% | 11% |
| Sinusitis | 10% | 12% | 12% |
| Leukorrhea | 10% | 8% | 9% |
| Vaginitis | 9% | 13% | 13% |
| Vaginal hemorrhage | 3% | 6% | 12% |
One-year studies comparing CombiPatch with an estradiol-only patch (Vivelle 0.05 mg per day); there was no placebo group. Shown are rows at 10% or more in any group. Values are percent of women.
After 1 year, endometrial hyperplasia on the continuous combined regimen was 1 of 123 (<1%) on 0.05/0.14 mg and 1 of 98 (1%) on 0.05/0.25 mg, vs 39 of 103 (38%) on the estradiol-only patch (Table 5). On the continuous sequential regimen it was 1 of 117 (<1%) and 1 of 114 (<1%), vs 23 of 115 (20%) (Table 6).
On the continuous combined regimen, the share of women with no bleeding or spotting in cycles 10 through 12 was 53 percent on 0.05/0.14 mg and 39 percent on 0.05/0.25 mg.
Across 6 trials of 1,287 women, the patch fully stuck to the skin nearly 90 percent of the time over its 3- to 4-day wear; less than 2 percent needed to reapply or replace a patch, and 2 women (0.2 percent) stopped because of poor sticking.
WHI CE plus MPA vs placebo, per 10,000 women-years: stroke 33 vs 25; DVT 26 vs 13; pulmonary embolism 18 vs 8; all VTE 35 vs 17; invasive breast cancer 41 vs 33. WHIMS probable dementia: 45 vs 22 per 10,000 women-years (relative risk 2.05).
Reported after approval: endometrial hyperplasia, polyps, fibroids, uterine spasms, breast cancer, high blood pressure, varicose veins, cholestatic jaundice, gallstones, raised liver enzymes, skin discoloration, mood swings, libido changes, migraine, vertigo, angioedema, hypersensitivity and weight gain.
The Warnings and Precautions part of the label lists these. Each line gives the label's heading and what it means in plain words.
Who should not use it. Women with undiagnosed abnormal genital bleeding, known, suspected or past breast cancer, estrogen-dependent cancer, active or past DVT, pulmonary embolism, stroke or heart attack, a known anaphylactic reaction, angioedema or hypersensitivity with CombiPatch, liver impairment or disease, protein C, protein S or antithrombin deficiency or other clotting disorders, or known or suspected pregnancy.
Blood clots, stroke and heart attack. Estrogen plus progestin raised the risk of pulmonary embolism, DVT, stroke and heart attack, and treatment is stopped right away if one occurs or is suspected. If feasible, estrogens are stopped 4 to 6 weeks before surgery linked to clots or during long immobilization.
Breast, endometrial and ovarian cancer. CE plus MPA raised invasive breast cancer risk in the WHI, and hormone therapy has been linked to more abnormal mammograms. Estrogen without a progestin raises endometrial cancer risk 2 to 12 times in women with a uterus. A meta-analysis linked hormone therapy to a higher ovarian cancer risk (relative risk 1.41 with current use).
Probable dementia. In women 65 to 79, probable dementia was more common on CE plus MPA (relative risk 2.05) and on CE alone (1.49) than on placebo. Whether this applies to younger women is unknown.
Gallbladder, calcium and vision. Estrogens are linked to a 2- to 4-fold rise in gallbladder disease needing surgery, severe high calcium in breast cancer spread to bone, and blood clots in the retina; the patch is stopped pending exam for sudden vision changes.
Angioedema and severe allergic reactions. Swelling of the eyes, face, throat, tongue or limbs, and anaphylactic reactions needing emergency care, have been reported after approval. A woman who develops angioedema on CombiPatch does not receive it again.
Other conditions. Estrogens can raise blood pressure in rare reactions, raise triglycerides with a risk of pancreatitis, raise thyroid hormone needs, cause fluid retention and low calcium in hypoparathyroidism, and worsen endometriosis, asthma, diabetes, epilepsy, migraine, porphyria, lupus and liver hemangiomas.
From the Patient Information that comes with CombiPatch:
Dose Track has a side-effect log. Each entry records the symptom, a severity (none, mild, moderate, severe or life-threatening), the date and an optional note, and can be tied to a specific dose or logged on its own. The history screen shows what you logged over time, which makes it easier to tell your prescriber when a reaction started and whether it is easing. The app records what you enter; it does not judge whether a symptom is serious. For anything on the label's call-your-doctor list, call your doctor.
This page is what the FDA label says, in plain words. It is not medical advice. Follow your prescriber, and ask them or your pharmacist about anything here.