COMBIPATCH
Clinical safety rating: caution
Comprehensive clinical and safety monograph for COMBIPATCH (COMBIPATCH).
Combipatch contains estradiol, an estrogen, and norethindrone acetate, a progestin. Estrogens bind to estrogen receptors, leading to gene transcription and physiological effects. Norethindrone acetate transforms proliferative endometrium into secretory endometrium, reducing endometrial hyperplasia risk.
| Metabolism | Estradiol is metabolized primarily in the liver via hydroxylation by CYP450 enzymes (extensively) and conjugation to glucuronides and sulfates. Norethindrone acetate is deacetylated to norethindrone, which is metabolized by reduction and sulfate conjugation; CYP450-mediated oxidation is a minor pathway. |
| Excretion | Estradiol: 90% renal as glucuronide and sulfate conjugates, 10% biliary/fecal. Norethindrone: 60% renal, 40% biliary/fecal. |
| Half-life | Estradiol: 12-16 hours terminal half-life. Norethindrone: 8-10 hours. Steady-state reached by day 3-5. |
| Protein binding | Estradiol: 98-99% bound to SHBG and albumin. Norethindrone: 95-98% bound to SHBG and albumin. |
| Volume of Distribution | Estradiol: 1.2-1.6 L/kg. Norethindrone: 4-6 L/kg. Indicates extensive tissue distribution. |
| Bioavailability | Transdermal: Estradiol 100% (avoid first-pass). Oral estradiol: 2-10% (not applicable for Combipatch). Norethindrone: transdermal 100%. |
| Onset of Action | Transdermal: Estradiol levels increase within 2-4 hours; clinical effect on vasomotor symptoms within 2-4 weeks. |
| Duration of Action | Transdermal patch provides continuous delivery over 7 days; sustained hormone levels for 7 days. Clinical duration for symptom relief persists as long as patch applied. |
Transdermal: One patch applied twice weekly (every 3-4 days). Each patch delivers estradiol 0.05 mg/day and norethindrone acetate 0.14 mg/day or 0.05/0.25 mg/day.
| Dosage form | FILM, EXTENDED RELEASE |
| Renal impairment | No dose adjustment necessary for mild to moderate renal impairment. Not studied in severe renal impairment (GFR <30 mL/min); use with caution. |
| Liver impairment | Contraindicated in patients with known or suspected liver disease, including hepatic impairment Child-Pugh class B or C. Use not recommended in any degree of hepatic impairment. |
| Pediatric use | Safety and efficacy have not been established in pediatric patients. Not indicated for use in children. |
| Geriatric use | No specific dose adjustment recommended based on age alone; use lowest effective dose for shortest duration due to increased risks of thromboembolism, stroke, dementia, and breast cancer in women over 65. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for COMBIPATCH (COMBIPATCH).
| Breastfeeding | Estradiol and norethindrone acetate are excreted in human milk. The milk-to-plasma ratio for estradiol is approximately 1:1. Norethindrone acetate has an M/P ratio of approximately 0.6. Use during lactation is not recommended as it may reduce milk production and quality. Effects on the nursing infant are unknown. |
| Teratogenic Risk | First trimester: Epidemiological studies suggest a small increased risk of congenital anomalies, particularly cardiac defects and hypospadias, with estrogen-progestin combinations. Second and third trimesters: Fetal exposure to estrogens may cause adverse effects including urogenital abnormalities and possibly neurodevelopmental effects. Combipatch is not indicated for use in pregnancy and should be discontinued if pregnancy occurs. |
■ FDA Black Box Warning
Estrogens plus progestin therapy should not be used for the prevention of cardiovascular disease or dementia. Increased risks of myocardial infarction, stroke, invasive breast cancer, pulmonary emboli, and deep vein thrombosis have been reported. Estrogen plus progestin therapy has been shown to increase the risk of probable dementia in postmenopausal women.
| Serious Effects |
["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 (e.g., stroke, MI) or history of these conditions","Known anaphylactic reaction or angioedema to any component","Hepatic impairment or disease","Known protein C, protein S, or antithrombin deficiency, or other thrombophilic disorders","Pregnancy"]
| Precautions | ["Cardiovascular disorders: Increased risk of stroke, DVT, pulmonary embolism, and myocardial infarction, especially in women >35 years who smoke.","Malignant neoplasms: Increased risk of endometrial cancer (unopposed estrogen), breast cancer (with progestin), and ovarian cancer.","Dementia: Increased risk of probable dementia in women ≥65 years.","Gallbladder disease: Increased risk.","Hypertriglyceridemia: Possible pancreatitis.","Fluid retention: Caution in cardiac or renal dysfunction.","Hypocalcemia and hypo- and hyperthyroidism: Monitor.","Hepatic hemangiomas: Enlargement possible."] |
Loading safety data…
| Fetal Monitoring | If inadvertently used during pregnancy, monitor fetal development with ultrasound to assess for congenital anomalies. No routine monitoring is required as Combipatch is contraindicated in pregnancy. |
| Fertility Effects | Estrogen-progestin combinations can suppress ovulation and delay return to fertility after discontinuation. Contraceptive use, including Combipatch, may mask early pregnancy. Upon discontinuation, return to fertility typically occurs within one to two menstrual cycles. |