Estradiol, Transdermal (Estradot, Climara, Estrogel, Divigel)

1. Health Canada Product Monograph — Estradiol, Transdermal

• Relief of moderate to severe vasomotor symptoms (hot flashes, night sweats) of menopause.
• May be used to help prevent postmenopausal osteoporosis in women at significant risk, generally after non-estrogen options have been considered, when the patient also has vasomotor symptoms.
• Often preferred over oral estrogen in women with additional venous thromboembolism risk factors, migraine, high triglycerides, hypertension, malabsorption conditions, low libido, or who smoke or work shift work, since the transdermal route avoids first-pass hepatic metabolism.
• Women who still have a uterus need an appropriate progestogen added to protect against overgrowth of the uterine lining.

Contraindicated in pregnancy. Confirm pregnancy status and discuss alternative therapy with the prescriber before dispensing.

• Contraindicated in known or suspected pregnancy.
• Discontinue immediately if pregnancy occurs during treatment.

• Not recommended during breastfeeding; estrogen can reduce the amount and quality of breast milk, and measurable amounts pass into breast milk.

• Combined estrogen-progestogen therapy in women 65 and older has been associated with an increased risk of probable dementia and stroke in large trials of oral formulations; the same class-level caution applies to the transdermal route.

• Not indicated in patients under 18 years of age; safety and efficacy have not been established.

• Patch (Estradot): apply 1 patch to clean, dry, unbroken skin on the lower abdomen or buttock, starting at 25-50 mcg/day, changed twice weekly; rotate the application site with each new patch and allow at least 1 week between uses of the same site.
• Patch (Climara): apply 1 patch at 25-100 mcg/day, changed once weekly, to the lower abdomen, rotating sites.
• Do not apply any patch to the breasts, or to skin that is oily, damaged, or at the waistline where clothing may rub it loose.
• Gel (Estrogel): apply 0.75-1.5 mg (1-2 pump actuations) once daily to the arm (shoulder to wrist) or inner thigh; do not apply to the breasts, and do not rotate the application site once established.
• Gel (Divigel): apply 0.25-1 mg (1 packet) once daily to the upper thigh, alternating the right and left thigh with each dose; spread over an area of approximately 5 x 7 inches and allow to dry fully before dressing.
• In women with an intact uterus, add a progestogen either cyclically (12-14 days each month) or continuously; women without a uterus use estrogen alone.
• Starting with a low or standard dose and titrating to symptom response after 3-4 weeks is reasonable; the lowest effective dose should be used, with periodic reassessment of the need for continued treatment.

If overdose is suspected, seek emergency medical attention immediately or contact your regional Poison Control Centre without delay.

• Reports of accidental large exposures have not shown serious acute harm; overdose in women may cause nausea, breast tenderness, fluid retention, bloating, or vaginal bleeding.
• No specific antidote exists; a patch should be removed and gel washed off, with supportive care as needed.

• Application-site redness, irritation, or itching (patch) may occur.
• Breakthrough bleeding or spotting may occur, especially in the first year of continuous combined use.
• Nausea, headache, breast tenderness, and bloating/fluid retention may occur.
• Mood changes, including irritability or low mood, may occur.

Serious side effects require immediate discussion with the prescriber or emergency care.

• Estrogen therapy, especially combined with a progestogen, increases the risk of stroke, blood clots (deep vein thrombosis, pulmonary embolism), and, with long-term combined use, invasive breast cancer; observational data suggest this risk may be lower with the transdermal route than with oral estrogen at equivalent doses, but it is not eliminated.
• Unopposed estrogen in a woman with an intact uterus increases the risk of endometrial hyperplasia and endometrial cancer.
• Gallbladder disease requiring surgery occurs more often with estrogen use.
• Seek urgent medical attention for chest pain, sudden shortness of breath, calf or leg swelling/pain, sudden severe headache, vision changes, weakness, numbness, or slurred speech.

• Do not apply the patch or gel to broken, irritated, or sunburned skin.
• Avoid prolonged direct heat (heating pads, saunas, hot tubs, sun exposure) over the application site, since heat can increase the rate of drug absorption.
• Use with caution in women with a history of migraine (particularly with aura), high triglycerides, liver or gallbladder disease, uterine fibroids, or cardiovascular risk factors.
• Estrogen therapy is generally stopped about 4 weeks before major surgery associated with an increased clotting risk, or during prolonged immobilization.

• Known or suspected pregnancy.
• Undiagnosed abnormal vaginal bleeding.
• Known, suspected, or past history of breast cancer or other estrogen-dependent cancer.
• Active liver disease, or liver function tests that have not returned to normal.
• Active or past history of venous thromboembolism (deep vein thrombosis, pulmonary embolism) or arterial thromboembolic disease (stroke, myocardial infarction).
• Known thrombophilia (e.g., protein C, protein S, or antithrombin deficiency).
• Known hypersensitivity to estradiol or any component of the formulation.

• The transdermal route bypasses first-pass hepatic metabolism, so it is less affected by hepatic enzyme-inducing or -inhibiting drugs than oral estrogen, though clinically relevant interactions can still occur with strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort) or inhibitors (e.g., ketoconazole, clarithromycin, ritonavir).
• Estradiol may reduce the effectiveness of anticoagulant, antidiabetic, and antihypertensive medications.
• Can affect the results of certain thyroid and liver function tests; inform laboratory staff of estrogen use.

• None significant; the transdermal route is not subject to first-pass gut/liver metabolism, so food and grapefruit juice do not meaningfully affect exposure the way they can with oral estrogen.

• Patch: applied on a fixed twice-weekly (Estradot) or once-weekly (Climara) schedule, rotating sites.
• Gel: applied once daily at approximately the same time, typically after showering, allowing the site to dry fully before dressing.

• Store patches at room temperature (15-30°C) in their original sealed pouch until use.
• Store gel at room temperature; Estrogel and Divigel are alcohol-based and flammable until fully dry — keep away from open flame or lit cigarettes until the application site has dried.

• Rotate the application site with every patch or gel dose and avoid applying to the breasts.
• The transdermal route may carry a lower blood clot risk than oral estrogen tablets, but hormone therapy risks are not eliminated — report leg swelling/pain, sudden shortness of breath, or stroke symptoms right away.
• Women who still have a uterus need a progestogen added to protect the uterine lining; report any unusual vaginal bleeding.
• Estrogel and Divigel gel are flammable until dry — avoid open flame near the application site until it has fully dried.