Rehanzil40 mg+1 mg+0.5 mg

Rehanzil is a fixed-dose combination of a GnRH receptor antagonist (relugolix) with low-dose "add-back" hormone therapy (estradiol and norethindrone acetate), indicated in premenopausal women for:

• Established/FDA-approved use: Management of moderate to severe pain associated with endometriosis.
• Established/FDA-approved use: Management of heavy menstrual bleeding associated with uterine fibroids (leiomyomas).

Rehanzil is not indicated for use in men; it is a women's-health combination product distinct from relugolix monotherapy used for advanced prostate cancer. It is not intended as a contraceptive, and effective non-hormonal contraception should be used if pregnancy is possible.

Each film-coated tablet of Relugolix + Estradiol + Norethindrone contains relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg as active ingredients, combined in a single fixed-dose tablet taken once daily.

Rehanzil combines a gonadotropin-releasing hormone (GnRH) receptor antagonist (relugolix) with low-dose estrogen (estradiol) and a progestin (norethindrone acetate) as "add-back" hormone therapy. Relugolix suppresses ovarian estrogen production by blocking pituitary GnRH receptors, which reduces estrogen-dependent pain and bleeding; the added low-dose estradiol and norethindrone acetate help offset hypoestrogenic effects such as bone mineral density loss and vasomotor symptoms that would otherwise occur with GnRH suppression alone.

Rehanzil belongs to the therapeutic class of GnRH receptor antagonists combined with hormone add-back therapy, used in reproductive endocrinology and gynecology for hormonally-driven gynecologic conditions.

Mechanism of Action

Relugolix + Estradiol + Norethindrone works through two complementary mechanisms:

• Relugolix is a non-peptide GnRH receptor antagonist that competitively binds pituitary GnRH receptors, rapidly suppressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. This suppresses ovarian estradiol and progesterone production, reducing estrogen-dependent uterine bleeding and endometriosis-associated pain.
• Estradiol and norethindrone acetate are added at low, fixed doses ("add-back therapy") to partially replace the estrogen and progestin lost due to ovarian suppression, which reduces hypoestrogenic side effects (hot flashes, bone mineral density loss) while still allowing clinical benefit on bleeding and pain.

Pharmacokinetics

Relugolix is absorbed orally with low bioavailability and is metabolized mainly via CYP3A4, with some involvement of P-glycoprotein transport. Estradiol and norethindrone acetate undergo hepatic metabolism typical of oral estrogen/progestin combinations. Steady-state suppression of ovarian estradiol is generally achieved within the first month of continuous once-daily dosing.

Rehanzil is administered orally, swallowed whole with water, once daily at approximately the same time each day, with or without food. Consistent daily timing helps maintain steady hormone suppression.

Rehanzil has the following well-established, clinically significant interactions:

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's Wort): may substantially decrease relugolix plasma concentrations and reduce efficacy; concomitant use should generally be avoided.
• P-glycoprotein (P-gp) inhibitors (e.g., certain macrolide antibiotics, cyclosporine): may increase relugolix plasma concentrations; administer relugolix-containing products at least 6 hours before a P-gp inhibitor and monitor for increased adverse effects.
• Other estrogen-containing products or hormonal contraceptives: concomitant use with additional exogenous estrogens or hormonal contraceptives is not recommended, as it may increase thromboembolic risk (see Precautions and Warnings).
• Hepatically-metabolized drugs: estradiol/norethindrone components can alter hepatic protein binding and metabolism of some co-administered drugs; clinical monitoring is advised when starting or stopping Rehanzil in patients on narrow-therapeutic-index hepatically cleared medications.

Adverse effects of Rehanzil differ somewhat by indication:

Uterine Fibroids (≥3% incidence)

• Hot flashes/vasomotor symptoms
• Abnormal or irregular uterine bleeding
• Hair loss (alopecia)
• Decreased libido

Endometriosis (≥3% incidence)

• Headache
• Hot flashes/vasomotor symptoms
• Mood changes (including depressed mood, anxiety)
• Abnormal uterine bleeding
• Nausea
• Toothache
• Back pain

Other effects include changes in bone mineral density and lipid parameters (see Precautions and Warnings for details, which are not repeated here).

Pregnancy: Rehanzil is contraindicated in pregnancy. It may cause early pregnancy loss based on its mechanism of action and animal reproduction data. Pregnancy should be excluded before starting treatment, and effective non-hormonal contraception is recommended during use, since Rehanzil does not reliably prevent ovulation-related fertility in all patients and its estrogen/progestin components are not intended as a standalone contraceptive. If pregnancy occurs or is suspected during treatment, Rehanzil should be discontinued immediately and a physician consulted.

Lactation: There is limited data on the presence of Rehanzil components in human milk or its effects on milk production or the breastfed infant. Use during breastfeeding is not recommended unless the potential benefit clearly justifies the potential risk to the infant; a physician should be consulted before use while breastfeeding.

Thromboembolic Risk

Rehanzil contains estrogen and is associated with an increased risk of venous and arterial thromboembolic events, including deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction. Caution is warranted in patients with risk factors such as smoking, obesity, or migraine with aura; Rehanzil is contraindicated in those with current or prior thromboembolic disease (see Contraindications).

Bone Mineral Density Loss

Use of Rehanzil is associated with dose-dependent loss of bone mineral density, which may not be fully reversible, particularly with treatment duration beyond the labeled maximum. Treatment should generally be limited to 24 months, and baseline and periodic bone mineral density monitoring is recommended, especially for extended use.

Mood Changes

Depression, anxiety, and, rarely, suicidal ideation have been reported. Patients should be monitored for new or worsening mood symptoms, and evaluated promptly if these occur.

Hepatic Effects

Elevations in liver enzymes and hepatic injury have been reported; periodic hepatic monitoring is advised, and Rehanzil is contraindicated in active liver disease.

Blood Pressure

Blood pressure should be monitored during treatment; Rehanzil should be discontinued if a significant increase in blood pressure occurs.

Bleeding Pattern Changes

Rehanzil often improves heavy menstrual bleeding, but irregular spotting or bleeding can occur, particularly during the initial months of treatment. Altered bleeding patterns may also delay recognition of pregnancy.

Contraception

Effective non-hormonal contraception is recommended during treatment, as discussed under Pregnancy and Lactation.

There is limited clinical experience with overdose of Rehanzil. In case of suspected overdose, seek immediate medical attention or contact a poison control center. Management should be supportive and symptomatic; there is no specific antidote. Do not attempt unsupervised home treatment for a suspected overdose.

Store at room temperature (below 30°C), away from light and moisture. Keep out of reach of children.

Renal Impairment

No dose adjustment is established; data in patients with severe renal impairment are limited, and Rehanzil should be used with caution in this group.

Hepatic Impairment

Rehanzil is contraindicated in patients with active liver disease or hepatic impairment (see Contraindications).

Elderly/Postmenopausal Women

Rehanzil is indicated only in premenopausal women; it is not intended for use in postmenopausal women.

Pediatric Patients

Safety and efficacy have not been established in pediatric or premenarchal patients.

Men

Rehanzil is not indicated for use in men; this fixed-dose combination is distinct from relugolix monotherapy used for prostate cancer.

Use of Rehanzil should generally be limited to 24 months due to the risk of continued, potentially irreversible bone mineral density loss with longer treatment duration. The need for continued therapy should be reassessed periodically by the prescribing physician, weighing symptom control against bone health monitoring.

Relugolix + Estradiol + Norethindrone is classified as a GnRH receptor antagonist (relugolix) combined with hormone add-back therapy (estrogen/progestin), used in gynecologic and reproductive endocrine disorders.

Relugolix + Estradiol + Norethindrone acts by having relugolix competitively block pituitary GnRH receptors, suppressing LH/FSH release and consequently ovarian estradiol and progesterone production, which reduces estrogen-driven uterine bleeding and endometriosis pain; the co-formulated low-dose estradiol and norethindrone acetate partially replace lost hormone levels to limit hypoestrogenic side effects such as vasomotor symptoms and bone loss.

Rehanzil is not indicated for use in pediatric patients. Safety and efficacy in patients who have not reached menarche, or in children and adolescents generally, have not been established.