Elagolix And Estradiol And Norethisterone

5 WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Vascular Events: Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs. Stop ORIAHNN if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately. ( 5.1 ) Bone Loss: Duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Baseline and periodic BMD assessments are recommended. Assess risk-benefit for women with additional risk factors for bone loss. ( 5.2 ) Suicidal Ideation and Mood Disorders: Advise patients to seek medical attention for suicidal ideation, suicidal behavior, new onset or worsening depression, anxiety, or other mood changes. ( 5.4 ) Hepatic Impairment and Transaminase Elevations: Counsel patients on signs and symptoms of liver injury. ( 5.5 ) Elevated Blood Pressure: Do not use in women with uncontrolled hypertension. For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly. ( 5.6 ) Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy: Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing ORIAHNN. ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it alters menstrual bleeding. Perform pregnancy testing if pregnancy is suspected and discontinue ORIAHNN if pregnancy is confirmed. ( 5.8 ) Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No 5): This product contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. ( 5.12 ) 5.1 Thromboembolic Disorders and Vascular Events ORIAHNN is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events [see Contraindications ( 4 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two thrombotic events occurred in 453 ORIAHNN-treated women (thrombosis in the calf and pulmonary embolism) [see Adverse Reactions ( 6.1 ) and Clinical Studies ( 14 ) ] . Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of ORIAHNN, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity. Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. If feasible, discontinue ORIAHNN at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Stop ORIAHNN immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported in patients receiving estrogens and progestins. 5.2 Bone Loss ORIAHNN is contraindicated in women with known osteoporosis [see Contraindications ( 4 )] . ORIAHNN may cause a decrease in bone mineral density (BMD) in some patients. BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions ( 6.1 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3) [see Clinical Studies ( 14 ) ] , seven out of 453 (1.5%) ORIAHNN-treated women experienced fractures, including one (0.2%) with a fragility fracture, compared to one out of 196 (0.5%) placebo-treated women (patient had a non-fragility fracture). Five of the seven ORIAHNN-treated women reported these fractures in the post-treatment follow-up period. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown. Consider the benefits and risks of ORIAHNN treatment in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, including taking medications that may decrease BMD (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or proton pump inhibitors). Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and periodically thereafter. Consider discontinuing ORIAHNN if the risk associated with bone loss exceeds the potential benefit of treatment. Limit the duration of use to 24 months to reduce the extent of bone loss [see Indications and Usage ( 1 ) and Dosage and Administration ( 2.1 ) ] . Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial. 5.3 Hormonally-Sensitive Malignancies ORIAHNN is contraindicated in women with current or history of breast cancer and in women at increased risk for hormonally-sensitive malignancies, such as those with mutations in BRCA genes [see Contraindications ( 4 ) ] . In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two (0.4%) cases of breast cancer in 453 ORIAHNN-treated women were observed. No breast cancer cases were seen in placebo-treated women [see Adverse Reactions ( 6.1 ) ] . The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. Surveillance measures, such as breast examinations and regular mammography, are recommended. Discontinue ORIAHNN if a hormonally-sensitive malignancy is diagnosed. 5.4 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), ORIAHNN-treated women had a higher incidence (3%) of depression, depressed mood, and/or tearfulness compared to placebo-treated women (1%) [see Adverse Reactions ( 6.1 ) ] . Suicidal ideation and behavior, including a completed suicide, occurred in women treated with lower doses of elagolix in clinical trials conducted for a different indication. Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORIAHNN if such events occur. 5.5 Hepatic Impairment and Transaminase Elevations Contraindication in Patients with Hepatic Impairment ORIAHNN is contraindicated in women with known hepatic impairment or disease [see Contraindications ( 4 ) , Use in Specific Populations ( 8.7 ) , and Clinical Pharmacology ( 12.3 ) ] . Transaminase Elevations In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), elevations (> 3 times the upper limit of the reference range) in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 1.1% (4/379) and 1.3% (5/379) of ORIAHNN-treated patients, respectively, compared to no elevations in placebo. Transaminases peaked at 8 times the upper limit for ALT and 6 times the upper limit for AST. No pattern in time to onset of these liver transaminase elevations was identified. Transaminase levels returned to baseline within 4 months after peak values in these patients. Instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice [see Adverse Reactions ( 6.1 ) ] . 5.6 Elevated Blood Pressure ORIAHNN is contraindicated in women with uncontrolled hypertension [see Contraindications ( 4 ) ] . In Studies UF-1 and UF-2, a maximum mean increase in systolic blood pressure of 5.1 mmHg [95% confidence interval (CI) 2.68, 7.59] occurred at Month 5, and a maximum mean increase in diastolic blood pressure of 2.1 mmHg (95% CI 0.43, 3.84) occurred at Month 4 in ORIAHNN-treated women, as compared to placebo-treated women [see Adverse Reactions ( 6.1 ) ] . For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly. Monitor blood pressure in normotensive women treated with ORIAHNN. 5.7 Gallbladder Disease or History of Cholestatic Jaundice Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Discontinue ORIAHNN if jaundice occurs. 5.8 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Adverse Reactions ( 6.1 ) ] . Perform pregnancy testing if pregnancy is suspected, and discontinue ORIAHNN if pregnancy is confirmed [see Use in Specific Populations ( 8.1 , 8.3 ) ] . The effect of hormonal contraceptives on the efficacy of ORIAHNN is unknown. Advise women to use non-hormonal contraception during treatment and for 28 days after discontinuing ORIAHNN [see Use in Specific Populations ( 8.1 , 8.3 ) ] . 5.9 Effects on Carbohydrate and Lipid Metabolism ORIAHNN may decrease glucose tolerance and result in increased glucose levels. More frequent monitoring in ORIAHNN-treated women with prediabetes and diabetes may be needed. In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Use of elagolix is associated with increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglycerides. Monitor lipid levels and consider discontinuing ORIAHNN if hypercholesterolemia or hypertriglyceridemia worsens [see Adverse Reactions ( 6.1 ) ] . 5.10 Alopecia In Phase 3 clinical trials (Studies UF-1 and UF-2), more women experienced alopecia, hair loss, and hair thinning with ORIAHNN (3.5%) compared to placebo (1.0%). In almost one-third (4/14) of affected ORIAHNN-treated women, alopecia was a reason for discontinuing treatment. No specific pattern was described. In the majority of affected women, hair loss was continuing when ORIAHNN was stopped. Whether the hair loss is reversible is unknown. Consider discontinuing ORIAHNN if hair loss becomes a concern [see Adverse Reactions ( 6.1 ) ] . 5.11 Effect on Other Laboratory Results The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce the free thyroid or corticosteroid hormone levels. Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively. The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose [see Pharmacodynamics ( 12.2 ) ] . 5.12 Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5) ORIAHNN contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.