Included as part of the "PRECAUTIONS" Section
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]. 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 and Clinical Studies]. 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.
ORIAHNN is contraindicated in women with known osteoporosis [see CONTRAINDICATIONS]. 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].
In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3) [see Clinical Studies], 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 nonfragility 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 lowtrauma 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 DOSAGE AND ADMINISTRATION].
Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial.
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].
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 placebotreated women [see ADVERSE REACTIONS].
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.
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]. 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.
Hepatic Impairment And Transaminase Elevations
Contraindication In Patients With Hepatic Impairment
ORIAHNN is contraindicated in women with known hepatic impairment or disease [see CONTRAINDICATIONS, Use In Specific Populations, and CLINICAL PHARMACOLOGY].
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].
Elevated Blood Pressure
ORIAHNN is contraindicated in women with uncontrolled hypertension [see CONTRAINDICATIONS]. 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].
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.
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.
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]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORIAHNN if pregnancy is confirmed [see Use In Specific Populations].
The effect of hormonal contraceptives on the efficacy of ORIAHNN is unknown. Advise women to use non-hormonal contraception during treatment and for one week after discontinuing ORIAHNN [see Use In Specific Populations].
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].
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].
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].
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Thromboembolic Disorders And Vascular Events
Advise patients that use of estrogen and progestin combinations may increase the risk of thromboembolic disorders and vascular events, especially in women at high risk for these events [see BOXED WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS].
Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise patients that oral iron supplement should not be taken at the same time as calcium and vitamin D [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Suicidal Ideation And Exacerbation Of Mood Disorders
Advise patients that suicidal ideation and exacerbation of mood disorders may occur with ORIAHNN use. Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Advise patients to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Change In Menstrual Bleeding Pattern
Advise patients that ORIAHNN may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking ORIAHNN and to discontinue ORIAHNN if pregnancy is diagnosed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORIAHNN during pregnancy [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].
Advise patients that alopecia, hair loss, and hair thinning in no specific pattern, may occur with ORIAHNN use. Advise patients that hair loss and hair thinning may not resolve completely after stopping ORIAHNN. Advise patients to contact their healthcare provider if they have concerns about changes to their hair [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking ORIAHNN [see DRUG INTERACTIONS].
ORIAHNN Missed Dose Instructions
Instruct patients about what to do in the event a dose is missed. See “If you miss a dose of ORIAHNN” section in FDA-approved Medication Guide.
ORIAHNN Disposal Instructions
Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, www.fda.gov/drugdisposal, and not to flush down the toilet.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Two-year carcinogenicity studies conducted in mice (50, 150, or 500 mg/kg/day) and rats (150, 300, or 800 mg/kg/day) that administered elagolix by the dietary route revealed no increase in tumors in mice at up to 11.9-fold the MRHD based on AUC. In the rat, there was an increase in thyroid (male and female) and liver (males only) tumors at the high dose (7.7- to 8.1-fold the MRHD). The rat tumors were likely species-specific and of negligible relevance to humans.
Elagolix was not genotoxic or mutagenic in a battery of tests, including the in vitro bacterial reverse mutation assay, the in vitro mammalian cell forward mutation assay at the thymidine kinase (TK+/-) locus in L5178Y mouse lymphoma cells, and the in vivo mouse micronucleus assay.
In a fertility study conducted in the rat, there was no effect of elagolix on fertility at any dose (50, 150, or 300 mg/kg/day). Based on AUC, the exposure multiple for the MRHD in women compared to the highest dose of 300 mg/kg/day in female rats is approximately 2.9-fold. However, because elagolix has low affinity for the GnRH receptor in the rat [see Use In Specific Populations], and because effects on fertility are most likely to be mediated via the GnRH receptor, these data have low relevance to humans.
Long-term continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver [see WARNINGS AND PRECAUTIONS].
Use In Specific Populations
Pregnancy Exposure Registry
There is a pregnancy registry that monitors outcomes in women who become pregnant while treated with ORIAHNN. Pregnant patients should be encouraged to enroll by calling 1-833-782- 7241.
Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNN if pregnancy occurs during treatment.
The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage [see Data].
When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 25 and 7 times the MRHD for the rat and rabbit, respectively [see Data].
There was one pregnancy reported in the 453 women who received ORIAHNN in the Phase 3 uterine fibroids clinical trials. The pregnancy resulted in a spontaneous abortion and the estimated fetal exposure to ORIAHNN occurred during the first 18 days of pregnancy.
Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600, and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).
In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 12 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest maternally toxic dose, which was 7 times the MRHD based on AUC. A single total litter loss occurred at a lower nonmaternally toxic dose of 150 mg/kg/day, which was 4 times the MRHD.
No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 25 and 7 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.
In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100, and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights, and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development, and behavioral endpoints were unaffected.
Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.04-fold and 0.1-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.
There is no information on the presence of elagolix in human milk, the effects on the breastfed child, or the effects on milk production. When estrogen and progestins are administered to lactating women, these compounds and/or their metabolites are detected in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. Advise the nursing female to use nonhormonal contraception until she discontinues breast-feeding. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ORIAHNN and any potential adverse effects on the breast-fed child from ORIAHNN or from the underlying maternal condition [see Data].
There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen and progestin combinations.
There are no adequate animal data on excretion of elagolix in milk.
Females And Males Of Reproductive Potential
Based on the mechanism of action of elagolix, there is a risk of early pregnancy loss if ORIAHNN is administered to a pregnant woman [see Pregnancy, CLINICAL PHARMACOLOGY].
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]. Exclude pregnancy before initiating treatment with ORIAHNN. Perform pregnancy testing if pregnancy is suspected during treatment with ORIAHNN and discontinue treatment if pregnancy is confirmed [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS].
Advise women to use non-hormonal contraception during treatment with ORIAHNN and for one week after discontinuing ORIAHNN [see WARNINGS AND PRECAUTIONS].
Safety and effectiveness of ORIAHNN in pediatric patients have not been established.
No dose adjustment of ORIAHNN is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis) [see CLINICAL PHARMACOLOGY].
ORIAHNN is contraindicated in women with any hepatic impairment or disease [see CONTRAINDICATIONS]. The use of estradiol (a component of ORIAHNN) in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the blood levels of estradiol and increase the risk of estradiol-associated adverse reactions.
Additionally, the use of elagolix (a component of ORIAHNN) in patients with moderate and severe hepatic impairment, compared to patients with normal hepatic function, increased elagolix exposures 3-fold and 7-fold, respectively, and this increases the risk of elagolix-associated adverse reactions [see CLINICAL PHARMACOLOGY].