ELAGOLIX Drug Interactions: What You Need to Know

INTERACTIONS See full prescribing information for a list of clinically important drug interactions ( 7 ).

7.1 Potential for ORILISSA to Affect Other Drugs Elagolix is: A weak to moderate inducer of cytochrome P450 (CYP) 3A. Co-administration with ORILISSA may decrease plasma concentrations of drugs that are substrates of CYP3A (see Table 7). A weak inhibitor of CYP 2C19. Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of CYP2C19 (see Table 7). An inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with ORILISSA may increase plasma concentrations of drugs that are substrates of P-gp (see Table 7). The effects of co-administration of ORILISSA on concentrations of concomitant drugs and the clinical recommendations for these drug interactions are summarized in Table 7.

Table

7.

Drug

Interactions: Effects of ORILISSA on Other Drugs Concomitant Drug Class: Drug Name Effect on Plasma Exposure of Concomitant Drug Clinical Recommendations Cardiac glycosides: digoxin ↑ digoxin Increase monitoring of digoxin concentrations and potential signs and symptoms of clinical toxicity when initiating ORILISSA in patients who are taking digoxin. If ORILISSA is discontinued, increase monitoring of digoxin concentrations. Benzodiazepines: oral midazolam ↓ midazolam Consider increasing the dose of midazolam by no more than 2-fold and individualize midazolam therapy based on the patient’s response. Statins: rosuvastatin ↓ rosuvastatin Monitor lipid levels and adjust the dose of rosuvastatin, if necessary. Proton pump inhibitors: omeprazole ↑ omeprazole No dose adjustment needed for omeprazole 40 mg once daily when co-administered with ORILISSA. When ORILISSA is used concomitantly with higher doses of omeprazole, consider dosage reduction of omeprazole. Combined hormonal contraceptives: oral ethinyl estradiol/levonorgestrel ↑ethinyl estradiol ↓levonorgestrel Advise women to use effective non-hormonal contraception during treatment with ORILISSA and for 28 days after discontinuing ORILISSA.

See Tables

10 and 11 [ see Clinical Pharmacology ( 12.3 )] . The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease).

7.2 Potential for Other Drugs to Affect ORILISSA Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Concomitant use of ORILISSA 200 mg twice daily and strong CYP3A inhibitors for more than 1 month is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and strong CYP3A inhibitors to 6 months. Co-administration of ORILISSA with strong CYP3A inducers may decrease elagolix plasma concentrations and may result in a decrease of the therapeutic effects of ORILISSA. Concomitant use of ORILISSA 200 mg twice daily and rifampin is not recommended. Limit concomitant use of ORILISSA 150 mg once daily and rifampin to 6 months. The effect of concomitant use of P-gp inhibitors or inducers on the pharmacokinetics of ORILISSA is unknown. OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations are contraindicated due to increased risk of elagolix-associated adverse reactions <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>.

ORILISSA is contraindicated in women: Who are pregnant [see Use in Specific Populations ( 8.1 )] . Exposure to ORILISSA early in pregnancy may increase the risk of early pregnancy loss. With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions ( 5.1 )] With severe hepatic impairment [see Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )] Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations [see Drug Interactions ( 7.2 )] With known hypersensitivity reaction to ORILISSA or any of its inactive components. Reactions have included anaphylaxis and angioedema [see Adverse Reactions ( 6.2 )] . Pregnancy ( 4 ) Known osteoporosis ( 4 ) Severe hepatic impairment ( 4 ) Organic anion transporting polypeptide (OATP) 1B1 inhibitors that significantly increase elagolix plasma concentrations ( 4 ) Hypersensitivity reactions ( 4 , 6.2 )

AND PRECAUTIONS Bone Loss : Dose- and duration-dependent decreases in bone mineral density (BMD) that may not be completely reversible. Assess BMD in women with additional risk factors for bone loss ( 5.1 )

Reduced

Ability to Recognize Pregnancy : ORILISSA may alter menstrual bleeding, which may reduce the ability to recognize pregnancy. Perform testing if pregnancy is suspected. Discontinue if pregnancy is confirmed ( 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 ( 5.3 )

Hepatic Transaminase

Elevations : Dose-dependent elevations in serum alanine aminotransferase (ALT). Counsel patients on signs and symptoms of liver injury ( 5.4 ) Interactions with Hormonal Contraceptives : Use non-hormonal contraception during treatment and for 28 days after discontinuing ORILISSA. Coadministration of ORILISSA 200 mg twice daily with an estrogen-containing contraceptive is not recommended because of the potential for increased estrogen-associated risks. Coadministration of ORILISSA with an estrogen-containing contraceptive may reduce the efficacy of ORILISSA. Coadministration with progestin-containing oral contraceptives may reduce the efficacy of the contraceptive. ( 5.5 )

5.1 Bone Loss ORILISSA causes a dose-dependent decrease in bone mineral density (BMD). BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . The impact of these BMD decreases on long-term bone health and future fracture risk are unknown. ORILISSA is contraindicated in women with known osteoporosis <span class="opacity-50 text-xs">[see Contraindications ( 4 )]</span>. Consider assessment of BMD in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss. Limit the duration of use to reduce the extent of bone loss <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients.

5.2 Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy Women who take ORILISSA may experience a reduction in the amount, intensity or duration of menstrual bleeding, which may reduce the ability to recognize the occurrence of a pregnancy in a timely manner <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Perform pregnancy testing if pregnancy is suspected, and discontinue ORILISSA if pregnancy is confirmed.

5.3 Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders Suicidal ideation and behavior, including one completed suicide, occurred in subjects treated with ORILISSA in the endometriosis clinical trials. ORILISSA subjects had a higher incidence of depression and mood changes compared to placebo, and ORILISSA subjects with a history of suicidality or depression had a higher incidence of depression compared to subjects without such a history <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 ORILISSA if such events occur.

5.4 Hepatic Transaminase Elevations In clinical trials, dose-dependent elevations of serum alanine aminotransferase (ALT) at least 3-times the upper limit of the reference range occurred with ORILISSA. Use the lowest effective dose of ORILISSA and instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice. Promptly evaluate patients with elevations in liver tests to determine whether the benefits of continued therapy outweigh the risks <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.5 Interactions with Hormonal Contraceptives Advise women to use effective non-hormonal contraceptives during treatment with ORILISSA and for 28 days after discontinuing ORILISSA <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ), Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span> . Increase in Estrogen Exposure and Potential Associated Increased Risks When ORILISSA 200 mg Twice Daily is Taken With Combined Hormonal Contraceptives Co-administration of a combined oral contraceptive (COC) (containing 20 mcg ethinyl estradiol/0.1 mg levonorgestrel) following administration of ORILISSA 200 mg twice daily for 14 days increases the plasma ethinyl estradiol concentration by 2.2-fold compared to this COC alone. ORILISSA 200 mg twice daily co-administered with a COC containing ethinyl estradiol may lead to increased risk of ethinyl estradiol-related adverse events including thromboembolic disorders and vascular events and is not recommended <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span> . Potential for Reduced Efficacy of Progestin -Containing Hormonal Contraceptives Co-administration of ORILISSA 200 mg twice daily and a COC containing 0.1 mg levonorgestrel decreases the plasma concentrations of levonorgestrel by 27%, potentially affecting contraceptive efficacy. Co-administration of ORILISSA with COCs containing norethindrone acetate did not show reduction in plasma concentrations of norethindrone <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ), Clinical Pharmacology ( 12.3 )]</span> . Co-administration of ORILISSA with progestin-containing intrauterine contraceptive systems has not been studied. Reduced efficacy of ORILISSA Based on the mechanism of action of ORILISSA, estrogen-containing contraceptives are expected to reduce the efficacy of ORILISSA. The effect of progestin-only contraceptives on the efficacy of ORILISSA is unknown.