relacorilant 100 MG Oral Capsule

INDICATIONS AND USAGE LIFYORLI is indicated in combination with nab-paclitaxel for the treatment of adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens, at least one of which included bevacizumab [see Clinical Studies ( 14 )] . LIFYORLI is a glucocorticoid receptor antagonist indicated in combination with nab-paclitaxel for the treatment of adults with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic treatment regimens, at least one of which included bevacizumab. ( 1 , 14 )

DOSAGE AND ADMINISTRATION The recommended dosage of LIFYORLI is 150 mg orally once on the day before, the day of, and the day after each nab-paclitaxel infusion. ( 2 ) 2.1 Important Dosage and Administration Information LIFYORLI Follow LIFYORLI dosing instructions provided on the blister card. Take LIFYORLI with food. Swallow capsules whole. Do not crush, chew, dissolve, or split the capsules. If a dose of LIFYORLI is missed by less than 12 hours, take the missed dose. If a dose of LIFYORLI is missed by 12 hours or more, skip the missed dose and take the next dose at the regularly scheduled time. Do not take 2 doses at the same time to make up for a missed dose. If vomiting occurs after taking LIFYORLI, do not take an additional dose. Nab-Paclitaxel The recommended dosage and dosage modifications for nab-paclitaxel when administered in combination with LIFYORLI differ from those for other nab-paclitaxel indications [see Dosage and Administration ( 2.2 and 2.3 ) and Clinical Studies ( 14 )] . Do not substitute with other paclitaxel formulations. 2.2 Recommended Dosage and Administration The recommended dosage of LIFYORLI is 150 mg orally once on the day before, the day of, and the day after each nab-paclitaxel infusion until disease progression or unacceptable toxicity. The recommended dosage for nab-paclitaxel is 80 mg/m 2 administered as an intravenous infusion on Days 1, 8 and 15 of each 28-day cycle until disease progression or unacceptable toxicity [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14 )]. Refer to the Prescribing Information for nab-paclitaxel for administration. 2.3 Dosage Modifications for Adverse Reactions Dose reduction levels are summarized in Table 1 and Table 2 . Table 1: Recommended Dosage Reductions for Adverse Reactions for Nab-Paclitaxel Dose Reduction Nab-Paclitaxel First 60 mg/m 2 on Days 1, 8 and 15 of each 28-day cycle Second 60 mg/m 2 on Days 1 and 15 of each 28-day cycle Third Permanently discontinue nab-paclitaxel if unable to tolerate after two dose reductions. Table 2: Recommended Dosage Reductions for Adverse Reactions for LIFYORLI Dose Reduction LIFYORLI First 125 mg once the day before, the day of and the day after the nab-paclitaxel infusion Second Permanently discontinue LIFYORLI in patients unable to tolerate after one dose reduction. The recommended dosage modifications for adverse reactions are provided in Tables 3 and 4 . Interrupt or discontinue LIFYORLI whenever nab-paclitaxel is interrupted or discontinued. Table 3: Dosage Modifications for Hematologic Adverse Reactions Adverse Reaction Severity a Dosage Modification a Unless otherwise specified, Grade per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b Supportive short acting G-CSF administered 24 hours after nab-paclitaxel for 2 days in accordance with clinical practice. c If the delay in nab-paclitaxel dosing exceeds 7 days, omit the nab-paclitaxel dose. Neutropenia Day 1 [see Warnings and Precautions ( 5.1 )] ANC 1,000 to < 1,500/mm 3 Nab-paclitaxel: Withhold until ≥ 1,500/mm 3 ; resume at same dose LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes ANC < 1,000/mm 3 Nab-paclitaxel: Withhold until ≥ 1,500/mm 3 ; resume at reduced dose LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Neutropenia Day 8 or 15 [see Warnings and Precautions ( 5.1 )] ANC < 1,000/mm 3 Nab-paclitaxel: Omit dose; resume at reduced dose or continue at the same dose with short acting G-CSF b,c LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Febrile neutropenia [see Warnings and Precautions ( 5.1 )] Grade 3 or 4 Nab-paclitaxel: Withhold until fever resolves and ANC ≥ 1,500/mm 3 ; resume at reduced dose c LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Thrombocytopenia Day 1 [see Adverse Reactions ( 6.1 )] Platelets < 100,000/mm 3 Nab-paclitaxel: Withhold until ≥ 100,000/mm 3 ; resume at the same dose LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Thrombocytopenia Day 8 or 15 [see Adverse Reactions ( 6.1 )] Platelets < 50,000/mm 3 Nab-paclitaxel: Omit dose; resume at reduced dose LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Other hematologic adverse reaction (excluding laboratory abnormalities that are not clinically relevant) [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Nab-paclitaxel: Withhold until Grade ≤ 1; resume at reduced dose c LIFYORLI: Withhold until Grade ≤ 1; resume at reduced dose Table 4: Dosage Modifications for non-Hematologic Adverse Reactions Adverse Reaction Severity a Dosage Modification a Unless otherwise specified, Grade per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. b If the delay in nab-paclitaxel dosing exceeds 7 days, omit the nab-paclitaxel dose. Peripheral neuropathy [see Adverse Reactions ( 6.1 )] Intolerable Grade 2 Nab-paclitaxel: Reduce dose LIFYORLI: No change Grade 3 Nab-paclitaxel: Withhold until Grade ≤ 2; resume at reduced dose b LIFYORLI: Withhold; resume at the same dose once nab-paclitaxel resumes Grade 4 Nab-paclitaxel: Permanently discontinue LIFYORLI: Permanently discontinue Cutaneous toxicity [see Adverse Reactions ( 6.1 )] Grade 3 Nab-paclitaxel: Withhold until Grade ≤ 1; resume at reduced dose b LIFYORLI: Resume at the same dose once nab-paclitaxel resumes Grade 4 Nab-paclitaxel: Permanently discontinue LIFYORLI: Permanently discontinue Mucositis or Diarrhea [see Adverse Reactions ( 6.1 )] Grade 3 or 4 Nab-paclitaxel: Withhold until Grade ≤ 1; resume at reduced dose b LIFYORLI: Resume at the same dose once nab-paclitaxel resumes. Other non-hematologic adverse reactions (excluding laboratory abnormalities that are not clinically relevant) [see Adverse Reactions ( 6.1 )] Grade 3 Nab-paclitaxel: Withhold until Grade ≤ 1; resume at reduced dose b LIFYORLI: Withhold until Grade ≤ 1; resume at reduced dose Grade 4 Nab-paclitaxel: Permanently discontinue LIFYORLI: Permanently discontinue

WARNINGS AND PRECAUTIONS Neutropenia and Severe Infections : Monitor complete blood counts prior to each weekly treatment with LIFYORLI in combination with nab-paclitaxel and as clinically indicated. Withhold, reduce the dose, or permanently discontinue LIFYORLI based on severity. ( 2.3 , 5.1 ) Adrenal insufficiency: Monitor for signs and symptoms of adrenal insufficiency. ( 5.2 ) Exacerbation of Conditions Treated with Glucocorticoids: LIFYORLI makes systemic glucocorticoids less effective in patients who have an ongoing requirement for systemic glucocorticoids. ( 5.3 ) Embryo-Fetal Toxicity : LIFYORLI can cause fetal harm. Advise females of reproductive potential of the risk to a fetus and to use effective contraception. ( 5.4 ) 5.1 Neutropenia and Severe Infections LIFYORLI in combination with nab-paclitaxel can cause neutropenia, including febrile neutropenia and severe infections. In ROSELLA, decreased neutrophil count occurred in 74% of patients treated with LIFYORLI in combination with nab-paclitaxel, 30% Grade 3, 15% Grade 4, and 3.7% febrile neutropenia. The median time to onset of neutropenia was 15 days (range: 8 to 329). Instances of neutropenia were temporally associated with infection in 16% of patients. There was one fatal event of septic shock with febrile neutropenia. Thirty-eight percent of patients initiated granulocyte colony-stimulating factor (G-CSF) during the first or second cycle of therapy. Monitor complete blood counts prior to each weekly treatment with LIFYORLI in combination with nab-paclitaxel and as clinically indicated. Based on the severity of neutropenia, delay, reduce dose or permanently discontinue LIFYORLI in combination with nab-paclitaxel. Consider short-acting G-CSF administration as applicable [see Dosage and Administration ( 2.3 )] . Consider the possibility of concurrent adrenal insufficiency, particularly in the setting of serious infection [see Warnings and Precautions ( 5.2 )] . Inform patients to promptly report any episodes of fever to their healthcare provider. 5.2 Adrenal Insufficiency LIFYORLI is a reversible glucocorticoid receptor antagonist and can cause adrenal insufficiency. Adrenal insufficiency can occur at any time during treatment with LIFYORLI. The risk of adrenal insufficiency is increased in situations of stress, such as acute illness, infection, or surgery. Consider whether supplemental glucocorticoids are required in the perioperative period in patients who have received LIFYORLI within 30 days of surgery. Monitor patients receiving LIFYORLI for signs and symptoms of adrenal insufficiency. Serum cortisol levels do not provide an accurate assessment of adrenal insufficiency in patients receiving LIFYORLI. Withhold LIFYORLI and administer glucocorticoid therapy if adrenal insufficiency is suspected. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor antagonism produced by LIFYORLI. When deciding on the duration of glucocorticoid treatment, consider the long half-life of relacorilant (27.5 hours) and that glucocorticoid receptor antagonism may occur for up to 6 days after the last dose of LIFYORLI [see Clinical Pharmacology ( 12.3 )] . After resolution of adrenal insufficiency, resume previous dose, reduce dose or permanently discontinue LIFYORLI based on severity [see Dosage and Administration ( 2.3 )] . Educate patients on the symptoms associated with adrenal insufficiency and advise them to contact a healthcare provider if they occur. 5.3 Exacerbation of Conditions Treated with Glucocorticoids Use of LIFYORLI in patients who are taking systemic glucocorticoids for other conditions (e.g., autoimmune disorders) may exacerbate these conditions. LIFYORLI is a glucocorticoid receptor antagonist which may make systemic glucocorticoids less effective. Similarly, coadministration of systemic glucocorticoids may make LIFYORLI less effective. Monitor patients for reduced effectiveness of LIFYORLI and glucocorticoids in patients receiving both [see Drug Interactions ( 7.3 )]. Patients who require chronic or frequent use of glucocorticoids were excluded from clinical trials of LIFYORLI in combination with nab-paclitaxel. LIFYORLI is contraindicated in patients receiving systemic glucocorticoids for lifesaving purposes, [see Contraindications ( 4 )] . 5.4 Embryo-Fetal Toxicity Based on data from animal studies, LIFYORLI can cause fetal harm when administered to a pregnant woman. Oral administration of relacorilant to pregnant rabbits resulted in adverse developmental outcomes, including embryo-fetal mortality. Advise pregnant women of the potential risk to a fetus. Verify pregnancy status of females of reproductive potential prior to initiating LIFYORLI treatment. Advise females of reproductive potential to use effective contraception during treatment with LIFYORLI and for 1 week after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with LIFYORLI and for 1 week after the last dose [see Use in Specific Populations ( 8.1 , 8.3 )] .

CONTRAINDICATIONS LIFYORLI is contraindicated in patients receiving systemic glucocorticoids for lifesaving purposes (e.g., immunosuppression after organ transplantation) because LIFYORLI antagonizes the effect of glucocorticoids [see Warnings and Precautions ( 5.3 )] . Concurrent systemic glucocorticoid therapy for a lifesaving indication. ( 4 )

Mechanism of Action Relacorilant is a reversible glucocorticoid receptor (GR) antagonist. In functional in vitro assays with the mineralocorticoid receptor, relacorilant showed no agonist or antagonist activity. In human cell-line derived xenograft models, relacorilant enhanced apoptosis and antitumor activity when administered with paclitaxel. Cortisol binding to the GR is immunosuppressive, decreasing secretion of pro‑inflammatory cytokines. GR antagonism may indirectly activate the immune system; relacorilant inhibited the cortisol-induced reduction of tumor necrosis factor alpha and interferon gamma in stimulated peripheral blood mononuclear cells.