LIFYORLI Capsule Ref.[116441] Active ingredients:

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)].

The following adverse reactions are discussed in more detail in other sections of the labeling:

• Neutropenia and Severe Infections [see Warnings and Precautions (5.1)].
• Adrenal Insufficiency [see Warnings and Precautions (5.2)].
• Exacerbation of Conditions Treated with Glucocorticoids [see Warnings and Precautions (5.3)].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of LIFYORLI in combination with nab-paclitaxel was evaluated in patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer in ROSELLA [see Clinical Studies (14)].

Patients received LIFYORLI (150 mg orally on the day before, the day of, and the day after each administration of nab-paclitaxel 80 mg/m² intravenous infusion on Days 1, 8 and 15 of each 28-day cycle (n=188) or nab-paclitaxel 100 mg/m² intravenous infusion (n=190) until disease progression or unacceptable toxicity. LIFYORLI dosing was interrupted whenever nab-paclitaxel was interrupted. The median duration of LIFYORLI treatment was 4.7 months (range: 0.2 to 24).

Serious adverse reactions occurred in 35% of patients who received LIFYORLI in combination with nab-paclitaxel. Serious adverse reactions in ≥2% of patients were neutropenia (4%), pneumonia (3.2%), pleural effusion (3.2%), febrile neutropenia (2.1%), and fatigue (2.1%). Fatal adverse reactions occurred in 2.1% of patients who received LIFYORLI in combination with nab-paclitaxel including septic shock (0.5%), cardiac arrest (0.5%), ischemic stroke (0.5%), and intestinal perforation (0.5%).

Permanent discontinuation of LIFYORLI in combination with nab-paclitaxel due to adverse reactions occurred in 9% of patients. The adverse reaction which resulted in permanent discontinuation of LIFYORLI in >2% of patients was intestinal obstruction (2.6%).

Dosage interruptions of LIFYORLI due to an adverse reaction occurred in 72% of patients. Adverse reactions which required dosage interruptions of LIFYORLI in combination with nab-paclitaxel in ≥5% of patients included neutropenia (44%), anemia (12%), and fatigue (7%).

Dose reductions of LIFYORLI due to an adverse reaction occurred in 7.4% of patients and dose reductions of nab-paclitaxel occurred in 48% of patients. Adverse reactions which required dose reductions of LIFYORLI included fatigue (1.6%), decreased appetite (1.2%), abdominal pain (0.5%), neutropenia (0.5%), edema (0.5%), and sciatica (0.5%).

The most common (>20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin, decreased neutrophils, fatigue, nausea, diarrhea, decreased platelets, rash, and decreased appetite.

Table 5 and 6 summarize adverse reactions and laboratory abnormalities, respectively, occurring in ≥10% of patients who received LIFYORLI in combination with nab-paclitaxel in ROSELLA.

Table 5. Adverse Reactions Occurring in ≥10% of Patients Who Received LIFYORLI in Combination with Nab-Paclitaxel in ROSELLA:

^a Includes multiple related terms

Clinically relevant adverse reactions occurring in <10% of patients who received LIFYORLI in combination with nab-paclitaxel in ROSELLA included dry eye (8.5%), hypotension (8.5%), hypertension (4.8%), acute kidney injury (4.3%), febrile neutropenia (3.7%), and syncope (2.7%).

Table 6. Select Laboratory Abnormalities ≥10% for All Grades, in Patients Who Received LIFYORLI in Combination with Nab-Paclitaxel in ROSELLA:

7.1 Effect of Other Drugs on LIFYORLI in Combination with Nab-Paclitaxel

Strong CYP3A Inducers

Avoid coadministration of LIFYORLI plus nab-paclitaxel with strong CYP3A inducers.

Both relacorilant and paclitaxel are CYP3A substrates. Coadministration of strong CYP3A inducers can decrease concentrations of relacorilant and paclitaxel, which may reduce their effectiveness [see Clinical Pharmacology (12.3)].

CYP2C8 Inducers and Moderate CYP3A Inducers

Monitor for reduced effectiveness of LIFYORLI plus nab-paclitaxel with CYP2C8 inducers and moderate CYP3A inducers.

Paclitaxel is a substrate of CYP2C8 and CYP3A and relacorilant is a CYP3A substrate. Coadministration of CYP2C8 inducers and moderate CYP3A inducers can decrease concentrations of paclitaxel and relacorilant, which may reduce their effectiveness.

CYP2C8 Inhibitors

Monitor for increased adverse reactions and modify the dosage for adverse reactions as recommended [see Dosage and Administration (2.3)].

Paclitaxel is a substrate of CYP2C8. Coadministration of CYP2C8 inhibitors may increase concentrations of paclitaxel, which may increase the risk of adverse reactions.

7.2 Effect of LIFYORLI on Other Drugs

CYP3A Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP3A substrates.

Relacorilant is a strong CYP3A inhibitor. Relacorilant increases exposure of CYP3A substrates [see Clinical Pharmacology (12.3)], which may increase the risk for adverse reactions related to these substrates.

Certain CYP2C8 Substrates

Avoid concomitant use unless otherwise recommended in the Prescribing Information for CYP2C8 substrates where minimal concentration changes may lead to reduced effectiveness. Relacorilant is a weak CYP2C8 inducer. Relacorilant decreases exposure of CYP2C8 substrates [see Clinical Pharmacology (12.3)], which may decrease the effectiveness related to these substrates.

7.3 Potential for Reduced Effectiveness of Glucocorticoids or LIFYORLI with Coadministration

LIFYORLI is contraindicated in patients receiving systemic glucocorticoids for lifesaving purposes (e.g., immunosuppression in organ transplantation) [see Contraindications (4)].

Avoid coadministration in patients with other medical conditions requiring systemic glucocorticoids when possible. If coadministration cannot be avoided, monitor patients for reduced effectiveness of LIFYORLI and glucocorticoids.

LIFYORLI is a glucocorticoid receptor antagonist, which may make systemic glucocorticoids less effective. Coadministration of systemic glucocorticoids may make LIFYORLI less effective.

Risk Summary

LIFYORLI is used in combination with nab-paclitaxel. Refer to the Prescribing Information of nab-paclitaxel for pregnancy information.

Based on findings in animals, LIFYORLI can cause fetal harm when administered to a pregnant woman. There are no available data on relacorilant use in pregnant women to inform drug-associated risk. In animal embryo-fetal development studies, oral administration of relacorilant to pregnant rabbits during the period of organogenesis resulted in embryo-fetal mortality and structural abnormalities at maternal doses of ≥10 mg/kg/day (0.6 times the human exposure based on area under the curve (AUC) at the recommended dose). Oral administration of relacorilant to pregnant rats during the period of organogenesis did not result in fetal malformations [see Data].

Advise pregnant women and females of reproductive potential of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is between 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

Relacorilant is a partial agonist of the glucocorticoid receptor in rats. In an embryo-fetal development study, relacorilant was administered to pregnant rats at oral doses of 1, 2.5, and 10 mg/kg/day during the period of organogenesis. Maternal toxicity (decreased body weight and food consumption) was observed at a dose of 10 mg/kg/day (3.8 times the human exposure based on AUC at the recommended dose). No developmental toxicity was noted at doses up to 10 mg/kg/day.

In an embryo-fetal development study, relacorilant administered to pregnant rabbits at oral doses of 1, 3, and 10 mg/kg/day during the period of organogenesis resulted in embryo-fetal mortality (increased post-implantation loss, fetal resorptions, and a decrease in litter size) at 10 mg/kg/day (0.6 times the human exposure based on AUC at the recommended dose). Fetal malformations (abnormal flexure of the forepaw, microcephaly, malrotated hindlimbs, absent interparietal bone, and fused sternebra in sternum) were observed at a dose of 10 mg/kg/day (0.6 times the human exposure based on AUC at the recommended dose). Additional adverse effects included skeletal variations of bipartite interparietal bone of the skull observed at doses ≥1 mg/kg/day (lower than the human exposure based on AUC at the recommended dose).

Risk Summary

LIFYORLI is used in combination with nab-paclitaxel. Refer to the Prescribing Information of nab-paclitaxel for lactation information.

There are no data on the presence of relacorilant or its metabolites in animal or human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with LIFYORLI and for one week after the last dose.

LIFYORLI is used in combination with nab-paclitaxel. Refer to the Prescribing Information of nab-paclitaxel for contraception and infertility information.

LIFYORLI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify pregnancy status in women of reproductive potential prior to initiating LIFYORLI.

Contraception

Females

Advise females of reproductive potential to use effective contraception during treatment with LIFYORLI and for 1 week after the last dose.

Males

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.

The safety and effectiveness of LIFYORLI in pediatric patients has not been established.

Of the 188 patients with platinum-resistant epithelial ovarian cancer who received LIFYORLI, 38% were 65 years or older and 9.6% were 75 years or older. A higher incidence of grade 3-4 adverse events and dosage modification occurred in patients 65 years or older when compared to younger adult patients. No overall differences in effectiveness were observed between patients in ≥65 years of age and younger patients.

Avoid LIFYORLI in combination with nab-paclitaxel in patients with moderate or severe hepatic impairment (total bilirubin >1.5 to 10x ULN and any AST) because of the potential for increased relacorilant and paclitaxel exposures [see Clinical Pharmacology (12.3)].