Everolimus

2. DOSAGE AND ADMINISTRATION Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total daily dose. ( 2.1 ) Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4. ( 2.1 ) Breast Cancer: 10 mg orally once daily. ( 2.2 ) NET: 10 mg orally once daily. ( 2.3 ) RCC: 10 mg orally once daily. ( 2.4 ) TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily. ( 2.5 ) TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. ( 2.6 , 2.8 ) TSC-Associated Partial-Onset Seizures: 5 mg/ m 2 orally once daily; adjust dose to attain trough concentrations of 5-­15 ng/mL. ( 2.7 , 2.8 ) 2.1 Important Dosage Information Everolimus tablets and everolimus tablets for oral suspension are two different dosage forms. Select the recommended dosage form based on the indication [see Indications and Usage (1) ] . Do not combine everolimus tablets and everolimus tablets for oral suspension to achieve the total dose. Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10 , 2.11 , 2.12) ]. 2.2 Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for Neuroendocrine Tumors (NET) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.4 Recommended Dosage for Renal Cell Carcinoma (RCC) The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of everolimus tablets is 10 mg orally once daily until disease progression or unacceptable toxicity. 2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of everolimus tablets/everolimus tablets for oral suspension is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8) ]. 2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The recommended starting dosage of everolimus tablets for oral suspension is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8) ]. 2.8 Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures Monitor everolimus whole blood trough concentrations at time points recommended in Table 1. Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL. Adjust the dose using the following equation: New dose The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration. = current dose × (target concentration divided by current concentration) When possible, use the same assay and laboratory for TDM throughout treatment. Table 1: Recommended Timing of Therapeutic Drug Monitoring Event When to Assess Trough Concentrations After Event Abbreviation: P-gp, P-glycoprotein. Initiation of everolimus tablets/everolimus tablets for oral suspension 1 to 2 weeks Modification of everolimus tablets/everolimus tablets for oral suspension dose 1 to 2 weeks Switch between everolimus tablets/everolimus tablets for oral suspension 1 to 2 weeks Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor 2 weeks Initiation or discontinuation of P-gp and strong CYP3A4 inducer 2 weeks Change in hepatic function 2 weeks Stable dose with changing body surface area (BSA) Every 3 to 6 months Stable dose with stable BSA Every 6 to 12 months 2.9 Dosage Modifications for Adverse Reactions Table 2 summarizes recommendations for dosage modifications of everolimus tablets/everolimus tablets for oral suspension for the management of adverse reactions. Table 2: Recommended Dosage Modifications for Everolimus Tablets/Everolimus Tablets for Oral Suspension for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis [see Warnings and Precautions (5.1) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Stomatitis [see Warnings and Precautions (5.5) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. Other non-hematologic toxicities Grade 2 If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 3 Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. Grade 4 Permanently discontinue. Thrombocytopenia [see Warnings and Precautions (5.10) ] Grade 2 Withhold until improvement to Grade 0 or 1. Resume at same dose. Grade 3 OR Grade 4 Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Neutropenia [see Warnings and Precautions (5.10) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. Grade 4 Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Febrile neutropenia [see Warnings and Precautions (5.10) ] Grade 3 Withhold until improvement to Grade 0, 1, or 2, and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Grade 4 Permanently discontinue. 2.10 Dosage Modifications for Hepatic Impairment The recommended dosages of everolimus tablets/everolimus tablets for oral suspension for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6) ] : Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex. Breast Cancer, NET, RCC, and TSC- Associated Renal Angiomyolipoma Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated. Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated. Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily. TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8) ]. 2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1) ]. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking everolimus tablets/everolimus tablets for oral suspension with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets/Everolimus Tablets for Oral Suspension With a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8) ]. 2.12 Dosage Modifications for P-gp and CYP3A4 Inducers Avoid concomitant use of St. John's Wort (Hypericum perforatum). Increase the dose for patients taking everolimus tablets/everolimus tablets for oral suspension with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ]. Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets/Everolimus Tablets for Oral Suspension With P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets/Everolimus Tablets for Oral Suspension Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days. TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures Double the daily dose using increments of 5 mg or less. Multiple increments may be required. Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8) ] . Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days. 2.13 Administration and Preparation Administer everolimus tablets/everolimus tablets for oral suspension at the same time each day. Administer everolimus tablets/everolimus tablets for oral suspension consistently either with or without food [see Clinical Pharmacology (12.3) ]. If a dose of everolimus…

8.4 Pediatric Use TSC-Associated SEGA The safety and effectiveness of everolimus tablets/everolimus tablets for oral suspension have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of everolimus tablets/everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.5) ] . The safety and effectiveness of everolimus tablets/everolimus tablets for oral suspension have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 everolimus tablets-treated patients < 6 years had at least one infection compared to 67% of 55 everolimus tablets-treated patients ≥ 6 years. Thirty-five percent of 23 everolimus tablets-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 everolimus tablets-treated patients ≥ 6 years. Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, everolimus tablets did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with everolimus tablets for a median duration of 4.1 years. TSC-Associated Partial-Onset Seizures The safety and effectiveness of everolimus tablets for oral suspension has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , Clinical Studies (14.6) ] . The safety and effectiveness of everolimus tablets for oral suspension and everolimus tablets have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures. The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 everolimus tablets for oral suspension-treated patients < 6 years had at least one infection, compared to 53% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years. Sixteen percent of 70 everolimus tablets for oral suspension-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients. Other Indications The safety and effectiveness of everolimus tablets/everolimus tablets for oral suspension in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma