Everolimusdosage

2. DOSAGE AND ADMINISTRATION Do not combine Yulithira tablets and everolimus tablets for oral suspension to achieve the total daily dose. Modify the dose for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4.

Breast Cancer: 10 mg orally once daily.

NET: 10 mg orally once daily.

RCC: 10 mg orally once daily.

TSC-Associated Renal Angiomyolipoma: 10 mg orally once daily.

TSC-Associated SEGA: 4.5 mg/m 2 orally once daily; adjust dose to attain trough concentrations of 5-15 ng/mL.

2.1 Important

Dosage Information Yulithira tablets and everolimus tablets for oral suspension are two different dosage forms. Do not combine Yulithira 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.

2.2 Recommended

Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of Yulithira 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 Yulithira 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 Yulithira 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 Yulithira 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 Yulithira tablets is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity.

2.8 Therapeutic

Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) 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 1 to 2 weeks Modification of everolimus tablets dose 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 Yulithira (everolimus) tablets for the management of adverse reactions.

Table 2: Recommended Dosage Modifications for Everolimus Tablets for Adverse Reactions Adverse Reaction Severity Dosage Modification Non-infectious pneumonitis 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 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) 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 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 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 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 Yulithira tablets for patients with hepatic impairment are described in Table 3: Table 3: Recommended Dosage Modifications for Patients with Hepatic Impairment Indication Dose Modification for Everolimus Tablets 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 Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended.

2.11 Dosage Modifications for P-gp and CYP3A4

Inhibitors Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors. Avoid ingesting grapefruit and grapefruit juice. Reduce the dose for patients taking Yulithira tablets with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4.

Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with a P-gp and Moderate CYP3A4 Inhibitor Indication Dose Modification for Everolimus Tablets 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 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.

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 Yulithira tablets with a P-gp and strong CYP3A4 inducer as recommended in Table 5.

Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with P-gp and Strong CYP3A4 Inducers Indication Dose Modification for Everolimus Tablets 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 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. Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

2.13 Administration and

Preparation Administer Yulithira tablets at the same time each day. Administer Yulithira tablets consistently either with or without food. If a dose of Yulithira tablets is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, Yulithira tablets should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed. Yulithira (everolimus) Tablets Yulithira Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.