EVEROLIMUS

EVEROLIMUS- everolimus tablet
Biocon Pharma Inc.

1 INDICATIONS AND USAGE

1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer

Everolimus Tablets are indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.

1.4 Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

Everolimus tablets are indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

1.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA)

Everolimus tablets are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

  • Everolimus tablets and AFINITOR DISPERZ 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 AFINITOR DISPERZ 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.

2.5 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 is 4.5 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)

  • 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* = current dose x (target concentration divided by current concentration)

* The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough 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 TroughConcentrations After Event
Initiation of Everolimus 1 to 2 weeks
Modification of Everolimus dose

Switch between Everolimus tablets and AFINITOR DISPERZ

1 to 2 weeks

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
Abbreviation: P-gp, P-glycoprotein

2.9 Dosage Modifications for Adverse Reactions

Table 2 summarizes recommendations for dosage modifications of everolimus for the management of adverse reactions.

Table 2: Recommended Dosage Modifications for Everolimus 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 3OR 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.

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