Everolimus: Package Insert and Label Information

EVEROLIMUS- everolimus tablet, for suspension
Mylan Pharmaceuticals Inc.

1 INDICATIONS AND USAGE

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

Everolimus tablets for oral suspension 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.

1.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures

Everolimus tablets for oral suspension are indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

2 DOSAGE AND ADMINISTRATION

2.1 Important Dosage Information

Do not combine AFINITOR 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)].

2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA)

The recommended starting dosage of everolimus tablets for oral suspension is 4.5 mg/m2 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* = 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 Trough Concentrations After Event

Initiation of everolimus tablets for oral suspension

1 to 2 weeks

Modification of everolimus tablets for oral suspension dose

1 to 2 weeks

Switch between AFINITOR and 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

Abbreviation: P-gp, P-glycoprotein.

2.9 Dosage Modifications for Adverse Reactions

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

Table 2: Recommended Dosage Modifications for 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 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 for Oral Suspension

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures

Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m2 orally once daily.
Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)].

Abbreviations: SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.

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 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 for Oral Suspension With a P-gp and Moderate CYP3A4 Inhibitor

Indication

Dose Modification for Everolimus Tablets for Oral Suspension

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 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 for Oral Suspension With P-gp and Strong CYP3A4 Inducers

Indication

Dose Modification for Everolimus Tablets for Oral Suspension

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.

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