MTOR inhibitors
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Afinitor Dosage

Drug Detail:Afinitor (Everolimus)

Generic Name: EVEROLIMUS 5mg

Dosage Form: tablet, tablet for oral suspension

Drug Class: MTOR inhibitors Selective immunosuppressants

Contents
Uses Warnings Before Taking Dosage Side effects Interactions FAQ

2.1 Important Dosage Information

  • AFINITOR 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 AFINITOR 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 AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

2.3 Recommended Dosage for Neuroendocrine Tumors (NET)

The recommended dosage of AFINITOR 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 AFINITOR 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 AFINITOR 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR DISPERZ 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
Abbreviation: P-gp, P-glycoprotein.
Event When to Assess Trough
Concentrations After Event
Initiation of AFINITOR/AFINITOR DISPERZ 1 to 2 weeks
Modification of AFINITOR/AFINITOR DISPERZ dose 1 to 2 weeks
Switch between AFINITOR and AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ for the management of adverse reactions.

Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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
Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.
Indication Dose Modification for AFINITOR/AFINITOR DISPERZ
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/m2 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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ With a P-gp and Moderate CYP3A4 Inhibitor
Indication Dose Modification for AFINITOR/AFINITOR DISPERZ
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 AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ With P-gp and Strong CYP3A4 Inducers
Indication Dose Modification for AFINITOR/AFINITOR DISPERZ
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 AFINITOR/AFINITOR DISPERZ at the same time each day.
  • Administer AFINITOR/AFINITOR DISPERZ consistently either with or without food [see Clinical Pharmacology (12.3)].
  • If a dose of AFINITOR/AFINITOR DISPERZ 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, AFINITOR/AFINITOR DISPERZ should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.

AFINITOR

  • AFINITOR should be swallowed whole with a glass of water. Do not break or crush tablets.

AFINITOR DISPERZ

  • Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person.
  • Administer as a suspension only.
  • Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation.
  • Prepare suspension in water only.

Using an Oral Syringe to Prepare Oral Suspension:

  • Place the prescribed dose into a 10-mL syringe. Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
  • Draw approximately 5 mL of water and 4 mL of air into the syringe.
  • Place the filled syringe into a container (tip up) for 3 minutes, until the tablets are in suspension.
  • Gently invert the syringe 5 times immediately prior to administration.
  • After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.

Using a Small Drinking Glass to Prepare Oral Suspension:

  • Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
  • Allow 3 minutes for suspension to occur.
  • Stir the contents gently with a spoon, immediately prior to drinking.
  • After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.
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