`
`• Infections: Monitor for signs and symptoms of infection. Withhold or
`
`
`
`
`permanently discontinue based on severity. (2.9, 5.2)
`
`
`
`• Severe Hypersensitivity Reactions: Permanently discontinue for clinically
`
`
`
`significant hypersensitivity. (5.3)
`
`
`• Angioedema: Patients taking concomitant ACE inhibitors may be at
`
`
`
`
`
`
`increased risk for angioedema. Permanently discontinue for angioedema.
`
`(5.4, 7.2)
`
`• Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting
`
`
`
`
`
`treatment. (5.5, 6.1)
`
`
`• Renal Failure: Monitor renal function prior to treatment and periodically
`
`
`
`
`
`
`thereafter. (5.6)
`
`
`• Impaired Wound Healing: Exercise caution in the peri-surgical period.
`
`
`
`
`
`(5.7)
`
`• Geriatric Patients: Monitor and adjust dose for adverse reactions. (5.8)
`
`
`
`• Metabolic Disorders: Monitor serum glucose and lipids prior to treatment
`
`
`
`
`
`
`
`and periodically thereafter. Withhold or permanently discontinue based on
`
`
`
`
`severity (2.9, 5.9)
`
`
`• Myelosuppression: Monitor hematologic parameters prior to treatment and
`
`
`
`
`periodically thereafter. Withhold or permanently discontinue based on
`
`severity. (2.9, 5.10)
`
`
`• Risk of Infection or Reduced Immune Response with Vaccination: Avoid
`
`
`
`
`
`
`
`
`live vaccines and close contact with those who have received live vaccines.
`
`
`
`
`Complete recommended childhood vaccinations prior to starting treatment.
`
`(5.11)
`
`• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of
`
`
`
`
`
`
`reproductive potential of the potential risk to a fetus and to use effective
`
`
`
`
`contraception. (5.12, 8.1, 8.3)
`
`------------------------------ADVERSE REACTIONS------------------------------­
`
`• Breast cancer, NET, RCC: Most common adverse reactions (incidence
`
`
`
`
`≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema,
`
`abdominal pain, nausea, fever, asthenia, cough, headache, and decreased
`
`
`
`appetite. (6.1)
`
`• TSC-Associated Renal Angiomyolipoma: Most common adverse reaction
`
`
`
`
`(incidence ≥ 30%) is stomatitis. (6.1)
`
`
`
`
`
`
`• TSC-Associated SEGA: Most common adverse reactions (incidence ≥
`
`
`
`
`30%) are stomatitis and respiratory tract infection. (6.1)
`
`• TSC-Associated Partial-Onset Seizures: Most common adverse reaction
`
`
`
`
`
`(incidence ≥ 30%) is stomatitis. (6.1)
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA­
`
`
`1088 or www.fda.gov/medwatch.
`
`
`------------------------------DRUG INTERACTIONS------------------------------­
`• P-gp and strong CYP3A4 inhibitors: Avoid concomitant use. (2.11, 7.1)
`
`
`
`
`
`• P-gp and moderate CYP3A4 inhibitors: Reduce the dose as recommended.
`
`
`
`
`(2.11, 7.1)
`
`
`• P-gp and strong CYP3A4 inducers: Increase the dose as recommended.
`
`
`
`
`
`(2.12, 7.1)
`
`
`-----------------------USE IN SPECIFIC POPULATIONS-----------------------­
`• For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma
`
`
`
`
`patients with hepatic impairment, reduce the dose. (2.10, 8.6)
`
`
`• For patients with TSC-associated SEGA or TSC-associated partial-onset
`
`
`
`
`
`
`
`seizures and severe hepatic impairment, reduce the starting dose and adjust
`
`
`
`
`dose to attain target trough concentrations. (2.8, 2.10, 8.6)
`
`
`
`
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`
`
`
`FDA-approved patient labeling.
`
`
`
`
`Revised: 12/2019
`
`
`
`
`
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
` These highlights do not include all the information needed to use
`
`
` AFINITOR/AFINITOR DISPERZ safely and effectively. See full
`
` prescribing information for AFINITOR/AFINITOR DISPERZ.
`
`
` AFINITOR® (everolimus) tablets, for oral use
`
`
`
`
`AFINITOR DISPERZ® (everolimus tablets for oral suspension)
`
`
`
`
`Initial U.S. Approval: 2009
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`
`AFINITOR is a kinase inhibitor 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. (1.1)
`
`• Adults with progressive neuroendocrine tumors of pancreatic origin
`
`
`
`
`(PNET) and adults with progressive, well-differentiated, non-functional
`
`
`
`
`neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that
`
`are unresectable, locally advanced or metastatic.
`
`
`Limitation of Use: AFINITOR is not indicated for the treatment of patients
`
`
`
`
`
`with functional carcinoid tumors. (1.2)
`
`
`
`• Adults with advanced renal cell carcinoma (RCC) after failure of treatment
`
`
`with sunitinib or sorafenib. (1.3)
`
`
`• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC),
`
`
`
`
`not requiring immediate surgery. (1.4)
`
`
`AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the
`
`
`
`
`treatment of adult and pediatric patients aged 1 year and older with TSC who
`have subependymal giant cell astrocytoma (SEGA) that requires therapeutic
`
`
`
`
`intervention but cannot be curatively resected. (1.5)
`
`AFINITOR DISPERZ is a kinase inhibitor indicated for the adjunctive
`
`
`
`treatment of adult and pediatric patients aged 2 years and older with TSC-
`
`
`
`
`associated partial-onset seizures. (1.6)
`------------------------DOSAGE AND ADMINISTRATION--------------------­
`
`Do not combine AFINITOR and AFINITOR DISPERZ 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/m2 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/m2 orally once daily; adjust dose to attain trough concentrations of 5­
`
`
`
`
`
`15 ng/mL. (2.7, 2.8)
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`• AFINITOR: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets (3)
`
`
`
`
`
`
`• AFINITOR DISPERZ: 2 mg, 3 mg, and 5 mg tablets (3)
`
`
`
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`Clinically significant hypersensitivity to everolimus or to other rapamycin
`
`
`
`
`derivatives. (4)
`
`
`
`
`
`---------------------------WARNINGS AND PRECAUTIONS-------------------­
`
`• Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological
`
`
`
`
`changes. Withhold or permanently discontinue based on severity. (2.9, 5.1)
`
`
`
`
`
`
`
`
`Reference ID: 4549924
`
`

`

`
`2
`
`
`
` FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`INDICATIONS AND USAGE
`
`
`1.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer
`
`
`
`1.2 Neuroendocrine Tumors (NET)
`
`
`
`1.3 Renal Cell Carcinoma (RCC)
`
`
`1.4
`Tuberous Sclerosis Complex (TSC)-Associated Renal
`
`
`
`Angiomyolipoma
`
`
`1.5
`Tuberous Sclerosis Complex (TSC)-Associated Subependymal
`
`
`
`Giant Cell Astrocytoma (SEGA)
`
`
`
`
`1.6
`Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset
`
`
`
`Seizures
`
`
`DOSAGE AND ADMINISTRATION
`
`
`2.1
`Important Dosage Information
`
`
`2.2 Recommended Dosage for Hormone Receptor-Positive, HER2­
`
`Negative Breast Cancer
`
`
`
`
`2.3 Recommended Dosage for Neuroendocrine Tumors (NET)
`
`
`
`
`2.4 Recommended Dosage for Renal Cell Carcinoma (RCC)
`
`
`
`2.5 Recommended Dosage for Tuberous Sclerosis Complex (TSC)­
`
`Associated Renal Angiomyolipoma
`
`
`
`2.6 Recommended Dosage for Tuberous Sclerosis Complex (TSC)­
`
`
`Associated Subependymal Giant Cell Astrocytoma (SEGA)
`
`
`
`2.7 Recommended Dosage for Tuberous Sclerosis Complex (TSC)­
`
`Associated Partial-Onset Seizures
`
`
`
`
`2.8
`Therapeutic Drug Monitoring and Dose Titration for Tuberous
`
`
`
`Sclerosis Complex (TSC)-Associated Subependymal Giant Cell
`
`
`Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures
`
`
`
`
`2.9 Dosage Modifications for Adverse Reactions
`
`
`
`2.10 Dosage Modifications for Hepatic Impairment
`
`
`
`
`2.11 Dosage Modifications for P-gp and CYP3A4 Inhibitors
`
`
`
`
`2.12 Dosage Modifications for P-gp and CYP3A4 Inducers
`
`
`
`2.13 Administration and Preparation
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`CONTRAINDICATIONS
`4
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`5.1 Non-infectious Pneumonitis
`
`
`
`5.2
`Infections
`
`
`
`5.3
`Severe Hypersensitivity Reactions
`
`
`5.4 Angioedema with Concomitant Use of Angiotensin-Converting
`
`
`Enzyme (ACE) Inhibitors
`
`
`
`
`5.5
`Stomatitis
`
`
`
`5.6 Renal Failure
`
`
`
`5.7
`Impaired Wound Healing
`
`
`
`6
`
`
`7
`
`
`8
`
`
`
`5.8 Geriatric Patients
`
`
`
`5.9 Metabolic Disorders
`
`
`
`5.10 Myelosuppression
`
`
`
`5.11 Risk of Infection or Reduced Immune Response with Vaccination
`
`
`
`
`5.12 Embryo-Fetal Toxicity
`
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`
`6.2
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`
`Effect of Other Drugs on AFINITOR/AFINITOR DISPERZ
`
`7.1
`
`7.2
`Effects of Combination Use of Angiotensin Converting Enzyme
`
`
`
`(ACE) Inhibitors
`
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`
`8.2
`Lactation
`
`
`
`8.3
`Females and Males of Reproductive Potential
`
`
`
`
`8.4
`Pediatric Use
`
`
`
`8.5 Geriatric Use
`
`
`
`8.6 Hepatic Impairment
`
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`
`12.2 Pharmacodynamics
`
`
`
`12.3 Pharmacokinetics
`
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
`
`13.2 Animal Toxicology and/or Pharmacology
`
`
`
`14 CLINICAL STUDIES
`
`
`14.1 Hormone Receptor-Positive, HER2-Negative Breast Cancer
`
`
`
`14.2 Neuroendocrine Tumors (NET)
`
`
`
`14.3 Renal Cell Carcinoma (RCC)
`
`
`14.4 Tuberous Sclerosis Complex (TSC)-Associated Renal
`
`
`
`
`Angiomyolipoma
`
`
`14.5 Tuberous Sclerosis Complex (TSC)-Associated Subependymal
`
`
`
`Giant Cell Astrocytoma (SEGA)
`
`
`
`
`14.6 Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset
`
`
`
`Seizures
`
`
`
`15 REFERENCES
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`17 PATIENT COUNSELING INFORMATION
` *Sections or subsections omitted from the full prescribing information are
`
`
`
` not listed
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4549924
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`
`
`INDICATIONS AND USAGE
`
`1
`
`
`1.1
`Hormone Receptor-Positive, HER2-Negative Breast Cancer
`
`
`AFINITOR® is 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.
`
`
`
`
`
`
`
`Neuroendocrine Tumors (NET)
`1.2
`
`
`AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin
`
`
`
`
`
`(PNET) with unresectable, locally advanced or metastatic disease.
`
`
`AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of
`
`
`
`
`
`
`gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.
`
`
`
`
`
`
`Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical
`
`
`
`
`Studies (14.2)].
`
`Renal Cell Carcinoma (RCC)
`1.3
`
`
`
`AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or
`
`
`
`
`
`
`sorafenib.
`
`Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma
`1.4
`
`
`
`AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate
`
`
`
`
`
`surgery.
`
`Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA)
`1.5
`
`
`
`
`AFINITOR and AFINITOR DISPERZ® 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
`
`
`
`
`AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with
`
`
`
`
`
`TSC-associated partial-onset seizures.
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`
`
`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)].
`
`
`Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer
`2.2
`
`
`
`
`The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
`
`
`
`
`
`Recommended Dosage for Neuroendocrine Tumors (NET)
`2.3
`
`
`
`The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
`
`
`
`Recommended Dosage for Renal Cell Carcinoma (RCC)
`2.4
`
`
`
`The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
`
`
`Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma
`2.5
`
`
`
`
`
`
`The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
`
`
`
`
`Reference ID: 4549924
`
`

`

`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)].
`
`
`
` Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures
`
`
` 2.7
` 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)].
`
`
`
` Therapeutic Drug Monitoring and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated
`
`
`
` 2.8
` 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 therapeutic drug monitoring throughout treatment.
`
` Table 1: Recommended Timing of Therapeutic Drug Monitoring
`
`
`
`Event
`
`
`
`
`
`
`
` When to Assess Trough
`
`
`Concentrations After Event
`
`
` Initiation of AFINITOR/AFINITOR DISPERZ
`
`
` Modification of AFINITOR/AFINITOR DISPERZ dose
`
`
` Switch between AFINITOR and AFINITOR DISPERZ
`
`
` Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor
` Initiation or discontinuation of P-gp and strong CYP3A4 inducer
`
`
`
`
` Change in hepatic function
`
` Stable dose with changing body surface area
`
` Stable dose with stable body surface area
`
`
` 1 to 2 weeks
`
`
` 1 to 2 weeks
`
`
` 1 to 2 weeks
`
`
` 2 weeks
`
`
` 2 weeks
`
`
` 2 weeks
`
` Every 3 to 6 months
`
`
` Every 6 to 12 months
`
`
`
`
`
` Dosage Modifications for Adverse Reactions
` 2.9
`
`
`
` Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the
`
` management of adverse reactions.
`
`
`
`
`
`
`
`Reference ID: 4549924
`
`

`

` Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ for Adverse Reactions
`
`
`
`
`
`
` Adverse Reaction
` Severity
` Dosage Modification
`Grade 2
`Withhold until improvement to Grade 0 or 1. Resume at 50% of previous
`Non-infectious
`
`
`
`
`pneumonitis
`dose; change to every other day dosing if the reduced dose is lower than
`
`
`
`
`the lowest available strength.
`
`[see Warnings and
`Precautions (5.1)]
`Permanently discontinue if toxicity does not resolve or improve to
`
`
`
`
`Grade 1 within 4 weeks.
`
`
`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.
`
`Permanently discontinue.
`
`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.
`
`
`
`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.
`
`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.
`
`
`Permanently discontinue.
`
`
`
`
`
`
`
`
`Grade 3
`
`
`
`Grade 4
`
`Grade 2
`
`
`
`Grade 3
`
`
`
`Grade 4
`
`Grade 3
`
`
`Grade 4
`
`
`
`
`
`Stomatitis
`
`[see Warnings and
`Precautions (5.5)]
`
`
`
`
`
`Metabolic events
`
`(e.g., hyperglycemia,
`dyslipidemia)
`
`[see Warnings and
`Precautions (5.9)]
`
`Other non-hematologic
`
`toxicities
`
`
`
`Grade 2
`
`
`Grade 3
`
`
`Grade 4
`
`Grade 2
`
`
`Grade 3
`OR
`
`
`Grade 4
`
`Grade 3
`
`Grade 4
`
`
`
`Grade 3
`
`
`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.
`
`
`
`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.
`
`Permanently discontinue.
`
`Withhold until improvement to Grade 0 or 1. Resume at same dose.
`
`
`
`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.
`
`
`Withhold until improvement to Grade 0, 1 or 2. Resume at same dose.
`
`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.
`
`
`
`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.
`
`
`
`
`Thrombocytopenia
`
`[see Warnings and
`Precautions (5.10)]
`
`
`
`Neutropenia
`[see Warnings and
`Precautions (5.10)]
`
`
`
`Febrile neutropenia
`[see Warnings and
`Precautions (5.10)]
`
`
`Reference ID: 4549924
`
`

`

`Dosage Modification
`Severity
`Adverse Reaction
`
`
`
`
`
`
`Permanently discontinue.
`Grade 4
`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
`
`
`
`
` Indication
` Dose Modification for AFINITOR/AFINITOR DISPERZ
`
`
`
`
`
`
`
`
` Breast Cancer, NET, RCC, and
`
` TSC-Associated Renal
`
`Angiomyolipoma
`
`TSC-Associated SEGA and TSC-
` Associated Partial-Onset Seizures
`
`
` • 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.
` • 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
`
`
`
`TSC-Associated SEGA and TSC-
` Associated Partial-Onset Seizures
`
`
`
`
`
` • 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.
`
` • 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)].
`
`
`
`
`
`Reference ID: 4549924
`
`

`

`
`Table 5: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ with P-gp
`
`
`
`
`and Strong CYP3A4 Inducers
`
`
`
` Indication
` Breast Cancer, NET, RCC, and
`
`
` TSC-Associated Renal
` Angiomyolipoma
`
`
`
`
`
`
`
`
`
`
` Dose Modification for AFINITOR/AFINITOR DISPERZ
`
`
`• 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.
`
` • 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.
`
`TSC-Associated SEGA and TSC-
` Associated Partial-Onset Seizures
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`•
`
`
`
`
`
` 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.
`
`Reference ID: 4549924
`
`

`

`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.
`
`
`
`
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`
`
`AFINITOR
`
`
`Tablets, white to slightly yellow and elongated with a bevelled edge:
`
`
`
`• 2.5 mg: engraved with “LCL” on one side and “NVR” on the other.
`
`
`
`
`
`• 5 mg: engraved with “5” on one side and “NVR” on the other.
`
`
`
`
`• 7.5 mg: engraved with “7P5” on one side and “NVR” on the other.
`
`
`
`
`
`• 10 mg: engraved with “UHE” on one side and “NVR” on the other.
`
`
`
`
`
`AFINITOR DISPERZ
`
`
`Tablets for oral suspension, white to slightly yellowish, round, and flat with a bevelled edge:
`
`
`
`
`
`
`• 2 mg: engraved with “D2” on one side and “NVR” on the other.
`
`
`
`
`
`• 3 mg: engraved with “D3” on one side and “NVR” on the other.
`
`
`
`
`
`
`• 5 mg: engraved with “D5” on one side and “NVR” on the other.
`
`
`
`
`
`
`CONTRAINDICATIONS
`4
`
`
`AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus
`
`
`
`
`
`or to other rapamycin derivatives [see Warnings and Precautions (5.3)].
`
`
`
`
`
`WARNINGS AND PRECAUTIONS
`5
`
`
`Non-infectious Pneumonitis
`5.1
`
`
`Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to
`
`
`19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases were reported with
`
`
`
`
`
`pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and
`
`
`
`4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes
`
`
`
`have been observed.
`
`Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and
`
`
`
`symptoms. Consider opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis.
`
`
`
`
`Advise patients to report promptly any new or worsening respiratory symptoms.
`
`
`Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes
`
`
`
`suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of
`
`
`
`
`
`clinical pneumonitis.
`
`For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ
`
`
`
`
`based on severity [see Dosage and Administration (2.9)]. Corticosteroids may be indicated until clinical symptoms
`
`
`
`
`resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are
`
`
`
`
`
`required. The development of pneumonitis has been reported even at a reduced dose.
`
`
`
`
`5.2
`Infections
`
`
`AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal,
`
`
`viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized
`
`
`and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal
`
`
`
`
`
`Reference ID: 4549924
`
`

`

`
`
`infections (e.g., aspergillosis, candidiasis, or PJP) and viral infections (e.g., reactivation of hepatitis B virus) have
`
`
`
`
`
`
`
`
`occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure)
`
`
`
`
`
`or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious
`
`
`
`infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4)].
`
`
`
`
`
`
`
`
`Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms
`
`
`
`
`of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection [see
`
`
`
`Dosage and Administration (2.9)].
`
`Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.
`
`
`
`
`
`Severe Hypersensitivity Reactions
`5.3
`
`
`
`Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea,
`
`
`flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see
`
`
`
`
`
`
`Contraindications (4)]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue
`
`
`
`
`AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.
`
`
`
`
`Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors
`5.4
`
`
`
`
`Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for
`
`
`
`angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of
`
`
`
`randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking AFINITOR with an ACE
`
`
`
`
`
`
`
`
`inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue
`
`
`
`
`
`AFINITOR/AFINITOR DISPERZ for angioedema.
`
`
`5.5
`Stomatitis
`
`
`Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR
`
`
`
`
`
`
`DISPERZ at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9%
`
`
`
`
`
`
`
`of patients [see Adverse Reactions (6.1)]. Stomatitis most often occurs within the first 8 weeks of treatment. When
`
`
`
`
`
`starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit
`
`
`
`
`
`
`mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)]. If stomatitis does occur,
`
`
`
`
`mouthwas