HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`AFINITOR safely and effectively. See full prescribing information for
`AFINITOR.
`
`AFINITOR (everolimus) tablets for oral administration
`Initial U.S. Approval: 2009
`----------------------------RECENT MAJOR CHANGES--------------------------
`Indications and Usage, Advanced Hormone Receptor-Positive, HER2-
`Negative Breast Cancer (1.1), Dosage and Administration (2.1, 2.2), Warnings
`and Precautions (5.1, 5.3, 5.5, 5.10)
`07/2012
`Indications and Usage (1.4, 1.5), Dosage and Administration (2.1, 2.2),
`Warnings and Precautions (5.1, 5.3, 5.8)
`04/2012
`Dosage and Administration (2.2, 2.4), Warnings and Precautions
`03/2012
`(5.7, 5.8)
`----------------------------INDICATIONS AND USAGE---------------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of:
`• postmenopausal women with advanced hormone receptor-positive, HER2-
`negative breast cancer (advanced HR+ BC) in combination with
`exemestane after failure of treatment with letrozole or anastrozole. (1.1)
`• adults with progressive neuroendocrine tumors of pancreatic origin (PNET)
`that is unresectable, locally advanced or metastatic. The safety and
`effectiveness of AFINITOR in the treatment of patients with carcinoid
`tumors have not been established. (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. The effectiveness of AFINITOR in
`treatment of renal angiomyolipoma is based on an analysis of durable
`objective responses in patients treated for a median of 8.3 months. Further
`follow-up of patients is required to determine long-term outcomes. (1.4)
`• adults and children ≥ 3 years of age with subependymal giant cell
`astrocytoma (SEGA) associated with tuberous sclerosis (TSC) who require
`therapeutic intervention but are not candidates for curative surgical
`resection. The effectiveness of AFINITOR is based on an analysis of
`change in SEGA volume. Clinical benefit such as improvement in disease-
`related symptoms or increase in overall survival has not been demonstrated.
`(1.5)
`------------------------DOSAGE AND ADMINISTRATION---------------------
`Advanced HR+ BC, advanced PNET, advanced RCC, or renal
`angiomyolipoma with TSC:
`• 10 mg once daily with or without food. (2.1)
`• For patients with hepatic impairment, reduce the AFINITOR dose. (2.2)
`• If moderate inhibitors of CYP3A4 and/or P-glycoprotein (PgP) are
`required, reduce the AFINITOR dose to 2.5 mg once daily; if tolerated,
`consider increasing to 5 mg once daily. (2.2)
`• If strong inducers of CYP3A4 are required, increase AFINITOR dose in 5
`mg increments to a maximum of 20 mg once daily. (2.2)
`SEGA:
`• Initial dose based on body surface area with subsequent titration to attain
`trough concentrations of 5-10 ng/mL. (2.3)
`• If moderate inhibitors of CYP3A4 and/or PgP are required, reduce the
`AFINITOR dose by approximately 50%. Subsequent dosing should be
`based on therapeutic drug monitoring (TDM). (2.4)
`• If strong inducers of CYP3A4 are required, double the AFINITOR dose.
`Subsequent dosing should be based on TDM. (2.4)
`Dose reduction or treatment interruption may be needed to manage adverse
`drug reactions. (2.2, 2.4)
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets with no score (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of
`the excipients (4)
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`• Non-infectious pneumonitis: Monitor for clinical symptoms or radiological
`changes; fatal cases have occurred. Manage by dose reduction or
`discontinuation until symptoms resolve, and consider use of
`corticosteroids. (5.1)
`• Infections: Increased risk of infections, some fatal. Monitor for signs and
`symptoms, and treat promptly. (5.2)
`• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common.
`Management includes mouthwashes (without alcohol or peroxide) and
`topical treatments. (5.3)
`• Renal failure: Cases of renal failure (including acute renal failure), some
`with a fatal outcome, have been observed in patients treated with
`AFINITOR. (5.4)
`• Laboratory test alterations: Elevations of serum creatinine, blood glucose,
`and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets
`may also occur. Monitor renal function, blood glucose, lipids, and
`hematologic parameters prior to treatment and periodically thereafter. (5.6)
`• Vaccinations: Avoid live vaccines and close contact with those who have
`received live vaccines. (5.9)
`• Embryo-fetal toxicity: Fetal harm can occur when administered to a
`pregnant woman. Apprise women of potential harm to the fetus. (5.10, 8.1)
`------------------------------ADVERSE REACTIONS-------------------------------
`Advanced HR+ BC, Advanced PNET, Advanced 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, 6.2, 6.3)
`Renal angiomyolipoma with TSC: Most common adverse reaction (incidence
`≥ 30%) is stomatitis. (6.4)
`SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis,
`upper respiratory tract infection, sinusitis, otitis media, and pyrexia. (6.5)
`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-------------------------------
`• Strong CYP3A4 inhibitors: Avoid concomitant use. (2.2, 2.4, 5.7, 7.1)
`• Moderate CYP3A4 and/or PgP inhibitors: If combination is required, use
`caution and reduce dose of AFINITOR. (2.2, 2.4, 5.7, 7.1)
`• Strong CYP3A4 inducers: Avoid concomitant use. If combination cannot
`be avoided, increase dose of AFINITOR. (2,2, 2.4, 5.7, 7.2)
`-----------------------USE IN SPECIFIC POPULATIONS------------------------
`• Nursing mothers: Discontinue drug or nursing, taking into consideration
`the importance of drug to the mother. (8.3)
`• Hepatic impairment: For advanced HR+ BC, advanced PNET, advanced
`RCC, and renal angiomyolipoma with TSC patients with hepatic
`impairment, reduce AFINITOR dose. For SEGA patients with Child-Pugh
`class A or Child-Pugh class B hepatic impairment, adjustment to the
`starting dose may not be needed; however, subsequent dosing should be
`based on TDM. AFINITOR should not be used in SEGA patients with
`Child-Pugh class C hepatic impairment. (2.2, 2.4, 5.8, 8.7)
`See 17 for PATIENT COUNSELING INFORMATION and
`FDA-approved patient labeling
`
`
`
`Revised: 07/2012
`
`

`

`FULL PRESCRIBING INFORMATION: CONTENTS*
`1 INDICATIONS AND USAGE
`1.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast
`Cancer (Advanced HR+ BC)
`1.2 Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
`1.3 Advanced Renal Cell Carcinoma (RCC)
`1.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
`1.5 Subependymal Giant Cell Astrocytoma (SEGA)
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose in Advanced Hormone Receptor-Positive,
`HER2-Negative Breast Cancer, Advanced PNET, Advanced
`RCC and Renal Angiomyolipoma with TSC
`2.2 Dose Modifications in Advanced Hormone Receptor-Positive,
`HER2-Negative Breast Cancer, Advanced PNET, Advanced
`RCC, and Renal Angiomyolipoma with TSC
`2.3 Recommended Dose in Subependymal Giant Cell Astrocytoma
`2.4 Dose Modifications in Subependymal Giant Cell Astrocytoma
`2.5 Therapeutic Drug Monitoring in Subependymal Giant Cell
`Astrocytoma
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Non-infectious Pneumonitis
`5.2 Infections
`5.3 Oral Ulceration
`5.4 Renal Failure
`5.5 Geriatric Patients
`5.6 Laboratory Tests and Monitoring
`5.7 Drug-drug Interactions
`5.8 Hepatic Impairment
`5.9 Vaccinations
`5.10 Embryo-fetal Toxicity
`6 ADVERSE REACTIONS
`6.1 Clinical Study Experience in Advanced Hormone-Receptor-
`Positive, HER2-Negative Breast Cancer
`6.2 Clinical Study Experience in Advanced Pancreatic
`Neuroendocrine Tumors
`6.3 Clinical Study Experience in Advanced Renal Cell Carcinoma
`6.4 Clinical Study Experience in Renal Angiomyolipoma with
`Tuberous Sclerosis Complex
`6.5 Clinical Study Experience in Subependymal Giant Cell
`Astrocytoma
`
`7 DRUG INTERACTIONS
`7.1 Agents that may Increase Everolimus Blood Concentrations
`7.2 Agents that may Decrease Everolimus Blood Concentrations
`7.3 Agents whose Plasma Concentrations may be Altered by
`Everolimus
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`8.7 Hepatic Impairment
`10 OVERDOSAGE
`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 Advanced Hormone Receptor-Positive, HER2-Negative Breast
`Cancer
`14.2 Advanced Neuroendocrine Tumors
`14.3 Advanced Renal Cell Carcinoma
`14.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex
`14.5 Subependymal Giant Cell Astrocytoma
`15 REFERENCES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Non-infectious Pneumonitis
`17.2 Infections
`17.3 Oral Ulceration
`17.4 Renal Failure
`17.5 Laboratory Tests and Monitoring
`17.6 Drug-drug Interactions
`17.7 Vaccinations
`17.8 Pregnancy
`17.9 Dosing Instructions
`* Sections or subsections omitted from the full prescribing information are
`not listed
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC)
`AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-
`negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or
`anastrozole.
`1.2 Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
`AFINITOR® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin
`(PNET) with unresectable, locally advanced or metastatic disease.
`The safety and effectiveness of AFINITOR® in the treatment of patients with carcinoid tumors have not been established.
`1.3 Advanced Renal Cell Carcinoma (RCC)
`AFINITOR® is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or
`sorafenib.
`1.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
`AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex
`(TSC), not requiring immediate surgery.
`The effectiveness of AFINITOR in treatment of renal angiomyolipoma is based on an analysis of durable objective
`responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term
`outcomes.
`1.5 Subependymal Giant Cell Astrocytoma (SEGA)
`AFINITOR® is indicated for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA associated
`with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not candidates for curative surgical
`resection.
`The effectiveness of AFINITOR is based on an analysis of change in SEGA volume [see Clinical Studies (14.5)]. Clinical
`benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated.
`2 DOSAGE AND ADMINISTRATION
`AFINITOR should be administered orally once daily at the same time every day, either consistently with food or
`consistently without food [see Clinical Pharmacology (12.3)].
`AFINITOR tablets should be swallowed whole with a glass of water. AFINITOR tablets should not be crushed. Do not
`take tablets which are crushed or broken. For patients unable to swallow tablets, AFINITOR tablet(s) should be dispersed
`completely in a glass of water (containing approximately 30 mL) by gently stirring, immediately prior to drinking. The
`glass should be rinsed with the same volume of water and the rinse should be completely swallowed to ensure that the
`entire dose is administered.
`Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
`2.1 Recommended Dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced
`PNET, Advanced RCC and Renal Angiomyolipoma with TSC
`The recommended dose of AFINITOR is 10 mg, to be taken once daily.
`2.2 Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET,
`Advanced RCC, and Renal Angiomyolipoma with TSC
`Management of Adverse Reactions
`Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of
`AFINITOR therapy. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose
`previously administered [see Warnings and Precautions (5)].
`Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the
`management of adverse reactions. General management recommendations are also provided as applicable. Clinical
`judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk
`assessment.
`
`

`

`Table 1: AFINITOR Dose Adjustment and Management Recommendation for Adverse Reactions
`AFINITOR Dose Adjustmentb and Management
`Severitya
`Adverse Drug
`Reaction
`Recommendations
`Non-infectious
`No dose adjustment required.
`pneumonitis
`Initiate appropriate monitoring.
`
`Grade 1
`Asymptomatic,
`radiographic findings only
`Grade 2
`Symptomatic,
`not interfering with ADLc
`
`Grade 3
`Symptomatic,
`interfering with ADLc;
`O2 indicated
`
`Grade 4
`Life-threatening,
`ventilatory support indicated
`Grade 1
`Minimal symptoms,
`normal diet
`Grade 2
`Symptomatic but can eat and
`swallow modified diet
`
`Grade 3
`Symptomatic and unable to
`adequately aliment or
`hydrate orally
`
`Grade 4
`Symptoms associated with
`life-threatening
`consequences
`Grade 1
`
`Grade 2
`
`Grade 3
`
`Grade 4
`Grade 1
`
`Grade 2
`
`
`
`
`
`
`
`Stomatitis
`
`
`
`
`
`
`
`Other non-
`hematologic
`toxicities
`(excluding metabolic
`events)
`
`
`
`
`Metabolic events
`(e.g. hyperglycemia,
`dyslipidemia)
`
`Consider interruption of therapy, rule out infection and consider
`treatment with corticosteroids until symptoms improve to ≤ grade 1.
`Re-initiate AFINITOR at a lower dose.
`Discontinue treatment if failure to recover within 4 wks.
`Interrupt AFINITOR until symptoms resolve to ≤ grade 1.
`Rule out infection, and consider treatment with corticosteroids.
`Consider re-initiating AFINITOR at a lower dose. If toxicity recurs
`at grade 3, consider discontinuation.
`
`Discontinue AFINITOR, rule out infection, and consider treatment
`with corticosteroids.
`
`No dose adjustment required.
`Manage with non-alcoholic or salt water (0.9%) mouth wash several
`times a day.
`Temporary dose interruption until recovery to grade ≤1.
`Re-initiate AFINITOR at the same dose.
`If stomatitis recurs at grade 2, interrupt dose until recovery to grade
`≤1. Re-initiate AFINITOR at a lower dose.
`Manage with topical analgesic mouth treatments (e.g. benzocaine,
`butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol)
`with or without topical corticosteroids (i.e. triamcinolone oral
`paste).d
`Temporary dose interruption until recovery to grade ≤1.
`Re-initiate AFINITOR at a lower dose.
`Manage with topical analgesic mouth treatments (i.e. benzocaine,
`butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol)
`with or without topical corticosteroids (i.e. triamcinolone oral
`paste).d
`Discontinue AFINITOR and treat with appropriate medical therapy.
`
`If toxicity is tolerable, no dose adjustment required.
`Initiate appropriate medical therapy and monitor.
`If toxicity is tolerable, no dose adjustment required.
`Initiate appropriate medical therapy and monitor.
`If toxicity becomes intolerable, temporary dose interruption until
`recovery to grade ≤1. Re-initiate AFINITOR at the same dose.
`If toxicity recurs at grade 2, interrupt AFINITOR until recovery to
`grade ≤1. Re-initiate AFINITOR at a lower dose.
`Temporary dose interruption until recovery to grade ≤1.
`Initiate appropriate medical therapy and monitor.
`Consider re-initiating AFINITOR at a lower dose. If toxicity recurs
`at grade 3, consider discontinuation.
`Discontinue AFINITOR and treat with appropriate medical therapy.
`No dose adjustment required.
`Initiate appropriate medical therapy and monitor.
`No dose adjustment required.
`Manage with appropriate medical therapy and monitor.
`
`

`

`Severitya
`
`Grade 3
`
`Adverse Drug
`Reaction
`
`
`AFINITOR Dose Adjustmentb and Management
`Recommendations
`Temporary dose interruption.
`Re-initiate Afinitor at a lower dose.
`Manage with appropriate medical therapy and monitor.
`Discontinue AFINITOR and treat with appropriate medical therapy.
`Grade 4
`
`a Severity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.
`b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered.
`c Activities of daily living (ADL)
`d Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may worsen mouth
`ulcers.
`Hepatic Impairment
`Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.8) and Use in Specific
`Populations (8.7)]. Dose adjustments are recommended:
`- Mild hepatic impairment (Child-Pugh class A) – The recommended dose is 7.5 mg daily; the dose may be decreased to 5
`mg if not well tolerated.
`- Moderate hepatic impairment (Child-Pugh class B) – The recommended dose is 5 mg daily; the dose may be decreased
`to 2.5 mg if not well tolerated.
`- Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may
`be used but must not be exceeded.
`Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
`CYP3A4 and/or P-glycoprotein (PgP) Inhibitors
`Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
`saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.7) and Drug
`Interactions (7.1)].
`Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir,
`aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4
`and/or PgP inhibitor, reduce the AFINITOR dose to 2.5 mg daily. The reduced dose of AFINITOR is predicted to adjust
`the area under the curve (AUC) to the range observed without inhibitors. An AFINITOR dose increase from 2.5 mg to 5
`mg may be considered based on patient tolerance. If the moderate inhibitor is discontinued, a washout period of
`approximately 2 to 3 days should be allowed before the AFINITOR dose is increased. If the moderate inhibitor is
`discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or
`PgP inhibitor.
`Strong CYP3A4 Inducers
`Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
`phenobarbital). If patients require co-administration of a strong CYP3A4 inducer, consider increasing the AFINITOR
`dose from 10 mg daily up to 20 mg daily, using 5 mg increments. This dose of AFINITOR is predicted, based on
`pharmacokinetic data, to adjust the AUC to the range observed without inducers. However, there are no clinical data with
`this dose adjustment in patients receiving strong CYP3A4 inducers. If the strong inducer is discontinued, the AFINITOR
`dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer [see Warnings and Precautions
`(5.7) and Drug Interactions (7.2)].
`Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase
`everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum perforatum) may decrease
`everolimus exposure unpredictably and should be avoided.
`
`

`

`2.3 Recommended Dose in Subependymal Giant Cell Astrocytoma
`The recommended starting dose of AFINITOR for treatment of patients with SEGA is according to Table 2:
`Table 2: Recommended Starting Dose of AFINITOR for Treatment of Patients with SEGA
`Body Surface Area (BSA)
`Starting Dose
`0.5 m2 to 1.2 m2
`2.5 mg once daily
`1.3 m2 to 2.1 m2
`5 mg once daily
`Greater than or equal to 2.2 m2
`7.5 mg once daily
`Patients receiving AFINITOR may require dose adjustments based on everolimus whole blood trough concentrations
`achieved, tolerability, individual response, and change in concomitant medications including CYP3A4-inducing
`antiepileptic drugs [see Warnings and Precautions (5.7) and Drug Interactions (7.1, 7.2)]. Dose adjustments can be made
`at two week intervals [see Dosage and Administration (2.4, 2.5)].
`Evaluate SEGA volume approximately 3 months after commencing AFINITOR therapy and periodically thereafter, with
`subsequent dose adjustments taking into consideration changes in SEGA volume, corresponding trough concentration, and
`tolerability. Responses have been observed at trough concentrations as low as 3 ng/mL; as such, once acceptable efficacy
`has been achieved, additional dose increases may not be necessary.
`AFINITOR has not been studied in patients with SEGA < 3 years of age or with BSA < 0.58 m2.
`The optimal duration of therapy for patients with SEGA is unknown.
`2.4 Dose Modifications in Subependymal Giant Cell Astrocytoma
`Management of Adverse Reactions
`Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of
`AFINITOR therapy. If a dose reduction is required, the suggested dose is approximately 50% lower than the dose
`previously administered [see Table 1 in Dosage and Administration (2.2) and Warnings and Precautions (5]. For dose
`reductions below the lowest available strength, consider alternate day dosing.
`Hepatic Impairment
`Adjustment to the recommended starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate
`(Child-Pugh class B) hepatic impairment may not be needed; however, subsequent dosing should be based on therapeutic
`drug monitoring (TDM).
`AFINITOR is not recommended for use in patients with SEGA who have severe hepatic impairment (Child-Pugh class
`C).
`Everolimus whole blood trough concentration should be assessed approximately 2 weeks after commencing treatment or
`after any change in hepatic status (Child-Pugh). Dosing should be titrated to attain trough concentrations of 5 to 10
`ng/mL [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].
`CYP3A4 and/or P-glycoprotein (PgP) Inhibitors
`Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone,
`saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.7) and Drug
`Interactions (7.1)].
`Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir,
`aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4
`and/or PgP inhibitor, reduce the AFINITOR dose by approximately 50% to maintain trough concentrations of 5 to 10
`ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing. Subsequent dosing
`should be individualized based on therapeutic drug monitoring. Everolimus trough concentrations should be assessed
`approximately 2 weeks after the addition of a moderate CYP3A4 and/or PgP inhibitor. If the moderate inhibitor is
`discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or
`PgP inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later [see Dosage
`and Administration (2.5), Warnings and Precautions (5.7) and Drug Interactions (7.1)].
`Strong CYP3A4 Inducers
`Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine,
`phenobarbital). For patients requiring a concomitant strong CYP3A4 inducer, double the AFINITOR dose. Subsequent
`
`

`

`dosing should be individualized based on therapeutic drug monitoring. If the strong inducer is discontinued, the
`AFINITOR dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer and the everolimus
`trough concentrations should be assessed approximately 2 weeks later [see Dosage and Administration (2.5), Warnings
`and Precautions (5.7) and Drug Interactions (7.2)].
`Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity may increase
`everolimus exposures and should be avoided during treatment. St. John’s Wort (Hypericum perforatum) may decrease
`everolimus exposure unpredictably and should be avoided.
`2.5 Therapeutic Drug Monitoring in Subependymal Giant Cell Astrocytoma
`Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using a
`validated assay. Trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing
`should be titrated to attain trough concentrations of 5 to 10 ng/mL.
`There is limited safety experience with patients having trough concentrations > 10 ng/mL. If concentrations are between
`10 and 15 ng/mL, and the patient has demonstrated adequate tolerability and tumor response, no dose reductions are
`needed. The dose of AFINITOR should be reduced if trough concentrations > 15 ng/mL are observed.
`If concentrations are < 5 ng/mL, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. Daily
`dose may be reduced by 2.5 mg every 2 weeks to attain a target of 5 to 10 ng/mL. If dose reduction is required for patients
`receiving 2.5 mg daily, alternate day dosing should be used.
`Trough concentrations should be assessed approximately 2 weeks after any change in dose, after an initiation or change in
`co-administration of CYP3A4 and/or PgP inducers or inhibitors, or after any change in hepatic status (Child-Pugh
`Classification) [see Dosage and Administration (2.4), Warnings and Precautions (5.7, 5.8), Drug Interactions (7.1, 7.2)].
`3 DOSAGE FORMS AND STRENGTHS
`2.5 mg tablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and
`“NVR” on the other.
`5 mg tablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR”
`on the other.
`7.5 mg tablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “7P5” on one side and
`“NVR” on the other.
`10 mg tablet
`White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and
`“NVR” on the other.
`4 CONTRAINDICATIONS
`Hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity
`reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema
`(e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and
`other rapamycin derivatives.
`5 WARNINGS AND PRECAUTIONS
`5.1 Non-infectious Pneumonitis
`Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis
`was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology
`Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively [see Adverse
`Reactions (6.1, 6.2, 6.3, 6.4, 6.5)]. Fatal outcomes have been observed.
`Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and
`symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have
`been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening
`respiratory symptoms.
`
`

`

`Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may
`continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical
`pneumonitis.
`If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be
`indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously
`administered [see Table 1 in Dosage and Administration (2.2)].
`For cases of grade 4 non-infectious pneumonitis, discontinue AFINITOR. Corticosteroids may be indicated until clinical
`symptoms resolve. For cases of grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or
`equal to grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously
`administered depending on the individual clinical circumstances [see Table 1 in Dosage and Administration (2.2)]. If
`toxicity recurs at grade 3, consider discontinuation of AFINITOR. The development of pneumonitis has been reported
`even at a reduced dose.
`5.2 Infections
`AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal
`infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1, 6.2, 6.3, 6.4, 6.5)]. Localized
`and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal
`infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have
`occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic
`failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete
`treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR,
`be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment
`promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection
`is made, discontinue AFINITOR and treat with appropriate antifungal therapy.
`5.3 Oral Ulceration
`Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging
`from 44-86% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4-8% of patients [see Adverse
`Reactions (6.1, 6.2, 6.3, 6.4, 6.5)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing
`mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal
`infection has been diagnosed [see Drug Interactions (7.1)].
`5.4 Renal Failure
`Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated
`with AFINITOR [see Laboratory Tests and Monitoring (5.6)].
`5.5 Geriatric Patients
`In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, the incidence of deaths due
`to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients
`< 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65
`years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for
`adverse reactions are recommended [see Dosage and Administration (2.2), Use in Specific Populations (8.5)].
`5.6 Laboratory Tests and Monitoring
`Renal Function
`Elevations of serum creatinine and proteinuria have been re