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 Pancreatic Neuroendocrine
`Tumors (1.1), Warnings and Precautions: Non-infectious
`Pneumonitis (5.1), Infections (5.2), Oral Ulceration (5.3), Renal Failure
`Events (5.4), Laboratory Tests and Monitoring (5.5)
`05/2011
`
`
`Indications and Usage, Subependymal Giant Cell Astrocytoma (1.3) 10/2010
`
`Dosage and Administration (2)
`10/2010
`
`Warnings and Precautions: Non-infectious Pneumonitis (5.1),
`Infections (5.2), Oral Ulceration (5.3), Drug-drug Interactions (5.6),
`Hepatic Impairment (5.7), Vaccinations (5.8), Use in Pregnancy (5.9) 10/2010
`
`----------------------------INDICATIONS AND USAGE---------------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of patients 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. (1.1)
`
`
`• advanced renal cell carcinoma (RCC) after failure of treatment with
`sunitinib or sorafenib. (1.2)
`
`• subependymal giant cell astrocytoma (SEGA) associated with tuberous
`sclerosis (TS) 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. (1.3)
`------------------------DOSAGE AND ADMINISTRATION---------------------
`Advanced PNET or advanced RCC:
`
`• 10 mg once daily with or without food. (2.1)
`
`
`
`• For patients with Child-Pugh class B hepatic impairment, reduce the
`AFINITOR dose to 5 mg once daily. (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 and/or treatment interruption may be needed to manage
`adverse drug reactions. (2.2, 2.4)
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`2.5 mg, 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 events: 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. (5.5)
`
`• Vaccinations: Avoid live vaccines and close contact with those who have
`received live vaccines. (5.8)
`
`• Use in pregnancy: Fetal harm can occur when administered to a pregnant
`
`woman. Apprise women of potential harm to the fetus. (5.9, 8.1)
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Advanced PNET: Most common adverse reactions (incidence ≥30%) are
`
`
`stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and
`
`headache. (6.1)
`
`Advanced RCC: Most common adverse reactions (incidence ≥30%) are
`
`stomatitis, infections, asthenia, fatigue, cough, and diarrhea. (6.2)
`
`SEGA: Most common adverse reactions (incidence ≥30%) are stomatitis,
`
`upper respiratory tract infection, sinusitis, otitis media, and pyrexia. (6.3)
`
`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, 5.6, 7.1)
`
`
`• Moderate CYP3A4 and/or PgP inhibitors: If combination is required, use
`caution and reduce dose of AFINITOR. (2.2, 2.4, 5.6, 7.1)
`
`
`• Strong CYP3A4 inducers: Avoid concomitant use. If combination cannot
`
`be avoided, increase dose of AFINITOR. (2.2, 2.4, 5.6, 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: AFINITOR should not be used in patients with Child-
`Pugh class C hepatic impairment. For advanced PNET and advanced RCC
`patients with Child-Pugh class B hepatic impairment, reduce AFINITOR
`dose. For SEGA patients with Child-Pugh class B hepatic impairment,
`
`adjustment to the starting dose may not be needed; however, subsequent
`dosing should be based on TDM. (2.2, 2.5, 5.7, 8.7)
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`
`
`Revised: 05/2011
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
` 
`1 INDICATIONS AND USAGE
` 
`1.1 Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
` 
`1.2 Advanced Renal Cell Carcinoma (RCC)
` 
`1.3 Subependymal Giant Cell Astrocytoma (SEGA)
` 
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose in Advanced Pancreatic Neuroendocrine
` 
`Tumors and Advanced Renal Cell Carcinoma
`2.2 Dose Modifications in Advanced Pancreatic Neuroendocrine
` 
`Tumors and Advanced Renal Cell Carcinoma
` 
`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
`
`Reference ID: 2942958
`
` 
`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 Events
` 
`5.5 Laboratory Tests and Monitoring
` 
`5.6 Drug-drug Interactions
` 
`5.7 Hepatic Impairment
` 
`5.8 Vaccinations
` 
`5.9 Use in Pregnancy
` 
`6 ADVERSE REACTIONS
`6.1 Clinical Study Experience in Advanced Pancreatic
`
` 
`Neuroendocrine Tumors
`
`

`

` 
`
` 6.2 Clinical Study Experience in Advanced Renal Cell Carcinoma
`
`6.3 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 Neuroendocrine Tumors
`
` 
`14.2 Advanced Renal Cell Carcinoma
`
` 
`14.3 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 Events
`
`
` 
`17.5 Laboratory Tests and Monitoring
`
`
` 
`17.6 Drug-drug Interactions
`
` 
`17.7 Hepatic Impairment
`
` 
`17.8 Vaccinations
`
` 
`17.9 Pregnancy
`
` 
`17.10 Dosing Instructions
`
`* Sections or subsections omitted from the full prescribing information are
`
`
`not listed
`
`Reference ID: 2942958
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
`AFINITOR® is indicated for the treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients
`
`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.
`1.2 Advanced Renal Cell Carcinoma (RCC)
`AFINITOR® is indicated for the treatment of patients with advanced RCC after failure of treatment with sunitinib or
`
`sorafenib.
`1.3 Subependymal Giant Cell Astrocytoma (SEGA)
`AFINITOR® is indicated for the treatment of patients with SEGA associated with tuberous sclerosis (TS) 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 (14.2)]. 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. The tablets should not be chewed or crushed. 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 Pancreatic Neuroendocrine Tumors and Advanced Renal Cell Carcinoma
`The recommended dose of AFINITOR for treatment of advanced PNET and advanced RCC is 10 mg, to be taken once
`daily.
`Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
`2.2 Dose Modifications in Advanced Pancreatic Neuroendocrine Tumors and Advanced Renal Cell Carcinoma
`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 5 mg daily [see Warnings and Precautions (5.1)].
`
`Hepatic Impairment
`For patients with moderate hepatic impairment (Child-Pugh class B), reduce the dose to 5 mg daily. AFINITOR has not
`been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this patient
`population [see Warnings and Precautions (5.7) and Use in Specific Populations (8.7)].
`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 (5.6) 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
`
`
`
`Reference ID: 2942958
`
`

`

` 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 (based on pharmacokinetic data), using 5 mg increments. This dose of
`AFINITOR is predicted 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 (5.6) 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 1:
`Table 1: Recommended Starting Dose of AFINITOR for Treatment of Patients with SEGA
`Starting Dose
`Body Surface Area (BSA)
`
`
` 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 trough blood concentrations achieved,
`
`tolerability, individual response, and change in concomitant medications including CYP3A4-inducing antiepileptic drugs
`[see Warnings and Precautions (5.6) 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 severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of
`AFINITOR therapy [see Warnings and Precautions (5.1)]. If dose reduction is required for patients receiving 2.5 mg
`
`
`daily, consider alternate day dosing.
`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 (5.5) 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 Warnings
`and Precautions (5.6) 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
`
`Reference ID: 2942958
`
`

`

`
`
` trough concentrations should be assessed approximately 2 weeks later [see Warnings and Precautions (5.6) 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 to 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, or after an initiation or change
`
`in co-administration of CYP3A4 and/or PgP inducers or inhibitors [see Dosage and Administration (2.4), Warnings and
`Precautions (5.6), 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.
`
`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 11-14% of patients treated with AFINITOR. The incidence of Common Terminology Criteria (CTC)
`grade 3 and 4 non-infectious pneumonitis was 1.6-4.0% and 0.1%, 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 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.
`
`In patients with advanced PNET and advanced RCC, AFINITOR may be reintroduced at 5 mg daily.
`•
`
`Reference ID: 2942958
`
`

`

`
`•
`
`
`•
`
`
`
` In patients with SEGA, AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose
`previously administered.
`For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy. Corticosteroids
`may be indicated until clinical symptoms resolve.
`
`In patients with advanced PNET and advanced RCC, therapy with AFINITOR may be re-initiated at a reduced
`•
`dose of 5 mg daily depending on the individual clinical circumstances. The development of pneumonitis has been
`reported even at a reduced dose.
`In patients with SEGA, therapy with AFINITOR may be re-initiated at a daily dose approximately 50% lower
`than the dose previously administered depending on the individual clinical circumstances.
`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)]. 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. Approximately 44%-64%
`of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 or 2
`[see Adverse Reactions (6.1)]. Grade 3 or 4 stomatitis was reported in 6% of patients with neuroendocrine tumors. In the
`
`
`SEGA study, 86% of AFINITOR-treated patients developed stomatitis which was mostly CTCAE grade 1 or 2 [see
`
`Adverse Reactions (6.2)]. 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 Events
`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 (5.5)].
`
`5.5 Laboratory Tests and Monitoring
`Renal Function
`Elevations of serum creatinine and proteinuria have been reported in clinical trials [see Adverse Reactions (6.1, 6.2)].
`Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine,
`
`is recommended prior to the start of AFINITOR therapy and periodically thereafter.
`Blood Glucose and Lipids
`Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions
`(6.1, 6.2)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy
`
`and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient
`on AFINITOR.
`Hematologic Parameters
`Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse
`Reactions (6.1, 6.2)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and
`periodically thereafter.
`5.6 Drug-drug Interactions
`Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be
`avoided [see Dosage and Administration (2.2, 2.4) and Drug Interactions (7.1)].
`
`
`Reference ID: 2942958
`
`

`

`A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 and/or PgP
`inhibitor [see Dosage and Administration (2.2, 2.4) and Drug Interactions (7.1)].
`An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer [see Dosage
`and Administration (2.2, 2.4) and Drug Interactions (7.2)].
`5.7 Hepatic Impairment
`Exposure of everolimus was increased in patients with moderate hepatic impairment [see Clinical Pharmacology (12.3)].
`For advanced PNET and advanced RCC patients with moderate hepatic impairment (Child-Pugh class B), a dose
`reduction is recommended [see Dosage and Administration (2.2)].
`
`For SEGA patients with moderate hepatic impairment (Child-Pugh class B), adjustment to the starting dose may not be
`needed. However, subsequent dosing should be individualized based on therapeutic drug monitoring [see Dosage and
`Administration (2.5)].
`AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used
`in this population.
`
`5.8 Vaccinations
`The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment
`with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow
`
`fever, varicella, and TY21a typhoid vaccines.
`The timing of routine vaccinations in pediatric patients with SEGA should be considered prior to the start of everolimus
`
`therapy.
`5.9 Use in Pregnancy
`
`There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on the mechanism
`of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal
`toxicities in animals at maternal exposures that were lower than human exposures for advanced PNET, advanced RCC,
`
`and SEGA patients. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the
`patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use
`an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment [see Use in
`Specific Populations (8.1)].
`
`6 ADVERSE REACTIONS
`
`The following serious adverse reactions are discussed in greater detail in another section of the label:
`
`• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].
`
`Infections [see Warnings and Precautions (5.2)].
`•
`Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be
`
`directly compared to rates in other trials and may not reflect the rates observed in clinical practice.
`6.1 Clinical Study Experience in Advanced Pancreatic Neuroendocrine Tumors
`In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the
`
`median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm
`could cross over to open-label AFINITOR upon disease progression.
`The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain,
`nausea, fever, and headache. The most common grade 3/4 adverse reactions (incidence ≥ 5%) were stomatitis and
`diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia,
`alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST).
`The most common grade 3/4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased
`hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST),
`potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an AE was the primary cause
`occurred in 7 patients on AFINITOR and 1 patient on placebo. Causes of death on the AFINITOR arm included one case
`
`of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic
`failure, pneumonia, and sepsis. There was 1 death due to pulmonary embolism on the placebo arm. After cross-over to
`
`open-label AFINITOR, there were 3 additional deaths, one due to hypoglycemia and cardiac arrest in a patient with
`
`Reference ID: 2942958
`
`

`

`insulinoma, one due to MI with CHF, and the other due to sudden death. The rates of treatment-emergent adverse events
`resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively.
`Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure
`occurred in 6 patients in the everolimus arm and 3 patients in the placebo arm. Thrombotic events included 5 patients with
`pulmonary embolus in the everolimus arm and 1 in the placebo arm as well as 3 patients with thrombosis in the
`
`everolimus arm and 2 in the placebo arm.
`
`Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients
`receiving AFINITOR 10 mg daily versus placebo.
` Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced PNET
`
`AFINITOR
`N=204
`Grade 3
`%
`49
`
`All grades
`%
`100
`
`
`
`Any adverse reaction
`
`Gastrointestinal disorders
`Stomatitisa
`
`
`70
`Diarrheab
`
`
`50
`
`36
`Abdominal pain
`32
`Nausea
`29
`Vomiting
`14
`Constipation
`
`
`11
`Dry mouth
`General disorders and administration site conditions
`
`
`Fatigue/malaise
`45
`
`
`Edema (general and peripheral)
`39
`
`Fever
`31
`Asthenia
`19
`Infections and infestations
`
`Nasopharyngitis/rhinitis/URI
`Urinary tract infection
`Investigations
` Weight decreased
`
`Metabolism and nutrition disorders
`
`
`
`Decreased appetite
`Diabetes mellitus
`
`
`
`25
`16
`
`28
`
`30
`10
`
`
`
`Musculoskeletal and connective tissue disorders
`
`
`15
`Arthralgia
`
`Back pain
`15
`
`
`Pain in extremity
`14
`
`
`Muscle spasms
`10
`
`
`
`Nervous system disorders
`
`Headache/migraine
`
`Dysgeusia
`
`Dizziness
`Psychiatric disorders
`
`
`14
`Insomnia
`Respiratory, thoracic and mediastinal disorders
`
`25
`Cough/productive cough
`Epistaxis
`22
`Dyspnea/dyspnea exertional
`20
`Pneumonitisc
`
`17
`Oropharyngeal pain
`11
`Skin and subcutaneous disorders
`
`Rash
`Nail disorders
`Pruritus/pruritus generalized
`
`30
`19
`12
`
`59
`22
`21
`
`
`
`
`Reference ID: 2942958
`
`Grade 4
`%
`13
`
`All grades
`%
`98
`
`Placebo
`N=203
`Grade 3
`%
`32
`
`Grade 4
`%
`8
`
`7
`5
`4
`2
`1
`0
`0
`
`3
`1
`0.5
`3
`
`0
`0
`
`0.5
`
`1
`2
`
`1
`1
`0.5
`0
`
`0.5
`0
`0.5
`
`0
`
`0.5
`0
`2
`3
`0
`
`0.5
`0.5
`