`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Silver Spring MD 20993
`
`
`
`ACCELERATED APPROVAL
`
`
`
`NDA 22334/S-17
`
`Novartis Pharmaceuticals Corporation
`Attention: Yanina Gutman, PharmD
`Associate Director, Drug Regulatory Affairs
`One Health Plaza
`East Hanover, NJ 07936
`
`Dear Dr. Gutman:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated December 19. 2011,
`received December 19, 2011, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Afinitor (everolimus) Tablets 2.5 mg, 5 mg, 7.5 mg, and 10 mg
`
`tablets.
`
`We acknowledge receipt of your amendments dated February 24, March 29, and April 5, 13, 16,
`19, 23, and 24, 2012.
`
`This “Prior Approval” supplemental new drug application provides for the treatment of adults
`with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate
`surgery.
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert, text for the
`
`patient package insert, Medication Guide), with the addition of any labeling changes in pending
`“Changes Being Effected” (CBE) supplements, as well as annual reportable changes not
`included in the enclosed labeling.
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`
`
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 001
`
`

`

` NDA 22334/S-17
`
`Page 2
`
`
`The SPL will be accessible from publicly available labeling repositories.
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes, and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`ACCELERATED APPROVAL REQUIREMENTS
`
`Products approved under the accelerated approval regulations, 21 CFR 314.510, require further
`adequate and well-controlled studies/clinical trials to verify and describe clinical benefit.
`Therefore, you are required to conduct the following:
`
`PMR #1892-1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`To complete the ongoing clinical trial CRAD001M2302 entitled “A
`Randomized, Double-blind, Placebo-controlled Study of RAD001 in the
`Treatment of Angiomyolipoma in Patients with either Tuberous Sclerosis
`Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM)” to
`further verify and describe the ultimate clinical outcomes of the duration
`of objective responses, incidence of nephrectomy and of renal
`embolization four years after randomization of the last patient in the study,
`as specified in the original protocol. You will submit the final
`comprehensive clinical study report, inclusive of all data collected in the
`clinical trial, as described in ICH E3.
`
`
`The timetable you submitted on April 23, 2012, states you will conduct this trial according
`to the following schedule:
`
`
`June 10, 2010
`
`Final Protocol Submission:
`January 2015
`
`Study/Trial Completion:
`Final Report Submission: August 2015
`
`
`
`Submit final reports to this NDA as a supplemental application. For administrative purposes, all
`submissions relating to this postmarketing requirement must be clearly designated “Subpart H
`Postmarketing Requirement.”
`
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`
`
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 002
`
`

`

` NDA 22334/S-17
`
`Page 3
`
`
`Because your request for orphan drug designation was granted, you are exempt from this
`requirement.
`
`PROMOTIONAL MATERIALS
`
`
`As required by 21 CFR 314.550, submit all promotional materials at least 30 days before the
`intended time of initial distribution of labeling or initial publication of the advertisement. Send
`two copies of all promotional materials directly to:
`
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, please call Ms. Sharon Sickafuse, Senior Regulatory Health Project
`Manager, at (301) 796-2320.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Patricia Keegan, M.D.
`Director
`
`Division of Oncology Products 2
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE:
`Content of Labeling
`
`
`
`
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 003
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`PATRICIA KEEGAN
`04/26/2012
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 004
`
`

`

`03/2012
`
`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, Renal Angiomyolipoma with Tuberous Sclerosis
`Complex (1.3), Subependymal Giant Cell Astrocytoma (1.4), Dosage and
`Administration (2.1, 2.2), Warnings and Precautions (5.1, 5.3, 5.7)
`04/2012
`Dosage and Administration (2.2, 2.4), Warnings and Precautions
`(5.6, 5.7)
`Indications and Usage, Advanced Pancreatic Neuroendocrine
`05/2011
`Tumors (1.1), Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5)
`----------------------------INDICATIONS AND USAGE---------------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of:
`
`
` 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. (1.1)
`
` adults with advanced renal cell carcinoma (RCC) after failure of treatment
`with sunitinib or sorafenib. (1.2)
`
` 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. (1.3)
`
`
` 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.
`
`
`
`(1.4)
`------------------------DOSAGE AND ADMINISTRATION---------------------
`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)
`
`
`
`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 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
` 
`1.4 Subependymal Giant Cell Astrocytoma (SEGA)
` 
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose in Advanced PNET, Advanced RCC and
` 
`Renal Angiomyolipoma with TSC
`2.2 Dose Modifications in Advanced PNET, Advanced RCC, and
` 
`Renal Angiomyolipoma with TSC
`
`Reference ID: 3122590
`
`-------------------------------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. (5.5)
`
` 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)
`
`Renal angiomyolipoma with TSC: Most common adverse reaction (incidence
`
`≥ 30%) is stomatitis. (6.3)
`
`SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis,
`
`
`upper respiratory tract infection, sinusitis, otitis media, and pyrexia. (6.4)
`
`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: For 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, 5.7, 8.7)
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`
`
`Revised: 04/2012
`
`
` 
`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 Laboratory Tests and Monitoring
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 005
`
`

`

` 
`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 Renal Angiomyolipoma with
`
` 
`Tuberous Sclerosis Complex
`
`6.4 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 Renal Angiomyolipoma with Tuberous Sclerosis Complex
`
` 
`14.4 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
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 006
`
`

`

`FULL PRESCRIBING INFORMATION
`1 INDICATIONS AND USAGE
`1.1 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.
`1.2 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.
`1.3 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.
`1.4 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 (14.4)]. 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. 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 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 PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
`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 5 mg daily [see Warnings and Precautions (5.1)].
`
`Hepatic Impairment
`Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.7) 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.
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 007
`
`

`

` 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
`
`
` 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
`
`(5.6) 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
`Body Surface Area (BSA)
`Starting Dose
`
`0.5 m2 to 1.2 m 2
` 2.5 mg once daily
`
`
`1.3 m2 to 2.1 m 2
`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 (5.6) 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
`Adverse Reactions
`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.
`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).
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 008
`
`

`

`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 (5.6) 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 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 (5.6) 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
`trough concentrations should be assessed approximately 2 weeks later [see Dosage and Administration (2.5), 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 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 (5.6, 5.7), 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
`
`Reference ID: 3122590
`
`West-Ward Exhibit 1107
`AFINITOR Apr 26 2012 Approval
`Page 009
`
`

`

` 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 14% 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 0.1%, respectively [see Adverse
`
`Reactions (6.1, 6.2, 6.3, 6.4)]. 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.
`For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy. Corticosteroids
`may be indicated until clinical symptoms resolve. AFINITOR may be re-initiated at a daily dose approximately 50%
`lower than the dose previously administered depending on the individual clinical circumstances. 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)]. 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