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` NDA APPROVAL
`
`Sibylle R. Jennings, Ph.D.
`Senior Associate Director, Drug Regulatory Affairs
`
`
`
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`
`
`
`
`
`
`Public Health Service
`
`Food and Drug Administration
`
`Rockville, MD 20857
`
`
`
`
`
`
`NDA 22-334
`
`
`
`Novartis Pharmaceuticals Corporation
`One Health Plaza
`East Hanover, NJ 07936-1080
`
`Attention:
`
`
`
`Dear Dr. Jennings:
`
`
`Please refer to your new drug application (NDA) dated June 27, 2008, received June 30, 2008,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Afinitor® (everolimus) tablets 5 mg and 10 mg.
`
`We acknowledge receipt of your submissions dated July 29, August 4, 20, 21 (2), 26, 29,
`September 5 (2), 9, 11, 25 (2), 29 (2), 30 (2), October 14, 17, 20, 21, 24, 28, 31, November 11,
`19, 26, December 5, 10, 22, 2008, January 12, 20, 30, February 5, 10, 17, 18, 20, 23 (2), 25, 26,
`27, March 3, 10, 11, 12, 20, 25, and 27, 2009.
`
`This new drug application provides for the use of Afinitor® (everolimus) tablets for the treatment
`of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`An expiration dating period of 24 months is granted when stored as recommended in the
`approved product labeling. You may extend the expiration dating based on accrual of real-time
`stability data and report this in an annual report for this NDA.
`
`This application was not taken to a meeting of the Oncologic Drugs Advisory Committee
`(ODAC) because the application is based on a trial demonstrating a clinically and statistically
`significant improvement in progression-free survival with an acceptable benefit/risk ratio.
`Progression-free survival has previously been used as the basis for approval of drugs for the
`treatment of advanced renal cell carcinoma and the safety profile is similar to that of other drugs
`
`approved for this indication.
`
`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
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 001
`
`
`

`

`NDA 22-334
`Page 2
`
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`We are waiving the pediatric study requirement for this application because necessary studies are
`impossible or highly impracticable since this disease does not occur in the pediatric population.
`
`POSTMARKETING REQUIREMENTS UNDER 505 (o)
`
`
`Title IX, Subtitle A, Section 901 of the Food and Drug Administration Amendments Act of 2007
`(FDAAA) amends the FDCA to authorize FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute (section 505(o)(3)(A), 21 U.S.C.
`355(o)(3)(A)). This provision took effect on March 25, 2008.
`
`Trial A2303 evaluated everolimus in patients with moderate hepatic impairment (Child Pugh
`Class B) and due to increases in everolimus exposure, a dose reduction is needed in these
`patients. No exposure data are available for patients with severe hepatic impairment and
`current labeling recommends that Afinitor® (everolimus) should not be used in these
`patients.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to identify an unexpected serious
`risk of increased drug exposure when Afinitor® (everolimus) is administered to patients with
`severe hepatic impairment.
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess these serious
`risks.
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or
`observational study) will be sufficient to assess the unexpected serious risk of increased drug
`exposure when Afinitor® (everolimus) is administered to patients with severe hepatic
`impairment.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required,
`pursuant to section 505(o)(3) of the FDCA, to complete the following postmarketing clinical
`
`trial:
`
`
`
`
`
`
`
`1. Conduct a trial in patients with severe hepatic impairment (Child Pugh Class C). This
`trial need not be conducted in patients with cancer and a single dose evaluation will be
`appropriate. The protocol should be submitted prior to initiation for review and
`concurrence.
`
`The timetable you submitted on March 3, 2009 states that you will conduct this trial
`according to the following timetable:
`
`Final Protocol Submission:
`
`Trial Start Date:
`Final Report Submission:
`
`
`
`
`
`May 14, 2009
`October 14, 2009
`April 14, 2011
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 002
`
`

`

`NDA 22-334
`Page 3
`
`
`Submit protocols to your IND 66,279, with a cross-reference letter to this NDA 22-334. Submit
`all final report(s) to your NDA. Use the following designators to prominently label all
`submissions, including supplements, relating to this postmarketing requirement as appropriate:
`
`
`
`• Required Postmarketing Protocol under 505(o)
`
`
`• Required Postmarketing Final Report under 505(o)
`
`
`• Required Postmarketing Correspondence under 505(o)
`
`
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
`
`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
`
`POSTMARKETING COMMITMENTS
`
`
`We remind you of your postmarketing commitments in your submission dated March 27, 2009.
`These commitments are listed below.
`
`
`
`
`
`
`
`
`
`
`
`2. Submit the final, per-protocol overall survival analysis of protocol C2240 which was to
`be conducted 2 years after randomization of the last patient.
`
`
`
`Protocol Submission:
`
`Trial Start Date:
`Final Report Submission:
`
`July 27, 2006
`December 6, 2006
`June 2010
`
`3.
`
`
`Protocol Submission Date: May 14, 2009
`
`Final Report Submission:
`January 14, 2010
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 003
`
`

`

`NDA 22-334
`Page 4
`
`Submit clinical protocols to your IND for this product. Submit nonclinical and chemistry,
`manufacturing, and controls protocols and all final reports to this NDA. In addition, under 21
`CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii), you should include a status summary of each
`commitment in your annual report to this NDA. The status summary should include expected
`summary completion and final report submission dates, any changes in plans since the last
`annual report, and, for clinical trials number of patients entered into each trial. All submissions,
`including supplements, relating to these postmarketing commitments should be prominently
`labeled “Postmarketing Commitment Protocol”, “Postmarketing Commitment Final
`Report”, or “Postmarketing Commitment Correspondence.”
`
`CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, please submit the
`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format as described
`at http://www.fda.gov/oc/datacouncil/spl.html that is identical to the enclosed labeling (text for
`the package insert and patient package insert). Upon receipt, we will transmit that version to the
`National Library of Medicine for public dissemination. For administrative purposes, please
`designate this submission, “SPL for approved NDA 22-334.”
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed. Please submit these labels electronically according to the guidance for industry titled
`Providing Regulatory Submissions in Electronic Format – Human Pharmaceutical Product
`Applications and Related Submissions Using the eCTD Specifications (October 2005).
`Alternatively, you may submit 12 paper copies, with 6 of the copies individually mounted on
`heavy-weight paper or similar material. For administrative purposes, designate this submission
`“Final Printed Carton and Container Labels for approved NDA 22-334.” Approval of this
`submission by FDA is not required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`PROMOTIONAL MATERIALS
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert(s)
`to:
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 004
`
`

`

`NDA 22-334
`Page 5
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert(s), at the time of initial dissemination or publication, accompanied by a Form
`
`FDA 2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For
`more information about submission of promotional materials to the Division of Drug Marketing,
`Advertising, and Communications (DDMAC), see www.fda.gov/cder/ddmac.
`
`METHODS VALIDATION
`
`
`We have not completed validation of the regulatory methods. However, we expect your
`continued cooperation to resolve any problems that may be identified.
`
`LETTERS TO HEALTH CARE PROFESSIONALS
`
`
`If you issue a letter communicating important safety related information about this drug product
`(i.e., a “Dear Health Care Professional” letter), we request that you submit an electronic copy of
`the letter to both this NDA and to the following address:
`
`
`
`MedWatch
`
`Food and Drug Administration
`
`Suite 12B05
`
`5600 Fishers Lane
`
`Rockville, MD 20857
`
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA (21
`CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`
`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at www.fda.gov/medwatch/report/mmp.htm.
`
`
`If you have any questions, call Christy Cottrell, Regulatory Project Manager, at (301) 796-4256.
`
`
`
`
`Sincerely,
`
` {See appended electronic signature page}
`
`Richard Pazdur, M.D.
`
`Director
`Office of Oncology Drug Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 005
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
`/s/
`
`---------------------
`Richard Pazdur
`
`3/30/2009 01:00:32 PM
`
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 006
`
`

`

`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
`
`----------------------------INDICATIONS AND USAGE---------------------------
`AFINITOR is a kinase inhibitor indicated for the treatment of patients with
`advanced renal cell carcinoma after failure of treatment with sunitinib or
`sorafenib. (1)
`
`
`------------------------DOSAGE AND ADMINISTRATION---------------------
`
`• 10 mg once daily with or without food. (2.1)
`
`
`
`• Treatment interruption and/or dose reduction to 5 mg once daily may be
`needed to manage adverse drug reactions. (2.2)
`
`• For patients with Child-Pugh class B hepatic impairment, reduce dose 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)
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`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)
`
`• 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. (5.4)
`
`• Vaccinations: Avoid live vaccines and close contact with those who have
`received live vaccines. (5.7)
`
`• Use in pregnancy: Fetal harm can occur when administered to a pregnant
`
`woman. Apprise women of potential harm to the fetus. (5.8, 8.1)
`
`
`
`------------------------------ADVERSE REACTIONS-------------------------------
`Most common adverse reactions (incidence ≥30%) are stomatitis, infections,
`asthenia, fatigue, cough, and diarrhea. (6.1)
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Novartis
`
`Pharmaceuticals Corporation at 1-888-669-6682 or FDA at
`1-800-FDA-1088 or www.fda.gov/medwatch
`
`
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`• Strong and moderate CYP3A4 or PgP inhibitors: Avoid concomitant use.
`(5.5, 7.1)
`
`
`• Strong CYP3A4 inducers: Avoid concomitant use. If combination cannot
`
`be avoided, increase dose of AFINITOR. (2.2, 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 patients with Child-Pugh class B
`hepatic impairment, reduce dose to 5 mg daily. (2.2, 5.6, 8.7)
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and
`
`FDA-approved patient labeling
`
`
`
`Revised: 03/2009
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dose
`
`2.2 Dose Modifications
`
`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 Laboratory Tests and Monitoring
`
`5.5 Drug-drug Interactions
`
`5.6 Hepatic Impairment
`
`5.7 Vaccinations
`
`5.8 Use in Pregnancy
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Studies Experience
`
`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
`
`14 CLINICAL STUDIES
`
`
`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 Laboratory Tests and Monitoring
`
`
`17.5 Drug-drug Interactions
`
`17.6 Hepatic Impairment
`
`17.7 Vaccinations
`
`17.8 Pregnancy
`
`17.9 FDA-approved Patient Labeling
`* Sections or subsections omitted from the full prescribing information are
`
`
`not listed
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 007
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1 INDICATIONS AND USAGE
`AFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.
`
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dose
`The recommended dose of AFINITOR for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the same time every day, either with or
`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.
`
`Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
`2.2 Dose Modifications
`
`Management of severe and/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 (5.6) and Use in
`Specific Populations (8.7)].
`
`
`Strong CYP3A4 inducers: Avoid the use of concomitant strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin,
`
`
`
`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 Drug Interactions (7.2)].
`
`3 DOSAGE FORMS AND STRENGTHS
`
`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. In the randomized study, non-infectious pneumonitis was reported in
`14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,
`
`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. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be
`
`reintroduced at 5 mg daily.
`
`For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical
`
`symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.
`
`
`5.2 Infections
`AFINITOR has immunosuppressive properties and may predispose patients to infections, especially infections with opportunistic pathogens [see Adverse
`Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections and invasive fungal infections, such as aspergillosis or
`candidiasis, have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory failure) or fatal. Physicians and
`patients should be aware of the increased risk of infection with AFINITOR, be vigilant for signs and symptoms of infection and institute appropriate treatment
`
`promptly. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with 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. In the randomized study, approximately 44% of AFINITOR-
`treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. 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 Laboratory Tests and Monitoring
`Renal Function
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 008
`
`

`

`
`
`Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including
`
`
`
`
` measurement of blood urea nitrogen (BUN) 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)]. 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.
`Hematological Parameters
` Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood
`
`
` count is recommended prior to the start of AFINITOR therapy and periodically thereafter.
`5.5 Drug-drug Interactions
`Due to significant increases in exposure of everolimus, co-administration with strong or moderate inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole,
`
`
`clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir, voriconazole,
`
`aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil or diltazem) or P-glycoprotein (PgP) should be avoided [see Drug Interactions (7.1)].
`An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., dexamethasone, phenytoin, carbamazepine,
`
`
`rifampin, rifabutin, phenobarbital) [see Dosage and Administration (2.2) and Drug Interactions (7.2)].
`
`
`
`5.6 Hepatic Impairment
`The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight
`subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.
`
`AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and
`Administration (2.2) and Use in Specific Populations (8.7)].
`5.7 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.
`5.8 Use in Pregnancy
`Pregnancy Category D
`There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on 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 at the
`recommended dose of 10 mg daily. 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)].
`•
`6.1 Clinical Studies Experience
`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.
`
`The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell
`
`carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78%
`were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those
`receiving placebo.
`The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse
`reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory
`abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most
`
`common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths
`due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The
`
`
`
`rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo
`treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea.
`
`Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required
`
`
`during AFINITOR treatment were for infections, anemia, and stomatitis.
`Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus
`placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.
`
`
`Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm
`Table 1
`
`AFINITOR 10 mg/day
`Placebo
`N=274
`N=137
`Grade 3
`Grade 3
`%
`%
`52
`23
`
`
`
`Any Adverse Reaction
`
`
`All grades
`%
`97
`
`Grade 4
`%
`13
`
`All grades
`%
`93
`
`Grade 4
`%
`5
`
`West-Ward Exhibit 1070
`AFINITOR Mar 30 2009 Approval
`Page 009
`
`

`

`
`
`
`
`AFINITOR 10 mg/day
`N=274
`Grade 3
`%
`
`All grades
`%
`
`Grade 4
`%
`
`All grades
`%
`
`Placebo
`N=137
`Grade 3
`%
`
`Grade 4
`%
`
`
`
`29
`14
`13
`
`25
`
`0
`0
`0
`0
`1
`
`4
`3
`<1
`0
`0
`
`0
`3
`0
`0
`
`0
`0
`0
`
`<1
`
`<1
`0
`
`0
`60
`
`0
`0
`0
`0
`0
`
`0
`<1
`0
`0
`0
`
`0
`0
`0
`0
`
`0
`0
`0
`
`0
`
`0
`0
`
`0
`
`3
`5
`<1
`<1
`1
`
`
`
`Gastrointestinal Disorders
`
` Stomatitis a
`44
`
`30
`
`Diarrhea
`26
`
`Nausea
`20
`
`Vomiting
`37
`Infections and Infestations b
`
`General Disorders and Administration Site Conditions
`
`
`Asthenia
`33
`
`Fatigue
`31
`
`Edema peripheral
`25
`
`Pyrexia
`20
`
`Mucosal inflammation
`19
`Respiratory, Thoracic and Mediastinal Disorders
`
`Cough
`30
`
`Dyspnea
`24
`
`Epistaxis
`18
`Pneumonitis c
`
`
`14
`Skin and Subcutaneous Tissue Disorders
`
`
`Rash
`
`Pruritus
`
`Dry skin
`
`Metabolism and Nutrition Disorders
`
`
`
`Anorexia
`
`Nervous System Disorders
`
`
`19
`Headache
`
`10
`Dysgeusia
`Musculoskeletal and Connective Tissue Disorders
`
`
`
`Pain in extremity
`10
`Median Duration of Treatment (d)
`
`CTCAE Version 3.0
`
`a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
`
`b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%),
`
`
`
` urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).
`
`
`c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.
`
`
`
`4
`1
`1
`2
`7
`
`<1
`6
`0
`4
`
`1
`<1
`<1
`
`1
`
`<1
`0
`
`1
`141
`
`<1
`0
`0
`0
`3
`
`<1
`0
`0
`0
`0
`
`0
`1
`0
`0
`
`0
`0
`0
`
`0
`
`<1
`0
`
`0
`
`8
`7
`19
`12
`18
`
`23
`27
`8
`9
`1
`
`16
`15
`0
`0
`
`7
`7
`5
`
`14
`
`9
`2
`
`7
`
`
`Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include:
`
`Gas