CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`22-334
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`

`

`Date:
`
`To:
`
`Thru:
`
`From:
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Offce of Surveilance and Epidemiology
`
`March 19,2009
`
`Robert Justice, M.D., Director
`Division of Drug Oncology Products (DDOP)
`
`Claudia Karoski, Phar.D., Acting Director
`Division of Risk Management (DRISK)
`
`Scientific Lead:
`Jeane Perla Ph.D., Risk Management Analyst, DRISK
`
`Team Members:
`Suzanne Berkman Phar.D., Senior Risk Management Analyst and
`(acting) Team Leader, DRISK
`Mar Dempsey, Risk Management Program Coordinator, DRISK
`
`Subject: Review of Proposed "Safety Risk Management Plan" dated June 6,
`2008 and submitted June 30, 2008
`Drug Name(s): Afinitor (everolimus)
`Submission Number: 0000
`Application TypelNumber: NDA 22-334
`
`Applicant/sponsor: Novaris
`OSE RCM #: RCM 2009-83
`
`

`

`CONTENTS
`
`EXECUTIVE SUMMARY ............................................................................................................. 1
`I BACKGROUND .................................................................................................................... 1
`1.1 Introduction.................................................................................................................... I
`
`I .2 Regulatory History .......... ...... ..... ... ............. .......... ........ ... ... .......... ........... ........ ..... ..... ..... 2
`2 Material Reviewed ............. ... ........ ..... ..... ..... ... ... ..... ........... ..... .... .... ........... ....... ...... ......... ....... 2
`3 RESULTS OF Review............................................................................................................ 3
`3.1 Sponsor's Safety Concerns ............................................................................................3
`3.2 DDOP Safety Concerns .................................................................................................3
`
`a. Proposed Risk Management Plan ..................... ................ ............................. ..................... 4
`4 DISCUSSION.and Conclusion...............................................................................................5
`
`EXECUTIVE SUMY
`Everolimus (Afinitor) is a rapamycin derivative; mTOR (mammalian target ofrapamycin)
`patients with advance renal cell
`carcinoma (RCe). Afinitor for wil be available in 5 mg and 10 mg tablets; the recommended
`dose is 10 mg daily; dose reduction to 5 mg daily may be needed to manage adverse drug
`reactions.
`
`inhibitor. The proposed indication is for the treatment of
`
`Novaris has identified the following risks associated with Afinitor: non-infectious pneumonitis,
`severe infection, stomatitis, and increased creatinine. Potential safety concern identified by the
`Novartis are: cardiac failure, wound healing and drug-drug interactions.
`
`routine pharacovigilance. The Division of
`
`To manage these risks, the Sponsor proposes labeling, including a Patient Package Insert and
`Drug Oncology Products (DDOP) has not identified
`any additional safety concerns for Afinitor that warant consideration of a REMS at this time for
`the proposed indication. The risks and the routine risk management approach are consistent with
`other approved chemotherapeutic agents, immunosuppressive drugs, and mTOR inhibitors
`approved for the treatment ofRCC.
`
`Should the DDOP.raise further concerns with the risks outlined within this review or identify
`additional/new risks associated with everolimus waranting a risk evaluation and mitigation
`Risk Management.
`
`strategy, please send a consult to OSE Division of
`
`1 BACKGROUN
`
`1.1 INTRODUCTION
`
`This review follows a request from the DDOP for the Offce of Surveilance and Epidemiology
`COSE) to review and comment on the proposed "safety risk management plan" for Afmitor
`(everolimus) 5 and 10 mg Tablets dated June 6, 2008 (submitted on June 30, 2008, with the
`original NDA) and submitted to OSE for consultation on December 30 2008.
`
`

`

`Everolimus is a mTOR (mammalian target ofrapamycin) inhibitor. In vivo, everolimus appears
`to reduce cell proliferation, glycolysis and angiogenenesis of solid tumors. It has been submitted
`patients with advanced renal cell carcinoma (RCe). The proposed
`for review for the treatment of
`dose is 10 mg to be taken by mouth once daily at the same time every day - ~. A)
`Dose reduction to 5 mg daily may be needed to manage \l~
`adverse drug reactions. The medical offcer's review recommends approval of everolimus for the
`patients with advanced RCC "after disease progression following treatment with
`sunitinib or sorafenib."
`
`treatment of
`
`Everolimus is marketed in more than 60 countres under the tradename Certican for prophylaxis
`of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic,
`renal or cardiac transplant. The initial dose for ths indication is 1.5mg/day, a substantially lower
`dose than the proposed dose for RCC. Total exposure based solely upon commercial usage
`exceeds 10,000 patient-years.
`currently
`
`The sponsor notes that three products are approved for the treatment of advanced RCC: sorafenib
`(Nexavar; tyrosine kinase inbitor (TKI) that targets the vascular endothelial growt factor
`receptor, (VEGF)), sunitinib (Sutent; TKI-VEGF), and temsirolimus (Torisel). Temsirolimus is
`the ester analog of sirolimus (Rapamune)1 , and administered as a once weekly intravenous
`infusion. Temsirolimus and sirolimus are marketed without additional risk management
`measures beyond labeling and routine pharacovigilance.
`
`1.2 REGULATORY
`
`HISTORY
`
`Everolimus is not approved in the United States. It has been in clinical development as an
`investigational immunosuppressant drug for transplantation since 1996. Two
`NDAs for everolimus have been previously submitted by Novaris Pharaceuticals for use in b(4)
`transplant patients: - for the prophylaxis of organ rejection in allogeneic kidney
`transplantation and NDA 21-628 for the prophylaxis of organ rejection in cardiac transplantation.
`Both NDAs have received two Approvable actions on October 20,2003, and on August 27,2004,
`both letters cited insuffcient evidence of a safe dosing regimen for everolimus when used in
`combination with cyclosporine.
`
`Since November 2002, everolimus has also been in development to treat cancer patients both as b(Jl'.
`
`monotherapy .- under IND 66,279. Ii
`
`Novartis submitted an NDA for Afinitor on June 30, 2008 for priority review for the treatment of
`advance RCC. The goal date was extended by three months following submission of a major
`amendment. The extended user fee goal date is March 30,2009.
`
`2 MATERIAL REVIWED
`The following materials were reviewed:
`
`. Everolimus "Safety Risk Management Plan" dated June 6, 2008 and submitted on June 30,
`2008
`
`1 Rapamune (Wyeth; FDA approved in 1999)) is indicated for the prevention of organ rejection in renal
`
`transplant recipients aged 13 years or older who are at low to moderate risk of acute rejection. Rapamune is
`available as a tablet and oral solution.
`
`2
`
`

`

`· Everolimus draft labeling submitted June 30 2008.
`
`· Ryan Q. Clinical Review ofNDA 22-334; Afinitor (everolimus). DRAT provided on March
`11,2009.
`
`· Berkman, S. "Torisel Risk Management Plan Review." Signed by E. Unger on April 5,2007.
`
`· Rapamune Prescribing Information. Wyeth. March 2008.
`
`· Torisel Prescribing Information. Wyeth. September 2008.
`
`· MO Mid-cycle Slides dated Februar i i 2008
`
`3 RESULTS OF REVIEW
`
`3.1 SAFETY CONCERNS
`
`3.1.1 Sponsors' Safety Concerns
`
`pneumonitis was reported in approximately 20% of
`
`The sponsor has identified the following safety concerns: . .
`· Non-infectious pneumonitis: In study CRAOOIC22402, baseline non-infectious
`patients in both groups. New cases
`of pneumonitis were reported in 24 (8.9%) patients in the everolimus group and no one
`from the placebo group. The maximum severity grading was as follows: 4 patients
`(1.5%) with grade I, 12 patients (4.5%) with grade 2, and 9 patients (3.3%) with grade 3.
`No grade 4 cases were evident.
`
`· Stomatitis: In study CRAOO1
`
`C22402 stomatitis was experienced
`
`in 41.6% of
`
`C22402, severe infections were diagnosed in 67
`· Severe infection: In study CRAOO1
`patients (24.9%) in treatment group and 15 patients (11. I %) in the placebo group.
`the
`patients in the treatment group and 8.1 % of the patients in the placebo group. .
`patients in the everolimus an
`and 0.7% in the placebo an had increases in serum creatinine concentrations.
`
`· Increased creatinne: In study CRAOOIC22402, 7.8% of
`
`(n=17) of everolimus-treated patients vs. 3% (n=4) of
`
`The sponsor has identified the following potential safety concerns:
`· Cardiac failure: In study CRAOOIC22402, cardiac disorders were reported for 6.3%
`placebo-treated patients.
`· Wound healing: Wound healing complications were not identified in this study but have
`the rapamycin class.
`· Drug-Drug interactions: Everolimus is extensively metabolized by CYP3A4.
`Concurrent treatment with CYP3A4 inibitors wil decrease everolimus metabolism.
`Other inducers of CYP3A4 may increase the metabolism of everolimus and decrease
`everolimus blood levels.
`
`been observed in patients treated with other members of
`
`3.1.2 DDOP SAFETY CONCERNS
`
`The Medical Offcer identifies the following adverse reactions in the draft clinical review3 which
`"should be watched and managed appropriately during treatment:"
`
`2 Study CRAOO 1 C2240 had a total of 41 0 patients; Afiitor n= 272, control n=138.
`
`3 Ryan Q. Clinical Review ofNDA 22-334; Afinitor (everolimus). DRAFT provided on March 11,2009.
`
`3
`
`

`

`· Hyperlipidemia and hyperglycemia: Two fold increases in incidence were seen in the
`these are known class effects for
`
`everolimus arm comparing to the placebo ar. Both of
`
`rapamycin and its derivatives. 4
`
`· Renal function: Treatment related creatinine elevation and renal failure4 occurred 9%
`and 2% more, respectively, in the everolimus arm. The Medical Offcer recommends
`the serum creatinine and renal function.
`
`carefully monitoring of
`
`· Pneumonitis:4,5 A blinded central radiology review was conducted which reported new
`or worsening CT changes in 48.2% and 14.6% of everolimus and placebo arm patients,
`respectively. Clinically reported pneumonitis occured in only 13.5% everolimus patients
`and 0% placebo patients. Among patients in the placebo ar with a CT suggesting
`pneumonitis, no clinical cases of pneumonitis were reported. Therefore, monitoring
`everolimus treatment-emergent pneumonitis should combine the clinical presentation and
`CT results. Everolimus d.ose reduction was required for 50% (14/28) of grade 2 or 3 cases
`and treatment discontinuation for 36% (10/28). Therefore, criteria for dose reduction and
`discontinuation should be included in the proposed labeL.
`
`· Increased bleeding events among patients on the everolimus arm (8%) were associated
`patients. The number of
`thromboembolic events was similar between the two arms.
`
`with thrombocytopenia, which occurred in 23% of
`
`· Liver function test abnormalities were noted in everolimus treated patients with or
`without co-existing liver disease, 40% and 4%,.respectively. It does not appear that any
`senous adverse events (i.e., hepatic failure) were reported.
`
`· Mucositits:4 Significant numbers of patients developed mucositits in the everolimus arm.
`However, the severity and resolution course appeared to be acceptable with necessary
`supportive treatment per the Medical Officer.
`Deaths due to acute respiratory failure (1.9%), infection (1.1%), and renal failure (0.4%) were
`observed on the everolimus ar. No deaths due to an adverse reaction were seen in the placebo
`ar. The adverse reactions that caused treatment termination were pneumonitis, dyspnea, lung
`disorders, fatigue and renal failure. Mucositits, pneumonitis and symptoms related to both were
`the most common re.asons for treatment delay or dose reduction. The most common adverse
`reactions requiring medical interventions durig everolimus treatment were anemia,
`gastrointestinal, respiratory, and skin symptoms.
`
`The most common adverse reactions to everolimus were similar to other rapamycin derivatives.
`
`3.2 SPONSOR'S PROPOSED RISK MANAGEMENT PLAN
`
`4 Risk is included in the Torisel (temsirolimus) and/or Rapamune Prescribing Information.
`
`S Torisel PI refers to "interstitial lung disease" and includes the following:
`
`· WARNINGS: Cases of interstitial lung disease, some resulting in death, occurred in patients who
`received TORISEL. Some patients were asymptomatic with infitrates detected on computed
`tomography scan or chest radiograph. Others presented with symptoms such as dyspnea, cough,
`hypoxia, and fever. Some patients required discontinuation ofTORISEL and/or treatment with
`corticosteroids and/or antibiotics, while some patients continued treatment without additional
`intervention. Patients should be advised to report promptly any new or worsening respiratory
`symptoms.
`· ADVERSE REACTIONS: Respiratory, Thoracic and Mediastinal Disorders - Interstitial lung
`disease occurred in 5 patients (2%), including rare fatalities.
`
`4
`
`

`

`The sponsor's proposed "safety risk management plan" is consistent with the EMEA risk
`management template. The sponsor does not identify any risks beyond those common to
`chemotherapeutic agents, other immunosuppressive drugs, and/or mTOR inhibitors as a class.
`Therefore, Novaris proposes that routine measures (labeling and spontaneous adverse event
`reporting) are appropriate.
`
`We note that the sponsor has submitted a patient package insert (PPI) for review and did not
`their risk management approach. Sutent and Nexavar have PPIs
`these drugs have
`
`while Torisel does not have FDA-approved patient labeling. None of
`
`specifically cite this as part of
`
`Medication Guides.
`
`4 DISCUSSION AN CONCLUSION
`
`that pneumonitis/interstitial
`
`The risk management proposal for everolimus is consistent with routine pharacovigilance.
`Largely, it appears that the risks identified by the sponsor and DDOP are consistent with other
`approved chemotherapeutic agents, immunosuppressive drgs, and/or other rapamycin/mTOR
`inhibitors. And, in general, these products manage such risks through routine measures (labeling
`and spontaneous adverse event reporting). Temsirolimus and sirolimus are marketed without
`additional risk management measures beyond labeling and routine pharacovigilance. We note
`lung disease is a concern however, DDOP does not believe that
`additional measures beyond labeling are necessar at this time. We recommend expedited '\
`reporting of spontaneously reported serious pulmonar events. In addition, DRISK recommends b~~J
`pneumonitis in the product labeling to be
`consistent with Torisel unless there is a compellng reason otherwise.
`
`the use of
`
`the term . - instead of
`
`Based on the information provided at this time and considering the patient population, severity of
`RCC, mortlity ofRCC, limited treatment options6 (Proleukin7, Sutent8, Nexavar9, interferon
`. alfa, and Torisei1o), comparable level of risks associated with other treatment options and with
`the prescribing
`population; it appears that the Sponsor's proposal is a reasonable approach to manage the risks at
`this time.
`
`other chemotherapeutic agents in general, along with the limited scope of
`
`Should the DDOP raise furter concerns with the risks outlined above or identify additional/new
`risks associated with everolimus warranting a risk evaluation and mitigation strategy (REMS),
`Risk Management.
`
`please send a consult to aSE Division of
`
`6 Cohen HT, McGovern FJ. Renal-cell carcinoma. (Review arcle). NEJM 2005.353(23):2477-2490.
`
`7 Proleukin (aldesJeukin) Package Insert. Chiron. September 2000.
`
`S Sutent (sunitinib) Package Insert, Pfizer. November 2008.
`
`9 Nexavar (sorafenib) Package Insert. August 2006.
`
`10 Torisel Prescribing Information. Wyeth. September 2008.
`
`5
`
`

`

`----------...._.-...._......_-_._-_..__.__...__.......-......_---....._...__......._-..__...._-----_._------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`-_.._-_._--------........_.__.._.._._---_._----_.__._-._---_..._---_.._--_.._--....._-_.__..._-_._-----------..._-_..
`/s/
`Mary Dempsey
`3/19/2009 11:12:22 AM
`DRUG SAFETY OFFICE REVIEWER
`
`Claudia Karwoski
`3/19/2009 11: 22: 56 AM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`Department of Health and Human Services
`
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Offce of Surveilance and Epidemiology
`
`December 8, 2008
`
`Robert Justice, M.D., Director
`Division of Drug Oncology Products
`KeIIe Taylor, Phan, MPH, Team Leader
`Denise Toyer, Phan, Deputy Director
`Carol Holquist, R.Ph., Director
`Division of Medication Error Prevention and Analysis
`Melina Griffs, R.Ph., Safety Evaluator
`Division of Medication Error Prevention and Analysis
`
`Label and Labeling Review
`
`Date:
`
`To:
`
`Th:
`
`From:.
`
`Subject:
`
`Drug Name(s):
`
`Afinitor (Everolimus) Tablets 5 mg and 10 mg
`
`. Application Type/Number: NDA 22-334
`
`Applicant/sponsor:
`
`Novartis Pharmaceuticals
`
`OSERCM#:
`
`2008-1236
`
`**This document contains proprietaiy drug use data obtained by FDA under contract. The drug
`use data/information cannot be released to the public/non-FDA personnel without contractor
`approval obtained through the FDA/CDER Offce of Surveillance and Epidemiology. *
`
`

`

`CONTENTS
`
`EXECUTIVE SUMRY ............................................................................................................. 1
`BACKGROUN..................................................................................................................... 1
`1.1 Introduction ............. ........ ... ........... ........... ...... .......... ............. ..... ...... ............ .................. i
`1.2 Regulatoiy History .. ..................... .... .... ....... ...... ..... ...... ............ ...... ... ..... .... ...... .... .......... 1
`i.3 Product Information ............ .... ........ ... ......... .... ...... .... ....... .... ... ....... ........ ....... ... ..... ...... ... 1
`METHODS -AND MATERIALS ............................................................................................ 1
`RESULTS................................................................................................................................2
`DISCUSSION ....................................................................................................................;.... 2
`CONCLUSIONS and RECOMMENDA nONS .................................................................... 2
`5.1 Comments To the Division .................................................... ~...................................... 2
`5.2 Comments To The Applicant......................................................................................... 3
`
`2 3 4 5
`
`1
`
`

`

`EXECUTIV SUMY
`
`The Division of
`
`Medication Error Prevention and Analysis reviewed the caron, container and
`insert labeling and noted areas of needed improvement with respect to the positioning and
`the product strengt. Our recommendations are provided in section 5.2 ofthis
`prominence of
`review. Please forward these recommendations to the Applicant prior to approvaL.
`
`1 BACKGROUN
`
`1.1 INTRODUCTION
`
`This review is in response to a request from the Division of
`
`assessment of
`
`the proposed labels and labeling for Afinitor.
`
`Drug Oncology Products for
`
`1.2 REGULATORY HISTORY
`
`The proposed proprietary name, Afinitor, was determined to be acceptable by DMEPA in a
`previous review (OSE 2008-257 dated Augut 1 I, 2008).
`
`1.3 PRODUCT INFORMTION
`
`Afinitor (Everolimus) is an mTOR inbitor indicated for the treatment of advanced renal cell
`carcinoma. It wil be available in 5 mg and 10 mg tablets and the recommended dose is 10 mg to h'''\
`be administered once daily at the same time every day ;. U\'l'
`". ùose reduction may. be needed to manage adverse drug reactions, therefore,
`the dose may be réduced to 5 mg daily.
`
`2 METHODS AN MATERIALS
`
`This section describes the methods and materials used by the Division of
`
`Medication Error
`Prevention and Analysis medication error staff to. conduct a label, labeling, and/or packaging risk
`assessment (see section 3 Results). The primar focus ofthe assessments is to identify and
`remedy potential sources of medication errors prior to drug approval. The Division defines a
`medication error as any preventable event that may cause or lead to inappropriate medication use
`or patient har while the medication is in the control.ofthe health care professional, patient, or
`consumer.
`
`The label and labeling of a drug product are the priary means by which practitioners and
`patients (depending on configuration) interact with the pharmaceutical product. The caron
`labeling and container labels communicate critical information including proprietar and
`established name, strength, dosage form, container quantity, expiration, and so on. The insert
`labeling is intended to communicate to practitioners all information relevant to the approved uses
`of the drug, including the correct dosing and administration.
`
`Given the critical role that the label and labeling has in the safe use of drg products, it is not
`surprising that 33 percent of medication errors reported to the USP-ISMP Medication Error
`Reportng Program may be attibuted to the packaging and labeling of drug products, including
`30 percent of fatal errors.
`
`1
`
`

`

`Because the Division of
`
`Medication Error Prevention sta analyze reported misuse of drugs, the
`staff are able to use this experience to identify potential errors with all medication similarly
`human factors to identify
`potential sources of error with the proposed product labels and insert labeling, and provided
`recommendations that aim at reducing the risk of medication errors.
`
`packaged, labeled or prescribed. We use FMEA and the principles of
`
`For this product the Applicant submitted on June 27, 2008 the following labels for our review
`(see Appendices A and B for images):
`
`. Blister card container labels (5 mg, 10 mg and professional sample)
`. Carton labels (5 mg, 10 mg and professional sample)
`
`3 RESULTSI
`
`'0\1')
`
`~
`
`2
`
`

`

`L/ Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`V Draft Labeling (b4)
`
`Draft Labeling (bS)
`
`Deliberative Process (bS)
`
`Withheld Track Number: Label Review- 1
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`/s/
`Melina Griffis
`12/8/2008 03: 15: 43 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Denise Toyer
`12/10/2 008 12: 56 : 08 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Carol Holquist
`12/11/2 008 04: 2 0 : 29 PM
`DRUG SAFETY OFFICE REVIEWER
`
`

`

`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Offce of Surveilance and Epidemiology
`Date: Februar 16,2009
`To: Robert L. Justice, M.D., Director
`Division of Drug Oncology Products
`
`Through: Jodi Duckhom, MA, Team Leader
`Patient Labeling and Education Team
`Division of Risk Management
`
`From: Nancy Carothèrs, RN, BA
`Patient Product Information Reviewer
`Patient Labeling and Education Team
`Division of Risk Management
`
`Subject: DRISK Review of
`
`Patient Labeling (patient Package Insert) #2
`
`Drug Name(s): Afinitoril Tablets, oral (everolimus)
`
`Application Type/Number: NDA 22-334
`
`Applicant/sponsor: Novaris Phara Stein AG
`OSE RCM #: 2008-2055
`
`

`

`Ä Page(s) Withheld
`
`Trade Secret / Confidential (b4)
`
`v Draft Labeling (b4)
`
`Draft Labeling (b5)
`
`Deliberative Process (b5)
`
`Withheld Track Number: Patient Labeling Review- B
`
`

`

`..-----------_.._........_._._----------_._.._--_.......-............_-_.._._-_..__.-.._---..-----_._._-_..._---_.------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`.._--------_.__._-------_......._.._._......_....._...-_._.._--_.._.__._.__.._._-----------_..._--_...._.._---------
`/s/
`Nancy B Carothers
`2/17/2009 04: 58: 46 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Jodi Duckhorn
`2/18/2009 08: 25: 57 AM
`DRUG SAFETY OFFICE REVIEWER
`
`