`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202324Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Final Risk Evaluation and Mitigation Strategy (REMS) Review
`
`Date:
`
`December 15, 2011
`
`
`
`Reviewer(s):
`
`Joyce Weaver, Pharm.D., Division of Risk Management
`(DRISK)
`
`Cynthia LaCivita, Pharm.D., DRISK
`Team Leader:
`Claudia Karwoski, Pharm.D., DRISK
`Division Director
`Axitinib (Inlyta)
`Drug Name(s):
`Kinase inhibitor
`Therapeutic Class:
`5mg twice daily, orally
`Dosage and Route:
`Application Type/Number: NDA 202324
`Submission Number:
`1
`Applicant/sponsor:
`Pfizer
`OSE RCM #:
`2011-1289
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3059098
`
`
`
`CONTENTS
`
`INTRODUCTION....................................................................................................... 1
`1
`2 MATERIALS REVIEWED ........................................................................................ 1
`3 RESULTS OF REVIEW OF PROPOSED INLYTA RISK EVALUATION AND
`MITIGATION STRATEGY............................................................................................... 1
`3.1
`Overview of Clinical Program or Postmarketing Exposure ............................... 1
`3.2
`Safety Concerns .................................................................................................. 1
`3.3
`Risk Management Proposed by Applicant.......................................................... 2
`4 DISCUSSION.............................................................................................................. 2
`5 CONCLUSION ........................................................................................................... 2
`6 RECOMMENDATIONS............................................................................................. 2
`
`Reference ID: 3059098
`
`
`
`1
`INTRODUCTION
`An application for axitinib (Inlyta) was submitted April 14, 2011 with a proposed
`indication of treatment of patients with advanced renal cell carcinoma (RCC). The
`Oncologic Drugs Advisory Committee (ODAC) convened December 7, 2011 to consider
`the application. The committee advised unanimously that the application should be
`approved. Risk management was not discussed at the meeting.
`
`2 MATERIALS REVIEWED
`Risk Management Plan submitted with application April 14, 2011
`
`3 RESULTS OF REVIEW OF PROPOSED INLYTA RISK EVALUATION
`AND MITIGATION STRATEGY
`
`3.1 OVERVIEW OF CLINICAL PROGRAM OR POSTMARKETING EXPOSURE
`The data supporting the indication comprised a single, randomized study in patients with
`RCC. Patients had failed one prior regimen. Patients in the axitinib arm had a median
`progression-free survival (PFS) of 6.7 months compared with 4.7 months in the
`comparator (sorafenib) arm.
`
`3.2 SAFETY CONCERNS
`The FDA-edited draft labeling for axitinib lists the following safety concerns, listed in
`order of level of concern:
`
` Hypertension including hypertensive crisis
`
` Hypothyroidism requiring thyroid hormone replacement
`
` Arterial and venous thrombotic events
`
` Hemorrhagic events, including fatal events
`
` Gastrointestinal perforation and fistula, including death
`
` Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
`
` Proteinuria
`
` Fetal harm
`The adverse events observed in the clinical trial are largely known events for the class of
`kinase inhibitors. Compared with sorafenib, the axitinib arm had a higher incidence of
`gastrointestinal effects, fatigue, asthenia, hypertension, dysphonia, and hypothyroidism.
`The sorafenib arm had a higher incidence of palmar-plantar erythrodysaesthesia, rash,
`pruritis, alopecia, erythema, and anemia. Evaluating the side effect profile of axitinib,
`ODAC indicated that they judged the degree of toxicity to be similar to other agents in
`the class.
`
`Reference ID: 3059098
`
`
`
`
`
`3.3 RISK MANAGEMENT PROPOSED BY APPLICANT
`The applicant proposes routine measures (labeling and routine pharmacovigilance) to
`manage the risks of axitinib.
`
`4 DISCUSSION
`The safety concerns for axitinib are similar to other approved kinase inhibitors used to
`treat renal cell carcinoma, sorafenib and sunitinib. Sorafenib and sunitinib do not have
`REMS in place to manage the risks.
`Based on the mechanism of action, all three drugs are expected to cause fetal harm if
`used by a pregnant woman. The Surveillance Epidemiology and End Results cancer data
`estimates that about 23,800 women are diagnosed with renal cancer yearly, with 25% of
`the women being under the age of 54 years. Nine percent of the women diagnosed are
`younger than 45 years of age. Based on this, it is possible that fetal exposure might occur
`with axitinib. Based on recent guidance from senior management within CDER, it is
`expected that the oncology community manages the risk of fetal harm from agents used
`to treat cancer without additional FDA-imposed risk management measures in place.
`Fetal toxicity occurs with many oncology agents, and it is reasonable for drugs likely to
`cause fetal harm to be used within the oncology community without a REMS.
`
`5 CONCLUSION
`The applicant’s proposal for labeling and routine pharmacovigilance is reasonable, and is
`consistent with other agents in the class used for the same indication.
`
`6 RECOMMENDATIONS
`Axitinib (Inlyta) can be approved without a REMS.
`
`
`
`Reference ID: 3059098
`
` 2
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOYCE P WEAVER
`12/15/2011
`
`CLAUDIA B KARWOSKI
`12/15/2011
`concur
`
`Reference ID: 3059098
`
`
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