CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`202343Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`

`

`202343
`
` (sitagliptin/simvastatin) Tablets
`Merck Sharp & Dohme Corporation
`Mary H. Parks, M.D.
`August 2, 2011
`
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`REMS Retraction
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE of Drug Evaluation II
`DIVISION of Metabolism and Endocrinology Products
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`
`NDA/BLA #s:
`Products:
`APPLICANT:
`FROM:
`DATE:
`
`
`The purpose of this memorandum is to document the rationale for retracting the requirement for
`a risk evaluation and mitigation strategy (REMS) for
` (sitagliptin/simvastatin) Tablets. On
`February 16, 2011, we notified the applicant for the pending NDA for
`
`(sitagliptin/simvastatin) that a REMS was necessary to ensure the benefits of the drug outweigh
`the risk of acute pancreatitis, including necrotizing pancreatitis. The REMS was to consist of a
`Medication Guide, and a timetable for submission of assessments of the REMS. The same
`REMS requirement had been issued for other products containing sitagliptin.
`
`On March 25, 2011, the applicant submitted a proposed REMS which included a Medication
`Guide and a timetable for submission of assessments of the REMS.
`
`The February 2011 Draft Guidance for Industry, Medication Guides — Distribution
`Requirements and Inclusion in Risk Evaluation and Mitigation Strategies (REMS), states that the
`FDA may approve a Medication Guide under 21 CFR 208 without requiring the Medication
`Guide to be a part of a REMS when the Medication Guide is adequate to address the serious and
`significant public health concern and meets the standard set forth under that regulation.
`
`On April 14, 2011 we issued Release REMS Requirement letters for NDA 021995/S-017
`JANUVIA (sitagliptin) and NDA 022044/S-016 JANUMET (sitagliptin/metformin
`hydrochloride) and on July 22, 2011 we issued a REMS Retraction letter for NDA 202270
`JANUMET XR (sitagliptin and extended-release metformin hydrochloride fixed-dose
`combination) after a determination was made that a REMS for these products was no longer
`necessary to ensure the benefits of the drug outweigh the risk described above. The applicant
`also amended their NDA application to request that they be released from the REMS requirement
`for
` (sitagliptin/simvastatin).
`
`After consultations between the Division of Metabolism and Endocrinology Products (DMEP) in
`the Office of New Drugs (OND) and the Division of Risk Management (DRISK) in the Office of
`Surveillance and Epidemiology (OSE), we have determined that a REMS for
`
`(sitagliptin/simvastatin) will not be necessary to ensure the benefits of the drug outweigh the risks
`described above. If
` (sitagliptin/simvastatin) is approved, the Medication Guide would
`be approved as part of the labeling and would be adequate to describe the serious risks. The
`
`
`
`Reference ID: 3002402
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`Medication Guide would be part of the approved labeling and be subject to the requirements
`under 21 CFR 208. Like other labeling, Medication Guides are subject to the safety labeling
`change provisions of section 505(o)(4) of the FDCA.
`
`
`
`
`
`Reference ID: 3002402
`
`2
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`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`08/18/2011
`Amy Egan for Mary Parks
`
`Reference ID: 3002402
`
`

`

`
`
`Risk Evaluation and Mitigation Strategy (REMS) Memorandum
`
`U.S. FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`OFFICE OF DRUG EVALUATION II
`DIVISION OF METABOLISM AND ENDOCRINOLOGY PRODUCTS
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`202343
`
` (sitagliptin/simvastatin) Tablets
`Merck Sharp & Dohme Corporation
`Mary H. Parks, M.D.
`February 4, 2011
`
`
`NDA/BLA #s:
`Products:
`APPLICANT:
`FROM:
`DATE:
`
`
`Section 505-1 of the Federal Food, Drug, and Cosmetic Act (FDCA) authorizes FDA to require
`the submission of a risk evaluation and mitigation strategy (REMS) if FDA determines that such
`a strategy is necessary to ensure that the benefits of the drug outweigh the risks
`[section 505-1(a)]. Section 505-1(a)(1) provides the following factors:
`
`
`
`
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________
`
`(A) The estimated size of the population likely to use the drug involved;
`(B) The seriousness of the disease or condition that is to be treated with the drug;
`(C) The expected benefit of the drug with respect to such disease or condition;
`(D) The expected or actual duration of treatment with the drug;
`(E) The seriousness of any known or potential adverse events that may be related to the
`drug and the background incidence of such events in the population likely to use the
`drug;
`(F) Whether the drug is a new molecular entity (NME).
`
`After consultations between the Office of New Drugs and the Office of Surveillance and
`Epidemiology, we have determined that a REMS is necessary for
` (sitagliptin/
`simvastatin) to ensure that the benefits of the drug outweigh the risks of acute pancreatitis,
`including necrotizing pancreatitis. In reaching this determination, we considered the following:
`
`A. Approximately 24 million people in the U.S. have type 2 diabetes, of whom more than one-
`third will require more than one anti-diabetic agent to maintain adequate glycemic control
`within several years of initiation of drug therapy. From marketing (October 2006) through
`December 2008, an estimated
` prescriptions of JANUVIA (sitagliptin), one of the
`components of
` (sitagliptin/simvastatin), have been dispensed. Adults with
`diabetes have heart disease death rates about 2 to 4 times higher than adults without diabetes.
`Improved control of LDL cholesterol can reduce cardiovascular complications by 20-50%.
`(sitagliptin/simvastatin) is a therapeutic option for patients to achieve both
`glycemic control and lipid lowering.
`
`
`B. Patients with type 2 diabetes who require anti-diabetic medication for glycemic control are at
`risk for a variety of complications including heart disease, stroke, blindness, kidney failure,
`nervous system damage, amputations, and death if untreated.
` (sitagliptin/
`
`
`Reference ID: 2902709
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`C.
`
`simvastatin) is an option for those individuals for whom treatment with both sitagliptin and
`simvastatin is considered appropriate.
`
`(sitagliptin/simvastatin) has been shown to achieve mean placebo-adjusted
`reductions in HbA1c of 0.8% for sitagliptin 100 mg, and a mean percent decrease from
`baseline LDL cholesterol of 30%, 38%, and 41% for simvastatin doses 10, 20, and 40 mg,
`respectively, in patients with primary and mixed hyperlipidemia.
`
`
`D. The expected duration of therapy is over a patient’s lifetime.
`
`E. In addition to post-marketing reports of acute pancreatitis, including necrotizing pancreatitis,
`observed with JANUVIA (sitagliptin), various other adverse effects have been observed,
`including hypoglycemia when used in combination with a sulfonylurea, hypersensitivity
`reactions, and renal impairment. Simvastatin has been associated with various other adverse
`effects including myopathy and rhabdomyolysis, and liver enzyme abnormalities.
`
` (sitagliptin/simvastatin) is not a new molecular entity.
`
`
`F.
`
`In accordance with section 505-1 of FDCA and under 21 CFR 208, FDA has determined that a
`Medication Guide is required for
` (sitagliptin/simvastatin). FDA has determined that
`(sitagliptin/simvastatin) poses a serious and significant public health concern
`requiring the distribution of a Medication Guide. The Medication Guide is necessary for
`patients’ safe and effective use of
` (sitagliptin/simvastatin). FDA has determined that
` (sitagliptin/simvastatin) is a product for which patient labeling could help prevent
`serious adverse effects and that has serious risks (relative to benefits) of which patients should be
`made aware because information concerning the risks could affect patients’ decisions to use, or
`continue to use
` (sitagliptin/simvastatin).
`
`The elements of the REMS will be a Medication Guide and a timetable for submission of
`assessments of the REMS.
`
`
`
`Reference ID: 2902709
`
`2
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AMY G EGAN
`02/08/2011
`
`MARY H PARKS
`02/08/2011
`
`Reference ID: 2902709
`
`