CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-044
`
`RISK ASSESSMENT and RISK MITIGATION
`
`REVIEWg S!
`
`

`

`”ah
`MEMORANDUM
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`
`FOOD AND DRUG ADMINISTRATION
`
`.
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`DATE:
`
`February 20, 2007
`
`TO:
`
`Mary Parks, M.D., Director
`Division of Metabolic and Endocrine Products
`
`THROUGH: Ellis Unger, M.D., Acting Deputy Director
`Office of Surveillance and Epidemiology
`
`FROM:
`
`Office of Surveillance and Epidemiology (OSE) Risk Management Team
`
`DRUG:
`
`Janumet (sitagliptin phosphate / metformin hydrochloride) Tablets
`
`NDA#:
`
`22-044
`
`SPONSOR: Merck & Co.
`
`SUBJECT: Review of Proposed Risk Management Plan (RMP) submitted
`May 22, 2006
`
`RCM #:
`
`2006-668
`
`INTRODUCTION/BACKGROUND
`
`This consult follows a request by the Division of Metabolic and Endocrine Products
`(DMEP), for the Office of Surveillance and Epidemiology (OSE) to review and comment
`on the Sponsor’s proposed Risk Management Plan (RMP) for Janumet (sitagliptin
`phosphate / metformin hydrochloride fixed-dose combination) Tablets.
`
`Janumet is a fixed-dose combination of Sitagliptin, a dipeptidyl peptidase IV (DPP4)
`inhibitor approved October 16, 2006 as a single-ingredient product (Januvia) and
`meforrnin, a biguanide approved March 3, 1995 as a single~ingredient product
`(Glucophage). Sitagliptin exerts glycemic control in patients with type 2 diabetes by
`preventingthe rapid degradation of incretin hormones. Incretin hormones, including
`glucagon-like peptide-l (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are
`released by the intestine throughout the day, and levels are increased in response to a
`meal. Metformin acts by decreasing hepatic glucose output and improving insulin
`sensitivity in liver and muscle. The proposed indication for Janumet is as an adjunct to
`
`

`

`diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus
`who fail to achieve adequate control with diet and exercise and either ingredient alone, or
`in patients who are already being treated with both single-ingredient products. The
`proposed dosage is sitagliptin 50mg and metformin 500mg orally twice daily or
`sitagliptin 50mg and metformin 1000mg orally twice daily.
`
`The safety information for Janumet consists of data from four studies in which patients
`were co-administered sitagliptin and metformin. In the four studies combified, 1569
`subjects received metformin at daily dOSes Z 1500mg and sitagliptin at daily doses of
`100mg. In these studies, the subjects received combination therapy with sitagliptin and
`metformin for a mean period of 36.4 weeks. The Sponsor did not identify any safety
`signals or potential risks in any of the studies that would warrant risk management
`measures beyond routine labeling and pharmacovigilance. They noted that there is one
`important potential risk, necrotic skin lesions in the monkey, which has been identified
`with another DPP4 inhibitor. To date, this event has not been seen with sitagliptin.
`Additionally, there are no safety data in the following patient populations: children,
`pregnant women, patients with congestive heart failure, and patients with renal function
`impairment (metformin is contraindicated for patientswith congestive heart failure or
`renal function impairment).
`
`The Ilan Irony, M.D., the medical officer assigned to the clinical review of this NDA,
`indicated in a draft review1 that there are no new concerns regarding the safety of the co-
`administration of sitagliptin and metformin than those already noted in the review of the
`sitagliptin NDA and the known safety profile of metformin. Neither of these products has
`a Risk Minimization Action Plan (RiskMAP). Dr. Irony agrees with the routine risk
`management activity proposed by the Sponsor.
`
`REVIEW OF SPONSOR’S RMP
`
`The Sponsor does not believe that a RiskMAP is warranted for this product. They are
`proposing the following pharmacovigilance/ surveillance and post—marketing safety
`activities:
`-
`
`0 Labeling — professional labeling and the patient package insert will be utilized to
`convey to prescribers, other healthcare professionals, and patients about the risks
`associated with Janumet.
`
`o Routine Pharmacovigilance Practices — reporting of adverse event information will be
`accomplished in accordance with the relevant legal requirements.
`' o Necrotic skin lesions in monkeys — based on the Agency’s concern regarding animal
`data indicating that the administration of DPP-IV inhibitors to monkeys results in
`dose-dependent and duration-dependent increases in necrotic skin lesions, the
`Sponsor is undertaking an oral toxicity study in monkeys over a range of doses forlup
`to 3 months duration, the design of which has been reviewed and agreed upon by the
`US. FDA.
`
`1 [Ian Irony, MD, Medical Officer. Clinical Review of Janumet (sitagliptin phosphate and metformin
`hydrochloride fixed-dose combination), NDA 22—044; drafi clinical review forwarded 2/7/07.
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`0
`
`Pregnancy Registry — In order to develop a better assessment ofthe safety profile of
`sitagliptin in pregnant women and for exposed fetuses, the Sponsor is establishing 21
`~ pregnancy registry for follow-up of sitagliptin pregnancy exposures. The pregnancy
`registry will be an enhanced surveillance program ofwomen exposed to sitagliptin,
`including women exposed to sitagliptin and metformin tablets, at any time from the
`date of the last menstrual period through the duration of the pregnancy.
`-.
`
`CONCLUSION
`
`The Sponsor’s proposed RMP does not differ substantially from routine risk management
`measures, such as FDA-approved professional labeling and routine post-marketing
`surveillance. The Sponsor has proposed other risk assessment measures for sitagliptin,
`including a plan to undertake an oral toxicity study in monkeys to assess the risk of
`necrotic skin lesions over,a range of doses and a pregnancy registry to determine if there
`is any risk to the pregnant woman or developing fetuses.
`
`OSE concludes that the Sponsor’s proposal for routine risk management measures and '
`planned pharmacovigilance activities is sufficient at this time. Ifthe Sponsor or the
`reviewing division identifies a safety concern in the fixture that might warrant a
`RiskMAP, or if the reviewing division wants OSE to review any proposed Phase IV
`protocols or epidemiological post-marketing studies, please provide a consult request.
`
`Appears This Way
`On Original
`
`OSE Risk Management Team
`Mary Dempsey, Risk Management Program Coordinator
`Claudia Karwoski, PharmD, Team Leader, Risk Management Team
`Joyce Weaver, PharmD, Senior Risk Management Analyst
`Mary ~Willy, PhD, Senior Risk Management Epidemiologist
`
`

`

`This is a representation of'an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`
`Mary Dempsey
`2/20/2007 04:30:50 PM
`DRUG SAFETY OFFICE REVIEWER
`
`Ellis Unger
`-2/20/2007 04:42:10 PM
`MEDICAL OFFICER
`
`Appears This Way
`On Original
`
`