CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`209803Orig1s000
`209805Orig1s000
`209806Orig1s000
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
`
`
`
`
`
`

`

`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`209803, 209805, 209806
`December 19, 2017
`2017-2926, 2017-2929, 2017-2930
`
`Naomi Redd, Pharm.D.
`Elizabeth Everhart, RN, MSN
`Cynthia LaCivita, Pharm.D.
`August 24, 2017
`Evaluation of Need for a REMS
`
`Ertugliflozin, ertugliflozin/sitagliptin, ertugliflozin/metformin
`Steglatro, Steglujan, Segluromet
`Merck, Sharpe and Dohme
`Anti-glycemic Agents
`
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`
`
`
`
`Reference ID: 4144428
`
`1
`
`

`

`Table of Contents
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 4
`2.1
`Product Information ........................................................................................................................................... 4
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 5
`3.1
`Description of the Medical Condition .......................................................................................................... 5
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 6
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7
`Expected Postmarket Use ........................................................................................................................................... 7
`6
`7 Risk Management Activities Proposed by the Applicant ............................................................................... 8
`8 Discussion of Need for a REMS ................................................................................................................................. 8
`9
`Conclusion & Recommendations ............................................................................................................................. 8
`10
`Appendices .................................................................................................................................................................. 9
`10.1 References ............................................................................................................................................................. 10
`
`
`
`
`
`Reference ID: 4144428
`
`2
`
`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Steglatro (ertugliflozin) as well as its
`combination products Steglujan (ertugliflozin/sitagliptin) and Segluromet (ertugliflozin/metformin) is
`necessary to ensure the benefits outweigh its risks. Merck, Sharp and Dohme submitted a NDA 209803
`for ertugliflozin and NDAs 209805 for ertugliflozin/sitagliptin and 209806 for ertugliflozin/metformin
`with the proposed indication as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus. The risks associated with ertugliflozin include: hypotension, ketoacidosis,
`acute kidney injury/renal impairment, urosepsis, and hypoglycemia. In the combination products of
`ertugliflozin/sitagliptin and ertugliflozin/metformin careful monitoring of renal impairment must be
`done due to the nature of the individual agents in the combination products potential to cause renal
`impairment. Ertugliflozin/metformin is the only NDA out of these submitted that carries a Boxed
`Warning due to the risk of metformin associated lactic acidosis. All other adverse events will be
`communicated in Warnings and Precautions for ertugliflozin and ertugliflozin/sitagliptin. The Applicant
`did not submit a proposed REMS or risk management plan with these applications.
`
`Ertugliflozin belongs to a relatively new anti-hyperglycemic drug class, sodium glucose co-transporter 2
`(SGLT2) inhibitors; however, the adverse events of this drug class are not uncommon to other
`pharmacologic agents currently approved for the treatment of type 2 diabetes mellitus. None of the
`currently approved oral anti-hyperglycemic agents are currently approved with a REMS; all adverse
`events and dosage adjustments in regards to use in renal impairment are outlined in labeling.
`Ertugliflozin and its combination products with sitagliptin and metformin will likely be prescribed by a
`wide variety of physicians and healthcare providers that are familiar with the risk factors and
`management of diabetic patients, and potential adverse events that could occur with the
`pharmacological therapy for this disease. For these reasons, this reviewer concludes that a REMS is not
`needed to ensure that the benefits of ertugliflozin, ertugliflozin/sitagliptin and ertugliflozin/metformin
`outweigh its risks.
`
`1 Introduction
`This review by DRISK evaluates whether a REMS for the NME Steglatro (ertugliflozin) as well as its
`combination products Steglujan (ertugliflozin/sitagliptin) and Segluromet (ertugliflozin/metformin) is
`necessary to ensure that the benefits outweigh its risks. Merck, Sharp and Dohme submitted a NDA
`209803 for ertugliflozin and NDAs 209805 for ertugliflozin/sitagliptin and 209806 for
`ertugliflozin/metformin with the proposed indication as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus. This application is under review in the Division
`of Metabolic and Endocrine Products (DMEP). The applicant did not submit a proposed REMS or risk
`management plan with this application.
`
`
`
`
`
`Reference ID: 4144428
`
`
`3
`
`

`

`2 Background
`2.1 PRODUCT INFORMATION
`Ertugliflozin1- exerts its antiglycemic effects by inhibition of a glucose transporter, SGLT2. Inhibition of
`this transporter reduces renal re-absorption of filtered glucose and lowers the renal threshold for
`glucose, and thereby increases urinary glucose excretion. The Applicant’s proposed indication is to be
`used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
`
`Ertugliflozin/sitagliptin2 – is a combination of ertugliflozin, a SGLT2 inhibitor as described above with
`sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. Sitagliptin exerts its antiglycemic actions in
`patients with type 2 diabetes by slowing the inactivation of incretin hormones. The Applicant’s proposed
`indication is to be used as an adjunct to diet and exercise to improve glycemic control in adults with type
`2 diabetes mellitus when treatment with both ertugliflozin and sitagliptin is appropriate.
`
`Ertugliflozin/metformin3 - is a combination of ertugliflozin, a SGLT2 inhibitor as described above, and
`metformin, a biguanide, indicated as an adjunct to diet and exercise to improve glycemic control in
`adults with type 2 diabetes mellitus
`
` Metformin decreases hepatic glucose production and intestinal absorption of glucose, and
`improves insulin sensitivity by increasing peripheral glucose uptake and utlization, which in turn, lowers
`both basal and postprandial plasma glucose.
`
`Ertugliflozin is a NME and is not currently marketed in any jurisdiction. Sitagliptin (marketed as Januvia)
`and metformin (marketed as Glucophage, Fortamet) have been approved in the United States since
`2006 and 1995 respectively. The combination of ertugliflozin/sitagliptin or ertugliflozin/metformin is
`currently not marketed in any jurisdication. The Applicant is proposing several dosages for each product
`as oral tablet formulations. Table 1 in the Appendix provide the details of each dose and dosage form of
`each product.a
`
`
`Ertugliflozin is a NME, and thus the components of the combination products are also classified as
`NMEs.b The labeling for the SGLT2 inhibitor class and DPP-4 class of antiglycemic agents does not
`include any boxed warnings. Metformin, a biguanide, has a Boxed Warning for metformin-associated
`lactic acidosis; this product has been on the United States market since 1995. None of these products
`were required to be approved with a REMS
`
`There are no plans to discuss these products at an Advisory Committee. These products are on a
`standard review clock with a PDUFA date of December 19, 2017.
`
`2.2 REGULATORY HISTORY
`
`a Section 505-1 (a) of the FD&C Act: FDAAA factor (D): The expected or actual duration of treatment with the drug.
`
`b Section 505-1 (a) of the FD&C Act: FDAAA factor (F): Whether the drug is a new molecular entity.
`
`Reference ID: 4144428
`
`
`4
`
`(b) (4)
`
`

`

`The following is a summary of the regulatory history for NDAs 209803, 209805 and 209806 relevant to
`this review:
`
`• 09/28/2012: IND 106447 for ertugliflozin, IND 122329 for ertugliflozin/metformin and IND
`122330 for ertugliflozin/sitagliptin submitted
`
`• 09/06/2016: Pre-NDA meeting; the Applicant was informed that a need for a REMS would be
`determined upon review of NDAs.
`
`• 12/19/2016: NDAs 209803 ertugliflozin, 209805 ertugliflozin/sitagliptin and 209806
`ertugliflozin/metformin submission received
`
`• 06/23/2017: A Post Mid-cycle meeting was held between the Agency and the Applicant via
`teleconference. The Agency informed the Applicant that based on the currently available data,
`there were no safety issues that require a REMS for any of the NDAs submitted
`
` 3
`
` Therapeutic Context and Treatment Options
`3.1 DESCRIPTION OF THE MEDICAL CONDITION
`Type 2 diabetes mellitus is a result of hyperglycemia due to insulin resistance, inadequate insulin
`secretion, and excessive or inappropriate glucagon secretion.4 Common clinical manifestations of type 2
`diabetes include polyuria, polydipsia, and polyphagia with more severe symptoms resulting in multi-
`organ damage if improperly treated. Diabetes is the major cause of kidney failure, blindness, and non-
`traumatic leg amputation among adults in the United States, and is also the leading cause of coronary
`heart disease and stroke. Life expectancy can be reduced by as much as 10 years in people with type 2
`diabetes.5, c As of 2015, diabetes remains the 7th leading cause of death in the United States affecting
`over 30 million people or 9.4% of all adults and 25% of adults over 65 years old. Approximately 1.5
`million Americans are diagnosed with diabetes each year, and as described above, there can be multi-
`system organ damage if left untreated, or poorly treated.6,d
`
`3.2 DESCRIPTION OF CURRENT TREATMENT OPTIONS
`Ertugliflozin belongs to the class of SGLT2 inhibitors, a relatively new class of antiglycemic drugs and
`includes Invokana (canagliflozin, approved March 2013), Farxiga (dapagliflozin, approved January 2014)
`and Jardiance (empagliflozin, approved January 2014). With the exception of Invokana, the SGLT2
`inhibitor class does not include a Boxed Warning. In patients with type 2 diabetes who have established
`cardiovascular disease, or at risk for cardiovascular disease, Invokana has been associated with lower
`limb amputations, most frequently of the toe and midfoot; some also involved the leg. When combined
`with metformin (marketed as Invokanamet and Invokamet XR), it also carries the Boxed Warning
`
`c Section 505-1 (a) of the FD&C Act: FDAAA factor (B): The seriousness of the disease or condition that is to be
`treated with the drug.
`
`d Section 505-1 (a) of the FD&C Act: FDAAA factor (A): The estimated size of the population likely to use the drug
`involved.
`
`Reference ID: 4144428
`
`
`5
`
`

`

`associated with metformin-associated lactic acidosis. The SGLT2 inhibitor class of drugs has a novel
`mode of action that appears capable of adding a further glucose-lowering effect in combination with
`many other classes. This effect, typically in the range of 0.5 to 1.0% Hemoglobin A1C (Hgb A1C), is
`clinically relevant although perhaps less than that of some other agents. By itself, it does not cause
`hypoglycemia. By causing loss of glucose in the urine, the SGLT2 agents favor weight loss, and by
`increasing clearance of sodium, they may assist in control of edema and hypertension.7
`
`At present there are several different treatments, both oral and injectable, available for the treatment
`of type 2 diabetes mellitus (T2DM). Treatment algorithms are designed to reduce the development or
`progression of the complications of diabetes which emphasizes the need for effective glycemic control. 8
`
`Improving glycemic control with lifestyle changes sometimes alone or in addition to pharmacological
`interventions can significantly reduce complications of diabetes, however, as many as 50% of patients
`fail to achieve target Hgb A1C levels.5 There is still a need for newer therapies that provide a systemic
`and combined approached for managing this disease.
`
`4 Benefit Assessment
`The efficacy and safety of ertugliflozin has been studied as monotherapy and in combination with
`metformin and/or a DPP-4 inhibitor in 7 multicenter, randomized, double-blind, placebo- or active
`comparator-controlled, Phase 3 clinical studies involving 4,863 patients with type 2 diabetes. These
`studies included White, Hispanic, Black, Asian, and other racial and ethnic groups, and patients with an
`average age of approximately 57.8 years1. Labeling negotiations were ongoing at the time of this
`writing. Please see the full clinical statistical review in DARRTS August 16, 2017 for details on all study
`design and outcomes. The section below provides a summary of the 3 initial studies for each NDA of
`these submissions.
`Ertugliflozin1: A total of 461 patients with type 2 diabetes inadequately controlled (HbA1c between 7%
`and 10.5%) on diet and exercise participated in a randomized, double-blind, multi-center, 26-week,
`placebo-controlled study to evaluate the efficacy and safety of ertugliflozin monotherapy. These
`patients, who were either treatment naïve or not receiving any background antiglycemic treatment ≥8
`weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to placebo,
`ertugliflozin 5 mg, or ertugliflozin 15 mg, taken orally once daily.
`
`
`At Week 26, treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically significant
`reductions in HbA1c, fasting plasma glucose (FPG), body weight, and 2-hour post prandial glucose (PPG)
`compared to placebo. Ertugliflozin also resulted in a greater proportion of patients achieving an HbA1c
`<7% compared with placebo.
`Ertugliflozin with sitagliptin1: A total of 291 patients with type 2 diabetes inadequately controlled
`(HbA1c between 8% and 10.5%) on diet and exercise participated in a randomized, double-blind, multi-
`center, placebo-controlled 26-week study to evaluate the efficacy and safety of ertugliflozin in
`combination with sitagliptin. These patients, who were not receiving any background antiglycemic
`treatment for ≥8 weeks, entered a 2-week, single-blind, placebo run-in period and were randomized to
`placebo, ertugliflozin 5 mg or ertugliflozin 15 mg in combination with sitagliptin (100 mg) once daily.
`
`Reference ID: 4144428
`
`
`6
`
`

`

`
`At Week 26, treatment with ertugliflozin 5 mg and 15 mg in combination with sitagliptin at 100 mg daily
`provided significant reductions in HbA1c, FPG, body weight, 2-hour PPG, and systolic blood pressure
`compared to placebo. Ertugliflozin 5 mg and 15 mg in combination with sitagliptin at 100 mg daily also
`resulted in a significantly higher proportion of patients achieving an HbA1c <7% compared with placebo.
`Ertugliflozin with metformin1: A total of 621 patients with type 2 diabetes inadequately controlled
`(HbA1c between 7% and 10.5%) on metformin monotherapy (≥1,500 mg/day for ≥8 weeks) participated
`in a randomized, double-blind, multi-center, 26-week, placebo-controlled study to evaluate the efficacy
`and safety of ertugliflozin in combination with metformin. Patients entered a 2-week, single-blind,
`placebo run-in, and were randomized to placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg administered
`once daily in addition to continuation of background metformin therapy.
`
`At Week 26, the addition of treatment with ertugliflozin at 5 mg or 15 mg daily provided statistically
`significant reductions in HbA1c, FPG, and body weight compared to placebo.
`
`5 Risk Assessment & Safe-Use Conditions
`At the time of this writing, there was no expectation of having a boxed warning for ertugliflozin alone, or
`with the combination of sitagliptin, however labeling discussions are onoing. If approved, ertugliflozin
`will be the first SGLT-2 inhibitor combined with a DPP-4 inhibitor; in this case, sitagliptin. As with
`Invokanamet and Invokanmet XR, there is a Boxed Warning for ertugliflozin in combination with
`metformin for the risk of metformin associated lactic acidosis, which is present across all metformin and
`metformin containing drug products. Neither of these drug classes (SGLT-2 inhibitors, DPP-4 inhibitors,
`or the biguanide metformin) presently have a REMS.
`
`Adverse reactions described for ertugliflozin will be consistent with labeling for the other drugs in the
`SGLT-2inhibitorclass. Hypotension, ketoacidosis, acute kidney injury/renal impairment, urosepsis, and
`hypoglycemia are the events that will be highlighted in Warnings and Precautions. These adverse events
`are not unusual to antidiabetic drugs as a whole, or in this drug class. Labeling negotiations are currently
`ongoing at the time of this review.
`
`6 Expected Postmarket Use
`Ertugliflozin and its combination products are expected to be prescribed by a wide variety of physicians,
`including endocrinologists, primary care physicians and midlevel providers, often involved in the care of
`outpatient, ambulatory care diabetic patients. Although ertugliflozin is an NME, it does not belong to an
`unknown class of drugs. Adverse events of these medications have been well documented in the
`literature and prescribers are likely aware of the care and management of these patients.
`
`
`
`
`
`Reference ID: 4144428
`
`
`7
`
`

`

`7 Risk Management Activities Proposed by the Applicant
`The Applicant did not propose any risk management activities for ertugliflozin or any of its combination
`products beyond routine pharmacovigilance and labeling.
`
`8 Discussion of Need for a REMS
`The Clinical Reviewer recommends approval of ertugliflozin, ertugliflozin/sitagliptin and
`ertugliflozin/metformin on the basis of the efficacy and safety information currently available; however
`labeling negotiations were ongoing at the time of this review.
`
`In the clinical trials, ertugliflozin did not exhibit any new or worsening adverse events that are not
`consistent with the SGLT-2 inhibitor class, and therefore, the labeling will be consistent with the other
`drugs in this class. In patients with renal impairment, the use of ertugliflozin/metformin may increase
`the risk of metformin associated lactic acidosis. The risk lactic acidosis for ertugliflozin/metformin label
`will be communicated in the Box as well as section 5.1 of the label. Similar labeling of this risk is also in
`the Invokanamet and Invokanamet XR label. Metformin has been approved for over 20 years, with
`extensive use and literature on its renal effects in diabetic patients; therefore prescribers should be
`aware of the need for clinical monitoring and management of potential adverse events that could occur
`from metformin therapy, either alone or in combination with another antiglycemic agent. There have
`been postmarketing cases with sitagliptin worsening renal function, including acute renal failure which
`sometimes has required dialysis. Recommendations in the sitagliptin prescribing information inform
`providers of these risks, as well as provide dosage adjustments in patients with moderate, severe and
`end-stage renal disease. These recommendations will also be communicated in the labeling for the
`combination products. Although ertugliflozin belongs to a relatively new class of antiglycemic
`medications, its adverse events are not new or uncommonly seen in the treatment of diabetes, in
`particular renal function adverse events. Due to the nature of chronic diabetes illness and its long term
`effects on vascular systems, these patients are likely to have consistent follow-up and monitoring of
`renal function as well as other multi-organ monitoring.
`
`None of the antiglycemic drugs, or drug classes presented for this NDA review were approved with a
`REMS. All of the medications in the Applicant’s submission are given via the oral route, and will be likely
`prescribed by a variety of healthcare providers that are educated on the monitoring of diabetic patients,
`their risk factors, and the management of adverse events that could be a result of antiglycemic
`pharmacological therapy. No risks were identified that would require a REMS to ensure the benefits of
`ertugliflozin weighs it’s risks. For these reasons, this reviewer does not recommend a REMS for approval
`of ertugliflozin, ertugliflozin/sitagliptin, or ertugliflozin/metformin.
`
`9 Conclusion & Recommendations
`Based on the clinical review, the benefit-risk profile is favorable. Therefore, a REMS is not necessary for
`ertugliflozin, ertugliflozin/sitagliptin or ertugliflozin/metformin to ensure the benefits outweigh the
`risks. At the time of this review, evaluation of safety information and labeling was ongoing. Please
`
`8
`
`Reference ID: 4144428
`
`
`

`

`notify DRISK if new safety information becomes available that changes the benefit-risk profile so that
`this recommendation can be reevaluated if needed.
`
`10 Appendices
`Table 1: Dose and Dosage forms of Ertugliflozin, Ertugliflozin/Sitagliptin and
`Ertugliflozin/Metformin1,2,3
`
`
`
`Ertugliflozin
`
`Dose
`
`Dosage Form
`
`5mg by mouth once daily
`
`5mg and 15mg tablets
`
`Ertugliflozin/Sitagliptin
`
`5mg ertugliflozin/100mg
`sitagliptin once daily
`
`Ertugliflozin/Metformin
`
`Starting dose is recommend
`based on the patient’s current
`regimen; maximum
`recommended dose is 7.5mg
`ertugliflozin/1,000mg metformin
`twice daily
`
`Ertugliflozin 5mg/sitagliptin
`100mg
`
`Ertugliflozin 15mg/sitagliptin
`100mg
`
`Ertugliflozin 2.5mg/metformin
`HCL 500mg
`
`Ertugliflozin 2.5mg/metformin
`HCL 1,000mg
`
`Ertugliflozin 7.5mg/metformin
`HCL 500mg
`
`Ertugliflozin 7.5mg/metformin
`HCL 1,000mg
`
`HCL = hydrochloride; Initiation of ertugliflozin and any of its combination products are not
`recommended in patients with a creatinine clearance less than
`
`
`
`
`
`
`
`
`
`Reference ID: 4144428
`
`
`9
`
`(b) (4)
`
`(b) (4)
`
`

`

`10.1 REFERENCES
`
`1 Ertugliflozin Draft Prescribing Information, August 7, 2017
`
`2 Ertugliflozin/sitagliptin Draft Prescribing Information, August 7, 2017
`
`3 Ertugliflozin/metformin Draft Prescribing Information, August 7, 2017
`
`4 Khardor R et al. Type 2 Diabetes Mellitus. Drugs & Diseases, Endocrinology. July 25, 2017
`www.emedicine.medscape.com/article117853-overview accessed August 8, 2017
`
`5 Fox CS. Cardiovascular disease risk factors, type 2 diabetes mellitus, and the Framingham Heart Study. Trends
`Cardiovasc Med. 2010 Apri;20(3):90-5
`
`6 http://www.diabetes.org/diabetes-basics/statistics/ accessed August 16, 2017
`
`7 Cefalu W, et al. SGLT2 inhibitors: the latest “new kids on the block.” Diabetes Care. 2015 Mar;38(3):352-354
`
`8 Marin-Penalver J et al. Update on the treatment of type 2 diabetes mellitus. World Journal of Diabetes. 2016
`September 15; 7(17): 354-395
`
`Reference ID: 4144428
`
`
`10
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NAOMI B REDD
`08/25/2017
`
`CYNTHIA L LACIVITA
`08/25/2017
`Concur
`
`Reference ID: 4144428
`
`

`

`Division of Risk Management (DRISK)
`Office of Medication Error Prevention and Risk Management (OMEPRM)
`Office of Surveillance and Epidemiology (OSE)
`Center for Drug Evaluation and Research (CDER)
`
`NDA
`209803, 209805, 209806
`December 19, 2017
`2017-2926, 2017-2929, 2017-2930
`
`Naomi Redd, Pharm.D.
`Elizabeth Everhart, RN, MSN
`Cynthia LaCivita, Pharm.D.
`August 24, 2017
`Evaluation of Need for a REMS
`
`Ertugliflozin, ertugliflozin/sitagliptin, ertugliflozin/metformin
`Steglatro, Steglujan, Segluromet
`Merck, Sharpe and Dohme
`Anti-glycemic Agents
`
`
`
`Application Type
`Application Number
`PDUFA Goal Date
`OSE RCM #
`
`Reviewer Name(s)
`Team Leader
`Division Director
`Review Completion Date
`Subject
`
`Established Name
`Trade Name
`Name of Applicant
`Therapeutic Class
`
`
`
`
`Reference ID: 4143844
`
`1
`
`

`

`Table of Contents
`EXECUTIVE SUMMARY ......................................................................................................................................................... 3
`1
`Introduction ..................................................................................................................................................................... 3
`2 Background ...................................................................................................................................................................... 4
`2.1
`Product Information ........................................................................................................................................... 4
`2.2
`Regulatory History............................................................................................................................................... 4
`3
`Therapeutic Context and Treatment Options .................................................................................................... 5
`3.1
`Description of the Medical Condition .......................................................................................................... 5
`3.2
`Description of Current Treatment Options ............................................................................................... 5
`4 Benefit Assessment ....................................................................................................................................................... 6
`5 Risk Assessment & Safe-Use Conditions .............................................................................................................. 7
`Expected Postmarket Use ........................................................................................................................................... 7
`6
`7 Risk Management Activities Proposed by the Applicant ............................................................................... 8
`8 Discussion of Need for a REMS ................................................................................................................................. 8
`9
`Conclusion & Recommendations ............................................................................................................................. 8
`10
`Appendices .................................................................................................................................................................. 9
`10.1 References ............................................................................................................................................................. 10
`
`
`
`
`
`Reference ID: 4143844
`
`2
`
`

`

`EXECUTIVE SUMMARY
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation and
`mitigation strategy (REMS) for the new molecular entity (NME) Steglatro (ertugliflozin) as well as its
`combination products Steglujan (ertugliflozin/sitagliptin) and Segluromet (ertugliflozin/metformin) is
`necessary to ensure the benefits outweigh its risks. Merck, Sharp and Dohme submitted a NDA 209803
`for ertugliflozin and NDAs 209805 for ertugliflozin/sitagliptin and 209806 for ertugliflozin/metformin
`with the proposed indication as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus. The risks associated with ertugliflozin include: hypotension, ketoacidosis,
`acute kidney injury/renal impairment, urosepsis, and hypoglycemia. In the combination products of
`ertugliflozin/sitagliptin and ertugliflozin/metformin careful monitoring of renal impairment must be
`done due to the nature of the individual agents in the combination products potential to cause renal
`impairment. Ertugliflozin/metformin is the only NDA out of these submitted that carries a Boxed
`Warning due to the risk of metformin associated lactic acidosis. All other adverse events will be
`communicated in Warnings and Precautions for ertugliflozin and ertugliflozin/sitagliptin. The Applicant
`did not submit a proposed REMS or risk management plan with these applications.
`
`Ertugliflozin belongs to a relatively new anti-hyperglycemic drug class, sodium glucose co-transporter 2
`(SGLT2) inhibitors; however, the adverse events of this drug class are not uncommon to other
`pharmacologic agents currently approved for the treatment of type 2 diabetes mellitus. None of the
`currently approved oral anti-hyperglycemic agents are currently approved with a REMS; all adverse
`events and dosage adjustments in regards to use in renal impairment are outlined in labeling.
`Ertugliflozin and its combination products with sitagliptin and metformin will likely be prescribed by a
`wide variety of physicians and healthcare providers that are familiar with the risk factors and
`management of diabetic patients, and potential adverse events that could occur with the
`pharmacological therapy for this disease. For these reasons, this reviewer concludes that a REMS is not
`needed to ensure that the benefits of ertugliflozin, ertugliflozin/sitagliptin and ertugliflozin/metformin
`outweigh its risks.
`
`1 Introduction
`This review by DRISK evaluates whether a REMS for the NME Steglatro (ertugliflozin) as well as its
`combination products Steglujan (ertugliflozin/sitagliptin) and Segluromet (ertugliflozin/metformin) is
`necessary to ensure that the benefits outweigh its risks. Merck, Sharp and Dohme submitted a NDA
`209803 for ertugliflozin and NDAs 209805 for ertugliflozin/sitagliptin and 209806 for
`ertugliflozin/metformin with the proposed indication as an adjunct to diet and exercise to improve
`glycemic control in adults with type 2 diabetes mellitus. This application is under review in the Division
`of Metabolic and Endocrine Products (DMEP). The applicant did not submit a proposed REMS or risk
`management plan with this application.
`
`
`
`
`
`Reference ID: 4143844
`
`
`3
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`

`

`2 Background
`2.1 PRODUCT INFORMATION
`Ertugliflozin1- exerts its antiglycemic effects by inhibition of a glucose transporter, SGLT2. Inhibition of
`this transporter reduces renal re-absorption of filtered glucose and lowers the renal threshold for
`glucose, and thereby increases urinary glucose excretion. The Applicant’s proposed indication is to be
`used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes
`mellitus.
`
`Ertugliflozin/sitagliptin2 – is a combination of ertugliflozin, a SGLT2 in