DPP-4 Inhibitors and Combinations Step Therapy and Quantity Limit

Program Summary

Preferred agents in this program are Januvia, Janumet, Janumet XR. Non-preferred agents in this program are Jentadueto, Jentadueto XR, Kazano, Kombiglyze XR, Nesina, Onglyza, Oseni, Tradjenta. All agents are subject to Quantity Limits.

FDA APPROVED INDICATIONS AND DOSAGE2-11, 13 Dosage and Drug Indication Limitations for use Administration DPP-4 Inhibitors Januvia® Indicated as an • Should not be used in 25 mg, 50 mg, 100 (sitagliptin) adjunct to diet and patients with type 1 mg; 1 tablet per day, exercise to improve diabetes or for the maximum daily dose tablet glycemic control in treatment of diabetic of 100 mg adults with type 2 ketoacidosis, as it would diabetes mellitus not be effective in these settings. • Has not been studied in patients with a history of pancreatitis. Nesina® Indicated as an • Is not indicated for the 6.25 mg, 12.5 mg, 25 (alogliptin) adjunct to diet and treatment of type 1 mg; 1 dose per day, exercise to improve diabetes mellitus or maximum daily dose tablet glycemic control in diabetic ketoacidosis, as it of 25 mg adults with type 2 would not be effective in diabetes mellitus these settings.

Onglyza® Indicated as an • Is not indicated for the 2.5 mg, 5 mg; 1 dose (saxagliptin) adjunct to diet and treatment of type 1 per day, maximum exercise to improve diabetes mellitus or daily dose of 5 mg tablet glycemic control in diabetic ketoacidosis, as it adults with type 2 would not be effective in diabetes mellitus these settings.

Tradjenta® Indicated as an • Should not be used in 5 mg; 1 dose per day, (linagliptin) adjunct to diet and patients with type 1 maximum daily dose exercise to improve diabetes or for the of 5 mg tablet glycemic control in treatment of diabetic adults with type 2 ketoacidosis, as it would diabetes mellitus not be effective in these settings • Has not been studied in patients with a history of pancreatitis

Important limitations Dosage and Drug Indication for use Administration DPP-4 Inhibitor Combinations

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© Copyright Prime Therapeutics LLC. 12/2020 All Rights Reserved Effective 01/01/2021 Important limitations Dosage and Drug Indication for use Administration Janumet® Indicated as an • Should not be used in 50 mg/500 mg (sitagliptin/ metformin) adjunct to diet patients with type 1 – 100 mg/1000 and exercise to diabetes or for the mg per day; tablet improve treatment of diabetic two doses per glycemic control ketoacidosis. day, maximum in adult patients • Has not been studied daily dose of with type 2 in patients with a 100 mg/2000 diabetes mellitus history of pancreatitis mg Janumet® XR (sitagliptin/ Indicated as an • Should not be used in 50 mg/500 mg, metformin extended-release) adjunct to diet patients with type 1 50 mg /1000 and exercise to diabetes mellitus or mg, 100 tablet improve for the treatment of mg/1000 mg; glycemic control diabetic ketoacidosis. one dose per in adults with • Has not been studied day, maximum type 2 diabetes in patients with a daily dose of mellitus history of 100 mg/2000 pancreatitis. mg Jentadueto® (linagliptin/ Indicated as an • Should not be used in 2.5 mg/500 mg, metformin) adjunct to diet patients with type 1 2.5 mg/850 mg, and exercise to diabetes or for the 2.5 mg/1000 tablet improve treatment of diabetic mg; glycemic control ketoacidosis, as it two doses per in adults with would not be effective day, maximum type 2 diabetes in these settings. daily dose of 5 mellitus when • Has not been studied mg/2000 mg treatment with in patients with a both linagliptin history of and metformin is pancreatitis. appropriate Jentadueto XR® Indicated as an • Should not be used in 2.5 mg/1000 (linagliptin/ metformin adjunct to diet patients with type 1 mg, 5 mg/2000 extended release) and exercise to diabetes or for the mg; improve treatment of diabetic one dose per Tablet glycemic control ketoacidosis. day, maximum in adults with • Has not been studied daily dose of 5 type 2 diabetes in patients with a mg/2000 mg mellitus when history of treatment with pancreatitis. both linagliptin and metformin is appropriate

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© Copyright Prime Therapeutics LLC. 12/2020 All Rights Reserved Effective 01/01/2021 Important limitations Dosage and Drug Indication for use Administration Kazano™ Indicated as an • Not indicated for the 12.5 mg/500 (alogliptin/ metformin) adjunct to diet treatment of type 1 mg, 12.5 and exercise to diabetes mellitus or mg/1000; two tablet improve diabetic ketoacidosis, doses per day, glycemic control as it would not be maximum daily in adults with effective in these dose of 25 type 2 diabetes settings. mg/2000 mg mellitus when treatment with both alogliptin and metformin is appropriate Kombiglyze XR™ Indicated as an • Not indicated for the 2.5 mg/1000 (saxagliptin/ metformin adjunct to diet treatment of type 1 mg, 5 mg/500 extended-release) and exercise to diabetes mellitus or mg, 5 mg/1000 improve diabetic ketoacidosis. mg; one dose tablet glycemic control per day, in adults with maximum daily type 2 diabetes dose of 5 mellitus when mg/2000 mg treatment with both saxagliptin and metformin is appropriate Oseni™ Indicated as an • Not indicated for the 12.5 mg/15 mg, (alogliptin/ pioglitazone) adjunct to diet treatment of type 1 12.5 mg/30 mg, and exercise to diabetes mellitus or 12.5 mg/45 mg, tablet improve diabetic ketoacidosis, 25 mg/15 mg, glycemic control as it would not be 25 mg/30 mg, in adults with effective in these 25 mg/45 mg; type 2 diabetes settings. one dose per mellitus when day, maximum treatment with daily dose of 25 both alogliptin mg/45 mg and pioglitazone is appropriate.

CLINICAL RATIONALE The American Diabetes Association (ADA) and American Association of Clinical Endocrinologists (AACE) recommend metformin as the preferred first-line drug in type II diabetes mellitus.1,12 Two-drug combinations should be considered if metformin fails to achieve A1c target after approximately 3 months. The choice of the second agent (sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitor, basal insulin, glucagon-like peptide 1 agonist) is based upon patient and drug characteristics, with the goal of improving glycemic control while minimizing side effects and patient burden. 1

For additional clinical information see the Prime Therapeutics Formulary Chapters 4.6H: Combination Antidiabetic Agents and 4.6K: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors.

SAFETY Jentadueto, Jentadueto XR, Kazano, and Kombiglyze XR carry a black box warning for lactic acidosis.

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© Copyright Prime Therapeutics LLC. 12/2020 All Rights Reserved Effective 01/01/2021 • Post-marketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels (> 5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/ml • Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment. • Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high-risk groups are provided in the full prescribing information • If metformin-associated lactic acidosis is suspected, immediately discontinue the medication and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended. 6,7,10,13

Oseni carries a black box warning for congestive heart failure. • Thiazolidinediones, including pioglitazone, cause or exacerbate congestive heart failure in some patients. • After initiation of Oseni and after dose increases, monitor patients carefully for signs and symptoms of heart failure (e.g., excessive, rapid weight gain, dyspnea and/or edema). If heart failure develops, it should be managed according to current standards of care and discontinuation or dose reduction of pioglitazone in Oseni must be considered. • OSENI is not recommended in patients with symptomatic heart failure. Initiation of Oseni in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated.11

REFERENCES 1. American Diabetes Association. Standards of medical care in diabetes-2019. Accessed 8/27/2019. Available at https://care.diabetesjournals.org/content/diacare/suppl/2018/12/17/42.Supplement_1.DC 1/DC_42_S1_2019_UPDATED.pdf 2. Januvia prescribing information. Merck & Co., Inc. August 2019. 3. Onglyza prescribing information. Astra Zeneca. June 2019. 4. Tradjenta prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. July 2019. 5. Janumet prescribing information. Merck & Co., Inc. August 2019. 6. Kombiglyze XR prescribing information. Bristol-Meyers Squibb Company/AstraZeneca Pharmaceuticals LP. June 2019. 7. Jentadueto prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. July 2019. 8. Janumet XR prescribing information. Merck & Co., Inc. August 2019. 9. Nesina prescribing information. Takeda Pharmaceuticals America, Inc. June 2019. 10. Kazano prescribing information. Takeda Pharmaceuticals America, Inc. June 2019. 11. Oseni prescribing information. Takeda Pharmaceuticals America, Inc. June 2019. 12. Garber AJ, Abrahamson MB, Barzilay J, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2019 Executive Summary. Accessed 8/27/2019. Available at https://journals.aace.com/doi/pdf/10.4158/CS-2018-0535 13. Jentadueto XR prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. July 2019.

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TARGET AGENTS Jentadueto® (linagliptin/metformin) Jentadueto XR® (linagliptin/metformin ER) Kazano™ (alogliptin/metformin) Kombiglyze XR™ (saxagliptin/metformin ER) Nesina® (alogliptin) Onglyza® (saxagliptin) Oseni™ (alogliptin/pioglitazone) Tradjenta® (linagliptin)

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL Target Agents will be approved when ONE of the following is met: 1. The patient’s medication history includes use of one or more of the following: Januvia, Janumet, Janumet XR OR 2. The patient has an intolerance or hypersensitivity to sitagliptin OR 3. The patient has an FDA labeled contraindication to sitagliptin

Length of approval: 12 months

NOTE: Quantity Limit program applies, please refer to Quantity Limit documents.

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