ONGLYZA, Saxagliptin HCl GLYXAMBI, Empagliflozin-Linagliptin NESINA, Alogliptin Benzoate Form

The following agents contain a dipeptidyl peptidase-4 (DPP-4) inhibitor and require prior authorization: alogliptin (Nesina®), alogliptin/metformin (Kazano®), alogliptin/pioglitazone (Oseni®), linagliptin (Tradjenta®), linagliptin/metformin (Jentadueto®, Jentadueto® XR), saxagliptin (Onglyza®), saxagliptin/metformin (Kombiglyze XR®), sitagliptin (Zituvio™), and sitagliptin/metformin (Zituvimet™). If request is for a combination DPP-4 inhibitor and sodium glucose co-transporter 2 (SGLT2) inhibitor (e.g., linagliptin/empagliflozin [Glyxambi®], linagliptin/empagliflozin /metformin [Trijardy™ XR], saxagliptin/dapagliflozin [Qtern®], sitagliptin/ertugliflozin [Steglujan™]), refer to HIM.PA.91 SGLT2 Inhibitors. FDA Approved Indication(s) DPP-4 inhibitors are indicated as adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitation(s) of use:
• DPP-4 inhibitors should not be used in patients with type 1 diabetes. • Onglyza and Kombiglyze should not be used for the treatment of diabetic ketoacidosis. • Tradjenta, Jentadueto, Jentadueto XR, Zituvimet, and Zituvio have not been studied in patients with a history of pancreatitis. Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that DPP-4 inhibitors are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Type 2 Diabetes Mellitus (must meet all):

1. Diagnosis of type 2 diabetes mellitus;
2. Age ≥ 18 years;

3. Member meets one of the following (a or b): a. Failure of ≥ 3 consecutive months of metformin, unless contraindicated or clinically significant adverse effects are experienced; b. For antidiabetic medication-naïve members, requested agent is approvable if intended for concurrent use with metformin due to HbA1c ≥ 8.5% (drawn within the past 3 months); Page 1 of 8

   Confidential CLINICAL POLICY Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

   4. Failure of ≥ 3 consecutive months of a preferred sitagliptin-containing product (e.g., sitagliptin [Januvia®], sitagliptin/metformin [Janumet®, Janumet® XR]), unless clinically significant adverse effects are experienced or all are contraindicated;
4. Dose does not exceed the FDA approved maximum recommended dose (see Section V). Approval duration: 12 months
   B. Other diagnoses/indications (must meet 1 or 2):
   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace.
      II. Continued Therapy A. Type 2 Diabetes Mellitus (must meet all):
   3. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
5. Member is responding positively to therapy;

6. If request is for a dose increase, new dose does not exceed the FDA approved maximum recommended dose (see Section V).
   Approval duration: 12 months
   B. Other diagnoses/indications (must meet 1 or 2):

   1. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace; or Page 2 of 8

   Confidential CLINICAL POLICY Dipeptidyl Peptidase-4 (DPP-4) Inhibitors

   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace.
      III. Diagnoses/Indications for which coverage is NOT authorized: Not applicable A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – HIM.PA.154 for health insurance marketplace or evidence of coverage documents.
      IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AACE: American Association of Clinical Endocrinologists
      ACE: American College of Endocrinology ADA: American Diabetes Association ASCVD: atherosclerotic cardiovascular disease DPP-4: dipeptidyl peptidase-4 FDA: Food and Drug Administration
      GLP-1: glucagon-like peptide-1 HbA1c: glycated hemoglobin HF: heart failure SGLT2: sodium-glucose co-transporter 2 Appendix B: Therapeutic Alternatives
      This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
      Drug Name Dosing Regimen metformin (Fortamet®, Glucophage®, Glucophage® XR, Glumetza®) Regular-release (Glucophage): 500 mg PO BID or 850 mg PO QD; increase as needed in increments of 500 mg/week or 850 mg every 2 weeks
      Dose Limit/ Maximum Dose Regular-release: 2,550 mg/day Extended-release: • Fortamet, Glumetza: 1,000 mg PO QD; increase as needed in increments of 500 mg/week
      • Glucophage XR: 500 mg PO QD; increase as needed in increments of 500 mg/week
      Extended- release: 2,000 mg/day 100 mg PO QD Individualized dose PO BID Januvia (sitagliptin) Janumet (sitagliptin/metformin)
      Janumet XR (sitagliptin/metformin)
      Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. 100 mg/day 100/2,000 mg/day 100/2,000 mg/day Individualized dose PO QD Page 3 of 8

   Confidential CLINICAL POLICY Dipeptidyl Peptidase-4 (DPP-4) Inhibitors Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
   o History of serious hypersensitivity reaction to the requested drug product
   o Severe renal impairment (metformin-containing products) o Acute or chronic metabolic acidosis, including diabetic ketoacidosis (metformin- containing products only) o NYHA Class III or IV heart failure (Oseni only) • Boxed warning(s): lactic acidosis (metformin-containing products only), congestive heart failure (Oseni only) Appendix D: General Information • Per the American Diabetes Association (ADA) and American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) guidelines: o Metformin is recommended for all patients with type 2 diabetes. It is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death. Monotherapy is recommended for most patients; however:  Starting with dual therapy (i.e., metformin plus another agent, such as a sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, glucagon-like peptide 1 [GLP-1] receptor agonist, or basal insulin) may be considered for patients with baseline HbA1c ≥ 1.5% above their target. According to the ADA, a reasonable HbA1c target for many non-pregnant adults is < 7% (≤ 6.5% per the AACE/ACE).  Starting with combination therapy with insulin may be considered for patients with baseline HbA1c > 10% or if symptoms of hyperglycemia are present.
   o If the target HbA1c is not achieved after approximately 3 months of monotherapy, dual therapy should be initiated. If dual therapy is inadequate after 3 months, triple therapy should be initiated. Finally, if triple therapy fails to bring a patient to goal, combination therapy with insulin should be initiated. Each non-insulin agent added to initial therapy can lower HbA1c by 0.7-1%. V. Dosage and Administration
   Drug Name Jentadueto (linagliptin/metformin) Jentadueto XR (linagliptin/metformin) Kazano (alogliptin/metformin) Kombiglyze XR (saxagliptin/metformin) Nesina (alogliptin) Onglyza (saxagliptin) Oseni (alogliptin/pioglitazone) Tradjenta (linagliptin) Zituvimet (sitagliptin/metformin) Zituvio (sitagliptin) Dosing Regimen Individualized dose PO BID Individualized dose PO QD Individualized dose PO BID Individualized dose PO QD Maximum Dose 5/2,000 mg/day 5/2,000 mg/day 25/2,000 mg/day 5/2,000 mg/day 25 mg PO QD 2.5 or 5 mg PO QD Individualized dose PO QD 5 mg PO QD Individualized dose PO BID 100 mg PO QD 25 mg/day 5 mg/day 25/45 mg/day 5 mg/day 100/2,000 mg/day 100 mg/day Page 4 of 8

   CLINICAL POLICY Dipeptidyl Peptidase-4 (DPP-4) Inhibitors VI. Product Availability
   Confidential Availability Tablets: 2.5/500 mg, 2.5/850 mg, 2.5/1,000 mg Drug Name Jentadueto (linagliptin/metformin) Jentadueto XR (linagliptin/metformin) Tablets: 5/1,000 mg, 2.5/1,000 mg Kazano (alogliptin/metformin) Kombiglyze XR (saxagliptin/metformin) Nesina (alogliptin) Onglyza (saxagliptin) Oseni (alogliptin/pioglitazone) Tablets: 12.5/500 mg, 12.5/1,000 mg Tablets: 5/500 mg, 5/1,000 mg, 2.5/1,000 mg Tablets: 6.25 mg, 12.5 mg, 25 mg Tablets: 2.5 mg, 5 mg Tablets: 12.5/15 mg, 12.5/30 mg, 12.5/45 mg, 25/15 mg, 25/30 mg, 25/45 mg Tablets: 5 mg Tablets: 50/500 mg, 50/1,000 mg Tablets: 25 mg, 50 mg, 100 mg Tradjenta (linagliptin) Zituvimet (sitagliptin/metformin) Zituvio (sitagliptin) VII.