KOMBIGLYZE™ XR
(saxagliptin and metformin HCI
extended-release) tablets

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For your appropriate type 2 diabetes adult patients in addition to diet and exercise

Onglyza® (saxagliptin) Added to Insulin

Trial Design

Phase 3b, 24-week, multicenter, randomized, double-blind, placebo-controlled study in adults with type 2 diabetes with inadequate glycemic control (A1C ≥7.5% to ≤11%) on a stable dose of insulin alone (≥ 30 units/day, ≤150 units/day) or in combination with a stable dose of metformin IR. See Full Trial Design

In addition to diet and exercise, Onglyza 5 mg significantly improved A1C in combination with insulin at Week 24 with an incidence of adverse events similar to placebo, except for confirmed hypoglycemia

Significant A1C Reductions When Added to Metformin, Glyburide, a TZD

IR = Immediate release; ± = with or without metformin IR

*Intent-to-treat population using last observation on study or last observation prior to insulin rescue therapy for patients needing rescue.

The percentage of patients who discontinued for lack of glycemic control or who were rescued in the Onglyza® (saxagliptin) 5 mg plus insulin with or without metformin IR and the placebo plus insulin with or without metformin IR group was 23% and 32%, respectively.

Incidence of Averse Events

*Based on fingerstick glucose ≤50 mg/dL and associated symptoms.
A concurrent glucose measurement was not required or was normal in some patients. Therefore, it is not possible to conclusively determine that all these reports reflected true hypoglycemia.
Prior to rescue.

Select Warnings and Precautions

Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA.
Click here for Additional Important Safety Information.

Full Trial Design

Study Purpose

Evaluate the efficacy and safety of Onglyza as add-on therapy in patients with inadequate glycemic control on insulin alone or insulin combined with metformin

Study Design

Phase 3b, multicenter, randomized, double-blind, placebo-controlled

Study Length

24 weeks

Key Inclusion Criteria

  • Adults with type 2 diabetes with inadequate glycemic control (A1C ≥7.5% to ≤11%) on a stable dose of insulin alone (≥30 units/day, ≤150 units/day with ≤ 20% variation in total daily dose for ≥ 8 weeks prior to screening) or in combination with a stable dose of metformin

Patient Population

41.3% male, 78% white, 57.2 years old, duration of diabetes 12 years (mean), A1C 8.7% (N=455) Mean daily insulin dose at baseline was 53 units with Onglyza (saxagliptin) 5 mg and 55 units with placebo, 69% of patients were on metformin

Dosing

Patients were randomized 2:1 with either Onglyza 5 mg plus insulin with or without metformin (n=304) or placebo plus insulin with or without metformin (n=151). Insulin type was intermediate acting or long acting (basal) or pre-mixed (pre-mixed formulation could include short- or rapid-acting insulin as one component). Doses of antidiabetic therapies were to remain stable, but patients were rescued and allowed to adjust the insulin regimen if specific glycemic goals were not met or if patient self-increased the insulin dose by >20%.

Primary Efficacy Endpoints

A1C change from baseline at 24 weeks

Secondary and Other Efficacy Endpoints

  • FPG change from baseline at 24 weeks
  • Percent of patients achieving A1C <7.0% at 24 weeks
  • Change from baseline in PPG 180-minute area under the curve and 120-minute PPG in response to meal tolerance test
  • Change from baseline in mean total daily insulin dose (regardless of rescue)

Contraindications

  • History of a serious hypersensitivity reaction to ONGLYZA® (saxagliptin) (eg, anaphylaxis, angioedema, or exfoliative skin conditions)

Warnings and Precautions

  • Pancreatitis: There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA® (saxagliptin). After initiating ONGLYZA® (saxagliptin), observe patients carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue ONGLYZA® (saxagliptin) and initiate appropriate management. It is unknown whether patients with a history of pancreatitis are at increased risk of developing pancreatitis while using ONGLYZA® (saxagliptin).
  • Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin: When ONGLYZA® (saxagliptin) was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA® (saxagliptin).
  • Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA® (saxagliptin), including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA® (saxagliptin), with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA® (saxagliptin), assess for other potential causes for the event, and institute alternative treatment for diabetes. Use caution in patients with a history of angioedema to another DPP-4 inhibitor as it is unknown whether they will be predisposed to angioedema with ONGLYZA® (saxagliptin).
  • Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA® (saxagliptin) or any other antidiabetic drug.

Most Common Adverse Reactions

  • Most common adverse reactions reported in ≥5% of patients treated with ONGLYZA® (saxagliptin) and more commonly than in patients treated with control were upper respiratory tract infection (7.7%, 7.6%), headache (7.5%, 5.2%), nasopharyngitis (6.9%, 4.0%) and urinary tract infection (6.8%, 6.1%).
  • When used as add-on combination therapy with a thiazolidinedione, the incidence of peripheral edema for ONGLYZA® (saxagliptin) 2.5 mg, 5 mg, and placebo was 3.1%, 8.1% and 4.3%, respectively.
  • Confirmed hypoglycemia was reported more commonly in patients treated with ONGLYZA® (saxagliptin) 2.5 mg and ONGLYZA® (saxagliptin) 5 mg compared to placebo in the add-on to glyburide trial (2.4%, 0.8% and 0.7%, respectively), with ONGLYZA® (saxagliptin) 5 mg compared to placebo in the add-on to insulin (with or without metformin) trial (5.3% and 3.3%, respectively),with ONGLYZA® (saxagliptin) 2.5 mg compared to placebo in the renal impairment trial (4.7% and 3.5%, respectively), and with ONGLYZA® (saxagliptin) 5 mg compared to placebo in the add-on to metformin plus sulfonylurea trial (1.6% and 0.0%, respectively).

Drug Interactions

Because ketoconazole, a strong CYP3A4/5 inhibitor, increased saxagliptin exposure, the dose of ONGLYZA® (saxagliptin) should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).

Use in Specific Populations

  • Patients with Renal Impairment: The dose of ONGLYZA® (saxagliptin) is 2.5 mg once daily for patients with moderate or severe renal impairment, or with end-stage renal disease requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). ONGLYZA® (saxagliptin) should be administered following hemodialysis. ONGLYZA® (saxagliptin) has not been studied in patients undergoing peritoneal dialysis. Assessment of renal function is recommended prior to initiation of ONGLYZA® (saxagliptin) and periodically thereafter.
  • Pregnant and Nursing Women: There are no adequate and well-controlled studies in pregnant women. ONGLYZA® (saxagliptin), like other antidiabetic medications, should be used during pregnancy only if clearly needed. It is not known whether saxagliptin is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when ONGLYZA® (saxagliptin) is administered to a nursing woman.
  • Pediatric Patients: Safety and effectiveness of ONGLYZA® (saxagliptin) in pediatric patients have not been established.

ONGLYZA® (saxagliptin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings.

ONGLYZA® (saxagliptin) should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ONGLYZA® (saxagliptin) has not been studied in patients with a history of pancreatitis.


Please click here for US Full Prescribing Information and Medication Guide for ONGLYZA® (saxagliptin)

Reference

  1. Barnett AH, Charbonnel B, Donovan M, et al. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28(4):513-523.
   
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