For US Health Care Professionals
WARNING FOR KOMBIGLYZE XR: LACTIC ACIDOSIS
US Full Prescribing Information including Boxed WARNING about lactic acidosis, and Medication Guide
Lactic acidosis is a rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure.
The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.
If acidosis is suspected, KOMBIGLYZE™ XR (saxagliptin and metformin HCl extended-release) should be discontinued and the patient hospitalized immediately. [See Warnings and Precautions]
Click here for Important Safety Information including complete Boxed WARNING about lactic acidosis
A TREATMENT FOR ADULTS WITH TYPE 2 DIABETES MELLITUS, IN ADDITION TO DIET AND EXERCISE
ADD-ON COMBINATION THERAPY
SIGNIFICANT A1C REDUCTIONS1,2
Saxagliptin 5 mg + metformin IR provided statistically significant reductions in A1C levels vs placebo + metformin IR at 6 months1,2,a,b
(95% Cl: -1.0%, -0.6%)
GREATER REDUCTION WITH SAXAGLIPTIN 5 MG + METFORMIN IR
GREATER REDUCTION WITH SAXAGLIPTIN 5 MG + METFORMIN IR
-0.8%
(95% Cl: -1.0%, -0.6%)
P<0.0001 vs placebo + metformin IR.
aIn these studies, saxagliptin 5 mg and metformin IR were administered as separate tablets.
bIntent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.
Uncontrolled on Metformin Monotherapy
- A1C reduction with saxagliptin 2.5 mg when added to metformin IR was -0.6% (P<0.0001 vs metformin IR + placebo, n=186, baseline 8.1%) at 6 months1,2
- The proportion of patients who discontinued or who were rescued in the saxagliptin 2.5 mg + metformin IR, saxagliptin 5 mg + metformin IR, and placebo + metformin groups was 15%, 13%, and 27%, respectively1
SIGNIFICANTLY REDUCED FPG AND PPG AT 6 MONTHS1,2
Saxagliptin 5 mg + metformin IR delivered statistically significant reductions in fasting plasma glucose (FPG) and postprandial glucose (PPG) vs placebo + metformin IR at 6 months1,2,c,d
GREATER REDUCTIONS WITH SAXAGLIPTIN 5 MG + METFORMIN IR
FPG
-23 mg/dL
(95% Cl: -30 mg/dL, -16 mg/dL)
GREATER REDUCTIONS WITH SAXAGLIPTIN 5 MG + METFORMIN IR
2-HOUR PPG
-40 mg/dL
(95% Cl: -56 mg/dL, -24 mg/dL)
FPG
-23 mg/dL(95% Cl: -30 mg/dL, -16 mg/dL)
2-HOUR PPG
-40 mg/dL(95% Cl: -56 mg/dL, -24 mg/dL)
P<0.05 vs placebo + metformin IR.
cIn these studies, saxagliptin 5 mg and metformin IR were administered as separate tablets.
dIntent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.
- Reductions with saxagliptin 2.5 mg + metformin IR were: FPG -14 mg/dL (P<0.05 vs placebo + metformin IR, n=188, baseline FPG 174 mg/dL) and PPG -62 mg/dL (P<0.05 vs placebo + metformin IR, n=155, baseline PPG 294 mg/dL) at 6 months1,2
STUDY DESIGN1,2
Add-on Combination Therapy
Phase 3, 24-week, multicenter, randomized, double-blind, placebo-controlled study
A1C ≥7.0% and ≤10.0% (n=743)
*Metformin IR dose was between 1500 and 2500 mg daily.
Study Objective
Evaluate the efficacy and safety of saxagliptin, in addition to diet and exercise, as add-on to metformin IR compared to placebo + metformin IR.
Primary Efficacy End Point
A1C change from baseline at 6 months
Secondary and Other Efficacy End Points
- FPG change from baseline at 6 months
- Percent of patients achieving A1C <7.0%
- PPG change from baseline following an oral glucose tolerance test at 6 months
Study Length
6 months
Study Length
6 months
Key Inclusion Criteria
Key Inclusion Criteria
Demographic: Men and women age 18–77 years
Diagnosis: Type 2 diabetes mellitus (T2DM)
A1C: ≥7.0% and ≤10.0%
Metformin Dose: Stable monotherapy ≥1500 mg/day but not >2550 mg/day for at least 8 weeks prior to enrollment
Fasting C-peptide: ≥1.0 ng/mL
Body Mass Index: ≤40 kg/m2
Study Dosing
Study Dosing
After the lead-in period, eligible patients were randomly assigned 1:1:1:1 (permuted blocks stratified by site) by an interactive voice response system to 2.5, 5, or 10 mg saxagliptin or placebo for 24 weeks in addition to their lead-in dose of open-label metformin.
Primary Efficacy End Point
A1C change from baseline at 6 months
Secondary and Other Efficacy End Points
- FPG change from baseline at 6 months
- Percent of patients achieving A1C <7.0%
- PPG change from baseline following an oral glucose tolerance test at 6 months
Primary Efficacy End Point
A1C change from baseline at 6 months
Secondary and Other Efficacy End Points
- FPG change from baseline at 6 months
- Percent of patients achieving A1C <7.0%
- PPG change from baseline following an oral glucose tolerance test at 6 months
Important Safety Information for KOMBIGLYZE XR
Risk factors include renal impairment, concomitant use of certain drugs, age >65 years old, radiological studies with contrast, surgery and other procedures, hypoxic states, 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 lactic acidosis is suspected, discontinue KOMBIGLYZE XR and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.
Contraindications
- Severe renal impairment (eGFR below 30 mL/min/1.73 m2)
- Prior serious hypersensitivity reaction to saxagliptin or hypersensitivity to metformin hydrochloride
- Metabolic acidosis, including diabetic ketoacidosis
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Indication and Limitations of Use
Warnings and Precautions
Pancreatitis: There have been post-marketing reports of acute pancreatitis in patients taking saxagliptin, and in the SAVOR cardiovascular outcomes trial. Observe for pancreatitis. If pancreatitis is suspected, discontinue KOMBIGLYZE XR.
Heart Failure: In the SAVOR cardiovascular outcomes trial, more patients treated with saxagliptin were hospitalized for heart failure compared to placebo. Patients with a prior history of heart failure or renal impairment had a higher risk for hospitalization for heart failure. Consider the risks and benefits of KOMBIGLYZE XR in patients who have known risk factors for heart failure. Monitor for signs and symptoms. If heart failure develops, consider discontinuation of KOMBIGLYZE XR.
Vitamin B12 Deficiency: Metformin may lower vitamin B12 levels. Measure hematological parameters annually.
Hypoglycemia: When saxagliptin was used in combination with a sulfonylurea or with insulin, the incidence of confirmed hypoglycemia was increased over that of placebo. Consider lowering the dose of these agents when coadministered with KOMBIGLYZE XR.
Hypoglycemia could occur when caloric intake is deficient, strenuous exercise is not compensated by caloric supplementation, or when KOMBIGLYZE XR is used with other glucose-lowering agents or ethanol.
Hypersensitivity: Serious reactions have been reported in patients treated with saxagliptin, including anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with saxagliptin, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue KOMBIGLYZE XR. Use caution in patients with a history of angioedema to another DPP-4 inhibitor.
Severe and Disabling Arthralgia has been reported in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation. A subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider discontinuing drug if appropriate.
Bullous Pemphigoid: There have been postmarketing reports of bullous pemphigoid requiring hospitalization in patients taking DPP-4 inhibitors. Tell patients to report development of blisters or erosions. If suspected, discontinue KOMBIGLYZE XR.
Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with KOMBIGLYZE XR.
Adverse Reactions
Most common adverse reactions reported in ≥5% of patients treated with saxagliptin and more commonly than in patients treated with placebo were upper respiratory tract infection (7.7%, 7.6%), urinary tract infection (6.8%, 6.1%), and headache (6.5%, 5.9%).
Adverse reactions reported in >5% of patients treated with metformin XR and more commonly than in patients treated with placebo were diarrhea (9.6% vs 2.6%) and nausea/vomiting (6.5% vs 1.5%).
Adverse reactions reported in ≥5% of treatment-naive patients treated with coadministered saxagliptin and metformin IR and more commonly than in patients treated with metformin IR alone were headache (7.5% vs 5.2%) and nasopharyngitis (6.9% vs 4.0%).
Drug Interactions
Strong CYP3A4/5 inhibitors (eg, ketoconazole): Coadministration with KOMBIGLYZE XR significantly increases saxagliptin concentrations. Recommend limiting saxagliptin dosage to 2.5 mg once daily.
Use in Specific Populations
Assess renal function prior to initiation of KOMBIGLYZE XR and periodically thereafter. If eGFR falls below 45 mL/minute/1.73 m2, assess the benefit risk of continuing therapy and limit dose of the saxagliptin component to 2.5 mg once daily. Discontinue KOMBIGLYZE XR if eGFR falls below 30 mL/minute/1.73 m2.
Indication and Limitations of Use
- KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate
- KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis
Please see US Full Prescribing Information for KOMBIGLYZE XR (5/500•5/1000•2.5/1000 mg tablets), including Boxed WARNING about lactic acidosis, and Medication Guide.
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.FDA.gov/medwatch or call 1-800-FDA-1088.
This product information is intended for US Health Care Professionals only.
KOMBIGLYZE XR is a registered trademark and AZ&Me is a trademark of the AstraZeneca group of companies.
KOMBIGLYZE XR is a registered trademark of the AstraZeneca group of companies.
Fingertip Formulary is a registered trademark of Fingertip Formulary, LLC.
©2017 AstraZeneca. All rights reserved. US-8577; US-15269 Last Updated 11/17
Indication and Limitations of Use for KOMBIGLYZE® XR (saxagliptin and metformin HCl extended-release) tablets
KOMBIGLYZE XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both saxagliptin and metformin is appropriate.
KOMBIGLYZE XR is not indicated for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
