Qternmet XR - Drug Monograph

Introduction

Qternmet XR is a fixed-dose combination medication containing three antidiabetic agents: saxagliptin (a dipeptidyl peptidase-4 inhibitor), metformin hydrochloride (a biguanide), and dapagliflozin (a sodium-glucose cotransporter 2 inhibitor). This extended-release formulation is designed to provide comprehensive glycemic control for adults with type 2 diabetes mellitus through complementary mechanisms of action.

Mechanism of Action

Qternmet XR combines three distinct mechanisms:

• Saxagliptin: Inhibits dipeptidyl peptidase-4 (DPP-4), increasing incretin hormones (GLP-1 and GIP), which stimulates glucose-dependent insulin release and reduces glucagon secretion
• Metformin: Decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity
• Dapagliflozin: Inhibits sodium-glucose cotransporter 2 (SGLT2) in the proximal renal tubules, reducing glucose reabsorption and increasing urinary glucose excretion

Indications

Qternmet XR is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with all three components (saxagliptin, metformin, and dapagliflozin) is appropriate.

Dosage and Administration

• Saxagliptin 5 mg/dapagliflozin 10 mg/metformin HCl 1000 mg XR
• Saxagliptin 5 mg/dapagliflozin 10 mg/metformin HCl 500 mg XR

• Initiate at the lowest available dose and titrate based on efficacy and tolerability
• Maximum recommended daily dose: Saxagliptin 5 mg/dapagliflozin 10 mg/metformin 2000 mg
• Renal impairment: Not recommended when eGFR <60 mL/min/1.73 m²; contraindicated when eGFR <30 mL/min/1.73 m²
• Hepatic impairment: Use with caution; not recommended in patients with hepatic disease
• Geriatric patients: Monitor renal function regularly
• Swallow tablets whole; do not crush or chew

Pharmacokinetics

• Saxagliptin: Tmax 2 hours; bioavailability 67%
• Dapagliflozin: Tmax 2 hours; bioavailability 78%
• Metformin XR: Tmax 7 hours; bioavailability 70-80% under fasting conditions

• Saxagliptin: Vd 151 L; protein binding <10%
• Dapagliflozin: Vd 118 L; protein binding 91%
• Metformin: Vd 654 L; minimal protein binding

• Saxagliptin: Primarily hepatic via CYP3A4/5 to active metabolite
• Dapagliflozin: Hepatic via UGT1A9 to inactive metabolites
• Metformin: Not metabolized

• Saxagliptin: Renal excretion (75%); half-life 2.5 hours
• Dapagliflozin: Renal (61%) and fecal (39%) excretion; half-life 12.9 hours
• Metformin: Renal excretion (90%); half-life 6.5 hours

Contraindications

• Hypersensitivity to any component
• Severe renal impairment (eGFR <30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• History of serious hypersensitivity reaction to saxagliptin or dapagliflozin
• End-stage renal disease requiring dialysis

Warnings and Precautions

• Risk factors: Renal impairment, congestive heart failure, dehydration, excess alcohol intake

• Ketoacidosis: Reports with SGLT2 inhibitors; monitor for symptoms
• Acute kidney injury: Monitor renal function periodically
• Lower limb amputations: Increased risk observed with SGLT2 inhibitors
• Genital mycotic infections: Higher incidence with dapagliflozin
• Hypersensitivity reactions: Angioedema, urticaria reported with DPP-4 inhibitors
• Heart failure: Monitor for signs and symptoms
• Vitamin B12 deficiency: Long-term metformin use may decrease absorption

Drug Interactions

• Carbonic anhydrase inhibitors (topiramate, zonisamide): Increased risk of lactic acidosis
• Drugs that reduce renal function (NSAIDs, diuretics): Increased metformin accumulation
• Strong CYP3A4 inhibitors (ketoconazole, clarithromycin): May increase saxagliptin exposure
• Inducers of UGT1A9: May decrease dapagliflozin efficacy
• Other hypoglycemic agents: Increased risk of hypoglycemia
• Alcohol: Increased risk of lactic acidosis

Adverse Effects

• Nasopharyngitis (6%)
• Headache (6%)
• Female genital mycotic infections (8%)
• Urinary tract infections (7%)
• Diarrhea (6%)
• Nausea (5%)

• Lactic acidosis
• Pancreatitis
• Ketoacidosis
• Acute kidney injury
• Severe hypersensitivity reactions
• Fournier's gangrene
• Bone fractures

Monitoring Parameters

• Renal function (eGFR, serum creatinine)
• Hepatic function
• Volume status
• Hemoglobin A1c
• Complete blood count (for vitamin B12 deficiency)

• Renal function every 3-6 months
• Hemoglobin A1c every 3 months until stable
• Signs and symptoms of hypoglycemia
• Volume status and blood pressure
• Genital hygiene and signs of infection
• Lower limb examinations
• Signs of heart failure

Patient Education

• Take with evening meal to reduce gastrointestinal effects
• Swallow tablets whole; do not crush or chew
• Maintain adequate hydration
• Recognize symptoms of hypoglycemia (shaking, sweating, confusion)
• Report symptoms of lactic acidosis (muscle pain, breathing difficulties, abdominal discomfort)
• Monitor for signs of genital infections or urinary tract infections
• Practice regular foot care and inspection
• Avoid excessive alcohol consumption
• Inform all healthcare providers about all medications being taken
• Continue diet and exercise recommendations

• Seek immediate medical attention for difficulty breathing, swelling of face or throat, or severe abdominal pain
• Contact healthcare provider for symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue)

References

1. FDA Prescribing Information: Qternmet XR (saxagliptin, dapagliflozin, and metformin HCl extended-release) tablets. 2022. 2. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care 2023;46(Suppl 1):S1-S291. 3. DeFronzo RA, et al. Efficacy and safety of fixed-dose combination therapy with saxagliptin, dapagliflozin, and metformin in patients with type 2 diabetes. Diabetes Obes Metab 2021;23(5):1099-1108. 4. Davies MJ, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2022;45(11):2753-2786. 5. Product Monograph: Qternmet XR. AstraZeneca Pharmaceuticals LP. 6. ClinicalTrials.gov: Studies on saxagliptin/dapagliflozin/metformin combination therapy.