Synjardy - Drug Monograph

Introduction

Synjardy (empagliflozin and metformin hydrochloride) is a fixed-dose combination oral medication approved for the management of type 2 diabetes mellitus. This dual-therapy approach combines two complementary mechanisms of action to improve glycemic control while addressing different pathophysiological aspects of diabetes.

Mechanism of Action

Synjardy exerts its glucose-lowering effects through two distinct mechanisms:

• Empagliflozin: A sodium-glucose cotransporter 2 (SGLT2) inhibitor that reduces renal glucose reabsorption in the proximal tubule, promoting glucosuria
• Metformin: Decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity by activating AMP-activated protein kinase (AMPK)

Indications

• Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
• Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis

Dosage and Administration

• 5 mg empagliflozin/500 mg metformin
• 12.5 mg empagliflozin/500 mg metformin
• 5 mg empagliflozin/1000 mg metformin
• 12.5 mg empagliflozin/1000 mg metformin

• Initial dose based on current metformin regimen or treatment-naïve patients
• Maximum recommended daily dose: 25 mg empagliflozin/2000 mg metformin
• Administer twice daily with meals to reduce gastrointestinal effects
• Dose titration should occur gradually to minimize gastrointestinal adverse effects

• Renal impairment: Not recommended when eGFR <45 mL/min/1.73m²
• Hepatic impairment: Use with caution
• Geriatric patients: Monitor renal function regularly
• Pediatrics: Safety and effectiveness not established

Pharmacokinetics

• Bioavailability: Empagliflozin ~78%; Metformin ~50-60%
• Tmax: Empagliflozin 1.5 hours; Metformin 2.5 hours
• Food delays absorption but does not significantly affect overall exposure

• Protein binding: Empagliflozin ~86%; Metformin negligible
• Apparent volume of distribution: Empagliflozin ~73.8 L

• Empagliflozin: Undergoes glucuronidation by UGT2B7, UGT1A3, UGT1A8, and UGT1A9
• Metformin: Not metabolized

• Elimination half-life: Empagliflozin ~12.4 hours; Metformin ~6.2 hours
• Excretion: Empagliflozin (41% urine, 54% feces); Metformin (primarily renal)

Contraindications

• Hypersensitivity to any component
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis
• Acute decompensated heart failure requiring hospitalization

Warnings and Precautions

• Risk factors: Renal impairment, congestive heart failure, excessive alcohol intake
• Discontinue immediately if suspected

• Volume depletion and hypotension
• Ketoacidosis
• Acute kidney injury and impairment in renal function
• Urosepsis and pyelonephritis
• Hypoglycemia with concomitant insulin or insulin secretagogues
• Genital mycotic infections
• Vitamin B12 deficiency with prolonged metformin use
• Fournier's gangrene

Drug Interactions

• Carbonic anhydrase inhibitors (may increase lactic acidosis risk)
• Drugs that reduce renal function (NSAIDs, ACE inhibitors)
• Alcohol (increases lactic acidosis risk)
• Cationic drugs (eliminated by renal tubular secretion)
• Insulin and insulin secretagogues (increased hypoglycemia risk)
• Inducers of UGT enzymes (may reduce empagliflozin efficacy)

Adverse Effects

• Gastrointestinal: Diarrhea, nausea, vomiting
• Genitourinary: Urinary tract infections, genital mycotic infections
• Metabolic: Hypoglycemia (when used with insulin or sulfonylureas)
• Other: Headache, nasopharyngitis

• Lactic acidosis
• Ketoacidosis
• Acute kidney injury
• Severe urinary tract infections
• Hypersensitivity reactions
• Fournier's gangrene

Monitoring Parameters

• HbA1c every 3 months until stable, then every 6 months
• Renal function (serum creatinine, eGFR) at baseline and regularly thereafter
• Volume status and electrolytes
• Vitamin B12 levels annually with prolonged use
• Signs and symptoms of urinary tract and genital infections
• Blood glucose monitoring, especially during dose adjustments
• Hepatic function tests periodically

Patient Education

• Take with meals to reduce gastrointestinal upset
• Maintain adequate hydration
• Recognize symptoms of hypoglycemia and hyperglycemia
• Report symptoms of urinary tract infections or genital itching/discharge
• Seek immediate medical attention for symptoms of lactic acidosis (muscle pain, difficulty breathing, stomach pain, dizziness)
• Avoid excessive alcohol consumption
• Inform all healthcare providers about Synjardy use before procedures
• Regular follow-up with healthcare provider for monitoring
• Do not discontinue without medical advice

References

1. FDA Prescribing Information: Synjardy (empagliflozin and metformin hydrochloride) tablets. 2022. 2. American Diabetes Association. Standards of Medical Care in Diabetes—2023. Diabetes Care. 2023;46(Suppl 1):S1-S291. 3. Zinman B, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. 4. Inzucchi SE, 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. Davies MJ, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2018;41(12):2669-2701.