Emjard M XR

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
  As an adjunct to diet and exercise to improve glycemic control in adults when treatment with both empagliflozin and metformin is appropriate.
• Cardiovascular Risk Reduction:
  To reduce the risk of cardiovascular death in adults with T2DM and established cardiovascular disease.

Important Off-Label or Clinically Accepted Uses:

• Prevention of Heart Failure Hospitalizations in patients with T2DM and high CV risk (supported by outcomes trials).
• Possible Use in Polycystic Ovary Syndrome (PCOS):
  While not approved, metformin (component) is frequently used for insulin resistance management in PCOS; empagliflozin is under research for similar indications.

General Administration Guidelines:

• Administer orally twice daily with meals to reduce gastrointestinal side effects from metformin.
• Swallow tablets whole; do not crush, split, or chew.

Adult Dosage:

• Initial Dose:
  Based on patient’s current regimen:
• If switching from individual agents: Empagliflozin 5 mg + Metformin 500 mg twice daily.
• Adjust gradually depending on therapeutic response and tolerability.
• Maintenance Dose:
  Maximum dose: Empagliflozin 25 mg + Metformin 2000 mg daily (divided into 2 doses).

Elderly:

• Start with low doses of metformin due to age-related renal decline; renal function monitoring is crucial.

Renal Impairment:

• eGFR ≥ 45 mL/min/1.73 m²:
  Use with caution and monitor renal function regularly.
• eGFR 30–44 mL/min/1.73 m²:
  Empagliflozin use not recommended; metformin dose adjustment or discontinuation based on clinical judgment.
• eGFR < 30 mL/min/1.73 m²:
  Contraindicated due to increased risk of lactic acidosis from metformin and reduced efficacy of empagliflozin.

Hepatic Impairment:

• Use with caution; metformin is not recommended in hepatic impairment due to lactic acidosis risk.

Pediatric Use:

• Not approved for individuals under 18 years of age.

Empagliflozin is a highly selective sodium-glucose co-transporter-2 (SGLT2) inhibitor that reduces glucose reabsorption in the proximal renal tubules. This promotes urinary glucose excretion, thereby lowering blood glucose levels independently of insulin.
Metformin Hydrochloride primarily reduces hepatic glucose production (gluconeogenesis) and enhances insulin sensitivity in peripheral tissues, especially skeletal muscles. It also decreases intestinal glucose absorption. The combination provides complementary mechanisms—insulin-independent glucose excretion via kidneys and insulin sensitization through hepatic and peripheral actions.

Empagliflozin:

• Absorption: Rapidly absorbed; peak plasma levels within 1.5 hours.
• Bioavailability: Approximately 78%.
• Distribution: ~73% plasma protein binding.
• Metabolism: Minimal hepatic metabolism; primarily via glucuronidation (UGT enzymes).
• Half-life: ~12 hours.
• Excretion: ~40% unchanged in feces; 55% in urine.

Metformin Hydrochloride:

• Absorption: ~50–60%; food delays and reduces peak concentration.
• Distribution: Minimal plasma protein binding.
• Metabolism: Not metabolized.
• Half-life: 4–8.7 hours.
• Excretion: Renally excreted unchanged.

Pregnancy:

• No specific FDA pregnancy category assigned under new labeling rules.
• Empagliflozin: Animal studies show adverse effects on kidney development in late gestation. Avoid especially in second and third trimesters.
• Metformin: Considered relatively safe in pregnancy; widely used in gestational diabetes.

Lactation:

• Empagliflozin: Unknown if excreted in human milk; avoid breastfeeding during use.
• Metformin: Excreted in breast milk in small amounts; generally considered safe. Monitor infant for GI disturbances.

Summary: Use only if potential benefits outweigh risks. Avoid during breastfeeding or consider switching therapy.

• Primary Class: Antidiabetic Combination
• Subclasses:
• Empagliflozin – SGLT2 Inhibitor
• Metformin – Biguanide Antihyperglycemic Agent

• Known hypersensitivity to empagliflozin, metformin, or any excipients
• Severe renal impairment (eGFR < 30 mL/min/1.73 m²)
• Acute or chronic metabolic acidosis (including diabetic ketoacidosis)
• Conditions predisposing to hypoxia or dehydration (e.g., heart failure, sepsis)
• Hepatic failure (risk of lactic acidosis)
• Pregnancy and lactation (use not recommended)

• Lactic Acidosis: A rare but life-threatening complication from metformin. Monitor renal function and avoid use in risk-prone patients.
• Ketoacidosis: SGLT2 inhibitors may precipitate euglycemic diabetic ketoacidosis; watch for symptoms like nausea, abdominal pain, and confusion.
• Volume Depletion: Empagliflozin increases urine output; monitor in elderly or those on diuretics.
• Genital Mycotic Infections: Common with SGLT2 inhibitors; maintain hygiene and consider prophylaxis in recurrent cases.
• Hypoglycemia: Low risk unless combined with insulin or sulfonylureas.
• Renal Monitoring: Required before initiation and periodically during therapy.
• Vitamin B12 Deficiency: Long-term metformin use can impair absorption; consider monitoring annually.

Common Side Effects:

• Gastrointestinal: Nausea, diarrhea, abdominal discomfort (mainly due to metformin)
• Genitourinary: Genital yeast infections, urinary tract infections
• Metabolic: Increased urination, weight loss
• Other: Fatigue, dizziness, increased thirst

Serious/Rare Side Effects:

• Lactic acidosis (metformin-associated)
• Euglycemic diabetic ketoacidosis (empagliflozin-related)
• Acute kidney injury
• Hypersensitivity reactions
• Hypoglycemia (especially with insulin/sulfonylureas)

Timing & Severity:

• GI symptoms typically begin early in treatment.
• Genital infections and dehydration risk increase with higher empagliflozin doses.

Major Interactions:

• Diuretics (e.g., furosemide): Increased risk of dehydration and hypotension.
• Insulin/Sulfonylureas: Enhanced hypoglycemic risk.
• Cationic Drugs (e.g., ranolazine, dolutegravir): May increase metformin levels.
• Alcohol: Potentiates lactic acidosis risk.
• Iodinated Contrast Agents: Can precipitate acute renal failure—temporarily discontinue metformin before imaging procedures.
• CYP System: Empagliflozin is minimally metabolized by CYP enzymes, reducing drug-drug interaction potential.

• FDA & EMA Updates:
• Expanded CV indication for empagliflozin + metformin combination in high-risk T2DM patients.
• KDIGO 2022 Guidelines:
• Recommend SGLT2 inhibitors in CKD patients with diabetes and eGFR ≥ 20 mL/min/1.73 m².
• ADA 2024 Diabetes Standards:
• Reiterate first-line metformin and early initiation of SGLT2 inhibitors in patients with heart failure or CKD.

• Temperature: Store below 30°C (room temperature).
• Humidity: Keep in a dry place; avoid humid environments like bathrooms.
• Light Protection: Store in original packaging to protect from light.
• Handling:
• Do not freeze.
• Protect from moisture.
• No reconstitution required.