Ligazid M

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
• As an adjunct to diet and exercise to improve glycemic control in adults inadequately controlled on metformin alone or already being treated with linagliptin and metformin as separate agents.
• For use as initial combination therapy in adults with HbA1c levels >9% where dual therapy is appropriate.
• In combination with other antidiabetic agents (e.g., sulfonylureas or insulin) when additional glycemic control is needed.

Clinically Accepted (Off-label) Uses:

• Polycystic Ovary Syndrome (PCOS):
• Occasionally used off-label to improve insulin resistance and metabolic parameters (effect mainly attributed to metformin).

General Administration:

• Administer orally, twice daily with meals to reduce gastrointestinal side effects associated with metformin.

Adults:

• Initial Dose (in treatment-naïve patients):
• Linagliptin 2.5 mg + Metformin 500 mg orally twice daily.
• Patients already on metformin:
• Switch to a combination product that matches the current metformin dose (not exceeding maximum limits).
• Maximum Dose:
• Linagliptin 5 mg + Metformin 1000 mg twice daily.

Renal Impairment:

• eGFR ≥60 mL/min/1.73 m²: No dose adjustment required.
• eGFR 45–59 mL/min/1.73 m²: Use with caution; do not exceed metformin 1000 mg/day.
• eGFR 30–44 mL/min/1.73 m²: Initiation not recommended; existing users may continue cautiously with max 500 mg metformin twice daily.
• eGFR <30 mL/min/1.73 m²: Contraindicated.

Hepatic Impairment:

• Not recommended due to risk of lactic acidosis (from metformin).

Geriatric Use:

• Dose selection should be cautious based on renal function.

Pediatric Use:

• Safety and efficacy not established in individuals below 18 years of age.

Linagliptin is a selective, reversible inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), which prevents the degradation of endogenous incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretins stimulate insulin release and suppress glucagon secretion in a glucose-dependent manner. Metformin, a biguanide, reduces hepatic glucose production by inhibiting gluconeogenesis, enhances insulin sensitivity, and increases peripheral glucose uptake and utilization. The combination results in complementary antihyperglycemic effects through distinct mechanisms.

Linagliptin:

• Absorption: Rapid; peak plasma concentration in 1.5 hours.
• Bioavailability: ~30%.
• Distribution: Large volume of distribution (~1110 L); highly protein bound (~99%).
• Metabolism: Minimal; mainly excreted unchanged. Minor CYP3A4 involvement.
• Elimination: ~80% via feces (unchanged); ~5% via urine.
• Half-life: Terminal half-life ~100 hours; pharmacodynamic effect lasts ~24 hours.

Metformin Hydrochloride:

• Absorption: Bioavailability 50–60%; peak concentration ~2.5 hours post-dose.
• Distribution: Not protein bound.
• Metabolism: Not metabolized.
• Elimination: Renally excreted unchanged via tubular secretion.
• Half-life: ~6.2 hours.

Pregnancy:

• FDA Classification: Not assigned (new labeling rule).
• Risk Summary: Animal data with linagliptin shows no teratogenicity. Metformin has established safety in pregnancy and is used for gestational diabetes. However, combination use requires caution due to limited human data.

Lactation:

• Excretion into Breast Milk:
• Metformin: Present in low levels.
• Linagliptin: Human data unavailable; animal studies show excretion in milk.
• Recommendation: Use with caution. Monitor breastfed infants for hypoglycemia or gastrointestinal symptoms.

• Primary Therapeutic Class: Oral Antidiabetic Agent
• Subclasses:
• Linagliptin: Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
• Metformin: Biguanide

• Hypersensitivity to linagliptin, metformin, or any component of the formulation.
• Severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Conditions associated with increased risk of lactic acidosis (e.g., sepsis, dehydration, hypoxia).

• Lactic Acidosis: Rare but serious risk due to metformin; fatal if not promptly recognized. Risk increases with renal impairment, elderly age, alcohol use, or heart failure.
• Pancreatitis: Reported in association with DPP-4 inhibitors. Discontinue if suspected.
• Hypoglycemia: May occur when used with insulin or insulin secretagogues.
• Vitamin B12 Deficiency: Long-term metformin use may decrease B12 levels.
• Renal Function Monitoring: Assess renal function before initiating and periodically thereafter.
• Hepatic Impairment: Not recommended due to lactic acidosis risk.

Common:

• Gastrointestinal (Metformin-related):
• Diarrhea
• Nausea
• Abdominal discomfort
• Flatulence
• Respiratory:
• Nasopharyngitis
• Cough

Less Common:

• Headache
• Dizziness
• Arthralgia

Serious:

• Lactic acidosis (rare but life-threatening)
• Acute pancreatitis
• Hypersensitivity reactions (angioedema, urticaria, exfoliative skin conditions)
• Hepatic dysfunction (rare)

• Alcohol: Increases risk of lactic acidosis with metformin.
• Rifampin: May decrease linagliptin efficacy via CYP3A4 induction.
• Cationic drugs (e.g., dolutegravir, ranolazine): May elevate metformin concentrations.
• Diuretics and ACE inhibitors: May impair renal function, affecting metformin clearance.
• Digoxin: Linagliptin may slightly increase digoxin levels.
• CYP450 Involvement: Linagliptin is a minor substrate of CYP3A4; minimal potential for enzyme induction or inhibition.

• ADA 2024 Guidelines: Endorse early combination therapy (e.g., linagliptin + metformin) in adults with high baseline HbA1c (≥1.5% above target).
• FDA Safety Labeling (2023): Reinforced lactic acidosis warnings; emphasized caution in elderly and renally impaired patients.
• Dose Optimization: EMA and FDA support individualized combination therapy to enhance glycemic control and minimize side effects.

• Temperature: Store below 30°C (86°F).
• Light & Humidity: Protect from light and excessive moisture.
• Handling: Keep tightly closed in original packaging.
• Reconstitution: Not applicable.
• Refrigeration: Not required.