Singlin

A. Approved Indications

• Type 2 Diabetes Mellitus (T2DM):
  Repaglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). It may be used:
• As monotherapy
• In combination with metformin
• With thiazolidinediones when dual therapy is needed to maintain glycemic targets

B. Off-Label or Clinically Accepted Uses

• Management of postprandial hyperglycemia in patients who:
• Have irregular meal schedules
• Require short-acting insulin secretagogues
• Alternative for patients intolerant to sulfonylureas

A. Adults

• Initial Dose (treatment-naïve or HbA1c <8%):
• 0.5 mg orally before each main meal (2–4 times daily)
• Initial Dose (patients previously treated or HbA1c ≥8%):
• 1 mg or 2 mg orally before each meal
• Maintenance Dose:
• Titrate weekly based on blood glucose levels
• Range: 0.5 mg to 4 mg before each meal
• Maximum daily dose: 16 mg (in divided doses)

B. Elderly:

• Start at the lowest dose (0.5 mg)
• Monitor blood glucose closely to avoid hypoglycemia

C. Hepatic Impairment:

• In moderate hepatic impairment, start with 0.5 mg before meals
• Avoid use in severe hepatic impairment due to increased risk of hypoglycemia

D. Renal Impairment:

• No dose adjustment needed for mild to moderate impairment
• Use with caution in severe renal impairment

E. Pediatric Use:

• Not recommended (safety and efficacy not established)

Route of Administration:

• Oral

Administration Notes:

• Take 15–30 minutes before meals
• If a meal is skipped, skip the dose to avoid hypoglycemia
• Do not take additional doses after meals

Repaglinide is a rapid-acting, short-duration insulin secretagogue. It binds to the ATP-sensitive potassium (K⁺) channels on pancreatic beta cells, causing membrane depolarization. This opens voltage-dependent calcium channels, increasing intracellular calcium and stimulating insulin release from the pancreas. Its effect is glucose-dependent, meaning it enhances insulin secretion primarily when blood glucose levels are elevated. Its rapid onset and brief duration of action make it especially effective for controlling postprandial glucose spikes.

• Absorption:
• Rapidly absorbed after oral administration
• Peak plasma concentration (Tmax): ~1 hour
• Bioavailability: ~56%
• Distribution:
• Volume of distribution: ~31 L
• Highly protein bound: >98%
• Metabolism:
• Extensively metabolized in the liver by CYP2C8 and CYP3A4
• Metabolites are inactive
• Elimination:
• Terminal half-life: ~1 hour
• Excreted mainly via feces (90%) and urine (8%) as metabolites
• Onset of Action:
• Within 30 minutes of oral intake
• Duration of Effect:
• About 4 hours

Pregnancy:

• FDA Category C
• Animal studies have shown adverse fetal effects at high doses
• No well-controlled studies in humans
• Use only if potential benefit outweighs potential risk

Lactation:

• Unknown if repaglinide is excreted into human breast milk
• Animal studies show minimal excretion into milk
• Use with caution in breastfeeding mothers; monitor infant for signs of hypoglycemia

• Class: Oral Antidiabetic Agent
• Subclass: Meglitinide analog (non-sulfonylurea insulin secretagogue)

• Hypersensitivity to repaglinide or any of its excipients
• Type 1 diabetes mellitus
• Diabetic ketoacidosis (DKA) with or without coma
• Concomitant use with gemfibrozil (risk of severe hypoglycemia due to CYP2C8 inhibition)

• Hypoglycemia Risk:
• Major adverse effect; higher in elderly, hepatic impairment, or with skipped meals
• Requires education on symptoms and management
• Hepatic Impairment:
• Increases drug exposure and hypoglycemia risk; avoid in severe impairment
• Weight Gain:
• Possible due to insulin-stimulating effects
• CYP Enzyme Interactions:
• Multiple drug interactions through CYP2C8 and CYP3A4 pathways
• Temporary Insulin Use:
• Consider switching to insulin during acute illness, surgery, or major stress

Common (≥1%):

• Metabolic: Hypoglycemia
• Gastrointestinal: Nausea, vomiting, diarrhea, constipation
• Neurologic: Headache, dizziness
• Musculoskeletal: Back pain
• Respiratory: Upper respiratory tract infection

Serious or Rare:

• Severe hypoglycemia (especially with drug interactions or hepatic dysfunction)
• Liver enzyme elevation (rare)
• Hypersensitivity reactions (e.g., rash, pruritus)

Timing & Severity:

• Most side effects occur shortly after dosing, especially post-meal
• Hypoglycemia is dose-related and more frequent when meals are delayed or skipped

A. Major Drug Interactions:

• Gemfibrozil (CYP2C8 inhibitor):
• Contraindicated — increases repaglinide plasma levels and hypoglycemia risk
• Clopidogrel:
• May increase repaglinide exposure via CYP2C8 inhibition
• Rifampin (CYP3A4 and CYP2C8 inducer):
• Reduces repaglinide effectiveness
• Ketoconazole, Clarithromycin (CYP3A4 inhibitors):
• May increase repaglinide levels; monitor glucose closely
• Beta-blockers:
• May mask signs of hypoglycemia

B. Food and Alcohol:

• Take with meals to reduce hypoglycemia
• Excess alcohol may increase hypoglycemia risk

• ADA 2024 Diabetes Guidelines:
• Meglitinides are less preferred than newer agents (e.g., GLP-1 RAs, SGLT2 inhibitors) but still an option for:
• Patients with meal-time glucose spikes
• Those with sulfonylurea intolerance
• Elderly patients requiring flexible meal-time dosing
• EMA & FDA Recommendations:
• Continued contraindication with gemfibrozil emphasized
• Awareness of CYP-mediated interactions highlighted in recent safety updates

• Temperature:
• Store at 20°C to 25°C (68°F to 77°F)
• Allowable range: 15°C to 30°C (59°F to 86°F)
• Humidity & Light:
• Protect from excessive moisture and direct sunlight
• Keep in original blister pack or tightly closed container
• Handling Precautions:
• Do not use if tablets are discolored or damaged
• No refrigeration or shaking needed