Usage
- Repaglinide is prescribed for type 2 diabetes mellitus in adults. It is used as an adjunct to diet and exercise to improve glycemic control. It is not indicated for type 1 diabetes or diabetic ketoacidosis.
- Pharmacological classification: Antidiabetic agent, Meglitinide.
- Mechanism of Action: Repaglinide stimulates insulin release from the pancreas by blocking ATP-sensitive potassium channels in pancreatic beta cells. This depolarizes the cell membrane, leading to calcium influx and subsequent insulin secretion. It is a short-acting insulin secretagogue. Its action is glucose-dependent; it works best when blood glucose levels are elevated and has little effect when levels are normal.
Alternate Names
- International Nonproprietary Name (INN): Repaglinide
- Brand names: Prandin, NovoNorm, Repaglinide Teva, and others depending on the region/country.
How It Works
- Pharmacodynamics: Repaglinide lowers blood glucose levels by stimulating insulin secretion from the pancreas. The effect is glucose-dependent, minimizing the risk of hypoglycemia when blood sugar levels are normal.
- Pharmacokinetics:
- Absorption: Rapidly absorbed after oral administration, reaching peak plasma concentration within one hour. Food intake slows absorption but increases the overall amount absorbed (AUC).
- Metabolism: Extensively metabolized in the liver, primarily by CYP3A4 and CYP2C8 enzymes.
- Elimination: Mainly excreted in the bile and feces, with a small amount excreted in the urine. Reduced clearance in patients with hepatic impairment.
- Mode of Action: Repaglinide binds to and blocks ATP-sensitive potassium channels on the surface of pancreatic beta cells. This closure depolarizes the cell membrane, opening voltage-gated calcium channels. The influx of calcium triggers the release of preformed insulin.
- Receptor Binding/Enzyme Inhibition: Binds to a distinct site on the ATP-sensitive potassium channel different from the sulfonylurea binding site. Not an enzyme inhibitor.
Dosage
Standard Dosage
Adults:
- Initial: 0.5 mg orally before each main meal (preprandially) for patients with HbA1c < 8%. 1-2 mg orally before each main meal for patients with HbA1c ≥ 8% or those previously treated with other oral hypoglycemics.
- Maintenance: Adjust dose based on blood glucose response. Double the dose (up to 4 mg) with each meal until adequate glycemic control is achieved. Wait at least one week between dose adjustments. Maximum daily dose: 16 mg. Skip the dose if a meal is skipped. Reduce dose if hypoglycemia occurs. Administer within 15-30 minutes before a meal.
Children:
- Not recommended for use in children under 18 years of age as safety and efficacy have not been established.
Special Cases:
- Elderly Patients: No specific dosage adjustments are necessary, but initiate therapy conservatively and titrate carefully, as elderly patients may be more sensitive to the effects of repaglinide, particularly those with renal or hepatic impairment. No studies in patients >75 years.
- Patients with Renal Impairment: For creatinine clearance (CrCl) 20-40 mL/min, start with 0.5 mg before meals and titrate slowly. For CrCl <20 mL/min, data are limited, and use with caution.
- Patients with Hepatic Dysfunction: Use cautiously. Initiate with a lower dose and adjust slowly due to reduced clearance. Monitor closely.
- Patients with Comorbid Conditions: Careful monitoring is essential. Dose adjustments may be needed depending on the specific comorbid conditions. If the patient is under stress (e.g., infection, fever, trauma, or surgery), temporary discontinuation and insulin therapy may be necessary.
Clinical Use Cases Clinical use cases outside of Type 2 diabetes mellitus are not indicated. Cases such as Intubation, Surgical Procedures, Mechanical Ventilation, Intensive Care Unit (ICU) Use, or Emergency Situations might require adjusting insulin depending on the patient’s medical condition.
Dosage Adjustments
- Dose adjustments are recommended when using strong CYP3A4 or CYP2C8 inhibitors or inducers. Gemfibrozil is contraindicated. Avoid clopidogrel; if coadministration is unavoidable, initiate repaglinide at 0.5 mg before each meal and do not exceed 4 mg daily. Limit the total daily dose to 6 mg with cyclosporine.
Side Effects
Common Side Effects:
- Hypoglycemia
- Upper respiratory tract infection, sore throat
- Headache
- Rhinitis
- Joint pain
- Nausea
- Diarrhea
- Back pain
Rare but Serious Side Effects:
- Severe hypoglycemia
- Serious allergic reactions (anaphylaxis)
- Liver dysfunction (jaundice)
Long-Term Effects: No long-term effects have been reported.
Contraindications
- Hypersensitivity to repaglinide
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Severe hepatic impairment
- Concomitant use of gemfibrozil
Drug Interactions
- Gemfibrozil: Contraindicated due to significant increase in repaglinide concentrations.
- Clopidogrel, Cyclosporine, Trimethoprim, Deferasirox: Increased risk of hypoglycemia due to CYP2C8 inhibition. Adjust repaglinide dose.
- CYP3A4 inducers (e.g., rifampin, barbiturates, St. John’s wort): Decreased repaglinide efficacy.
- CYP3A4 inhibitors (e.g., azole antifungals, macrolide antibiotics): Increased risk of hypoglycemia.
- Beta-blockers: May mask symptoms of hypoglycemia.
- Alcohol: May potentiate the hypoglycemic effect.
Pregnancy and Breastfeeding
- Pregnancy: Pregnancy Category C. Not recommended. Potential embryotoxicity and abnormal limb development have been observed in animal studies.
- Breastfeeding: Not recommended. Measurable levels of repaglinide have been detected in the breast milk of rats, with lowered blood glucose in offspring. It is unknown if repaglinide is excreted in human milk.
Drug Profile Summary
- Mechanism of Action: Short-acting insulin secretagogue; stimulates insulin release from pancreatic beta cells.
- Side Effects: Hypoglycemia, upper respiratory tract infection, headache, rhinitis, joint pain, nausea, diarrhea, back pain.
- Contraindications: Hypersensitivity, type 1 diabetes, diabetic ketoacidosis, severe hepatic impairment, gemfibrozil.
- Drug Interactions: Gemfibrozil (contraindicated), clopidogrel, cyclosporine, CYP3A4 inducers/inhibitors.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: 0.5-4 mg preprandially, max 16 mg/day. Adjust for renal/hepatic impairment and drug interactions.
- Monitoring Parameters: Blood glucose levels, HbA1c.
Popular Combinations
- Metformin: Repaglinide can be added to metformin therapy when metformin alone does not provide adequate glycemic control.
Precautions
- General Precautions: Monitor blood glucose regularly. Screen for allergies, renal and hepatic dysfunction. Assess risk factors for hypoglycemia.
- Specific Populations: See “Dosage - Special Cases”.
- Lifestyle Considerations: Counsel patients on diet, exercise, and alcohol consumption.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Repaglinide?
A: Adults: Initial dose is 0.5 mg preprandially before each main meal if HbA1c < 8%, or 1-2 mg if HbA1c ≥ 8%. Titrate up to 4 mg per meal as needed based on blood glucose, to a maximum of 16mg per day. Not recommended for pediatric patients.
Q2: How does Repaglinide work?
A: Repaglinide stimulates insulin release from the pancreas by binding to and closing ATP-sensitive potassium channels in beta cells.
Q3: What are the common side effects of Repaglinide?
A: Hypoglycemia, upper respiratory infection, headache, rhinitis, joint pain.
Q4: Is Repaglinide safe in pregnancy?
A: No. Repaglinide is Pregnancy Category C and is not recommended during pregnancy.
A: Yes, Repaglinide can be used in combination with Metformin when Metformin alone does not provide adequate glycemic control.
Q6: What should be done if a patient misses a dose of Repaglinide?
A: Skip the missed dose and take the next dose as usual before the next meal. Do not double the dose.
A: Primarily metabolized by CYP3A4 and CYP2C8 in the liver.
Q8: What are the contraindications for using Repaglinide?
A: Type 1 diabetes, diabetic ketoacidosis, hypersensitivity to repaglinide, severe hepatic impairment, and concomitant use of gemfibrozil.
Q9: How should Repaglinide be taken?
A: Orally, within 15-30 minutes before each main meal. If a meal is skipped, the corresponding dose should also be skipped.
Q10: What is the maximum daily dose of Repaglinide?
A: 16 mg.
