NOVONORM 2.0 MG

Indications

• Type 2 diabetes mellitus (as monotherapy or in combination with metformin when metformin alone is inadequate)

Dosage

Adults: Initially 500 micrograms, adjusted according to response, with a maximum dose of 4 mg per dose. The dose should be taken within 30 minutes before main meals.

Mechanism of action

Repaglinide acts by inhibiting ATP-sensitive potassium channels in pancreatic beta cells. This inhibition leads to membrane depolarization and the subsequent opening of L-type calcium channels, resulting in an influx of calcium ions that stimulate the exocytosis of insulin granules. Unlike sulfonylureas, repaglinide's insulinotropic effect is dependent on the presence of glucose, meaning it does not stimulate insulin release in the absence of glucose.

Pharmacodynamics

The pharmacodynamic profile of repaglinide indicates its selectivity for pancreatic beta cells, where it enhances insulin secretion in response to glucose. This effect is most pronounced at intermediate glucose levels (3 to 10 mmol/L). Repaglinide has minimal impact on insulin release at high glucose levels (greater than 15 mmol/L) and does not affect insulin levels during fasting or overnight periods.

Pharmacokinetics

Repaglinide is rapidly absorbed after oral administration, with peak plasma concentrations occurring within 1 hour. It is metabolized primarily in the liver via the cytochrome P450 system, predominantly CYP2C8 and CYP3A4. The elimination half-life is approximately 1 hour, and it is excreted mainly via the bile, with a smaller fraction eliminated in urine. Food intake can affect the absorption of repaglinide, and it is recommended to take the medication before meals.

Contra-indications

• Ketoacidosis
• Severe hepatic impairment

Adverse effects

• Hypoglycaemia
• Abdominal pain
• Diarrhoea
• Constipation
• Nausea
• Vomiting
• Skin reactions
• Vision disorders
• Hepatic function abnormal
• Cardiovascular disease
• Acute coronary syndrome
• Hypoglycaemic coma

Interactions

• Gemfibrozil (severe increase in exposure)
• Deferasirox (severe increase in exposure)
• Letermovir (severe increase in concentration)
• Selpercatinib (severe increase in exposure)
• Mitotane (moderate decrease in exposure)
• Roxadustat (moderate increase in exposure)
• Rifampicin (moderate decrease in exposure)
• Darolutamide (unknown increase in concentration)
• Bulevirtide (unknown increase in exposure)
• Ciclosporin (unknown increase in exposure)

Precautions

• Use with caution in renal impairment
• Patients exposed to stress (fever, trauma, infection, surgery) may require treatment interruption and temporary replacement with insulin

Pregnancy

Avoid use during pregnancy.

Breast-feeding

Avoid use during breastfeeding, as it is present in milk in animal studies.

Storage

Store in a cool, dry place away from light. Keep in the original package.

Formulations

• Tablets

Mechanism of action

Repaglinide activity is dependent on the presence functioning β cells and glucose. In contrast to sulfonylurea insulin secretatogogues, repaglinide has no effect on insulin release in the absence of glucose. Rather, it potentiates the effect of extracellular glucose on ATP-sensitive potassium channel and has little effect on insulin levels between meals and overnight. As such, repaglinide is more effective at reducing postprandial blood glucose levels than fasting blood glucose levels and requires a longer duration of therapy (approximately one month) before decreases in fasting blood glucose are observed. The insulinotropic effects of repaglinide are highest at intermediate glucose levels (3 to 10 mmol/L) and it does not increase insulin release already stimulated by high glucose concentrations (greater than 15 mmol/L). Repaglinide appears to be selective for pancreatic β cells and does not appear to affect skeletal or cardiac muscle or thyroid tissue.

Pharmacodynamics

Insulin secretion by pancreatic β cells is partly controlled by cellular membrane potential. Membrane potential is regulated through an inverse relationship between the activity of cell membrane ATP-sensitive potassium channels (ABCC8) and extracellular glucose concentrations. Extracellular glucose enters the cell via GLUT2 (SLC2A2) transporters. Once inside the cell, glucose is metabolized to produce ATP. High concentrations of ATP inhibit ATP-sensitive potassium channels causing membrane depolarization. When extracellular glucose concentrations are low, ATP-sensitive potassium channels open causing membrane repolarization. High glucose concentrations cause ATP-sensitive potassium channels to close resulting in membrane depolarization and opening of L-type calcium channels. The influx of calcium ions stimulates calcium-dependent exocytosis of insulin granules. Repaglinide increases insulin release by inhibiting ATP-sensitive potassium channels in a glucose-dependent manner.