Repaglinide

Registered South African indications:

• Type 2 diabetes mellitus
  - As an adjunct to diet and exercise to lower blood glucose in patients whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise alone
  - In combination with metformin or thiazolidinedione to lower blood glucose in patients whose glycaemia cannot be controlled by exercise, diet and either repaglinide, metformin or thiazolidinedione alone
  - In combination with insulin for patients not satisfactorily controlled on sulphonylureas or repaglinide alone

Contraindications

Registered South African contraindications

• Known hypersensitivity to repaglinide or any of the excipients
• Type 1 diabetes (juvenile insulin-dependent diabetes mellitus)
• Diabetes ketoacidosis, with or without coma
• Children
• Severe renal impairment
• Severe hepatic impairment
• Pregnancy
• Lactation
• Coadministration with gemfibrozil
• Coadministration with deferasirox

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Diabetes mellitus type 1, C-peptide negative
• Diabetic ketoacidosis, with or without coma
• Severe hepatic function disorder
• Coadministration with gemfibrozil

Caution

• Pregnancy (Recommendations in other jurisdictions)
• Breastfeeding (Recommendations in other jurisdictions)
• Mild to moderate renal impairment (South African recommendations)
• Renal impairment  (Recommendations in other jurisdictions)
• Mild to moderate hepatic impairment
• Elderly
• Fever
• Trauma
• Infection
• Surgery
• Hypoglycaemia
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: tab

South African registered indications and dosages

Type 2 diabetes mellitus
- As an adjunct to diet and exercise to lower blood glucose in patients whose hyperglycaemia can no longer be controlled satisfactorily by diet, weight reduction and exercise alone
- In combination with insulin for patients not satisfactorily controlled on sulphonylureas or repaglinide alone

• Oral (tab): Initial: 0.5mg, 15-30min before meals (preprandially); Titrate at 1-2 week intervals as determined by blood glucose response; Maintenance: Up to 4mg with main meals; Max: 16mg/24hrs

- In combination with metformin or thiazolidinedione to lower blood glucose in patients whose glycaemia cannot be controlled by exercise, diet and either repaglinide, metformin or thiazolidinedione alone

• Oral (tab): Initial: 0.5mg, 8hrly 15-30min before meals; Titrate at 1-2 week intervals as determined by blood glucose response; Maintenance: Up to 4mg with main meals; Max: 16mg/24hrs

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Patients can be transferred directly from other hypoglycaemic agents to repaglinide. However, no exact dosage relationship exists between repaglinide and the other oral hypoglycaemic agents. The recommended maximum starting dose of patients transferred to repaglinide is 1mg before main meals

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For repaglinide-insulin combination therapy: Combination therapy with repaglinide and insulin may be used in secondary failure patients. Patients controlled on maximum dose may benefit from treatment with bedtime insulin. Insulin doses should be titrated according to therapeutic response and in accordance with recommendations for the marketed product. Periodic adjustments of insulin may be necessary during maintenance as guided by blood glucose and HbA1c levels

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Repaglinide is a treatment addition to diet and not a substitute for diet or a mechanism for avoiding dietary restraint

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The patient's blood glucose should be monitored periodically by the physician to determine the minimum effective dose. Glycosylated haemoglobin levels may also be useful for monitoring response to therapy

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Repaglinide should be taken 15 minutes before main meals but the time may vary from immediately preceding the main meal to as long as 30 minutes before main meals

Contraindicated

Pregnancy

South African recommendations

• Contraindicated
• Safety in pregnancy has not been established
• Repaglinide should not be used during pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• There are no studies of repaglinide in pregnant women
• Repaglinide should be avoided during pregnancy
• Repaglinide was shown not to be teratogenic in animal studies. Embryotoxicity, abnormal limb development in rat foetuses and newborn pups, was observed in female rats exposed to high doses in the last stage of pregnancy

Breastfeeding

South African recommendations

• Contraindicated
• Safety in lactation has not been established
• Repaglinide is excreted in milk and should not be used in women breastfeeding their infants

Recommendations in other jurisdictions

• Caution; not recommended
• There are no studies of repaglinide in pregnant women. Repaglinide should be avoided during breastfeeding and lactation
• Repaglinide was shown not to be teratogenic in animal studies. Abnormal limb development in newborn pups was observed in female rats exposed to high doses during the lactation period
• Repaglinide was detected in the milk of animals

Fertility

South African recommendations

• No information available

Recommendations in other jurisdictions

• Non-clinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential

Renal Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Initial dosage adjustment does not appear to be necessary but subsequent increase in repaglinide should be made carefully in patients who have renal function impairment or renal failure requiring haemodialysis
• Severe: Contraindicated

Recommendations in other jurisdictions

• Caution; no dose adjustment recommended
  Repaglinide is not affected by renal disorders. Eight percent of one dose of repaglinide is excreted through the kidneys and total plasma clearance of the product is decreased in patients with renal impairment. As insulin sensitivity is increased in diabetic patients with renal impairment, caution is advised when titrating these patients

Hepatic Impairment

South African recommendations

• Mild to moderate: Caution; dose adjustment recommended
  Repaglinide should be used cautiously in patients with impaired liver function. Longer intervals between dose adjustments should be utilised to allow full assessment of response
• Severe: Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; no information available
• Severe: Contraindicated

Elderly

South African recommendations

• Caution; no dose adjustment recommended
  Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals to repaglinide  therapy cannot be ruled out. Careful titration of the dose is advised in the elderly with impaired renal or hepatic function as elimination of repaglinide may be delayed in these patients

Recommendations in other jurisdictions

• Caution; no information available
  No clinical studies have been conducted in patients >75 years of age

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Permitted - No warnings

Cardiovascular Disorders

• Cardiovascular disease
• Acute coronary syndrome

Gastrointestinal Disorders

• Abdominal pain
• Diarrhoea
• Nausea and vomiting
• Constipation

Hepatobiliary Disorders

• Abnormal hepatic function

Endocrine and Metabolism Dsorders

• Hypoglycaemia
• Hypoglycaemic coma

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity

Immune, Blood and lymphatic System Disorders

• Allergic reactions

Sensory Disorders

• Refraction disorder

• Gemfibrozil
• CYP2C8 inhibitors
• CYP3A4 inhibitors
• OATP1B1 inhibitors
• Clarithromycin
• Itraconazole
• Ketokonazole
• Trimethoprim
• Ciclosporin
• Deferasirox
• Clopidogrel
• Antidiabetic agents
• Monoamine oxidase inhibitors
• Betal blockers
• Angiotensin converting enzyme inhibitors
• Salicylates
• Non-steroidal anti-inflammatory drugs
• Octreotide
• Alcohol
• Anabolic steroids
• CYP2C8 inhibitors
• Rifampicin
• Oral contraceptives
• Barbituates
• Carbamazepine
• Thiazides
• Corticosteroids
• Danazol
• Thyroid hormones
• Sympathomimetics

None routine

• In addition to the usual self-monitoring by the patient of blood and/or urinary glucose, the patient's blood glucose must be monitored periodically by the physician to determine the minimum effective dose of repaglinide for the patient

Repaglinide is a short-acting oral secretagogue. It stimulates the release of insulin from the pancreas by closing ATP-dependent potassium channels in the beta-cell cell-membrane causing depolarization, which subsequently leads to opening of the calcium channels. The calcium influx induces insulin secretions from the beta-cells.

Tablet 0.5mg 

• Novonorm (Novo Nordisk) originator

Tablet 1mg 

• Novonorm (Novo Nordisk) originator

Tablet 2mg

• Novonorm (Novo Nordisk) originator