Carbuce 500 mg. 850 mg. 1 000 mg. FC tablets)

CARBUCE is indicated for the treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

• In adults, CARBUCE film-coated tablets may be used as monotherapy or in combination with other oral antidiabetic agents or with insulin.
• In children over 12 years of age and adolescents with type 2 diabetes, CARBUCE film-coated tablets may be used as monotherapy or in combination with insulin.

Posology

It is important that CARBUCE tablets be taken in divided doses with meals.

Adults: Initially, one 500 mg tablet three times a day, or one 850 mg or 1 000 mg tablet twice a day, with or after food. After 10 to 15 days the dose should be adjusted according to blood glucose measurements. A slow increase in dose may improve gastrointestinal tolerability. Good diabetic control may be achieved within a few days, but it is not unusual for the full effect to be delayed for up to two weeks. If control is incomplete a cautious increase in dosage to a maximum of 2 550 mg daily is justified. Once control has been obtained it may be possible to reduce the dosage of CARBUCE.

Special Dosage Instructions:

Children and adolescents: The diagnosis of type 2 diabetes mellitus must be confirmed before treatment with CARBUCE is initiated. CARBUCE can be used in children from 12 years of age and adolescents. The usual starting dose is 500 mg or 850 mg once daily, given during meals or after meals. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of CARBUCE is 2 000 mg daily, taken in 2 or 3 divided doses.

Elderly: CARBUCE dose in the elderly should be adjusted based on renal function.

Patients with renal impairment: As CARBUCE is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:

• At least annually in patients with normal renal function.
• At least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects.

Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive therapy or diuretic therapy and when starting therapy with a NSAID.

CARBUCE is contra-indicated in the following:

• Hypersensitivity to metformin hydrochloride or to any of the excipients.
• Diabetic ketoacidosis and diabetic pre-coma.
• Renal failure or renal dysfunction (e.g., serum creatinine levels > 135 u03bcmol/L in males and > 110 u03bcmol/L in females).
• Acute conditions with the potential to alter renal function, such as:
• Dehydration.
• Severe infection.
• Shock.
• Intravascular administration of iodinated contrast agents (see section 4.4).
• Hepatic insufficiency, acute alcohol intoxication, alcoholism.
• Pregnancy and lactation.

Lactic acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment) metabolic complication that can occur due to CARBUCE accumulation. Reported cases of lactic acidosis in patients on CARBUCE have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by also assessing other associated risk factors, such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.

Diagnosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, CARBUCE should be discontinued and the patient should be hospitalised immediately.

Renal impairment: As CARBUCE is excreted by the kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:

Administration of iodinated contrast agents: As the intravascular administration of iodinated contrast materials in radiological studies can lead to renal failure, CARBUCE should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Surgery: CARBUCE should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards. No effect of CARBUCE on growth and puberty has been detected during controlled clinical studies of one-year duration, but no long-term data on these specific points are available. Therefore, a careful follow-up of the effect of CARBUCE on these parameters in CARBUCE-treated children, especially in prepubescent children, is recommended.

Other precautions:

• All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.
• The usual laboratory tests for diabetes monitoring should be performed regularly.
• CARBUCE alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas.

Use of CARBUCE with other medicines that lower blood glucose concentrations increases the risk of hypoglycaemia, while medicines that increase blood glucose may reduce the effect of CARBUCE therapy.

Inadvisable combinations:

Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:

• Fasting or malnutrition.
• Hepatic insufficiency.

Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast agents: Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in CARBUCE accumulation and a risk of lactic acidosis. CARBUCE should be discontinued prior to, or at the time of the test and not reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.

Combinations requiring precautions for use: Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust the dosage of the antidiabetic medicine during therapy with the other medicine and upon its discontinuation. ACE-inhibitors may decrease blood glucose levels. If necessary, adjust the dosage of the antidiabetic medicine during therapy with the other medicine and upon its discontinuation. Reduced renal clearance of CARBUCE has been reported during cimetidine therapy, so a dose reduction should be considered. An interaction between CARBUCE and anticoagulants is a possibility and dosage of the latter may need adjustment.

Pregnancy: CARBUCE is contra-indicated in pregnancy (see section 4.3).

Breastfeeding: CARBUCE is contra-indicated in breastfeeding (see section 4.3).

Fertility: No data on fertility is available.

CARBUCE has no influence on the ability to drive and use machines.

a. Summary of the safety profile

Not applicable

b. Tabulated summary of adverse reactions

MedDRA system organ class Frequency Adverse reactions

Blood and lymphatic system disorders Less Frequent Megaloblastic anaemia.

Metabolism and nutrition disorders Less Frequent Hypoglycaemia and lactic acidosis Unknown Decrease of vitamin B12 and folic acid absorption with decreased serum levels

Nervous system disorders Frequent Headache

Gastrointestinal disorders Frequent Nausea, vomiting, diarrhoea, loss of appetite, flatulence, dyspepsia and metallic taste. Unknown Abdominal pain

Skin and subcutaneous tissue disorders Unknown Mild erythema in some hypersensitive individuals

General disorders and administration site conditions Frequent Weight loss

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the u201c6.04 Adverse Drug Reactions Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8 The applicant can be reached at the following contact number: 010 045 2500.

Hypoglycaemia can occur when CARBUCE is given concomitantly with a sulphonylurea, insulin or alcohol. In excessive dosage, and particularly if there is a possibility of accumulation, lactic acidosis may develop. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and CARBUCE is haemodialysis. Intense symptomatic and supportive therapy is recommended which should be particularly directed at correcting fluid loss and correcting blood glucose levels.