Macloglymin 500 mg, 850 mg, 1000 mg FC tablets.

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

• In adults MACLOGLYMIN may be used as monotherapy or in combination with other oral antiu2013diabetic medicines or with insulin.
• In children over 12 years of age and adolescents with type II diabetes, MACLOGLYMIN may be used as monotherapy or in combination with insulin.

Posology: It is important MACLOGLYMIN 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 doses should be adjusted according to blood glucose measurements. A slow increase in dose may improve gastro-intestinal tolerability. Good diabetic control may be achieved within a few days, but it is not usual 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 2550 mg daily is justified. Once control has been obtained it may be possible to reduce the dosage of MACLOGLYMIN.

Children and adolescents: MACLOGLYMIN 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 metformin is 2000 mg daily, taken as 2 or 3 divided doses.

Elderly: MACLOGLYMIN dose in the elderly should be adjusted based on renal function. Combination therapy and adolescents: See section 4.4.

Method of administration: Orally. MACLOGLYMIN should be administered with or after food.

• Hypersensitivity to metformin hydrochloride or any of the excipients of MACLOGLYMIN (see section 6.1).
• Diabetic ketoacidosis, diabetic pre-coma.
• Renal failure or renal dysfunction (e.g. serum creatine levels > 135 u03bcmol/L in males and > 110 u03bcmol/L in females or creatinine clearance < 60 ml/min).
• 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)
• Acute or chronic disease which may cause tissue hypoxia such as:
• cardiac or respiratory failure
• recent myocardial infarction
• shock
• pancreatitis
• Hepatic insufficiency, acute alcohol intoxication, alcoholism.
• Pregnancy and lactation.

Warnings

Lactic acidosis: Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to MACLOGLYMIN accumulation. Reported cases of lactic acidosis in patients on MACLOGLYMIN have occurred primarily in diabetic patients with significant renal failure.

The incidence of lactic acidosis can and should be reduced by assessing also other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia. In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), MACLOGLYMIN should be temporarily discontinued and contact with a healthcare professional is recommended.

Medicines that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in MACLOGLYMIN-treated patients.

Diagnosis: Lactic acidosis is characterised by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH (< 7.35), plasma lactate levels above 5 mmol/L and an increased anion gap and lactate/pyruvate ratio. Lactic acidosis has occurred to a greater extent in patients with contraindications to therapy. In patients with a metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonaemia) lactic acidosis should be suspected and MACLOGLYMIN therapy stopped. Lactic acidosis is a medical emergency which must be treated in hospital.

Renal function: As MACLOGLYMIN 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.

Cardiac function Patients with heart failure are more at risk of hypoxia and renal insufficiency. For patients with acute or chronic heart failure, MACLOGLYMIN is contraindicated (see section 4.3).

Administration of iodinated contrast agents: As the intravascular administration of iodinated contrast materials in radiological studies can lead to renal failure, MACLOGLYMIN 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: MACLOGLYMIN should be discontinued 48 hours before elective surgery with general anaesthesia and clinical investigations such as intravenous urography and intravenous angiography and it should not be usually resumed earlier than 48 hours afterwards and only after control of renal function has been regained.

Children and adolescents: The diagnosis of type II diabetes mellitus must be confirmed before treatment with MACLOGLYMIN is initiated. No effect of MACLOGLYMIN 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 MACLOGLYMIN on these parameters in MACLOGLYMIN treated children, especially preu2013pubescent 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 test for diabetes monitoring should be performed regularly.
• Although MACLOGLYMIN alone never causes hypoglycaemia, caution is advised when it is used in combination with insulin or sulphonylureas.
• As Vitamin B12 deficiency and megaloblastic anaemia may develop with long-term MACLOGLYMIN use, Vitamin B12 levels should be assessed at least annually.
• MACLOGLYMIN is excreted by the kidney and regular monitoring of renal function is advised in all diabetics.
• The use of MACLOGLYMIN is not advised in conditions which may cause dehydration or in patients suffering from serious infections, trauma or on low calorie intake.
• During concomitant therapy with a sulphonylurea, blood glucose should be monitored because combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with MACLOGLYMIN and insulin should be carried out in hospital because of the possibility of hypoglycaemia until the correct ratio of the two medicines has been obtained.
• Contraindications should be carefully observed.

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 medicines.
• Iodinated contrast agents: Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in MACLOGLYMIN accumulation and a risk of lactic acidosis. MACLOGLYMIN 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 precaution 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 treatment. If necessary, adjust the dosage of the antidiabetic medicine during therapy with the other medicine and upon its discontinuation.
• ACEu2013inhibitors may decrease blood glucose levels. If necessary, adjust the dosage of the antidiabetic medicine during therapy with the ACE-inhibitor and upon its discontinuation.
• Reduced renal clearance of MACLOGLYMIN has been reported during cimetidine therapy, so a dose reduction should be considered.

An interaction between MACLOGLYMIN and anticoagulants is a possibility and dosage of the latter may need adjustment.

Organic cation transporters (OCT): Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with:

• Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.
• Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy of metformin.
• Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
• Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs are co-administered with metformin, as metformin plasma concentration may increase. If needed, dose adjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy of metformin.

Pregnancy: Safety in pregnancy and lactation has not been established in humans (See section 4.3). However, animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development. When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with MACLOGLYMIN but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

Lactation: Metformin is excreted in breastmilk. Limited data are available and therefore breastfeeding is not recommended during treatment with metformin (see Section 4.3).

Fertility: Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or use machines.

Table 1 side effects associated with MACLOGLYMIN therapy

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

Hypoglycaemia can occur when MACLOGLYMIN 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 MACLOGLYMIN is haemodialysis. Intense symptomatic and supportive therapy is recommended which should be particularly directed at correcting fluid loss and correcting blood glucose levels.