Diamet XR 500 ,750 and 1000 mg XR tablet

Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone do not result in adequate glycaemic control. Diamet XR can be given alone as initial therapy or can be administered in combination with other oral antidiabetic medicines or with insulin.

Diamet XR 500 mg: The usual starting dose is one tablet daily given with the evening meal. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability. The maximum recommended dosage is 4 tablets daily.

Dosage increases should be made in increments of 500 mg every 10 to 15 days, up to a maximum of 2000 mg once daily with an evening meal. If glycaemic control is not achieved with Diamet XR 500 mg 4 tablets once daily, Diamet XR 500 mg 2 tablets twice daily should be considered, with both doses given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.

Diamet XR 750 mg: The usual starting dose is one tablet daily given with the evening meal. After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastro-intestinal tolerability. The recommended dosage is 2 tablets once daily, with the evening meal. If glycaemic control is not achieved with Diamet XR 750 mg 2 tablets once daily, Diamet XR 750 mg may be increased to a maximum dose of 3 tablets once daily with the evening meal. If glycaemic control is not achieved on Diamet XR 750 mg 3 tablets once daily, one tablet of Diamet XR 750 mg in the morning and two tablets of Diamet XR 750 mg in the evening should be considered, with both doses being given with food. If glycaemic control is still not achieved, patients may be switched to standard metformin tablets to a maximum dose of 3000 mg daily.

Diamet XR 1000 mg: Diamet XR 1000 mg is intended as maintenance therapy for patients already treated with either 1000 mg (2 tablets of Diamet XR 500) or 2000 mg (4 tablets of Diamet XR 500) of sustained release metformin hydrochloride. If glycaemic control is not achieved, patients may be switched to standard metformin hydrochloride tablets to a maximum daily dose of 3000 mg daily.

Switching patients already treated with metformin tablets: In patients already treated with metformin tablets, the starting dose of Diamet XR prolonged release tablets should be equivalent to the daily dose of metformin immediate release tablets. In patients treated with metformin at a dose above 2000 mg daily, switching to Diamet XR prolonged release tablets is not recommended.

Switching patients from other oral antidiabetic medicines: If transfer from another oral antidiabetic medicine is intended, discontinue the other medicine and initiate Diamet XR prolonged release tablets at the doses indicated above.

Combination therapy with insulin: Diamet XR prolonged release tablets and insulin may be used in combination therapy to achieve better blood glucose control. The usual starting dose is Diamet XR 500 mg once daily with the evening meal, while insulin dosage is adjusted on the basis of blood glucose measurements. After titration, switch to Diamet XR 1000 mg may be considered.

Other combination therapy: See (section 4.4).

Special populations: Elderly: Due to the potential for decreased renal function in elderly subjects, the dosage for the Diamet XR range should be adjusted based on renal function. Regular assessment of renal function is necessary. (See section 4.4.)

Paediatric population: In the absence of available data, the Diamet XR range should not be used in children.

Method of administration: For oral use.

• Hypersensitivity to metformin or to any of the excipients listed in section 6.1.
• Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis).
• Diabetic pre-coma.
• Renal failure or renal dysfunction (Creatinine clearance < 60mL/min).
• Acute conditions with the potential to alter renal function such as:
• dehydration
• severe infection
• shock
• intravascular administration of iodinated contrast media
• Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronic disease) such as:
• decompensated heart failure
• respiratory failure
• recent myocardial infarction
• shock
• pancreatitis
• Hepatic insufficiency, acute alcohol intoxication, alcoholism (acute or chronic).
• The use of DIAMET XR during pregnancy is not advised.

Lactic acidosis: Lactic acidosis is associated with the use of Diamet XR range. Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to Diamet XR administration.

In patients presenting with a metabolic acidosis and not having evidence of ketoacidosis (ketonuria and ketonaemia), lactic acidosis should be suspected and Diamet XR range therapy should be stopped. Lactic acidosis is a medical emergency, which must be treated in hospital.

Diamet XR range is excreted by the kidney and regular monitoring of renal function is advised in all diabetic patients with type 2 diabetes mellitus. The incidence of lactic acidosis may be reduced by assessing also other associated risk factors such as poorly controlled diabetes mellitus, type 2: 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 a coma. Diagnostic laboratory findings include a decreased blood pH, plasma lactate levels above 5 mmol/l, and an increased anion gap and lactate/pyruvate ratio. If metabolic acidosis is suspected, Diamet XR should be discontinued and the patient should be hospitalised immediately.

Renal function: As Diamet XR 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.

Diamet XR range therapy should be stopped 2-3 days before surgery and before clinical investigations such as intravenous urography and intravenous angiography, and reinstated only after control of renal function has been regained.

The use of Diamet XR formulations is not advised in conditions which may cause dehydration, or in patients suffering from serious infections, trauma or on low calorie intake.

Patients on long-term treatment with Diamet XR formulations should have an annual estimation of vitamin B12 levels, since Diamet XR range may cause mal-absorption of vitamin B12, which may result in megaloblastic anaemia.

Cardiac function: Patients with heart failure are more at risk of hypoxia and renal insufficiency. In patients with stable chronic heart failure, Diamet XR may be used with a regular monitoring of cardiac and renal function. For patients with acute and unstable heart failure, Diamet XR is contraindicated (see section 4.3).

Elderly: Due to the limited therapeutic efficacy data in the reduction of risk or delay of type 2 diabetes in patients 75 years and older, Diamet XR initiation is not recommended in these patients.

Administration of iodinated contrast medicines: Intravascular administration of iodinated contrast medicines may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis. Diamet XR should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.5.

Surgery: Diamet XR should be discontinued 48 hours before elective surgery with general anaesthesia and should not be resumed earlier than 48 hours afterwards.

During concomitant treatment with a sulphonylurea, blood glucose should be monitored because combination therapy may cause hypoglycaemia. Stabilisation of diabetic patients with Diamet XR and insulin should be carried out in hospital because of the possibility of hypoglycaemia until the ratio of the two medicines has been obtained (see Contra- Indications). Contraindications should be carefully observed.

All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet.

Thenusual laboratory tests for diabetes monitoring should be performed regularly. The tablet shells may be present in the faeces. Patients should be advised that this is normal.

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. Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or other oral antidiabetics (e.g. sulphonylureas or meglitinides). The tablet shells may be present in the faeces. Patients should be advised that this is normal. This medicine contains less than 1mmol sodium (23mg) per dosage unit, that is to say it is essentially 'sodium free'.

Concomitant use not recommended: Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in case of fasting, malnutrition or hepatic impairment. Avoid consumption of alcohol and alcohol-containing medications.

Iodinated contrast medicines: Intravascular administration of iodinated contrast agents may lead to Diamet XR accumulation and a risk of lactic acidosis. Diamet XR must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and 4.4.

Combinations requiring precautions for use: Glucocorticoids (systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Medical practitioners should inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, the dosage of the antidiabetic medicines should be adjusted during therapy with the other medicine and upon its discontinuation.

ACE-inhibitors may decrease the blood glucose levels. If necessary, the dosage of the antidiabetic medicine should be adjusted during therapy with the other medicine and upon its discontinuation.

Cimetidine: Reduced renal clearance of Diamet XR has been reported during cimetidine therapy, so a dose reduction should be considered.

Anticoagulants: Diamet XR has been reported to diminish the activity of warfarin, and so dose adjustments and increased frequency of INR determinations should be considered.

Sulphonylurea: Concomitant therapy of Diamet XR with sulphonylurea may cause hypoglycaemia.

Vitamins: Long-term treatment with Diamet XR may cause vitamin B12 mal-absorption in the gastro-intestinal tract, thus a dose reduction of Diamet XR should be considered.

Some medicines can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.

Medicines with intrinsic hyperglycaemic activity (e.g. glucocorticoids (systemic and local routes), diuretics and sympathomimetics). More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the other drug and upon its discontinuation.

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, trimethoprim, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration. A dose reduction should be considered.
• 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 medicines 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.

The use of Diamet XR during pregnancy is contraindicated (see section 4.3).

Pregnancy: Uncontrolled diabetes during pregnancy (gestational or permanent) is associated with increased risk of congenital abnormalities and perinatal mortality. A limited amount of data from the use of metformin in pregnant women does not indicate an increased risk of congenital abnormalities. Animal studies do not indicate harmful effects with respect to pregnancy, embryonic or foetal development, parturition or postnatal development (see section 5.3).

When the patient plans to become pregnant and during pregnancy, it is recommended that impaired glycaemic control or diabetes are not treated with metformin. For diabetes it is recommended that insulin should be used to maintain blood glucose levels as close to normal as possible to reduce the risk of malformations of the foetus.

Breast-feeding: Metformin is excreted into human breast milk. No adverse effects were observed in breastfed newborns/infants. However, as only limited data are available, breastfeeding is not recommended during metformin treatment.

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 to use machines. However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic medicines (e.g. sulphonylureas, insulin, or meglitinides).

In post marketing data and in controlled clinical studies, adverse event reporting in patients treated with metformin as in Diamet XR was similar in nature and severity to that reported in patients treated with metformin as in Diamet immediate release. During treatment initiation, the most common adverse reactions are nausea, vomiting, diarrhoea, abdominal pain and loss of appetite, which resolve spontaneously in most cases.

The following adverse reactions may occur with Diamet XR.

Metabolism and nutrition disorders: Less frequent: Lactic acidosis (see section 4.4.). Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of metformin. Consideration of such an aetiology is recommended if a patient presents with megaloblastic anaemia.

Nervous system disorders: Frequent: Taste disturbance.

Gastrointestinal disorders: Frequent: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. A slow increase of the dose may also improve gastrointestinal tolerability.

Hepatobiliary disorders: Less frequent: Isolated reports of liver function tests abnormalities or hepatitis resolving upon metformin discontinuation.

Skin and subcutaneous tissue disorders: Less Frequent: Skin reactions such as erythema, pruritus, urticaria.

Reporting side effects: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of benefit/risk balance of the medicine. Health care providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who- umc.org) found on SAHPRA website.

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

Treatment of overdosage: There is no specific antidote for overdose with Diamet XR range. Treatment is supportive and symptomatic and should be directed at correcting fluid loss and metabolic disturbances. Haemodialysis is the most effective way to remove lactate and metformin.