Source: Pharmaceutical Benefits Scheme (AU) Revision Year: 2022 Publisher: Alphapharm Pty Ltd trading as Viatris, Level 1, 30 The Bond, 30-34 Hickson Road, Millers Point NSW 2000, www.viatris.com.au, Phone: 1800 274 276
Lactic acidosis is a rare but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to metformin accumulation. Reported cases of lactic acidosis in patients on metformin have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should be reduced by assessing other associated risk factors such as poorly controlled diabetes, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
The risk of lactic acidosis must be considered in the event of non-specific signs such as muscle cramps with digestive disorders such as abdominal pain and severe asthenia.
Lactic acidosis is characterised by acidotic dyspnea, 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, metformin should be discontinued and the patient should be hospitalised immediately (see Section 4.9 OVERDOSE – Treatment).
As metformin hydrochloride is excreted by the kidney, it is recommended that creatinine clearance and/or serum creatinine levels be determined before initiating treatment and regularly thereafter:
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 non-steroidal anti-inflammatory drug (NSAID).
The intravascular administration of iodinated contrast materials in radiologic studies can lead to renal failure. This may induce metformin accumulation and may expose to lactic acidosis. Therefore, metformin must be discontinued either 48 hours before the test when renal function is known to be impaired or from the time of the test when renal function is known to be normal. Metformin may not be reinstituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal (see Section 4.5 INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTIONS).
Metformin hydrochloride must be discontinued 48 hours before elective major surgery. Therapy may be restarted no earlier than 48 hours following surgery and only after renal function has been re-evaluated and found to be normal.
The risk of lactic acidosis, in association with metformin, is increased in elderly patients on long-term therapy due to the physiological alteration of the renal function and the possible accumulation of metformin. Metformin may be used in the elderly if Contraindications and Precautions are respected, the dosage is frequently reviewed and renal function monitored.
Decreased renal function in elderly subjects is frequent and asymptomatic. Special caution should be exercised in situations where renal function may become impaired.
Metformin is not recommended for use in children under 10 years of age.
The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with metformin is initiated.
No effect of metformin on growth and puberty has been detected during controlled clinical studies of one-year duration but clinical data in relation to the long-term effect of metformin on the development of skeletal and reproductive system in children and adolescents are not available. Therefore, a careful follow-up of the effect of metformin on these parameters in metformin-treated children, especially pre-pubescent children, is recommended.
No information is available.
Metformin must be discontinued either 48 hours before the test when renal function is known to be impaired, or from the time of the test when renal function is known to be normal (see Section 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE – Administration of iodinated contrast materials).
Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
Avoid consumption of alcohol and alcohol-containing medications. Alcohol may make the signs of hypoglycaemia less clear, and delayed hypoglycaemia can occur. The CNS depressant effects of alcohol plus hypoglycaemia can make driving or the operation of dangerous machinery much more hazardous.
Medicinal products with intrinsic hyperglycaemic activity (e.g. glucocorticoids and tetracosactides (systemic and local routes), beta-2-agonists, danazol, chlorpromazine at high dosages of 100 mg per day and diuretics.
More frequent blood glucose monitoring may be required, especially at the beginning of treatment. If necessary, adjust the metformin dosage during therapy with the respective medicinal product and upon discontinuation.
May increase the risk of lactic acidosis due to their potential to decrease renal function.
ACE-inhibitors may decrease the blood glucose levels. Therefore, dose adjustment of metformin hydrochloride may be necessary when such medicinal products are added or discontinued.
Calcium channel blockers may affect glucose control in diabetic patients; regular monitoring of glycaemic control is recommended.
Co-administration of metformin and beta-blockers may result in a potentiation of the anti-hyperglycaemic action. In addition, some of the premonitory signs of hypoglycaemia, in particular tachycardia, may be masked. Monitoring of blood glucose should be undertaken during dosage adjustment of either agent.
Reduced clearance of metformin has been reported during cimetidine therapy, so a dose reduction should be considered.
Metformin increases the elimination rate of vitamin K antagonists. Consequently, the prothrombin time should be closely monitored in patients in whom metformin and vitamin K antagonists are being co-administered. Cessation of metformin in patients receiving vitamin K antagonists can cause marked increases in the prothrombin time.
A single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of metformin and nifedipine increased plasma metformin Cmax and AUC by 20% and 9%, respectively, and increased the amount of metformin excreted in the urine. Tmax and half-life of metformin were unaffected. Nifedipine appears to enhance the absorption of metformin. Metformin had minimal effects on the pharmacokinetics of nifedipine.
Metformin is a substrate of both transporters OCT1 and OCT2.
Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with Metformin hydrochloride tablet may increase the risk for lactic acidosis. Consider more frequent monitoring of these patients.
May increase the risk of lactic acidosis and adversely affect renal function.
Therefore, caution is advised when these drugs are co-administered with metformin and a dose adjustment may be considered, particularly in patients with renal impairment.
Fertility of male or female rats was unaffected by metformin administration at doses up to 600 mg/kg/day, or approximately twice the maximum recommended daily dose on a body surface area basis.
Category C.
To date, no relevant epidemiological data is available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or foetal development, parturition or postnatal development.
Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day, or about two times the maximum recommended human daily dose on a body surface area basis. Determination of foetal concentrations demonstrated a partial placental barrier to metformin. Because animal reproduction studies are not always predictive of human response, any decision to use this drug should be balanced against the benefits and risks. The safety of metformin in pregnant women has not been established.
When the patient plans to become pregnant and during pregnancy, it is recommended that diabetes should not be treated with metformin 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.
Australian Categorisation Definition of Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
Metformin is excreted into milk in lactating rats. Similar data are not available in humans and a decision should be made whether to discontinue breastfeeding or to discontinue metformin, taking into account the importance of the drug to the mother.
Metformin monotherapy does not cause hypoglycaemia and therefore has no effect on the ability to drive or to use machinery.
However, patients should be alerted to the risk of hypoglycaemia when metformin is used in combination with other antidiabetic agents (sulphonylureas, glinides, insulin).
The following undesirable effects may occur under treatment with metformin hydrochloride. Frequencies are defined as follows: very common: ≥1/10; common ≥1/100, <1/10; uncommon ≥1/1,000, <1/100; rare ≥1/10,000, <1/1,000; very rare <1/10,000; not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Common: Taste disturbance.
Very common: Gastrointestinal disorders such as diarrhoea, nausea, vomiting, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Very rare: Skin reactions such as erythema, pruritus and urticaria.
Very rare:
Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon metformin discontinuation.
In clinical trials in children and adolescents with type 2 diabetes, the profile of adverse reactions was similar to that observed in adults.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.
Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
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