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METORED 500 (film coated tablets); METORED 850 (film coated
METORED 500 (film coated tablets)
METORED 850 (film coated tablets)
METORED 1000 (film coated tablets)
SCHEDULING STATUS
S3
PROPRIETARY NAME
(and dosage form):
METORED 500 (film coated tablets)
METORED 850 (film coated tablets)
METORED 1000 (film coated tablets)
COMPOSITION
Per film coated tablet:
METORED500: Metformin hydrochloride 500mg
METORED850: Metformin hydrochloride 850mg
METORED1000: Metformin hydrochloride 1000mg
PHARMACOLOGICAL CLASSIFICATION
A.21.2 Oral Hypoglycaemic
PHARMACOLOGICAL ACTION
Metformin is a biguanide oral anti-hyperglycaemic agent. Its mode of action is thought to be increased peripheral glucose utilization mediated by increased insulin sensitivity and inhibition of increased hepatic and renal gluconeogenesis.
Absorption
After an oral dose of metformin, Tmax is reached in 2.5hours. Absolute bioavailability of a 500mg or 850mg metformin tablet is approximately 50 to 60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20 to 30%.
After oral administration, metformin absorption is saturable and incomplete. It is assumed that the pharmacokinetics of metformin absorption is non-linear.
At the usual metformin doses and dosing schedules, steady state plasma concentrations are reached within 24 to 48hours and are generally less than 1microgram/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4micrograms/mL, even at maximum doses.
Food decreases the extent and slightly delays the absorption of metformin; following administration of a dose of 850mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Distribution
Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears at approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Volume of Distribution ranged between 63 to 276L.
Metabolism
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination
Renal clearance of metformin is >400mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5hours.
When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in plasma.
INDICATIONS
METORED is indicated for: TypeII diabetes mellitus when diet has failed and especially if the patient is overweight. METORED can be given alone as initial therapy, or can be administered in combination with a sulphonylurea or insulin.
CONTRA-INDICATIONS
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Hypersensitivity to metformin hydrochloride or any of the excipients. |
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Diabetic ketoacidosis, diabetic pre-coma, or the history thereof. |
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Renal failure or impaired renal function. |
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Pancreatitis. |
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Chronic liver disease. |
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History of or states associated with lactic acidosis such as shock or pulmonary insufficiency. |
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Cardiac failure and recent myocardial infarction. |
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Conditions associated with hypoxia. |
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Hepatic insufficiency, acute alcohol intoxication, alcoholism. |
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Safety in pregnancy and lactation has not been established. |
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Children, as safety and efficacy have not been established. |
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 METORED accumulation. Reported cases of lactic acidosis in patients on METORED 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 diabetics, ketosis, prolonged fasting, excessive alcohol intake, hepatic insufficiency and any condition associated with hypoxia.
Diagnosis
Lactic acidosis is characterized by acidotic dyspnoea, abdominal pain and hypothermia followed by coma. Diagnostic laboratory findings are decreased blood pH, plasma lactate levels above 5mmol/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.
Renal function
As METORED is excreted by kidney, serum creatinine levels should be determined before initiating treatment and regularly thereafter:
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At least annually in patients with normal renal function. |
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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.
The administration of METORED may be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet with insulin.
Administration of iodinated contrast agent
As the intravascular administration of iodinated contrast materials in radiological studies can lead to renal failure, METORED should be discontinued prior to, or at the time of the test and not reinstituted until 48hours afterwards, and only after renal function has been re-eva luated and found to be normal.
Surgery
METORED should be discontinued 48hours before elective surgery with general anaesthesia and should usually not be resumed earlier than 48hours afterwards.
Other precautions
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All patients should continue their diet with a regular distribution of carbohydrate intake during the day. Overweight patients should continue their energy-restricted diet. |
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The usual laboratory tests for diabetes monitoring should be performed regularly. |
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Although METORED alone never causes hypoglycaemia, caution is advised when it is used in combination with insulin or sulphonylureas. |
INTERACTIONS
Inadvisable combinations
Alcohol: Increased risk of lactic acidosis in acute alcohol intoxication, particularly in case of:
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fasting or malnutrition, |
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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 METORED accumulation and a risk of lactic acidosis.
METORED should be discontinued prior to, or at the time of the test and not reinstituted until 48hours afterwards, and only after renal function has been re-eva luated and found to be normal.
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 drug during therapy with the other drug and upon its discontinuation.
ACE-inhibitors may decrease the blood glucose levels. If necessary, adjust the dosage of the antidiabetic drug during therapy with the other drug and upon its discontinuation.
Cimetidine: Reduced renal clearance of METORED has been reported during cimetidine therapy, so a dose reduction should be considered.
Anticoagulants: METORED has been reported to diminish the activity of warfarin, and so dose adjustments of METORED should be considered.
Sulphonylurea: Concomitant therapy of METORED with sulphonylurea may cause hypoglycaemia.
Vitamins: Long-term treatment with METORED may cause vitamin B12 malabsorption in the gastro-intestinal tract, thus a dose reduction of METORED should be considered.
PREGNANCY AND LACTATION
The use of METORED during pregnancy is not advised. There is no information available concerning the safety of METORED during lactation.
DOSAGE AND DIRECTIONS FOR USE
It is important that METORED tablets be taken in divided doses with meals.
Adults: Initially, one 500mg tablet three times a day, with or after food.
After 10 to 15days the dose should be adjusted, or increased to 850mg or 1000mg twice daily. A slow increase in dose may improve gastro-intestinal tolerability. If control is incomplete a cautious increase in dosage to a maximum of 3g daily is justified. Once control has been obtained it may be possible to reduce the dosage of METORED.
Children: METORED is not recommended for use in Type1 diabetes mellitus.
Elderly: METORED is indicated in the elderly, but not when renal function is impaired (see Special precautions).
Combination therapy: See Special precautions.
SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Blood and the lymphatic system disorders
Less frequent: Megaloblastic anaemia.
Nervous system disorders
Frequent: Metallic taste.
Gastro-intestinal disorders
Frequent: Anorexia, nausea, vomiting, constipation and diarrhoea.
Renal and urinary disorders
Less frequent: Ketoacidosis and ketonuria.
Hepato-biliary disorders
Less frequent: Severe cholestatic hepatitis.
General disorders
Less frequent: Hypersensitivity, hypoglycaemia.
Special precautions
Lactic acidosis associated with the use of METORED. In patients with a metabolic acidosis and not having evidence of ketoacidosis (ketonuria and ketonaemia), lactic acidosis should be suspected and METORED therapy stopped. Lactic acidosis is a medical emergency, which must be treated in hospital.
METORED is excreted by the kidney and regular monitoring of renal function is advised in all diabetics.
METORED therapy should be stopped 2 to 3days 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 METORED 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 METORED should have an annual estimation of Vitamin B12levels, since METORED may cause malabsorption of Vitamin B12, which may result in megaloblastic anaemia.
During concomitant treatment with a sulphonylurea, blood glucose should be monitored because combined therapy may cause hypoglycaemia. Stabilisation of diabetic patients with METORED and insulin should be carried out in hospital because of the possibility of hypoglycaemia until the ratio of the two drugs has been obtained. Contra-indications should be carefully observed. |
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Hypoglycaemia can occur when METORED 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 METORED. Treatment is supportive and symptomatic and should be directed at correcting fluid loss and metabolic disturbances.
IDENTIFICATION
METORED500 film coated tablet is a circular, white to off-white coloured, film coated tablet debosssed with “397”on one side and plain on the other side.
METORED850 film coated tablet is a circular, white to off-white coloured, film coated tablet debosssed with “435”on one side and plain on the other side.
METORED1000 film coated tablet is an oval, white to off-white coloured, film coated tablet, scored and debosssed with “C/474” on one side and scored on the other side.
PRESENTATION
METORED tablets are packed in a white, round HDPE container with a white PP ribbed cap, having an induction liner with “sealed for your protection”, printed in black ink on the back side.
METORED500: 90 tablets.
METORED850: 60 tablets.
METORED1000: 60 tablets.
STORAGE INSTRUCTIONS
Store below 25ºC.
Store in the original package to protect from light and moisture.
KEEP OUT OF REACH OF CHILDREN.
REGISTRATION NUMBER
METORED500 film coated tablets: 41/21.2/1089
METORED850 film coated tablets: 41/21.2/1090
METORED1000 film coated tablets: 41/21.2/1091
NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
Midrand
DATE OF PUBLICATION OF THE PACKAGE INSERT
15 August 2008
New addition to this site: March 2009
Source: Pharmaceutical Industry
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