INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
METPHAGE 500 mg (Tablets)
METPHAGE 850 mg (Tablets)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

METPHAGE 500 mg (Tablets)
METPHAGE 850 mg (Tablets)

COMPOSITION:
Each METPHAGE 500 mg tabletcontains 500 mg metformin hydrochloride Each METPHAGE 850 mg tablet contains 850 mg metformin hydrochloride

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 utilisation mediated by increased insulin sensitivity and inhibition of increased hepatic and renal gluconeogenesis.
Absorption:
After an oral dose of metformin, Tmaxis reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg metformin tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in faeces was 20-30%.
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 48 hours and are generally less than 1 microgram/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 microgram/mL, even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin; following administration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute 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 63-276 litres.
Metabolism:
Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination:
Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours.
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:
METPHAGE is indicated for:
Type II diabetes mellitus when diet has failed and especially it the patient is overweight. METPHAGE can be given alone as initial therapy, or can be administered in combination with a sulphonylurea or insulin.

CONTRA-INDICATIONS:

•	Hypersensitivity to metformin hydrochloride or to any of the excipients
•	Diabetic ketoacidosis, diabetic pre-coma, or the history thereof.
•	Impaired proof failure function
•	Pancreatitis
•	Chronic liver disease
•	History of or states associated with lactic acidosis such as shock or pulmonary insufficiency
•	Cardiac failure and recent myocardial infarction
•	Conditions associated with hypoxia
•	Hepatic insufficiency, acute alcohol intoxication, alcoholism
•	Safety in pregnancy and lactation has not been established
•	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 METPHAGE accumulation. Reported cases of lactic acidosis in patients on METPHAGE have occurred primarily in diabetic patients with significant renal failure. The incidence of lactic acidosis can and should he 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.
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, metformin should be discontinued and the patient should be hospitalised immediately.
Renal Function
As METPHAGE is excreted by 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.
The administration of METPHAGE 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, METPHAGE should be discontinued prior to, or at the time of the test and not re-instituted until 48 hours afterwards, and only after renal function has been re-evaluated and found to be normal.
Surgery
METPHAGE should be discontinued 48 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.
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.
-	Although METPHAGE alone never causes hypoglycaemia, caution is advised when it is used in combination with insulin or sulfonylureas.

INTERACTIONS:
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 METPHAGE accumulation and a risk of lactic acidosis. METPHAGE 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.
Glucocarticoids (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-inhibitorsmay 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 METPHAGE has been reported during cimetidine therapy, so a dose reduction should be considered.
Anticoagulants: METPHAGE has been reported to diminish the activity of warfarin and so dose adjustments of METPHAGE should be considered.
Sulphonylurea: Concomitant therapy of METPHAGE with sulphonylurea may cause hypoglycaemia.
Vitamins: Long-term treatment with METPHAGE may cause Vitamin B12 malabsorption in the gastro-intestinal tract, thus a dose reduction of METPHAGE should be considered.

PREGNANCY AND LACTATION
The use of METPHAGE during pregnancy is not advised. There is no information available concerning the safety of METPHAGE during lactation.

DOSAGE AND DIRECTIONS FOR USE:
It is important that METPHAGE tablets be taken in divided doses with meals. Adults: Initially, one 500 mg tablet three times a day, with or after food. After 10 to 15 days the dose should be adjusted, or increased to 850 mg or 1000 mg 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 3 g daily is justified. Once control has been obtained it may be possible to reduce the dosage of METPHAGE.
Children: METPHAGE is not recommended for use in Type I diabetes mellitus.
Elderly: METPHAGE 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:
Haematological:
Less frequent: Megaloblastic anaemia.
Nervous system disorders:
Frequent: Metallic taste.
Gastro-intestinal:
Frequent: Anorexia, nausea, vomiting, diarrhoea, metallic taste
Has been reported but frequency is unknown: Constipation
Genitourinary/Kidney:
Has been reported but frequency is unknown: Ketoacidosis and ketonuria
Liver:
Has been reported but frequency is unknown: Severe cholestatic hepatitis
Other:
Has been requited but frequency is unknown: Hypersensitivity
Less frequent: Hypoglycaemia

Special Precautions:
Lactic acidosis associated with the use of METPHAGE. In patients with a metabolic acidosis and not having evidence of ketoacidosis (ketonuria and ketonaemia), lactic acidosis should he suspected and METPHAGE therapy stopped. Lactic acidosis is a medical emergency, which must be treated in hospital. METPHAGE is excreted by the kidney and regular monitoring of renal function is advised in all diabetics. METPHAGE 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 METPHAGE 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 METPHAGE should have an annual estimation of Vitamin B12levels, since METPHAGE 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 METPHAGE 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 METPHAGE 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 METPHAGE. Treatment is supportive and symptomatic and should be directed at correcting fluid loss and metabolic disturbances.

IDENTIFICATION:
METPHAGE 500 mg: A white to off-white film-coated, shallow round biconvex tablet with A49 embossed on one side.
METPHAGE 850 mg: A white to off-white film-coated, caplet-shaped deep biconvex tablet.

PRESENTATION:
Metphage 500 mg Tablets will be available in the following packaging type:
100's/500's: Securitainers:
The tablets are packed in a white, polypropylene securitainer, together with a white foam insert / rayon and silica gel sachet / desiccant disc. The securitainer is sealed with a white, low density polyethylene (LDPE), closure with a tamper evident seal. A package insert is placed on top of the foam / rayon prior to capping and a label is placed on the securitainer.
Metphage 850 mg Tablets will he available in the following packaging type:
60's/300's: Securitainers:
The tablets are packed in a white, polypropylene securitainer, together with a white foam insert / rayon and silica gel sachet / dessicant disc. The securitainer is sealed with a white, low density polyethylene (LDPE), closure with a tamper evident seal. A package insert is placed on top of the foam / rayon prior to capping and a label is placed on the securitainer.

STORAGE INSTRUCTIONS:
Store below 25ºC in a well-closed contained. Protect from light and moisture. KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER:
METPHAGE 500 MG: A40/21.2/0745
METPHAGE 850 MG: A40/21.2/0746

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Pharmacare Limited
Building 12
Healthcare Park
Woodlands Drive
Woodmead
Sandton
2148

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
05 April 2006

575196/070215

New addition to this site: February 2008
Source: Pharmaceutical Industry
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