INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION

Logo FORMINAL 500 (TABLETS)
FORMINAL 850 (TABLETS)

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

FORMINAL 500 (TABLETS)
FORMINAL 850 (TABLETS)

COMPOSITION:
Forminal 500: Each tablet contains
Metformin hydrochloride 500 mg
Forminal 850: Each tablet contains Metformin hydrochloride 850 mg

PHARMACOLOGICAL CLASSIFICATION:
A 21.2 Oral Hypoglycaemics

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, T max is 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 trails, maximum Metformin plasma levels (C
max) did not exceed 4 micrograms/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 L.
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:
FORMINAL
is indicated for:
Type II diabetes mellitus when diet has failed and especially if the patient is overweight. FORMINAL 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 Renal 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 FORMINAL accumulation. Reported cases of lactic acidosis in patients on FORMINAL 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.
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 FORMINAL 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 FORMINAL 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, FORMINAL 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:
FORMINAL
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 FORMINAL 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 medications.
Iodinated contrast agents
Intravascular administration of iodinated contrast agents may lead to renal failure, resulting in FORMINAL accumulation and a risk of lactic acidosis.
FORMINAL 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.
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 FORMINAL has been reported during cimetidine therapy, so a dose reduction should be considered.
Anticoagulants: FORMINAL has been reported to diminish the activity of warfarin, and so dose adjustments of FORMINAL should be considered.
Sulphonylurea: Concomitant therapy of FORMINAL with sulphonylurea may cause hypoglycaemia.
Vitamins: Long-term treatment with FORMINAL may cause vitamin B
12 malabsorption in the gastro-intestinal tract, thus a dose reduction of FORMINAL should be considered.

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

DOSAGE AND DIRECTIONS FOR USE:
It is important that FORMINAL 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 FORMINAL.
Children: FORMINAL is not recommended for use in type 1 diabetes mellitus.
Elderly: FORMINAL 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:
The following side effects may occur with FORMINAL.
Side effects that occur less frequently:
Haematological:       
• Megaloblastic anaemia
Genitourinary/Kidney:
• Ketoacidosis and ketonuria
Liver:
• Severe cholestatic hepatitis
Other:
• Hypersensitivity
• Hypoglycaemia
Side effects that occur more frequently:
Nervous System disorders:
• Metallic taste
Gastro-intestinal:
• Anorexia, nausea, vomiting, constipation, diarrhoea

Special Precautions:
LACTIC ACIDOSIS ASSOCIATED WITH THE USE OF FORMINAL IN PATIENTS WITH A METABOLIC ACIDOSIS AND NOT HAVING EVIDENCE OF KETOACIDOSIS (KETONURIA AND KETONAEMIA), LACTIC ACIDOSIS SHOULD BE SUSPECTED AND FORMINAL THERAPY STOPPED. LACTIC ACIDOSIS IS A MEDICAL EMERGENCY, WHICH MUST BE TREATED IN HOSPITAL. FORMINAL IS EXCRETED BY THE KIDNEY AND REGULAR MONITORING OF RENAL FUNCTION IS ADVISED IN ALL DIABETICS. FORMINAL 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 FUNCTIONS HAS BEEN REGAINED. THE USE OF FORMINAL 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 FORMINAL SHOULD HAVE AN ANNUAL ESTIMATION OF VITAMIN B
12 LEVELS, SINCE FORMINAL MAY CAUSE MALABSORPTION OF VITAMIN B12 WHICH MAY RESULT IN MEGALOBLASTIC ANAEMIA. DURING CONCOMITANT TREATMENT WITH A SULPHONYLUREAS, BLOOD GLUCOSE SHOULD BE MONITORED BECAUSE COMBINED THERAPY MAY CAUSE HYPOGLYCAEMIA. STABILISATION OF DIABETIC PATIENTS WITH FORMINAL 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 FORMINAL 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 FORMINAL. Treatment is supportive and symptomatic and should be directed at correcting fluid loss and metabolic disturbances.       

IDENTIFICATION:
Forminal 500: White to off-white, round, biconvex film-coated tablet, embossed with ‘115’on one side and ‘A’on other side
Forminal 850: White to off-white, round, biconvex film-coated scored tablet, embossed with ‘117’on one side of bisection and ‘A’on other side

PRESENTATION:
Forminal 500:
100 or 500 tablets in a HDPE container with an induction seal wad
100 tablets in PVA/Al blisters packed in unit carton
Forminal 850:
60 or 300 tablets in a HDPE container with an induction seal wad
60 tablets in PVA/Al blisters packed in unit carton

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

REGISTRATION NUMBER (OR REFERENCE NUMBER):
Forminal 500 - A38/21.2/0681
Forminal 850 –A38/21.2/0682

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Gulf Drug Company (Pty) Ltd
22 Burnside Drive
Old Mill Industrial Park
Mount Edgecombe, 4300

DATE OF PUBLICATION OF THE PACKAGE INSERT:
01/12/2006

New addition to this site: July 2010
Source: Pharmaceutical Industry

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