DATA SHEET

METFORMIN GENERIC HEALTH

Metformin hydrochloride 500mg and 850mg tablets
This product is may not be interchangeable with other products containing this ingredient
in the New Zealand Market.

Presentation
Metformin Generic Health tablets, 500mg: White to off white, round, bevelled edged
biconvex film coated tablets with 500 embossed on one side. Available in blister packs of
100 tablets.
Metformin Generic Health tablets, 850mg: White to off white, round, bevelled edged
biconvex film coated tablets with 850 embossed on one side. Available in blister packs of
60 tablets.

Uses
Actions
Metformin is a biguanide derivative producing an antihyperglycaemic effect in man only
when there is insulin secretion. It causes hypoglycaemia only when used at a near lethal
dose. Metformin has no effect on pancreatic beta cells. The mode of action of metformin is
not fully understood. It has been postulated that it might potentiate the effects of insulin or
that it might enhance the effect of insulin on peripheral receptor sites. This increased
sensitivity seems to follow an increase in the number of insulin receptors on cell surface
membranes. Other possible modes of action include inhibition of glucogenesis in the liver
and delay in glucose absorption from the gastrointestinal tract.
Metformin may also lower levels of VLD-lipoprotein cholesterol and total cholesterol.

Pharmacokinetics
Metformin absorption is relatively slow from the gastrointestinal tract with 50-60% being
absorbed and may extend over about 6 hours. It is thought that absorption decreases as
the dose increases. The drug is excreted in urine at a high renal clearance rate of about
450 mL/min. The initial elimination of metformin is rapid, with a half-life varying between
1.7 and 3 hours. It is not bound to plasma proteins. The terminal elimination phase
accounting for about 4 to 5% of the absorbed dose is slow with a half-life between 9 and

17 hours. Metformin is not metabolized. The main sites of concentration are the intestinal
mucosa and the salivary glands. The plasma concentration at steady state ranges from
about 1 to 2mcg/mL. In patients with significantly decreased renal function the plasma halflife of metformin is prolonged and renal clearance is decreased.

Indications
To control hyperglycaemia in metformin responsive, stable, mild, non-ketosis prone,
maturity onset type of diabetes (Type II) which cannot be controlled by proper dietary
management, exercise and weight reduction or when insulin therapy is not appropriate. It
may be used alone or in combination with sulphonylurea therapy.
Metformin can be of value for the treatment of obese diabetics.
It may also be used as adjuvant therapy in insulin-dependent diabetics especially if they
are overweight.

Dosage and Administration

Life threatening lactic acidosis can occur due to accumulation of metformin. Risk
factors include renal impairment, old age and doses of metformin above 2 g per day
(see Warnings and Precautions).
It is important that the tablets are taken in divided doses with meals.
Monotherapy and combination with other oral antidiabetic agents in adults with
normal renal function
Initially 500 mg should be taken once or twice a day and, if necessary, increased over a
few weeks up to a maximum of 1 g three times per day. The dose should be titrated with
gradual dose increments until the desired effect is obtained. A dose of 500 mg three times
a day is often sufficient to obtain diabetic control. Control may be attained within a few
days but occasionally requires up to two weeks. Once control has been obtained, the
dosage should be reviewed and reduced to the lowest maintenance level consistent with
good diabetic control.
The maximum dose of 3 g daily should only be used in patients with good renal function (ie
creatinine clearance greater than 120mL/min).
The action of Metformin is progressive and no final assessment of the patient's real
response should be made before the 21st day of treatment; blood sugar estimations are
recommended during the initial 15 days of stabilisation. Metformin will not produce a
hypoglycaemic state when used alone, however, it increases insulin effectiveness
Combination with insulin or sulphonylureas in adults
Metformin therapy with a sulphonylurea or insulin should be monitored by blood-sugar
readings because combined therapy may cause hypoglycaemia. If it is decided to stabilise
diabetic patients with metformin and insulin therapy, it is recommended that this is carried
out in hospital until the correct ratio of the two medicines is determined because of the
possibility of hypoglycaemia.

Elderly
The initial and maintenance dosing of metformin should be conservative in elderly patients,
due to the potential for decreased renal function in this population. Any dosage adjustment
should be based on a careful assessment of renal function. Generally, elderly patients
should not be titrated to the maximum dose of metformin.
Renal Impairment
The risk of lactic acidosis is increased in patients with renal impairment. Metformin is
contraindicated in patients with renal failure (creatinine clearance <15mL/min).(see
contraindications).
Metformin may be used in patients with stable renal impairment (but see warnings and
precautions). Where possible the dose should be titrated with gradual dose increments.
The maximum daily dose for patients with creatinine clearance between 15-30mL/min is
500mg.
The maximum daily dose for patients with creatinine clearance between 30-60mL/min is
1000mg.
The maximum daily dose for patients with creatinine clearance between 60-120mL/min is
2000mg.
It is recommended that metformin concentrations are checked after steady state has been
reached (after 48 hours) to ensure metformin concentrations remain below 5g/mL
(5mg/L).
Renal function should be closely monitored (every 3-6 months).
If the creatinine clearance drops below 15mL/min metformin must be discontinued.
Debilitated or malnourished patients
The dosing should be conservative and based on a careful assessment of renal function.
Children
Metformin is not recommended for use in children.

Contraindications
Metformin is contraindicated in the following conditions:

Juvenile diabetes mellitus that is uncomplicated and well regulated on insulin

Diabetes mellitus regulated by diet alone
During or immediately following surgery where insulin is essential
Hypersensitivity to metformin hydrochloride and other biguanides, or to any of the
excipients
Diabetic ketoacidosis, diabetic precoma
Renal failure (creatinine clearance <15 mL/minute),patients with unstable renal
function

Acute conditions with the potential to alter renal function such as dehydration,
severe infection, shock, intravascular administration of iodinated contrast agents
(see Warnings and Precautions)
Acute conditions which may cause tissue hypoxia such as cardiac failure, recent
myocardial infarction, respiratory failure, pulmonary embolism, acute significant
blood loss, sepsis, gangrene, pancreatitis
Severe hepatic insufficiency, acute alcohol intoxication, alcoholism
History of lactic acidosis
Lactation.

Warnings and Precautions

Lactic acidosis
Lactic acidosis is a rare but serious metabolic complication which can occur due to
metformin accumulation during treatment. When it occurs, it is fatal in more than 25% of
cases. Lactic acidosis is a medical emergency and must be treated in hospital
immediately.
The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's
age. Reported cases have occurred primarily in diabetic patients with acute conditions
causing a significant decrease in renal function or tissue hypoxia (see contraindications)
Hepatic dysfunction is also a risk as lactate clearance is reduced (see contraindications).
Patients with long-term stable conditions should be carefully assessed prior to treatment
for risk factors for lactic acidosis such as: poorly controlled diabetes, ketosis, prolonged
fasting, excessive alcohol intake, hepatic insufficiency and conditions associated with
hypoxia (see contraindications).
Particular caution should be paid in situations where renal function may become impaired
such as dehydration, when starting therapy with a diuretic or when starting therapy with a
non-steroidal anti-inflammatory drug (NSAID). In these situations metformin should be
temporarily discontinued.
When metformin is implicated as the cause of lactic acidosis, metformin plasma levels
greater than 5 g/mL (5mg/L) are generally found (see Pharmacokinetics).
Diagnosis
The risk of lactic acidosis must be considered in the event of non-specific signs such as
malaise, myalgia, muscle cramps, respiratory distress, increasing somnolence and nonspecific abdominal distress.
Patients should be instructed to notify these signs to their physician immediately.
As lactic acidosis progresses there may be associated hypothermia, hypotension and
resistant bradyarrhythmias with more marked acidosis This can be followed by acidotic
dyspnoea, and coma . Lactic acidosis is characterised by acidosis (decreased blood pH),
elevated lactate levels above 5mmol/L with increased lactate/pyruvate ratio and electrolyte
disturbances with an increased anion gap. If there is any suspicion of metabolic/lactic
acidosis metformin should be discontinued and the patient hospitalised immediately.

Prompt haemodialysis is recommended to correct the acidosis and remove accumulated

metformin (see overdose).
Renal Impairment
Underlying renal disease, or a deterioration in renal function, result in reduced clearance of
metformin and drug accumulation and are therefore major risk factors in lactic acidosis
(see Dosage and Administration). Creatinine clearance (this can be estimated from serum
creatinine levels by using the Cockcroft-Gault formula) should be determined before
initiating treatment and regularly thereafter:

At least annually in patients with normal renal function

At least twice a year in patients with impaired renal function and elderly patients

Decreased renal function in elderly subjects is frequent and asymptomatic.

Metformin therapy should be temporarily stopped in the presence of any condition
associated with hypoxaemia or dehydration, in patients suffering from serious infections or
trauma (particularly if gastrointestinal disturbances are noted or acidosis is suspected) and
in those undergoing surgery.
Prompt haemodialysis is recommended to correct the acidosis and remove accumulated
metformin (see Overdose)
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 an NSAID.
Metformin is contraindicated in patients with creatinine clearance below 15ml/min.
Hepatic Impairment
Impaired hepatic function may significantly limit the ability to clear lactate. Metformin
should be avoided in patients with severe hepatic insufficiency (see contraindications) and
used with caution in patients with milder disease.
Use in the elderly
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 when the issues raised
under Contraindications and Warning and Precautions have been taken into consideration,
the dosage is frequently reviewed and the renal function is closely monitored.
Heart Failure
Type 2 diabetic patients with heart failure are at an increased risk of hypoperfusion and
possible renal insufficiency. Careful monitoring of renal function is recommended when
metformin is used in patients with cardiac failure.
Administration of iodinated contrast media
Radiological studies involving the use of intravascular iodinated contrast materials (for
example intravenous urogram, intravenous cholangiography, angiography, any computed
tomography scans with intravascular contrast materials) can lead to acute alteration of
renal function and have been associated with lactic acidosis in patients receiving
metformin. Therefore, metformin should be stopped at least 48 hours prior to, during and
for 2 days after the radiological studies. For an emergency procedure, metformin should

be stopped on admission. Metformin should be reinstated only after renal function has
been re-evaluated and found to be normal.
Surgery
Metformin must be discontinued 48 hours before elective surgery under general, spinal or
peridural anaesthesia. Therapy may be restarted no earlier than 48 hours following
surgery or resumption of oral nutrition and only if normal renal function has been
established.
Alcohol
Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients
should therefore be warned against excessive alcohol intake, acute or chronic, while
taking metformin.
Other precautions
Periodic assessment of renal, hepatic and cardiovascular function is recommended during
prolonged periods of treatment with metformin.
Patients receiving continuous metformin therapy should have an annual estimation of
vitamin B12 levels because of reports of decreased vitamin B12 absorption.
Effects on ability to drive and use machines
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 agents

Use in Pregnancy and Lactation

Category C. It is recommended that insulin be used during pregnancy to maintain blood
glucose levels as close to normal as possible.
Metformin was not teratogenic in rats and rabbits at doses of up to 600mg/kg/day.
Determination of foetal concentrations has shown a partial placental barrier to metformin.
However because animal studies are not always predictive of human response, the use of
metformin during pregnancy is not recommended.
Studies in lactating rats show that metformin is excreted into milk and reached levels
comparable to those in plasma. Similar studies have not been conducted in nursing
mothers but caution should be exercised in such patients and a decision made whether to
continue nursing or to continue administering metformin taking into account the importance
of metformin to the mother.

Adverse Effects
Gastrointestinal disorders
Very common: Mild gastrointestinal symptoms (such as diarrhoea, nausea, vomiting, loss
of appetite) are the most frequent reactions to metformin (> 1/10), especially during the
initial treatment period. These symptoms are generally transient and resolve
spontaneously during continued treatment.

Gastrointestinal side effects can possibly be avoided if metformin is taken with meals and
if the dose is increased slowly. Occasionally, a temporary dose reduction can be
considered.
However occurrence of gastrointestinal symptoms, once a patient is stabilised on any dose
of metformin, could be due to lactic acidosis or other serious disease.
Metabolism and nutrition disorders
Very rare. Lactic acidosis (see Warnings and Precautions) is a very rare (< 1/10,000) but
serious metabolic complication that can occur due to metformin accumulation during
treatment
A decrease of vitamin B12 absorption with a decrease in serum levels has been observed
in patients treated long-term with metformin.
Skin and subcutaneous tissue disorders
Very rare: Mild erythema, pruritus and urticaria have been reported in some hypersensitive
individuals.
Nervous system disorders
Common Metallic taste (3%).
Hepatobiliary disorders
Very rare: Isolated reports of liver function test abnormalities or hepatitis resolving upon
metformin discontinuation.

Interactions
Certain drugs may potentiate the effect of metformin, particularly sulphonylurea type drugs
used in the treatment of diabetes. Administration of these two types of drugs could
produce a hypoglycaemic reaction, especially if they are given in patients already receiving
other drugs such as long-acting sulphonamides, tuberculostatics, phenylbutazone,
clofibrate, monoamine oxidase inhibitors, salicylates, probenecid and propranolol, which
may potentiate the hypoglycaemic effect of the sulphonylurea.
Other drugs produce hyperglycaemia and may lead to a loss of blood sugar control. These
include diuretics (thiazides, furosemide), corticosteroids, oral contraceptives (oestrogen
plus progestogen), thyroid products and nicotinic acid in pharmacologic doses.
Elimination rate of the anticoagulant, phenprocumon, may increase by 20% when used
concurrently with metformin. Patients receiving phenprocumon or other vitamin K
anticoagulants should be monitored. An increase of prothrombin time may occur upon
cessation of metformin therapy, with an increased risk of haemorrhage.
Cationic drugs e.g. amiloride, digoxin, morphine, procainamide, quinidine, quinine,
ranitidine, triamterene, trimethoprim and vancomycin that are excreted by renal tubular
secretion theoretically have the potential for interaction with metformin by competing for
common renal tubular transport systems. Such an interaction has been noted with the coadministration of cimetidine with metformin leading to reduced renal clearance of
metformin, and therefore increased plasma metformin concentrations. Dose reductions
should be considered in patients on cimetidine treatment.

Patients should be warned against using alcohol in excess while on metformin therapy
since it may mask the outward signs of hypoglycaemia. Alcohol in a diabetic subject may
cause an elevation of blood lactate. The combined effects of hypoglycaemia and the CNS
depressant effect of alcohol may reduce the patient's ability to drive a motor vehicle and/or
operate machinery.
Concomitant therapy with -blockers may mask the external signs of hypoglycaemia e.g.
tachycardia.

Overdosage
Symptoms:
Available information concerning treatment of a massive overdosage of metformin is very
limited. It would be expected that adverse reactions of a more intense character including
epigastric discomfort, nausea and vomiting followed by diarrhoea, drowsiness, weakness,
dizziness, malaise and headache may be seen. Should these symptoms persist, lactic
acidosis should be excluded. Hypoglycaemia has not been seen even with ingestion of up
to 85g metformin although lactic acidosis has occurred in such circumstances.
Hypoglycaemia may occur if excessive amounts of metformin are taken with a
sulphonylurea, insulin or alcohol.
Treatment:
Metformin should be discontinued and proper supportive therapy instituted. Metformin is
dialysable with a clearance of up to 170mL/min under good haemodynamic conditions.
Therefore haemodialysis may be useful for the removal of accumulated drug from patients
in whom metformin overdose is suspected.

Storage
Store below 30C. Protect from heat, light and moisture.
Keep container tightly closed.

Medicine Classification
Prescription Only Medicine

Package Quantities
METFORMIN GENERIC HEALTH 500mg tablets:
Blister packs of 100 tablets.

METFORMIN GENERIC HEALTH 850mg tablets:

Blister packs of 60 tablets.

Supplier
Douglas Pharmaceuticals Limited,
P O Box 45 027,
Lincoln,
Auckland 0651
Telephone: (09) 835 0660

Date of Preparation
18 July 2015