Read all of this leaflet carefully before you start taking this

medicine because it contains important information for you.

* Keep this leaflet. You may need to read it again.

* If you have any further questions, ask your doctor or

pharmacist.

* This medicine has been prescribed for you only.

Do not pass it on to others. It may harm them, even if their

signs of illness are the same as yours.

* If you get any side effects talk to your doctor or pharmacist.

This includes any possible side effects not listed in this leaflet.

See section 4.

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Metformin hydrochloride 850mg, 1000mg

1-DESCRIPTION:

FORTAMET

is an uncoated, round white color tablet.

2-COMPOSITION:

Each tablet contains 850mg of Metformin Hydrochloride.

Each tablet contains 1000mg of Metformin Hydrochloride.

Excipients: Starch, sodium starch glycolate, Polyvinylpyrrolidone

(PVK30), magnesium stearate, sodium benzoate.

3-THERAPEUTIC INDICATIONS

FORTAMET

(metformin hydrochloride) tablet is indicated as an

adjunct to diet and exercise to improve glycemic control in adults

and children with type 2 diabetes mellitus.

4-PHARMACOLOGICAL PROPERTIES

Mechanism of action

Metformin is an antihyperglycemic agent which improves glucose

tolerance in patients with type 2 diabetes, lowering both basal and

postprandial plasma glucose. Its pharmacologic mechanisms of

action are different from other classes of oral antihyperglycemic

agents. Metformin decreases hepatic glucose production,

decreases intestinal absorption of glucose, and improves insulin

sensitivity by increasing peripheral glucose uptake and utilization.

Unlike sulfonylureas, metformin does not produce hypoglycemia in

either patients with type 2 diabetes or normal subjects (except in

special circumstances, see PRECAUTIONS) and does not cause

hyperinsulinemia. With metformin therapy, insulin secretion

remains unchanged while fasting insulin levels and day-long

plasma insulin response may actually decrease.

5-PHARMACOKINETICS

Absorption

The absolute bioavailability of a metformin hydrochloride 500 mg

tablet given under fasting conditions is approximately 50-60%.

Studies using single oral doses of metformin hydrochloride tablets,

of 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there

is a lack of dose proportionality with increasing doses, which is due

to decreased absorption rather than an alteration in elimination.

Food decreases the extent of and slightly delays the absorption of

metformin, as shown by approximately a 40% lower mean peak

plasma concentration (Cmax), a 25% lower area under the plasma

concentration ) versus time curve (AUC), and a 35 minute

prolongation of time to peak plasma concentration (T following

administration of a single 850 mg tablet of metformin with food,

compared to the same tablet strength administered fasting. The

clinical relevance of these decreases is unknown.

Distribution

The apparent volume of distribution (V/F) of metformin following

single oral doses of 850 mg averaged 654 ± 358 L. Metformin is

negligibly bound to plasma proteins in contrast to sulfonylureas

which are more than 90% protein bound. Metformin partitions into

erythrocytes, most likely as a function of time. At usual clinical doses

and dosing schedules of metformin hydrochloride tablets, steady

state plasma concentrations of metformin are reached within

24-48 hours and are generally < 1 µg/mL. During controlled clinical

trials of metformin, maximum metformin plasma levels did not

exceed 5 µg/mL, even at maximum doses.

Metabolism and Excretion

Intravenous single-dose studies in normal subjects demonstrate

that metformin is excreted unchanged in the urine and does not

undergo hepatic metabolism (no metabolites have been identified

in humans) nor biliary excretion. Renal clearance is approximately

3.5 times greater than creatinine clearance which indicates that

tubular secretion is the major route of metformin elimination.

Following oral administration, approximately 90% of the absorbed

drug is eliminated via the renal route within the first 24 hours, with a

plasma elimination half-life of approximately 6.2 hours. In blood, the

elimination half-life is approximately 17.6 hours, suggesting that the

erythrocyte mass may be a compartment of distribution.

6-CONTRAINDICATIONS

FORTAMET

is contraindicated in the following situations:

• Severe renal impairment (eGFR below 30 mL/min/1.73 m2).

• Known hypersensitivity to metformin hydrochloride.

• Acute or chronic metabolic acidosis, including diabetic

ketoacidosis, with or without coma. Diabetic ketoacidosis should be

treated with insulin.

7-POSOLOGY

There is no fixed dosage regimen for the management of

hyperglycemia in patients with type 2 diabetes with metformin or

any other pharmacologic agent. Dosage of metformin must be

individualized on the basis of both effectiveness and tolerance,

while not exceeding the maximum recommended daily dose. The

maximum recommended daily dose of metformin hydrochloride

tablets, is 2550 mg in adults and 2000 mg in pediatric patients (10-16

years of age).

Metformin should be given in divided doses with meals and should

be started at a low dose, with gradual dose escalation, both to

reduce gastrointestinal side effects and to permit identification of

the minimum dose required for adequate glycemic control of the

patient. During treatment initiation and dose titration, fasting

plasma glucose should be used to determine the therapeutic

response to metformin and identify the minimum effective dose for

the patient. Thereafter, glycosylated hemoglobin should be

measured at intervals of approximately three months.

The therapeutic goal should be to decrease both fasting plasma

glucose and glycosylated hemoglobin levels to normal or near

normal by using the lowest effective dose of metformin hydrochlo-

ride tablets, either when used as monotherapy or in combination

with sulfonylureas or insulin. Monitoring of blood glucose and

glycosylated hemoglobin will also permit detection of primary

failure, i.e., inadequate lowering of blood glucose at the maximum

recommended dose of medication, and secondary failure, i.e., loss

of an adequate blood glucose lowering response after an initial

period of effectiveness. Short-term administration of metformin

may be sufficient during periods of transient loss of control in

patients usually well-controlled on diet alone.

Recommended dosing schedule

Adults —The usual starting dose of metformin hydrochloride

tablets, is 500 mg twice a day or 850 mg once a day, given with

meals. In general, clinically significant responses are not seen at

doses below 1500 mg per day. Dosage increases should be made in

increments of 500 mg weekly or 850 mg every 2 weeks, up to a total

of 2000 mg per day, given in divided doses. The dosage of

metformin hydrochloride tablets, must be individualized on the

basis of both effectiveness and tolerability. Patients can also be

titrated from 500 mg twice a day to 850 mg twice a day after 2

weeks. For those patients requiring additional glycemic control,

metformin may be given to a maximum daily dose of 2550 mg per

day. Doses above 2000 mg may be better tolerated given three

times a day with meals.

Pediatrics—The usual starting dose of metformin hydrochloride

tablets, is 500 mg twice a day, given with meals. Dosage increases

should be made in increments of 500 mg weekly up to a maximum

of 2000 mg per day, given in divided doses. The dosage of

metformin must be individualized on the basis of both

effectiveness and tolerability.

Use in renal impairment Assess renal function prior to initiation of

metformin and periodically thereafter. Metformin is contraindicat-

ed in patients with an estimated glomerular filtration rate (eGFR)

below 30 mL/min/1.73 m. Initiation of metformin in patients with an

eGFR between 30 – 45 mL/min/1.73 m is not recommended. In

patients taking metformin whose eGFR later falls below 45

mL/min/1.73 m, assess the benefit risk of continuing therapy.

Discontinue metformin if the patient’s eGFR later falls below 30

mL/min/1.73 m.

Discontinuation for Iodinated Contrast Imaging Procedures

Discontinue metformin at the time of, or prior to, an iodinated

contrast imaging procedure in patients with an eGFR between 30

and 60 mL/min/1.73 m2; in patients with a history of liver disease,

alcoholism, or heart failure; or in patients who will be administered

intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after

the imaging procedure; restart metformin if renal function is stable.

Concomitant Metformin Hydrochloride Tablets, and Oral

Sulfonylurea Therapy in Adult Patients

If patients have not responded to four weeks of the maximum dose

of metformin hydrochloride tablets, monotherapy, consideration

should be given to gradual addition of an oral sulfonylurea while

continuing metformin hydrochloride tablets, at the maximum dose,

even if prior primary or secondary failure to a sulfonylurea has

occurred. Clinical and pharmacokinetic drug-drug interaction data

are currently available only for metformin plus glyburide

(glibenclamide). With concomitant metformin hydrochloride

tablets, and sulfonylurea therapy, the desired control of blood

glucose may be obtained by adjusting the dose of each drug. In a

clinical trial of patients with type 2 diabetes and prior failure on

glyburide, patients started on metformin 500 mg and glyburide 20

mg were titrated to 1000/20 mg, 1500/20 mg, 2000/20 mg or 2500/20

mg of metformin and glyburide, respectively, to reach the goal of

glycemic control as measured by FPG, HbA and plasma glucose

response. However, attempts should be made to identify the

minimum effective dose of each drug to achieve this goal. With

concomitant metformin hydrochloride tablets, and sulfonylurea

therapy, the risk of hypoglycemia associated with sulfonylurea

therapy continues and may be increased. Appropriate precautions

should be taken. If patients have not satisfactorily responded to

one to three months of concomitant therapy with the maximum

dose of metformin and the maximum dose of an oral sulfonylurea,

consider therapeutic alternatives including switching to insulin with

or without metformin hydrochloride tablets.

Concomitant Metformin Hydrochloride Tablets, and Insulin

Therapy in Adult Patients

The current insulin dose should be continued upon initiation of

metformin hydrochloride tablets therapy. Metformin hydrochloride

tablets, therapy should be initiated at 500 mg once daily in patients

on insulin therapy. For patients not responding adequately, the

dose of metformin hydrochloride tablets, should be increased by

500 mg after approximately 1 week and by 500 mg every week

thereafter until adequate glycemic control is achieved. The

maximum recommended daily dose is 2500 mg for metformin

hydrochloride tablets. It is recommended that the insulin dose be

decreased by 10% to 25% when fasting plasma glucose concentra-

tions decrease to less than 120 mg/dL in patients receiving

concomitant insulin and metformin hydrochloride tablets. Further

adjustment should be individualized based on glucose-lowering

response.

8-WARNINGS

9-PRECAUTIONS

General

Lactic acidosis—There have been postmarketing cases of

metformin-associated lactic acidosis, including fatal cases. These

cases had a subtle onset and were accompanied by nonspecific

symptoms such as malaise, myalgias, abdominal pain, respiratory

distress, or increased somnolence; however, hypotension and

resistant bradyarrhythmia have occurred with severe acidosis.

Metformin-associated lactic acidosis was characterized by

elevated blood lactate concentrations (>5 mmol/L), anion gap

acidosis (without evidence of ketonuria or ketonemia), and an

increased lactate: pyruvate ratio; metformin plasma levels were

generally >5 mcg/mL. Metformin decreases liver uptake of lactate

increasing lactate blood levels which may increase the risk of lactic

acidosis, especially in patients at risk. If metformin-associated

lactic acidosis is suspected, general supportive measures should

be instituted promptly in a hospital setting, along with immediate

discontinuation of metformin. In metformin treated patients with a

diagnosis or strong suspicion of lactic acidosis, prompt hemodialy-

sis is recommended to correct the acidosis and remove

accumulated metformin (metformin hydrochloride is dialyzable

with a clearance of up to 170 mL/min under good hemodynamic

conditions). Hemodialysis has often resulted in reversal of

symptoms and recovery.

Educate patients and their families about the symptoms of lactic

acidosis and, if these symptoms occur, instruct them to discontinue

metformin and report these symptoms to their healthcare provider.

For each of the known and possible risk factors for metformin-asso-

ciated lactic acidosis, recommendations to reduce the risk of and

manage metformin-associated lactic acidosis are provided below:

• Renal impairment—The postmarketing metformin-associated

lactic acidosis cases primarily occurred in patients with significant

renal impairment.

The risk of metformin accumulation and metformin-associated

lactic acidosis increases with the severity of renal impairment

because metformin is substantially excreted by the kidney. Clinical

recommendations based upon the patient’s renal function include:

• Before initiating metformin, obtain an estimated glomerular

filtration rate (eGFR)

• Metformin is contraindicated in patients with an eGFR less than 30

mL/min/1.73 m2.

• Initiation of metformin is not recommended in patients with eGFR

between 30-45 mL/min/1.73 m2.

• Obtain an eGFR at least annually in all patients taking metformin.

In patients at risk for the development of renal impairment (e.g., the

elderly), renal function should be assessed more frequently.

• In patients taking metformin whose eGFR falls below 45

mL/min/1.73 m2, assess the benefit and risk of continuing therapy.

• Drug interactions—The concomitant use of metformin with

specific drugs may increase the risk of metformin-associated

lactic acidosis: those that impair renal function, result in significant

hemodynamic change, interfere with acid-base balance, or

increase metformin accumulation. Consider more frequent

monitoring of patients.

• Age 65 or greater—The risk of metformin-associated lactic

acidosis increases with the patient’s age because elderly patients

have a greater likelihood of having hepatic, renal, or cardiac

impairment than younger patients. Assess renal function more

frequently in elderly patients.

• Radiologic studies with contrast—Administration of intravascular

iodinated contrast agents in metformin-treated patients has led to

an acute decrease in renal function and the occurrence of lactic

acidosis. Stop metformin at the time of, or prior to, an iodinated

contrast imaging procedure in patients with an eGFR between 30

and 60 mL/min/1.73 m2; in patients with a history of hepatic

impairment, alcoholism or heart failure; or in patients who will be

administered intra-arterial iodinated contrast. Re-evaluate eGFR 48

hours after the imaging procedure, and restart metformin if renal

function is stable.

• Surgery and other procedures—Withholding of food and fluids

during surgical or other procedures may increase the risk for

volume depletion, hypotension, and renal impairment. Metformin

should be temporarily discontinued while patients have restricted

food and fluid intake.

• Hypoxic states—Several of the postmarketing cases of

metformin-associated lactic acidosis occurred in the setting of

acute congestive heart failure (particularly when accompanied by

hypoperfusion and hypoxemia). Cardiovascular collapse (shock),

acute myocardial infarction, sepsis, and other conditions

associated with hypoxemia have been associated with lactic

acidosis and may cause prerenal azotemia. When such an event

occurs, discontinue metformin.

• Excessive alcohol intake—Alcohol is known to potentiate the effect

of metformin on lactate metabolism. Patients, therefore, should be

warned against excessive alcohol intake, acute or chronic, while

receiving metformin.

• Hepatic impairment—Patients with hepatic impairment have

developed cases of metformin associated lactic acidosis. This may

be due to impaired lactate clearance resulting in higher lactate

blood levels. Therefore, avoid use of metformin in patients with

clinical or laboratory evidence of hepatic disease.

Vitamin B12 levels—In controlled clinical trials of metformin of 29

weeks duration, a decrease to subnormal levels of previously

normal serum vitamin B12 levels, without clinical manifestations,

was observed in approximately 7% of patients. Such decrease,

possibly due to interference with B12 absorption from the

B12-intrinsic factor complex, is, however, very rarely associated with

anemia and appears to be rapidly reversible with discontinuation

of metformin or vitamin B12 supplementation. Measurement of

hematologic parameters on an annual basis is advised in patients

on metformin and any apparent abnormalities should be

appropriately investigated and managed.

Certain individuals (those with inadequate vitamin B12 or calcium

intake or absorption) appear to be predisposed to developing

subnormal vitamin B12 levels. In these patients, routine serum

vitamin B12 measurements at 2- to 3-year intervals may be useful.

Hypoglycemia—Hypoglycemia does not occur in patients receiving

metformin alone under usual circumstances of use, but could

occur when caloric intake is deficient, when strenuous exercise is

not compensated by caloric supplementation, or during

concomitant use with other glucose-lowering agents (such as

sulfonylureas and insulin) or ethanol.

Elderly, debilitated, or malnourished patients, and those with

adrenal or pituitary insufficiency or alcohol intoxication are

particularly susceptible to hypoglycemic effects. Hypoglycemia

may be difficult to recognize in the elderly, and in people who are

taking beta-adrenergic blocking drugs. Macrovascular

outcomes—There have been no clinical studies establishing

conclusive evidence of macrovascular risk reduction with

metformin or any other antidiabetic drug.

10-SPECIFIC PATIENT POPULATIONS

Metformin is not recommended for use in pregnancy.

Metformin hydrochloride tablets, are not recommended in patients

below the age of 10 years.

The initial and maintenance dosing of metformin hydrochloride

tablets, should be conservative in patients with advanced age, due

to the potential for decreased renal function in this population. Any

dosage adjustment should be based on a careful assessment of

renal function.

11-DRUG INTERACTIONS

Glyburide— In a single-dose interaction study in type 2 diabetes

patients, co-administration of metformin and glyburide did not

result in any changes in either metformin pharmacokinetics or

pharmacodynamics.

Decreases in glyburide AUC and C were observed, but were highly

variable. The single-dose nature of this study and the lack of

correlation between glyburide blood levels and pharmacodynamic

effects, makes the clinical significance of this interaction uncertain.

Furosemide— A single-dose, metformin-furosemide drug

interaction study in healthy subjects demonstrated that

pharmacokinetic parameters of both compounds were affected

by coadministration. Furosemide increased the metformin plasma

and blood C by 22% and blood AUC by 15%, without any significant

change in metformin renal clearance. When administered with

metformin, the C and AUC of furosemide were 31% and 12% smaller,

respectively, than when administered alone, and the terminal

half-life was decreased by 32%, without any significant change in

furosemide renal clearance. No information is available about the

interaction of metformin and furosemide when co-administered

chronically.

Nifedipine— A single-dose, metformin-nifedipine drug interaction

study in normal healthy volunteers demonstrated that co

-administration of nifedipine increased plasma metformin C and

AUC by 20% and 9%, respectively, and increased the amount

excreted in the urine. T and half-life were unaffected. Nifedipine

appears to enhance the absorption of metformin. Metformin had

minimal effects on nifedipine.

Drugs that reduce metformin clearance- Concomitant use of

drugs that interfere with common renal tubular transport systems

involved in the renal elimination of metformin (e.g., organic cationic

transporter-2 [OCT2] / multidrug and toxin extrusion [MATE]

inhibitors such as ranolazine, vandetanib, dolutegravir, and

cimetidine) could increase systemic exposure to metformin and

may increase the risk for lactic acidosis. Consider the benefits and

risks of concomitant use. Such interaction between metformin and

oral cimetidine has been observed in normal healthy volunteers in

both single- and multiple-dose, metformin-cimetidine drug

interaction studies, with a 60% increase in peak metformin plasma

and whole blood concentrations and a 40% increase in plasma and

whole blood metformin AUC.

There was no change in elimination half-life in the single-dose

study. Metformin had no effect on cimetidine pharmacokinetics.

In healthy volunteers, the pharmacokinetics of metformin and

propranolol, and metformin and ibuprofen were not affected when

coadministered in single-dose interaction studies.

Metformin is negligibly bound to plasma proteins and is, therefore,

less likely to interact with highly protein-bound drugs such as

salicylates, sulfonamides, chloramphenicol, and probenecid, as

compared to the sulfonylureas, which are extensively bound to

serum proteins.

Other— Certain drugs tend to produce hyperglycemia and may

lead to loss of glycemic control. These drugs include thiazides and

other diuretics, corticosteroids, phenothiazines, thyroid products,

estrogens, oral contraceptives, phenytoin, nicotinic acid,

sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving

metformin, the patient should be observed closely for loss of blood

glucose control. When such drugs are withdrawn from a patient

receiving metformin, the patient should be observed closely for

hypoglycemia.

Carbonic anhydrase inhibitors– Topiramate or other carbonic

anhydrase inhibitors (e.g., zonisamide, acetazolamide or

dichlorphenamide) frequently cause a decrease in serum

bicarbonate and induce nonanion gap, hyperchloremic metabolic

acidosis. Concomitant use of these drugs with metformin may

increase the risk for lactic acidosis. Consider more frequent

monitoring of these patients.

Alcohol– Alcohol is known to potentiate the effect of metformin on

lactate metabolism. Warn patients against excessive alcohol

intake while receiving metformin.

12-ADVERSE REACTIONS

Lactic Acidosis: See WARNINGS, PRECAUTIONS, and OVERDOSAGE

Sections.

Gastrointestinal Reactions: Gastrointestinal symptoms (diarrhea,

nausea, vomiting, abdominal bloating, flatulence, and anorexia)

are the most common reactions to METFORMIN and are

approximately 30 % more frequent in patients on METFORMIN

monotherapy than in placebo-treated patients, particularly during

initiation of METFORMIN therapy. These symptoms are generally

transient and resolve spontaneously during continued treatment.

Occasionally, temporary dose reduction may be useful. Because

gastrointestinal symptoms during therapy initiation appear to be

dose-related, they may be decreased by gradual dose escalation

and by having patients take METFORMIN (metformin HCl) with meals

(. Because significant diarrhea and/or vomiting can cause

dehydration and prerenal azotemia, METFORMIN should be

temporarily discontinued, under such circumstances. For patients

who have been stabilized on METFORMIN, nonspecific gastrointesti-

nal symptoms should not be attributed to therapy unless

intercurrent illness or lactic acidosis have been excluded.

Special Senses: During initiation of METFORMIN therapy,

approximately 3 % patient may complain of an unpleasant or

metallic taste, which usually resolves spontaneously.

Dermatologic Reactions: The incidence of rash/dermatitis in

controlled clinical trials was comparable to placebo for metformin

monotherapy and to sulfonylurea for metformin /sulfonylurea

therapy.

Hematologic: During controlled clinical trials of 29 weeks duration,

approximately 9 % of patients on metformin HCl monotherapy and

6 % of patients on metformin HCl sulfonylurea therapy developed

asymptomatic subnormal serum vitamin B12 levels; serum folic

acid levels did not decrease significantly. However, only five cases

of megaloblastic anemia have been reported with metformin

administration (none during U.S. clinical studies) and no increased

incidence of neuropathy has been observed. Therefore, serum

vitamin B12 levels should be appropriately monitored or periodic

parenteral B12 supplementation considered.

13-OVERDOSAGE

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 diarrhea, drowsiness,

weakness, dizziness, malaise and headache might be seen. Should

those symptoms persist, lactic acidosis should be excluded. The

drug should be discontinued and proper supportive therapy

instituted.

Hypoglycemia has not been seen even with ingestion of up to 85

grams of metformin, although lactic acidosis has occurred in such

circumstances (see WARNINGS). Metformin is dialysable with a

clearance of up to 170 mL/min under good hemodynamic

conditions. Therefore, hemodialysis may be useful for removal of

accumulated drug from patients in whom metformin overdosage

is suspected.

14-STORAGE CONDITIONS

Keep this medicine out of the sight and reach of children

Store below 30

°C

Keep your medicine in a cool dry place and away from light in the

original package to protect it from moisture

Don’t use this medicine after the expiry date which is stated on the

outer packaging. The expiry date refers to the last day of that

month.

Don’t use this medicine if you notice any visible signs of

deterioration.

Don’t throw away any medicines via wastewater. Ask your

pharmacist how to throw away medicines you no longer use. These

measures will help protect the environment.

Manufacturer and Marketing Authorization Holder:

Date of Revision: March 5, 2026