Juformin Metformin HCl Tablets

Juformin®

500mg film coated tablets

 

Composition

Each tablet contains Metformin HCl 500mg as the active ingredient.

 

Indications

1. Diet-failed, maturity onset diabetics, especially if over-weight

(A) Alone as initial therapy

(B) Combination therapy with a suphonylurea

2. Adjuvant therapy in insulin-dependent diabetics, especially if overweight.

A reduction of diabetics complications has been shown in overweight type2 diabetic patients treated with Metformin as fist line therapy after diet failure.

 

Dosage and administration

Usual starting dose is 1 tablet 500mg 2 or 3 times given during or after meals.

After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements.

A slow increased dose may improve gastro intestinal tolerability.

 

Normal dosage range

1.5g (1 tab 500mg x 3) a day is often sufficient to obtain diabetic control.
The dose can be increased up to 3g daily.

It important that Juformin tablets should be taken in divided doses with meals. Control may be attained within a few days, but occasionally requires up to ten weeks. Once control has been obtained, it may be possible to reduce the dosage.

 

Contra-indications

Diabetic coma and ketroacidosis. As with all drugs primarily excreted by the kidney, seriously impaired renal function, chronic liver disease, cardiac failure, myocardial infarction, alcoholism, chronic or acute disease states associated with tissue hypoxia.

 

Precautions

Care is advised in cases of renal insufficiency. The use Juformin is not advised in pregnancy, although clinical investigation has revealed no evidence of any teratogenic effect; where decompensation has occurred temporarily as a result of infection, trauma, operation etc conditions that may cause dehydration.

Because of the possibility of hypoglycaemia in combination therapy with a suphonylurea or insulin, diabetic control should be monitored by blood sugar readings.

Recent work has indicated the possibility of an interaction between metformin and certain anticoagulants. Some adjustment of anticoagulant dosage may, therefore, be necessary.

 

Overdose

Hypoglycemia has not been seen with metformin doses of up to 85g.

 

Tolerance

Juformin is well tolerated with only minor, usually transient, gastro-intestinal upsets. These can generally be avoided by taking Juformin with meals, or occasionally by a temporary lowering of the dose. Only in about 3 percent of patients, it is necessary to withdraw Juformin therapy, and it is therefore, important that the treatment is not abandoned at the first sign of intolerance. Usually these upsets have disappeared by the time diabetes is controlled and do not return.

 

Further Information

Does not lower blood sugar in non-diabetics and in diabetics does not cause hypoglyceamia when used alone. (In combination therapy, please see precautions).

Reduces overweight. Lower levels of plasma insulin, cholesterol. triglycerides and pre-B-lipoproteins. Improves glucose assimilation. The few cases of lactic acidosis that have been reported occurred when the use of metformin was contra-indicated.

Patients should be periodically reassessed to ensure the absence of conditions predisposing to lactic acidosis especially in those patients over 60 years of age. Patients should be instructed to discontinue metformin therapy if there is sudden onset of nausea, vomiting, diarrhoea, hyperventilation, deep and rapid breathing, malaise, confusion, abdominal pains and loss of consciousness.

 

Presentation

Juformin is supplied as 500mg tablets in blister pack of 100 as well as tamper proof jars of 100 tablets.

 

Storage

Avoid exposure to sunlight, heat and moisture.

Keep this medicine out of the reach of all children.

 

Manufactured by

JUHEL NIGERIA LIMITED

35 Nkwubor Road, Emene,

Enugu Nigeria.

Osworth Metformin Hydrochloride Tablets

METFORMIN TABLETS (500MG)

An OSWORTH Medical Product

DESCRIPTION

Each tablet contains Metformin hydrochloride; it is an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N, N-demethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. Metformin hydrochloride is a white to off-white crystalline compound with a molecular formula of C4H11N5 HCl and a molecular weight of 165.63. Metformin hydrochloride is freely soluble in water and is practically insoluble in acetone, ether, and chloroform.

 

CLINICAL PHARMACOLOGY

Mechanism of Action

Metformin is an antihyperglycemic agent which improves glucose 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 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.

 

Pharmacokinetics

Absorption and bioavailability

The absolute bioavailability of a Metformin 500mg tablet given under fasting conditions is approximately 50-60%. Studies using single oral doses of Metformin 500mg and 850mg to 2550mg, 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 of a single 850mg tablet of Metformin (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850mg tablet of Metformin with food, compared to the same tablet strength administered fasting. The relevance of these decrease is known.

 

Distribution

The apparent volume of distribution (V/F) of Metformin following single oral doses of Metformin 850mg avecd 654±358L.

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, steady state plasma concentrations of Metformin are within 24-48 hours and are generally < 1ug/ml.

 

Metabolism and Elimination

Intravenous single-dose studies in normal subjects demonstrate that Metformin is excreted 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.

 

INDICATION AND USE

Metformin tablets, as monotherapy, are indicated as an adjunct to diet and exercise to improve glycemic control in patient with type 2 diabetes. Metformin is indicated in patients 10 years of age and older. Metformin may be used concomitantly with a sulfonylurea or insulin to improve glycemic control in adults (17 years of age and older).

 

DOSAGE AND ADMINISTRATION

There is no fixed dosage 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 minimum recommended daily doses. The maximum recommended daily dose of Metformin is 2550mg in adults and 2000mg in pediatric patients (10-16 years of age).

Metformin should be given in divided doses with meals. Metformin 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 (see recommended dosing schedule), 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, either when used as monotherapy or in combination with sulfonylurea 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 patents usually well-controlled on diet alone.

 

Recommended Dosing Schedule

Adults – in general, clinically significant responses are not seen at doses below 1500mg per day. However a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

The usual starting dose of Metformin hydrochloride tablets is 500mg twice a day or 850mg once a day, given with meals. Dosage increases should be made in increments of 500mg weekly or 850mg every 2 weeks, up to a total of 2000mg per day, given in divided doses. Patients can also be titrated from 500mg twice a day to 850mg twice a day after 2 weeks. For those patients requiring additional glycemic control, Metformin may be given to a maximum daily dose of 2550mg per day. Doses above 2000mg may be better tolerated given three times a day with meals.

Pediatrics– The usual starting dose of Metformin is 500mg twice a day, given with meals. Dosage increases should be made in increments of 500mg weekly up to a maximum of 2000mg per day, given in divided doses.

 

Concomitant Metformin and Insulin Therapy in Adult Patients

The current insulin dose should be continued upon initiation of Metformin therapy. Metformin therapy should be initiated at 500mg once daily in patients on insulin therapy. For patients not responding adequately the dose of Metformin should be increased by 500mg after approximately 1 weak and 500mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily close is 2500mg for Metformin. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120mg/dL in patient receiving concomitant insulin and Metformin. Further adjustment should be individualized based on glucose-lowering response.

 

Specific Patient Populations

Metformin is not recommended in use for pregnancy. Metformin is not recommended in patients below the age of 10 years.

The initial and maintenance dosing of Metformin should be conservative in patients with advanced age, due to the potential for decreases renal function in this population. Any dosage adjustment should be base on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of Metformin.

Monitory of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly.

 

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 Cmax 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 make 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 Cmax by 22% and blood AUC by 15%, without any significant change in Metformin renal clearance. When administered with Metformin the Cmax and AUC of furosemide were 31% and 12% smaller, respectively, than when administered alone and the terminal half-life was decreased to 32% without any significant change in furosemide renal clearance. No information is available about the interaction of Metformin and furosemide when co-administrated chronically.

Nifedipine – A single-dose, Metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that co-administration of nifedipine increased plasma Metformin Cmax and AUC by 20%, respectively; and increased the amount excreted in the urine. Tmax and half-life were unaffected. Nifedipine appeared to enhance the absorption of Metformin. Metformin had minimal effect on nifedipine.

Cationic drugs – Cationic drugs (e.g. amiloride, digozin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with Metformin by competing for common renal tubular transport systems. Such interactions 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 and whole blood 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. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of Metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal secretory system.

Other – Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the 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 closely observed for loss of blood glucose control. When such drugs are withdrawn from patient receiving Metformin, the patient should be observed closely for hypoglycemia.

In healthy volunteers, the pharmacokinetics of Metformin and propranolol, and Metformin ibuprofen were not affected when co-administered 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.

 

WARNINGS

Lactic Acidosis

Lactic acidosis is a rare but serious metabolic complication that can occur due to Metformin accumulation during treatment with Metformin, when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions including diabetes mellitus and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap and an increased lactate /pyruvate ratio. When Metformin is indicated as the cause of lactic acidosis Metformin plasma levels >µ5g/ml are generally found.

The reported incidence of lactic acidosis in patients receiving Metformin hydrochloride is very low (approximately 0.03 cases/ 1000 patient years with approximately 0.015 fatal cases/ 1000 patient years). In more than 20,000 patient years exposure to Metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency including both intrinsic and renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/ surgical problems and multiple concomitant medications.

 

PRECAUTION

General

Monitoring of renal function – Metformin is known to be substantially excreted by the kidney and the risk of Metformin accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients with serum creatinine levels above the upper limit of normal for their age should not receive Metformm. In patients with advanced age, Metformin should be carefully titrated to establish the minimum dose for adequate glycemic effect because aging is associated with reduced renal function. In elderly patients particularly those ≥ 80 years of age, renal function should be monitored regularly and, generally Metformin should not be titrated to the minimum dose. Before initiation of Metformin therapy and at least annually thereafter renal function should be assessed and verified as normal. In patient in whom development of renal dysfunction is anticipated renal function should be assessed more frequently and Metformin discontinued if evidence of renal impairment is present.

Use of concomitant medications that may affect renal function or Metformin disposition – Concomitant medication(s) that may affect or result in significant hemodynamic change or may interfere with the disposition of Metformin, such as cationic drugs that are eliminated by renal tubular secretion, should be used with caution.

Radiologic studies involving the use of intravascular iodinated contract materials (for example, intravenous urogram, intravenous cholangiography, and computed tomography (CT) scans with intravascular control materials – Intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and been associated with lactic acidosis in patients receiving Metformin (see CONTRAINDICATIONS). Therefore, in patients in whom any such study is planed, Metformin should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal.

Hypoxic states – Cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia . When such events occur in patients on Metformin therapy, the drug should be promptly discontinued.

Surgical procedures – Metformin therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient’s oral intake has resumed and renal function has been evaluated as normal.

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.

Impaired hepatic function – Since impaired hepatic function has been associated with some cases of lactic acidosis, Metformin should generally be avoided 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 level of previously normal serum vitamin B12 levels, clinical manifestations were observed in approximately 7% of patients. Such decrease, possible 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 with 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 two- to three-year intervals may be useful.

Change in clinical status of patients with previously controlled type 2 diabetes – A patient with type 2 diabetes previously well controlled on Metformin who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis. Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH, lactate, pyruvate, and Metformin levels. If acidosis of either form occurs, Metformin must be stopped immediately and other appropriate corrective measures initiated (see also WARNINGS).

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.

Loss of control of blood glucose – When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary to withhold Metformin and temporarily administer insulin. Metformin may be reinstituted after the acute episode is resolved.

 

Adverse Reactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900mg/kg/day and 1500ng/kg/day respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000mg based on body surface area comparisons. No evidence of carcinogenicity with Metformin was found on either male or female mice. Similarly; there was no tumorigenic potential observed with Metformin in male rats. There was, however, an increased incidence of benign stromal uterine polyps in female rats treated with 900mg/kg/day. There was no evidence of a mutagenic potential of Metformin in the following in vitro tests: Ames test (S. typhimurium), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the in vivo mouse micronucleus tests were also negative. Fertility of male or female rats were unaffected by Metformin when administered at doses as high as 600mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

 

Pregnancy

Teratogenic Effects: Pregnancy Category B

Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, Metformin should not be used during pregnancy unless clearly needed.

There are no adequate and well-controlled studies in pregnant women with Metformin. Metformin was not teratogenic in rats and rabbits at doses up to 600mg/kg/day. This represent an exposure of about two to six times the maximum recommended human daily dose of 2000mg based open body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial barrier to Metformin.

 

Nursing Mothers

Studies in lactating rats show that Metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drugs to the mother. If Metformin is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

 

Pediatric Use

The safety and effectiveness of Metformin for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin in this age group is supported by adequate and well-controlled studies of Metformin in adults with additional data from a controlled clinical study in pediatric patients ages 10 -16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. A maximum daily dose of 2000mg is recommended.

 

Geriatric Use

Controlled clinical studies of Metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients, although other reported clinical experience has not identified differences in responses between the elderly and younger patients. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin should only be used in patient with normal renal function. Because aging is associated with reduced renal function, Metformin should be used with caution as age increases. Care should be taken in doses selection and should be based on careful and regular monitoring of renal function. Generally elderly patients should not be titrated to the maximum dose of Metformin.

 

Symptoms of Overdosage

Hypoglycemia has not been seen even with ingestion of up to 85 grams of Metformin, although lactic acidosis has occurred in such circumstances. Overdose of Metformin hydrochloride has occurred; including ingestion of amounts greater than 50grams.
Hypoglycemia was reported in approximately 10% of cases, but no casual association with Metformin hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of Metformin overdose cases. Metformin is dialyzable with a clearance of up to 170ml/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom Metformin overdose is suspected.

 

Presentation

Each film coated tablet contains Metformin hydrochloride BP 500mg and comes in a pack of 84 tablets.

 

Storage Condition

Store in a cool and dry place.

Keep all Medicines out of reach of Children.

 

Manufactured for

Osworth Nigeria Limited

16, Oshifila Street, Anifowoshe

Ikeja, Lagos.

 

Manufactured by

May & Baker Nigeria Plc

3/5 Sapara Street, Industrial Estate

Ikeja, Lagos.

Aurobindo Metformin Hydrochloride Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

Metformin Tablets BP 500 mg, 850 mg and 1000 mg

Rx Only

 

NAME OF DRUG PRODUCT

Metformin Tablets BP 500 mg, 850 mg and 1000 mg.

 

(TRADE) NAME OF PRODUCT

Metformin Tablets BP 500 mg.

Metformin Tablets BP 850 mg.

Metformin Tablets BP 1000 mg.

 

STRENGTH

500 mg,  850 mg and 1000 mg.

 

PHARMACEUTICAL DOSAGE FORM

Tablet

 

QUALITATIVE AND QUANTITATIVE COMPOSITIONS

Metformin Tablets BP 500 mg

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 500 mg.

 

Metformin Tablets BP 850 mg.

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 850 mg

 

Metformin Tablets BP 1000 mg.

Each film-coated tablet contains:

Metformin Hydrochloride Ph. Eur. 1000 mg.

 

PHARMACEUTICAL FORM

Metformin Tablets BP 500 mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘60’ debossed on the other side.

Metformin Tablets BP 85O mg: White, biconvex, circular shaped film coated tablets with ‘A’ debossed on one side and ‘61’ debossed on the other side.

Metformin Tablets BP 1000 mg: White, biconvex, oval shaped film coated tablets with a scoreline in between ‘6’ and’2’ on one side and ‘A’ debossed on the other side.

 

CLINICAL PARTICULARS

Therapeutic indications

Treatment of type 2 diabetes mellitus, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycaemic control.

In adults, Metformin film-coated tablets may be used as monotherapy or in combination with other oral anti- diabetic agents or with insulin.

In children from 10 years of age and adolescents, Metformin film-coated tablets may be used as monotherapy or in combination with insulin.

A reduction of diabetic complications has been shown in overweight type 2 diabetic adult patients treated with Metformin as first-line therapy after diet failure (Pharmacodynamic properties).

 

Posology and method of administration

The maximum recommended daily dose of Metformin is 3000 mg in adults and 2000 mg in pediatric patients (10-16 years of age). Metformin is not recommended in patients below the age of 10 years. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.

 

Adults

The usual starting dose of metformin hydrochloride tablets is 500 mg twice a day or 850 mg once a day, given with meals. 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. 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 3000 mg per day. Doses above 2000 mg may be better tolerated given three times a day with meals.

Monotherapy and combination with other oral antidiabetic agents:

The usual starting dose is one tablet 2 or 3 times daily given during or after meals.
After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum recommended dose of Metformin is 3000 mg daily.

If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate Metformin at the dose indicated above.

Combination with insulin:

Metformin and insulin may be used in combination therapy to achieve better blood glucose control. Metformin is given at the usual starting dose of one tablet 2-3 times daily, while insulin dosage is adjusted on the basis of blood glucose measurements.

 

Elderly

Due to the potential for decreased renal function in elderly, the Metformin dosage should be djusted based on renal function. Regular assessment of renal function is necessary.

 

Children and adolescents

The usual starting dose of Metformin 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.

Monotherapy and combination with insulin:

Metformin film-coated tablets can be used in children from 10 years of age and adolescents. Metformin is not recommended in patients below the age of 10 years.
After 10 to 15 days the dose should be adjusted on the basis of blood glucose measurements. A slow increase of dose may improve gastrointestinal tolerability. The maximum dose of Metformin is 2 g daily, taken as 2 or 3 divided doses.

 

Pregnancy

Metformin is not recommended for use in pregnancy.

 

Contraindications

– Hypersensitivity to Metformin hydrochloride or to any of the excipients.

– Diabetic ketoacidosis, diabetic pre-coma.

– Renal failure or renal dysfunction (creatinine clearance < 60 ml / min).

– Acute conditions with the potential to function such as dehydration, severe shock, intravascular administration of contrast agents.

– Acute or chronic disease, which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock.

– Hepatic insufficiency, acute alcohol intoxication, alcoholism.

– Lactation.

 

Special warnings and precautions for use

Lactic acidosis

Lactic acidosis is a rare, but serious (high mortality in the absence of prompt treatment), metabolic complication that can occur due to Metformin accumulation. Lactic acidosis on Metformin may occur 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 dyspnea, 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 Metformin is excreted by the 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.

Decreased renal function in elderly 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 an NSAID.

Administration of iodinated contrast agent:

As the intravascular administration of iodinated contrast materials may lead to renal failure, Metformin 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:

Metformin hydrochloride should be discontinued 46 hours before elective surgery with general anaesthesia and should not be usually resumed earlier than 48 hours afterwards.

 

Children and adolescents

The diagnosis of type 2 diabetes mellitus should be confirmed before treatment with Metformin is initiated. A careful follow-up of the effect of Metformin in metformin-treated children, especially pre-pubescent children, is recommended.

Children aged between 10 and 12 years:

Caution is recommended when prescribing to children aged between 10 and 12 years.

 

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.

– Metformin alone never causes hypoglycaemia, although caution is advised when it is used in combination with insulin or sulphonylureas.

 

Interaction with other medicinal products and other forms of interaction

Concomitant use not recommended:

Alcohol

Increased risk of lactic acidiosis 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 Metformin accumulation and a risk of lactic acidosis.

Metformin 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 evaluated and found to be normal.

 

Combinations requiring precautions for use

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.

 

Pregnancy and lactation

When the patient plans to become pregnant and during pregnancy, diabetes should not be treated with Metformin but insulin should be used to maintain blood glucose levels as close to normal as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

 

Effects on ability to drive and use machines

Metformin monotherapy does not cause hpoglycaemia 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 (sulphonylureas, insulin, repaglinide).

 

Undesirable effects

The following undesirable effects may occur under treatment with Metformin.

Frequencies are defined as as follows: very common: >1/10; common >1/100, <1/10; uncommon >1/1000, <1/100; rare >1/10000, <1/1000; very rare <1/10000.

Metabolism and nutritional disorders:

Very rare: Decrease of vitamin B12 absorption with decrease of serum levels during long-term use of Metformin. Consideration of such aetiology is recommended if a patient presents with megaloplastic anaemia.

Very rare: Lactic acidosis

Nervous system disorders:

Common: Taste disturbance

Gastrointestinal disorders:

Very common: Gastrointestinal disorders such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite. These undesirable effects occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent them, it is recommended that Metformin be taken in 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.

Skin and subcutaneous tissue disorders:

Very rare: Skin reactions such as erythema, pruritus, urticaria.

 

Overdosage

Hypoglycaemia may not be seen with Metformin doses of up to 85 g, although lactic acidosis may occur in such circumstances. High overdose or concomitant risks of Metformin may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in hospital. The most effective method to remove lactate and Metformin is haemodialysis.

 

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

Metformin may act via 3 mechanisms:

(1) Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.

(2) In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.

(3) Delay of intestinal glucose absorption.

Metformin stimulates intracellular glycogen synthesis by acting on glycogen synthase.
Metformin increases the transport capacity of all types of membrane glucose transporters (GLUT).

In humans, independently of its action on glycaemia, Metformin has favourable effects on lipid metabolism. Metformin reduces total cholesterol, LDL, chlesterol and triglyceride level.

 

Pharmacokinetic properties

Absorption:

After an oral dose of Metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or 850 mg Metformin tablet is approximately 50-60%. 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 mg/ml.

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 occurs.

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 Vd ranged between 63-276l.

Metabolism:

Metformin is excreted unchanged in the urine.

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.

 

PHARMACEUTICAL PARTICULARS

List of excipients

Povidone, Magnesium stearate, Opadry, and Purified water.

 

Incompatibilities

None known.

 

Shelf life

48 months.

 

Special precautions for storage

Do not store above 30°C.

 

Nature and contents of container

Blister pack:

Metformin Tablets BP 500 mg and 850 mg : Blister of 14 tablets.

Metformin Tablets BP 1000 mg: Blister of 10 tablets.

 

HDPE container pack:

Metformin Tablet BP 500 mg and 850 mg: 100; 400 & 1000 tablets.

Metformin Tablets BP 1000mg : 60, 100 & 500 tablets.

 

MARKETING AUHORISATION HOLDER

Aurobindo Pharma Limited,

Plot NO.: 2, Maitrivihar,

Ameerpet, Hyderabad-500 038

Andhra Pradesh, India.

 

DATE OF PREPARATION OF THIS LEAFLET

February 2009.