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.

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