Fornidd/Fornidd XR

Fornidd/Fornidd XR

metformin

Manufacturer:

sanofi-aventis

Distributor:

Metro Drug
Full Prescribing Info
Contents
Metformin HCl.
Description
Fornidd: Each film-coated tablet contains: Metformin Hydrochloride 500 mg.
Fornidd XR: Each uncoated extended release tablet contains: Metformin Hydrochloride 500 mg and 1 g, respectively.
Metformin Hydrochloride (Fornidd XR) extended release tablets USP is an oral antihyperglycemic drug used in the management of type 2 diabetes.
The chemical name is N,N-dimethylimdodicarbonimidic diamide hydrochloride.
The empirical formula is C4H11N5 HCl and the molecular is 165.63.
Action
Pharmacotherapeutic Group: Oral Antidiabetics. ATC Code: A10BA02: Gastrointestinal tract and metabolism.
Pharmacology: Pharmacodynamics: Fornidd: Metformin is a biguanide with antihyperglycemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycemia.
Metformin may act via 3 mechanisms: Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis; in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization; and 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 on its action on glycemia, metformin has favorable effects on lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: Metformin reduces total cholesterol, LDL cholesterol and triglyceride levels (GLUT).
Clinical efficacy: The prospective randomized (UKPDS) study has established the long-term benefit of intensive blood glucose control in type 2 diabetes.
Analysis of the results for overweight patients treated with metformin after failure of diet alone showed: A significant reduction of the absolute risk of any diabetes-related complication in the metformin group (29.8 events/1,000 patient-years) versus diet alone (43.3 events/1,000 patient-years), p=0.0023, and versus the combined sulfonylurea and insulin monotherapy groups (40.1 events/1,000 patient-years), p=0.0034.
A significant reduction of the absolute risk of diabetes-related mortality: Metformin 7.5 events/1,000 patient-years, diet alone 12.7 events/1,000 years, p=0.017.
A significant reduction of the absolute risk of overall mortality: Metformin 13.5 events/1,000 patient-years versus diet alone 20.6 events/1,000 patient-years (p=0.011), and versus the combined sulfonylurea and insulin monotherapy groups 18.9 events/1,000 patient-years (p=0.021).
A significant reduction in the absolute risk of myocardial infarction: Metformin 11 events/1,000 patient-years, diet alone 18 events/1,000 patient life years (p=0.01).
For metformin used as 2nd-line therapy, in combination with a sulfonylurea, benefit regarding clinical outcome has not been shown.
In type 1 diabetes, the combination of metformin and insulin has been used in selected patients, but the clinical benefit of this combination has not yet been formally established.
Fornidd XR: Metformin HCl is an antihyperglycemic agent which improves glucose tolerance in non-insulin-dependent diabetes mellitus (NIDDM) (type 2 diabetes mellitus) subjects, lowering both basal and postprandial plasma glucose. Its pharmacological mechanisms of action are different from those of sulfonylureas.
Metformin decreases hepatic glucose production and improves insulin sensitivity (increases peripheral glucose uptake and utilization). Unlike sulfonylureas, metformin does not produce hypoglycemia in either diabetic or nondiabetic subjects, and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin levels may actually decrease.
Pharmacokinetics: Fornidd: Absorption: After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a metformin 500 mg or 850 mg tablet is approximately 50-60% in healthy subjects. After an oral dose, the non-absorbed fraction recovered in feces was 20-30%. After oral administration, metformin absorption is saturable and incomplete. It is assumed that 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 μg/mL. In controlled clinical trials, maximum metformin plasma levels (Cmax) did not exceed 4 μg/mL, even at maximum doses. Food decreases the extent and slightly delays the absorption of metformin. Following administration of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC (area under the curve) and a 35 minute prolongation of time to peak plasma concentration were observed. The clinical relevance of these decreases is unknown.
Distribution: Plasma protein binding is negligible. Metformin partitions into erythrocytes. The blood peak is lower than the plasma peak and appears approximately the same time. The red blood cells most likely represent a secondary compartment of distribution. The mean Vd ranged between 63-276 L.
Metabolism: Metformin is excreted unchanged in the urine. No metabolites have been identified in humans.
Elimination: Renal clearance of metformin is >400 mL/min, indicating that metformin is eliminated by glomerular filtration and tubular secretion. Following an oral dose, the apparent terminal elimination half-life is approximately 6.5 hours. When renal function is impaired, renal clearance is decreased in proportion to that of creatinine and thus the elimination half-life is prolonged, leading to increased levels of metformin in the plasma.
Fornidd XR: Following a single oral dose of sustained release Metformin, Cmax is achieved with a median value of 7 hours and a range of 4 hours to 8 hours. After repeated administration of a sustained-release formulation, Metformin does not accumulate in plasma. Although the extent of absorption of sustained-release Metformin increased by approximately 50% when given with food, there is no effect of food on Cmax and Tmax of Metformin.
The apparent volume of distribution (V/F) of Metformin following single oral dose of 850 mg is 654±358 L. Metformin is negligibly bound to plasma proteins. At usual clinical dosed and dosing schedules, steady state plasma concentrations of Metformin are reached within 24-48 hours and are generally <1 mg/mL.
Metformin is excreted unchanged in the urine, and does not undergo hepatic metabolism or 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 4.18 hours.
Absorption and Bioavailability: Following a single oral dose of sustained release metformin, Cmax is achieved with a median value of 7 hours and a range of 4 to 8 hours. After repeated administration of a sustained-release formulation, metformin does not accumulate in plasma. Although the extent of absorption of sustained-release metformin increased by approximately 50% when given with food, there is no effect of food on Cmax and Tmax of metformin.
Distribution: The apparent volume of distribution (V/F) of Metformin following single oral dose of 850 mg is 654±358 L. Metformin is negligibly bound to plasma proteins. At usual clinical doses and dosing schedules, steady-state plasma concentrations of metformin are reached within 24-48 hours and are generally <1 mg/mL.
Metabolism and Elimination: Metformin is excreted unchanged in the urine, and does not undergo hepatic metabolism or 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 4.18 hours.
Special Populations: Patients with type 2 diabetes and Gender: There are no reported differences in pharmacokinetics of Metformin Hydrochloride between patients with type 2 diabetes and normal subjects when analyzed according to gender.
Renal insufficiency: In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of Metformin hydrochloride is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance. This increased level may lead to condition of lactic acidosis.
Hepatic insufficiency: No pharmacokinetic studies of Metformin Hydrochloride have been conducted in patients with hepatic insufficiency.
Geriatrics: Reported data from controlled pharmacokinetic studies of Metformin Hydrochloride in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged and Cmax is increased, compared to healthy young subjects. From this data, it appears that the change in Metformin Hydrochloride pharmacokinetics with aging is primarily accounted for by a change in renal function.
Pediatrics: No pharmacokinetic studies of Hydrochloride in pediatric patients have been conducted.
Toxicology: Fornidd: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies on safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity reproduction.
Fornidd XR: Long-term carcinogenicity studies are performed with Metformin alone in rats (dosing duration of 140 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day respectively. These doses are both approximately four times the maximum recommended human daily dose of 2000 mg of Metformin. No evidence of carcinogenicity with Metformin was found in either male or female mice.
Similarly, there is no tumorigenic potential observed in male rats. There was however an increases incidence of benign stromal uterine polyps in female rats treated with 900 mg/kg/days of Metformin.
There was no evidence of mutagenic potential 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 micronucleus test were also negative.
Fertility of male and female rats was unaffected at doses as high as 600 mg/kg/day approximately three time the maximum recommended human daily dose. Metformin was not teratogenic in rats or rabbits at doses up to 600 mg/kg/day.
Indications/Uses
Treatment of type 2 diabetes mellitus in adults, particularly in overweight patients, when dietary management and exercise alone does not result in adequate glycemic control. Metformin may be used as monotherapy or in combination with other oral antidiabetic agents, or with insulin. A reduction of diabetic complications has been shown in overweight type 2 diabetic patients treated with metformin as first-line therapy after diet failure (see Pharmacology: Pharmacodynamics under Actions).
Dosage/Direction for Use
Fornidd: 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 3 g daily.
If transfer from another oral antidiabetic agent is intended: discontinue the other agent and initiate metformin at the dose indicated previously.
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 the elderly subjects, the metformin dosage should be adjusted based on renal function. Regular assessment of renal function is necessary (see Precautions).
Children: In the absence of data, Metformin should not be used in children.
Renal impairment: A GFR should be assessed before initiation of treatment with metformin-containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.
The maximum daily dose of metformin should preferably be divided into 2-3 daily doses. Factors that may increase the risk of lactic acidosis (see Precautions) should be reviewed before considering initiation of metformin in patients with GFR <60 mL/min. (See table.)

Click on icon to see table/diagram/image

Fornidd XR: Dosage of Metformin Hydrochloride must be individualized on the basis of both effectiveness and tolerance in patients. The maximum recommended daily dose of 2000 mg should not be exceeded.
The drug should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal adverse 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 the drug 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.
Short-term administration of the drug may be sufficient during periods of transient loss of blood glucose control in patients usually well-controlled on diet alone.
The usual starting dose of Metformin Hydrochloride (Fornidd XR) is 500 mg once daily with the evening meal. Dosage increase should be made in increments of 500 mg weekly, up to a maximum of 2,000 mg once daily with the evening meal. If glycemic control is not achieved on 2000 mg once daily, trial of 1000 mg twice daily should be considered.
Administration: The tablet should be swallowed whole and not to be chewed. The tablet should be taken after meals.
Overdosage
Hypoglycemia has not been seen with metformin doses of up to 85 g, although lactic acidosis has occurred 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 the hospital. The most effective method to remove lactate and metformin is hemodialysis.
Fornidd: Pancreatitis may occur in the context of metformin overdose.
Fornidd XR: Hemodialysis may be useful for the removal of accumulated drug from the patients in whom Metformin hydrochloride overdosage is suspected.
Contraindications
Hypersensitivity to metformin HCl or to any of the excipients of Fornidd/Fornidd XR.
Fornidd: Diabetic ketoacidosis and precoma; renal failure or dysfunction (e.g., serum creatinine levels >135 μmol/L in males and >110 μmol/L in females); acute conditions with the potential to alter renal function such as dehydration, severe infection, shock, intravascular administration of iodinated contrast agents (see Precautions); 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; any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis); severe renal failure (GFR <30 mL/min).
Fornidd XR: Renal or hepatic failure, alcoholism, NIDDM complicated by severe ketosis and acidosis, diabetic precoma and coma, undergoing surgery, after severe trauma or during infections, chronic obstructive pulmonary disease, coronary heart disease, cardiac failure, peripheral vascular disease, hypoglycemia, pregnancy.
Warnings
Lactic acidosis is a rare, but serious metabolic complication that can occur due to Metformin Hydrochloride accumulation. The reported incidence of lactic acidosis during Metformin Hydrochloride treatment is less than 0.1 case per 1000 patient-years, and the mortality risk is even lower.
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis, the drug should be discontinued immediately and general supportive measures promptly instituted.
Special Precautions
Fornidd: Lactic acidosis: Metformin accumulation occurs at acute worsening of renal function and increases the risk of lactic acidosis.
In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be temporarily discontinued and contact with a health care professional is recommended.
Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lactic acidosis are excessive alcohol intake, hepatic insufficiency, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products that may cause lactic acidosis (see Contraindications and Interactions).
Patients and/or care-givers should be informed of the risk of lactic acidosis. In case of suspected symptoms, the patients should stop taking metformin and seek immediate medical attention.
Diagnostic laboratory findings are decreased blood pH (<7.35), increased plasma lactate levels (>5 mmol/l) and an increased anion gap and lactate/pyruvate ratio.
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; and at least two to four times a year in patients with serum creatinine levels at the upper limit of normal and in elderly subjects. Decreased renal function in elderly subjects is frequent and asymptomatic.
Special caution should be exercised in situations where renal function may become impaired, for example when initiating antihypertensive or diuretic therapy and when starting therapy with an NSAID.
GRF should be assessed before treatment initiation and regularly thereafter, see Dosage & Administration. Metformin is contraindicated in patients with GFR <30 mL/min and should be temporarily discontinued in the presence of conditions that alter renal function, see Contraindications.
Administration of iodinated contrast agent: Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy, resulting in metformin accumulation and an increased risk of lactic acidosis.
Metformin should be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see Dosage & Administration and Interactions.
Surgery: Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia.
Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutrition and provided that renal function has been re-evaluated and found to be stable.
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 hypoglycemia, although caution is advised when it is used in combination with insulin or sulfonylureas.
Regular monitoring of thyroid-stimulating hormone (TSH) levels is recommended in patients with hypothyroidism (see Adverse Reactions).
Long-term treatment with metformin has been associated with a decrease in vitamin B12 serum levels which may cause peripheral neuropathy. Monitoring of the vitamin B12 levels is recommended (see Adverse Reactions).
Effects on the Ability to Drive and Use Machines: Metformin monotherapy does not cause hypoglycemia and therefore, has no effect on the ability to drive or to use machines. However, patients should be alerted to the risk of hypoglycemia when metformin is used in combination with other antidiabetic agents (sulfonylureas, insulin, repaglinide).
Fornidd XR: Adjust dose according to blood glucose levels during the first few months.
Lactation: Studies have not been conducted in nursing mothers, but caution should be exercised in such patients, and a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Use in Children: Safety and effectiveness in children has not been established.
Use in Elderly: As aging is associated with reduced renal function, care should be taken in dose selection and should be based on careful and regular monitoring of renal functions.
Use In Pregnancy & Lactation
Fornidd: To date, no relevant epidemiological data are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal or fetal development, parturition or postnatal development (see Pharmacology: Toxicology: Preclinical Safety Data under Actions). 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 as to normal as possible in order to lower the risk of fetal malformations associated with abnormal blood glucose levels.
Metformin is excreted into milk in lactating rats. Similar data is not available in humans and a decision should be made whether to discontinue nursing or discontinue metformin, taking into account the importance of the compound to the mother.
Fornidd XR: Lactation: Studies have not been conducted in nursing mothers, but caution should be exercised in such patients, and a decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Fornidd: Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain and loss of appetite (>10%) are very common: these occur most frequently during initiation of therapy and resolve spontaneously in most cases. To prevent these gastrointestinal symptoms, it is recommended that metformin be taken 2 or 3 daily doses during or after meals. A slow increase of the dose may also improve gastrointestinal tolerability.
Metallic taste (3%) is common.
Mild erythema has been reported in some hypersensitive individuals. The incidence of such effects is regarded as very rare (<0.01%).
A decrease of vitamin B12 absorption with decrease of serum levels has been observed in patients treated long-term with metformin and appears generally to be without clinical significance (<0.01%).
Lactic acidosis (0.03 cases/1000 patients-years) is very rare (see Warnings and Precautions).
Blood and lymphatic system disorders: Not known: Reduction of thyrotropin level in patients with hypothyroidism, hypomagnesemia in the context of diarrhea.
Nervous system disorder: Not known: Encephalopathy.
Skin and subcutaneous tissue disorders: Not known: Photosensitivity.
Metabolism and Nutrition disorders: Cases of peripheral neuropathy in patients with vitamin B12 deficiency have been reported in post-marketing experience (frequency not known) (see Warnings and Precautions).
Fornidd XR: Gastrointestinal disturbances: Nausea, diarrhea, gastric pain, constipation, vomiting, metallic taste in mouth.
Dermatological Effects: Rash, pruritus, urticaria, erythema and flushing.
Miscellaneous: Headache and dizziness. Impaired gastrointestinal absorption of vitamin B12 and folic acid has been associated with long-term Metformin Hydrochloride therapy.
However, if such symptoms occur, consult with the physician or pharmacist.
Drug Interactions
Fornidd: Concomitant use not recommended: Alcohol: Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.
Iodinated contrast agents: Metformin must be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see Dosage & Administration and Precautions.
Combinations requiring precautions for use: Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using such products in combination with metformin, close monitoring of renal function is necessary.
Others: Metformin may decrease the anticoagulant effect of phenprocoumon. Therefore, a close monitoring of the INR is recommended.
Levothyroxine can reduce the hypoglycemic effect of metformin. Monitoring of blood glucose levels is recommended, especially when thyroid hormone therapy is initiated or stopped, and the dosage of metformin must be adjusted if necessary.
Fornidd XR: Drug interactions of Metformin Hydrochloride is seen with phenprocoumon, hyperglycemic agents (e.g. thiazides, corticosteroids), alcohol, furosemide, nifedipine and cationic drugs (amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, cimetidine and vancomycin). Acarbose and guar gum may reduce the absorption of Metformin hydrochloride.
Storage
Fornidd: Store at temperatures not exceeding 30°C.
Fornidd XR: Store at temperatures not exceeding 25°C. Protect from light and moisture.
MIMS Class
ATC Classification
A10BA02 - metformin ; Belongs to the class of biguanides. Used in the treatment of diabetes.
Presentation/Packing
Fornidd: Tab 500 mg x 100's.
Fornidd XR: Tab 500 mg x 100's. 1 g x 100's.
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