Fortamet Information
Fortamet (Metformin) Description
Fortamet (Metformin) (metformin hydrochloride) Extended-Release Tablets contain an oral antihyperglycemic drug used in the management of type 2 diabetes. Metformin hydrochloride (N, N-dimethylimidodicarbonimidic diamide hydrochloride) is a member of the biguanide class of oral antihyperglycemics and is not chemically or pharmacologically related to any other class of oral antihyperglycemic agents. The empirical formula of metformin hydrochloride is CHN•HCl and its molecular weight is 165.63. Its structural formula is:
Metformin hydrochloride is a white to off-white crystalline powder that is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Fortamet (Metformin) Extended-Release Tablets are designed for once-a-day oral administration and deliver 500 mg or 1000 mg of metformin hydrochloride. In addition to the active ingredient metformin hydrochloride, each tablet contains the following inactive ingredients: candellila wax, cellulose acetate, hypromellose, magnesium stearate, polyethylene glycols (PEG 400, PEG 8000), polysorbate 80, povidone, sodium lauryl sulfate, synthetic black iron oxides, titanium dioxide, and triacetin.
Fortamet (Metformin) meets USP Dissolution Test 5.
Fortamet (Metformin) System Components And Performance
Fortamet (Metformin) was developed as an extended-release formulation of metformin hydrochloride and designed for once-a-day oral administration using the patented single-composition osmotic technology (SCOT™). The tablet is similar in appearance to other film-coated oral administered tablets but it consists of an osmotically active core formulation that is surrounded by a semipermeable membrane. Two laser drilled exit ports exist in the membrane, one on either side of the tablet. The core formulation is composed primarily of drug with small concentrations of excipients. The semipermeable membrane is permeable to water but not to higher molecular weight components of biological fluids. Upon ingestion, water is taken up through the membrane, which in turn dissolves the drug and excipients in the core formulation. The dissolved drug and excipients exit through the laser drilled ports in the membrane. The rate of drug delivery is constant and dependent upon the maintenance of a constant osmotic gradient across the membrane. This situation exists so long as there is undissolved drug present in the core tablet. Following the dissolution of the core materials, the rate of drug delivery slowly decreases until the osmotic gradient across the membrane falls to zero at which time delivery ceases. The membrane coating remains intact during the transit of the dosage form through the gastrointestinal tract and is excreted in the feces.
Fortamet (Metformin) Clinical Studies
In a double-blind, randomized, active-controlled, multicenter U.S. clinical study, which compared Fortamet (Metformin) q.d. to immediate-release metformin b.i.d., 680 patients with type 2 diabetes who had been taking metformin-containing medication at study entry were randomly assigned in equal numbers to double-blind treatment with either Fortamet (Metformin) or immediate-release metformin. Doses were adjusted during the first six weeks of treatment with study medication based on patients' FPG levels and were then held constant over a period of 20 weeks. The primary efficacy endpoint was the change in HbA from baseline to endpoint. The primary objective was to demonstrate the clinical non-inferiority of Fortamet (Metformin) compared to immediate-release metformin on the primary endpoint.
Fortamet (Metformin) and metformin patients had mean HbA changes from baseline to endpoint equal to +0.40 and +0.14, respectively (). The least-square (LS) mean treatment difference was 0.25 (95% CI = 0.14, 0.37) demonstrating that Fortamet (Metformin) was clinically similar to metformin according to the pre-defined criterion to establish efficacy.
Footnote: Patients were taking metformin-containing medications at baseline that were prescribed by their personal physician.
The mean changes for FPG () and plasma insulin () were small for both Fortamet (Metformin) and immediate-release metformin, and were not clinically meaningful. Seventy-six (22%) and 49 (14%) of the Fortamet (Metformin) and immediate-release patients, respectively, discontinued prematurely from the trial. Eighteen (5%) patients on Fortamet (Metformin) withdrew because of a stated lack of efficacy, as compared with 8 patients (2%) on immediate-release metformin (p=0.047).
Results from this study also indicated that neither Fortamet (Metformin) nor immediate-release metformin were associated with weight gain or increases in body mass index.
A 24-week, double blind, placebo-controlled study of immediate-release metformin plus insulin, versus insulin plus placebo, was conducted in patients with type 2 diabetes who failed to achieve adequate glycemic control on insulin alone (). Patients randomized to receive immediate-release metformin plus insulin achieved a reduction in HbA of 2.10%, compared to a 1.56% reduction in HbA achieved by insulin plus placebo. The improvement in glycemic control was achieved at the final study visit with 16% less insulin, 93.0 U/day versus 110.6 U/day, immediate-release metformin plus insulin versus insulin plus placebo, respectively, p=0.04.
A second double-blind, placebo-controlled study (n=51), with 16 weeks of randomized treatment, demonstrated that in patients with type 2 diabetes controlled on insulin for 8 weeks with an average HbA of 7.46 ± 0.97%, the addition of immediate-release metformin maintained similar glycemic control (HbA 7.15 ± 0.61 versus 6.97 ± 0.62 for immediate-release metformin plus insulin and placebo plus insulin, respectively) with 19% less insulin versus baseline (reduction of 23.68 ± 30.22 versus an increase of 0.43 ± 25.20 units for immediate-release metformin plus insulin and placebo plus insulin, p
Fortamet (Metformin) Indications And Usage
Fortamet (Metformin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
Fortamet (Metformin) Contraindications
Fortamet (Metformin) is contraindicated in patients with:
Fortamet (Metformin) should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials, because use of such products may result in acute alteration of renal function (see also ).
Fortamet (Metformin) Precautions
Patients should be informed of the potential risks and benefits of Fortamet (Metformin) and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose, glycosylated hemoglobin, renal function, and hematologic parameters.
The risks of lactic acidosis, its symptoms, and conditions that predispose to its development, as noted in the and sections, should be explained to patients. Patients should be advised to discontinue Fortamet (Metformin) immediately and to promptly notify their health practitioner if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur. Once a patient is stabilized on any dose level of Fortamet (Metformin) , gastrointestinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
Patients should be counseled against excessive alcohol intake, either acute or chronic, while receiving Fortamet (Metformin) .
Fortamet (Metformin) alone does not usually cause hypoglycemia, although it may occur when Fortamet (Metformin) is used in conjunction with oral sulfonylureas and insulin. When initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members (see Printed Below).
Patients should be informed that Fortamet (Metformin) must be swallowed whole and not chewed, cut, or crushed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet (see ).
Response to all diabetic therapies should be monitored by periodic measurements of fasting blood glucose and glycosylated hemoglobin levels, with a goal of decreasing these levels toward the normal range. During initial dose titration, fasting glucose can be used to determine the therapeutic response. Thereafter, both glucose and glycosylated hemoglobin should be monitored. Measurements of glycosylated hemoglobin may be especially useful for evaluating long-term control (see also ).
Initial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocrit and red blood cell indices) and renal function (serum creatinine) should be performed, at least on an annual basis. While megaloblastic anemia has rarely been seen with immediate-release metformin therapy, if this is suspected, Vitamin B deficiency should be excluded.
Long-term carcinogenicity studies with metformin have been performed in rats (dosing duration of 104 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 based on body surface area comparisons. No evidence of carcinogenicity with metformin was found in 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 900 mg/kg/day.
There was no evidence of mutagenic potential of metformin in the following tests: Ames test (), gene mutation test (mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes). Results in the mouse micronucleus test were also negative.
Fertility of male or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.
No pediatric clinical studies have been conducted with Fortamet (Metformin) . The safety and effectiveness of immediate-release 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 immediate-release metformin in this age group is supported by evidence from adequate and well-controlled studies of immediate-release 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 (see ). In this study, adverse effects were similar to those described in adults (see ). A maximum daily dose of 2000 mg of immediate-release metformin is recommended.
The safety and efficacy of Fortamet (Metformin) has not been evaluated in pediatric patients.
Of the 389 patients who received Fortamet (Metformin) in controlled Phase III clinical studies, 26.5% [103/389] were 65 years and older. No overall differences in effectiveness or safety were observed between these patients and younger patients.
Controlled clinical studies of immediate-release 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 of the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, immediate-release metformin should only be used in patients with normal renal function (see , , and ). Because aging is associated with reduced renal function, immediate-release metformin should be used with caution as age increases. Care should be taken in dose 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 immediate-release metformin (see also and ).
Fortamet (Metformin) Adverse Reactions
In the controlled clinical studies of Fortamet (Metformin) in patients with type 2 diabetes, a total of 424 patients received Fortamet (Metformin) therapy (up to 2500 mg/day) and 430 patients received immediate-release metformin. Adverse reactions reported in ≥5% of the Fortamet (Metformin) or immediate-release metformin patients are listed in . These pooled results show that the most frequently reported adverse reactions in the Fortamet (Metformin) group were infection, diarrhea, and nausea. Similar incidences of these adverse reactions were seen in the immediate-release metformin group.
The most frequent adverse events thought to be related to Fortamet (Metformin) were diarrhea, nausea, dyspepsia, flatulence, and abdominal pain. The frequency of dyspepsia was 4.2% in the Fortamet (Metformin) group compared to 5.1% in the immediate-release group, the frequency of flatulence was 3.5% in the Fortamet (Metformin) group compared to 3.7% in the immediate-release group, and the frequency of abdominal pain was 3.3% in the Fortamet (Metformin) group compared to 4.4% in the immediate-release group.
In the controlled studies, 4.7% of patients treated with Fortamet (Metformin) and 4.9% of patients treated with immediate-release metformin were discontinued due to adverse events.
Fortamet (Metformin) Overdosage
Hypoglycemia has not been seen even with ingestion of up to 85 grams of immediate-release metformin, although lactic acidosis has occurred in such circumstances (see ). Metformin is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions. Therefore, hemodialysis may be useful for removal of accumulated drug from patients in whom metformin over-dosage is suspected.
Fortamet (Metformin) Dosage And Administration
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with Fortamet (Metformin) or any other pharmacologic agent. Dosage of Fortamet (Metformin) must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily dose. The maximum recommended daily dose of Fortamet (Metformin) Extended-Release Tablets in adults is 2500 mg.
Fortamet (Metformin) should be taken with a full glass of water once daily with the evening meal. Fortamet (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 ), fasting plasma glucose should be used to determine the therapeutic response to Fortamet (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 Fortamet (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 Fortamet (Metformin) may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Fortamet (Metformin) How Supplied
Fortamet (Metformin) (metformin hydrochloride) Extended-Release Tablets are supplied as biconvex-shaped, film-coated extended-release tablets containing 500 mg or 1000 mg of metformin hydrochloride.
NDC 59630-574-60: 500 mg extended-release, white-colored tablets imprinted with Andrx logo and 574 on one side: bottles of 60.
NDC 59630-575-60: 1000 mg extended-release, white-colored tablets imprinted with Andrx logo and 575 on one side: bottles of 60.
Fortamet (Metformin)
Fortamet (Metformin)
Fortamet (Metformin) Principal Display Panel - Mg Tablet Bottle Label
Fortamet (Metformin) Principal Display Panel - Mg Tablet Bottle Label
