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TABLETS, USP · Blenheim Pharmacal, Inc.
Dosage Form
TABLETS, USP
Manufacturer
Blenheim Pharmacal, Inc.
This medication contains important usage instructions, warnings, and side effect information that you should review before use.
Metformin HCl extended-release tablets, USP are indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
There is no fixed dosage regimen for the management of hyperglycemia in patients with type 2 diabetes with metformin HCl extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin HCl extended-release tablets, USP must be individualized on the basis of both effectiveness and tolerance, while not exceeding the maximum recommended daily doses. The maximum recommended daily dose of metformin HCl extended-release tablets, USP in adults is 2000 mg.
Metformin HCl extended-release tablets, USP should generally be given once daily with the evening meal. Metformin HCl extended-release tablets, USP 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 HCl extended-release tablets, USP 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 HCl extended-release tablets, USP, 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 HCl extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Metformin HCl extended-release tablets, USP must be swallowed whole and never crushed or chewed. Occasionally, the inactive ingredients of metformin HCl extended-release tablets, USP will be eliminated in the feces as a soft, hydrated mass. (See Patient Information printed below.)
Recommended Dosing Schedule
Adults - In general, clinically significant responses are not seen at doses below 1500 mg per day. However, a lower recommended starting dose and gradually increased dosage is advised to minimize gastrointestinal symptoms.
The usual starting dose of metformin HCl extended-release tablets, USP is 500 mg once daily with the evening meal. Dosage increases should be made in increments of 500 mg weekly, up to a maximum of 2000 mg once daily with the evening meal. If glycemic control is not achieved on metformin HCl extended-release tablets, USP 2000 mg once daily, a trial of metformin HCl extended-release tablets, USP 1000 mg twice daily should be considered. (See CLINICAL PHARMACOLOGY, Clinical Studies .)
Pediatrics - Safety and effectiveness of metformin HCl extended-release tablets, USP in pediatric patients have not been established.
Transfer From Other Antidiabetic Therapy
When transferring patients from standard oral hypoglycemic agents other than chlorpropamide to metformin HCl extended-release tablets, USP, no transition period generally is necessary. When transferring patients from chlorpropamide, care should be exercised during the first two weeks because of the prolonged retention of chlorpropamide in the body, leading to overlapping drug effects and possible hypoglycemia.
Concomitant Metformin HCl Extended-Release Tablets, USP and Oral Sulfonylurea Therapy in Adult Patients
If patients have not responded to four weeks of the maximum dose of metformin HCl extended-release tablets, USP monotherapy, consideration should be given to gradual addition of an oral sulfonylurea while continuing metformin HCl extended-release tablets, USP at the maximum dose, even if prior primary or secondary failure to a sulfonylurea has occurred. Clinical and pharmacokinetic drug-drug interaction data are currently available only for metformin plus glyburide (glibenclamide).
With concomitant metformin HCl extended-release tablets, USP and sulfonylurea therapy, the desired control of blood glucose may be obtained by adjusting the dose of each drug. With concomitant metformin HCl extended-release tablets, USP and sulfonylurea therapy, the risk of hypoglycemia associated with sulfonylurea therapy continues and may be increased. Appropriate precautions should be taken. (See Package Insert of the respective sulfonylurea.)
If patients have not satisfactorily responded to one to three months of concomitant therapy with the maximum dose of metformin HCl extended-release tablets, USP and the maximum dose of an oral sulfonylurea, consider therapeutic alternatives including switching to insulin with or without metformin HCl extended-release tablets, USP.
Concomitant Metformin HCl Extended-Release Tablets, USP and Insulin Therapy in Adult Patients
The current insulin dose should be continued upon initiation of metformin HCl extended-release tablets, USP therapy. Metformin HCl extended-release tablets, USP therapy should be initiated at 500 mg once daily in patients on insulin therapy. For patients not responding adequately, the dose of metformin HCl extended-release tablets, USP should be increased by 500 mg after approximately 1 week and by 500 mg every week thereafter until adequate glycemic control is achieved. The maximum recommended daily dose is 2000 mg for metformin HCl extended-release tablets, USP. It is recommended that the insulin dose be decreased by 10% to 25% when fasting plasma glucose concentrations decrease to less than 120 mg/dL in patients receiving concomitant insulin and metformin HCl extended-release tablets, USP. Further adjustment should be individualized based on glucose-lowering response.
Specific Patient Populations
Metformin HCl extended-release tablets, USP are not recommended for use in pregnancy. Metformin HCl extended-release tablets, USP are not recommended in pediatric patients (below the age of 17 years).
The initial and maintenance dosing of metformin HCl extended-release tablets, USP should be conservative in patients with advanced age, due to the potential for decreased renal function in this population. Any dosage adjustment should be based on a careful assessment of renal function. Generally, elderly, debilitated, and malnourished patients should not be titrated to the maximum dose of metformin HCl extended-release tablets, USP.
Monitoring of renal function is necessary to aid in prevention of lactic acidosis, particularly in the elderly. (See WARNINGS .)
Metformin HCl extended-release tablets, USP are contraindicated in patients with:
1. Renal disease or renal dysfunction (e.g., as suggested by serum creatinine levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females] or abnormal creatinine clearance) which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia (see WARNINGS and PRECAUTIONS ).
2. Known hypersensitivity to metformin HCl, USP.
3. Acute or chronic metabolic acidosis, including diabetic ketoacidosis, without coma. Diabetic ketoacidosis should be treated with insulin.
Metformin HCl extended-release tablets, USP 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 PRECAUTIONS .)
In worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin HCl extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin HCl extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin HCl extended-release tablets patients, and that were more common in metformin HCl extended-release tablets - than placebo-treated patients, are listed in Table 5.
|
Metformin HCl
Extended-Release Tablets N=781 |
Placebo
N=195 |
|
| Adverse Reactions | % of Patients | |
| Diarrhea | 9.6 | 2.6 |
| Nausea / Vomiting | 6.5 | 1.5 |
*Reactions that were more common in metformin HCl extended-release tablets-than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin HCl extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin HCl extended-release tablets patients and were more commonly reported with metformin HCl extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Overdose of metformin HCl has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin HCl has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (see WARNINGS ). 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 overdosage is suspected.
Metformin hydrochloride (HCl) extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin HCl, USP ( N, N-dimethylimidodicarbonimidic diamide hydrochloride) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
[image: img_11a7210e-6775-67ac-e054-00144ff8d46c]
Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C 4H 11N 5 • HCl and a molecular weight of 165.63. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pK a of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68.
Metformin HCl extended-release tablets, USP contain 500 mg or 750 mg of metformin HCl, USP as the active ingredient.
Metformin HCl extended-release tablets, USP 500 mg contain the inactive ingredients; colloidal silicon dioxide, hypromellose, magnesium stearate and microcrystalline cellulose.
Metformin HCl extended-release tablets, USP 750 mg contain the inactive ingredients; colloidal silicon dioxide, hypromellose and magnesium stearate.
Dissolution Method: Test 10
System Components and Performance - Metformin HCl extended-release tablets, USP comprises a dual hydrophilic polymer matrix system. Metformin HCl, USP is combined with a drug release controlling polymer to form an "inner" phase, which is then incorporated as discrete particles into an "external" phase of a second polymer. After administration, fluid from the gastrointestinal (GI) tract enters the tablet, causing the polymers to hydrate and swell. Drug is released slowly from the dosage form by a process of diffusion through the gel matrix that is essentially independent of pH. The hydrated polymer system is not rigid and is expected to be broken up by normal peristalsis in the GI tract. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass.
Metformin Hydrochloride Extended-Release Tablets, USP 750mg
30 Tablets
NDC 10544-535-30
[image: img_11a7210e-677e-67ac-e054-00144ff8d46c]
Metformin HCl Extended-Release Tablets, USP 500 mg are white, capsule shaped, biconvex tablets debossed "IP 178" on one side and plain on the other side.
They are available as follows:
Bottles of 30: NDC 53746-178-30
Bottles of 90: NDC 53746-178-90
Bottles of 100: NDC 53746-178-01
Bottles of 500: NDC 53746-178-05
Bottles of 1000: NDC 53746-178-10
Metformin HCl Extended-Release Tablets, USP 750 mg are white, capsule shaped, biconvex tablets debossed "IP 179" on one side and plain on the other side.
They are available as follows:
Bottles of 30: NDC 53746-179-30
Bottles of 90: NDC 53746-179-90
Bottles of 100: NDC 53746-179-01
Bottles of 500: NDC 53746-179-05
Storage
Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].
Dispense in tight, light-resistant containers as defined in the USP.
Photos of the product and/or packaging supplied by the manufacturer.
Mechanism of Action
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS ) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
Pharmacokinetics
Absorption and Bioavailability
Following a single oral dose of metformin HCl extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 hours to 8 hours.
At steady-state, the AUC and C max are less than dose proportional for metformin HCl extended-release tablets within the range of 500 mg to 2000 mg administered once daily. Peak plasma levels are approximately 0.6, 1.1, 1.4, and 1.8 mcg/mL for 500, 1000, 1500, and 2000 mg once-daily doses, respectively. After repeated administration of metformin HCl extended-release tablets, metformin did not accumulate in plasma.
Although the extent of metformin absorption (as measured by AUC) from the metformin HCl extended-release tablets increased by approximately 50% when given with food, there was no effect of food on C max and T max of metformin. Both high and low fat meals had the same effect on the pharmacokinetics of metformin HCl extended-release tablets.
Metabolism and Elimination
Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.
Special Populations
Patients with Type 2 Diabetes
In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects nor is there any accumulation of metformin in either group at usual clinical doses.
The pharmacokinetics of metformin HCl extended-release tablets in patients with type 2 diabetes are comparable to those in healthy normal adults.
Renal Insufficiency
In patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see WARNINGS ).
Hepatic Insufficiency
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Geriatrics
Metformin HCl extended-release tablets treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see WARNINGS and DOSAGE AND ADMINISTRATION ).
Gender
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16).
Race
No studies of metformin pharmacokinetic parameters according to race have been performed.
Clinical Studies
Metformin HCl Extended-Release Tablets
A 24-week, double-blind, placebo-controlled study of metformin HCl extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7% to 10%, FPG 126 to 270 mg/dL). Patients entering the study had a mean baseline HbA 1c of 8% and a mean baseline FPG of 176 mg/dL. After 12 weeks treatment, mean HbA 1c had increased from baseline by 0.1% and mean FPG decreased from baseline by 2 mg/dL in the placebo group, compared with a decrease in mean HbA 1c of 0.6% and a decrease in mean FPG of 23 mg/dL in patients treated with metformin HCl extended-release tablets 1000 mg once daily.
Subsequently, the treatment dose was increased to 1500 mg once daily if HbA 1c was ≥7% but <8% (patients with HbA 1c ≥8% were discontinued from the study). At the final visit (24-week), mean HbA 1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin HCl extended-release tablets.
A 16-week, double-blind, placebo-controlled, dose-response study of metformin HCl extended-release tablets, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (HbA 1c 7% to 11%, FPG 126 to 280 mg/dL). Changes in glycemic control and body weight are shown in Table 1.
| Metformin HCl Extended-Release Tablets | ||||||
|
500 mg
Once Daily |
1000 mg
Once Daily |
1500 mg
Once Daily |
2000 mg
Once Daily |
1000 mg
Twice Daily |
Placebo | |
| Hemoglobin A 1c (%) | (n=115) | (n=115) | (n=111) | (n=125) | (n=112) | (n=111) |
| Baseline | 8.2 | 8.4 | 8.3 | 8.4 | 8.4 | 8.4 |
| Change at FINAL VISIT | -0.4 | -0.6 | -0.9 | -0.8 | -1.1 | 0.1 |
| p-value a | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | - |
| FPG (mg/dL) | (n=126) | (n=118) | (n=120) | (n=132) | (n=122) | (n=113) |
| Baseline | 182.7 | 183.7 | 178.9 | 181 | 181.6 | 179.6 |
| Change at FINAL VISIT | -15.2 | -19.3 | -28.5 | -29.9 | -33.6 | 7.6 |
| p-value a | <0.001 | <0.001 | <0.001 | <0.001 | <0.001 | - |
| Body Weight (lbs) | (n=125) | (n=119) | (n=117) | (n=131) | (n=119) | (n=113) |
| Baseline | 192.9 | 191.8 | 188.3 | 195.4 | 192.5 | 194.3 |
| Change at FINAL VISIT | -1.3 | -1.3 | -0.7 | -1.5 | -2.2 | -1.8 |
| p-value a | NS ** | NS ** | NS ** | NS ** | NS ** | - |
* All patients on diet therapy at Baseline
a All comparisons versus Placebo
** Not statistically significant
Compared with placebo, improvement in glycemic control was seen at all dose levels of metformin HCl extended-release tablets and treatment was not associated with any significant change in weight (see DOSAGE AND ADMINISTRATION ) for dosing recommendations for metformin HCl extended-release tablets.
A 24-week, double-blind, randomized study of metformin HCl extended-release tablets, taken once daily with the evening meal, was conducted in patients with type 2 diabetes who had been treated with metformin HCl 500 mg twice daily for at least 8 weeks prior to study entry.
The metformin HCl dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. Patients qualified for the study if HbA 1c was ≤8.5% and FPG was ≤200 mg/dL. Changes in glycemic control and body weight are shown in Table 2.
| Metformin HCl Extended-Release Tablets | ||
|
1000 mg
Once Daily |
1500 mg
Once Daily |
|
| Hemoglobin A 1c (%) | (n=72) | (n=66) |
| Baseline | 6.99 | 7.02 |
| Change at 12 Weeks | 0.23 | 0.04 |
| (95% CI) | (0.10, 0.36) | (-0.08, 0.15) |
| Change at FINAL VISIT | 0.27 | 0.13 |
| (95 % CI) | (0.11, 0.43) | (-0.02, 0.28) |
| FPG (mg/dL) | (n=72) | (n=70) |
| Baseline | 131 | 131.4 |
| Change at 12 Weeks | 9.5 | 3.7 |
| (95% CI) | (4.4, 14.6) | (-0.4, 7.8) |
| Change at FINAL VISIT | 11.5 | 7.6 |
| (95% CI) | (4.4, 18.6) | (1, 14.2) |
| Body Weight (lbs) | (n=74) | (n=71) |
| Baseline | 202.8 | 192.7 |
| Change at 12 Weeks | 0.9 | 0.7 |
| (95% CI) | (0, 2) | (-0.4, 1.8) |
| Change at FINAL VISIT | 1.1 | 0.9 |
| (95 % CI) | (-0.2, 2.4) | (-0.4, 2) |
After 12 weeks of treatment, there was an increase in mean HbA 1c in all groups; in the metformin HCl extended-release tablets 1000 mg group, the increase from baseline of 0.23% was statistically significant (see DOSAGE AND ADMINISTRATION ).
Changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin HCl extended-release tablets are shown in Table 3.
|
Metformin HCl
Extended-Release Tablets |
||||||
|
500 mg
Once Daily |
1000 mg
Once Daily |
1500 mg
Once Daily |
2000 mg
Once Daily |
1000 mg
Twice Daily |
Placebo | |
| Total Cholesterol (mg/dL) | (n=120) | (n=113) | (n=110) | (n=126) | (n=117) | (n=110) |
| Baseline | 210.3 | 218.1 | 214.6 | 204.4 | 208.2 | 208.6 |
| Mean % Change at FINAL VISIT | 1% | 1.7% | 0.7% | -1.6% | -2.6% | 2.6% |
| Total Triglycerides (mg/dL) | (n=120) | (n=113) | (n=110) | (n=126) | (n=117) | (n=110) |
| Baseline | 220.2 | 211.9 | 198 | 194.2 | 179 | 211.7 |
| Mean % Change at FINAL VISIT | 14.5% | 9.4% | 15.1% | 14.9% | 9.4% | 10.9% |
| LDL Cholesterol (mg/dL) | (n=119) | (n=113) | (n=109) | (n=126) | (n=117) | (n=107) |
| Baseline | 131 | 134.9 | 135.8 | 125.8 | 131.4 | 131.9 |
| Mean % Change at FINAL VISIT | -1.4% | -1.6% | -3.5% | -3.3% | -5.5% | 3.2% |
| HDL Cholesterol (mg/dL) | (n=120) | (n=108) | (n=108) | (n=125) | (n=117) | (n=108) |
| Baseline | 40.8 | 41.6 | 40.6 | 40.2 | 42.4 | 39.4 |
| Mean % Change at FINAL VISIT | 6.2% | 8.6% | 5.5% | 6.1% | 7.1% | 5.8% |
* All patients on diet therapy at Baseline
Changes in lipid parameters in the previously described study of metformin HCl extended-release tablets are shown in Table 4.
| Metformin HCl Extended-Release Tablets | ||
|
1000 mg
Once Daily |
1500 mg
Once Daily |
|
| Total Cholesterol (mg/dL) | (n=70) | (n=66) |
| Baseline | 201.9 | 201.6 |
| Mean % Change at FINAL VISIT | 1.3% | 0.1% |
| Total Triglycerides (mg/dL) | (n=70) | (n=66) |
| Baseline | 169.2 | 206.8 |
| Mean % Change at FINAL VISIT | 25.3% | 33.4% |
| LDL Cholesterol (mg/dL) | (n=70) | (n=66) |
| Baseline | 126.2 | 115.7 |
| Mean % Change at FINAL VISIT | -3.3% | -3.7% |
| HDL Cholesterol (mg/dL) | (n=70) | (n=65) |
| Baseline | 41.7 | 44.6 |
| Mean % Change at FINAL VISIT | 1% | -2.1% |
Manufactured by:
Amneal Pharmaceuticals of NY
Hauppauge, NY 11788
Distributed by:
Amneal Pharmaceuticals
Glasgow, KY 42141
Rev. 06-2012
Manufactured by:
Amneal Pharmaceuticals of NY
Hauppauge, NY 11788
Distributed by:
Amneal Pharmaceuticals
Glasgow, KY 42141
Rev. 06-2012
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