METFORMIN HYDROCHLORIDE- metformin hydrochloride tablet
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use METFORMIN HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for METFORMIN HYDROCHLORIDE TABLETS.
METFORMIN HYDROCHLORIDE tablets, for oral use
Initial U.S. Approval: 1995
WARNING: LACTIC ACIDOSIS
See full prescribing information for complete boxed warning.
INDICATIONS AND USAGE
Metformin hydrochloride tablets are biguanide indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients 10 years of age and older with type 2 diabetes mellitus. ( 1)
DOSAGE AND ADMINISTRATION
Adult Dosage for Metformin Hydrochloride Tablets:
Pediatric Dosage for Metformin Hydrochloride Tablets:
Discontinuation for Iodinated Contrast Imaging Procedures:
DOSAGE FORMS AND STRENGTHS
WARNINGS AND PRECAUTIONS
For metformin hydrochloride tablets, the most common adverse reactions (>5.0%) are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache. ( 6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Heritage Pharmaceuticals Inc. at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
USE IN SPECIFIC POPULATIONS
See 17 for PATIENT COUNSELING INFORMATION.
FULL PRESCRIBING INFORMATION: CONTENTS*
Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/Liter), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL [see Warnings and Precautions ( 5.1) ].
Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (e.g. carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment.
Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided [see Dosage and Administration ( 2.3), (2.7), Contraindications ( 4), Warnings and Precautions ( 5.1) ].
If metformin-associated lactic acidosis is suspected, immediately discontinue metformin hydrochloride tablets and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended [see Warnings and Precautions ( 5.1) ].
Discontinue metformin hydrochloride tablets at the time of, or prior to, an iodinated contrast imaging procedure in patients with an eGFR between 30 and 60 mL/min/1.73 m 2; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure; restart metformin hydrochloride tablets if renal function is stable.
There have been postmarketing cases of metformin-associated lactic acidosis, including fatal cases. These cases had a subtle onset and were accompanied by nonspecific symptoms such as malaise, myalgias, abdominal pain, respiratory distress, or increased somnolence; however, hypotension and resistant bradyarrhythmias have occurred with severe acidosis. Metformin associated lactic acidosis was characterized by elevated blood lactate concentrations (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), and an increased lactate: pyruvate ratio; metformin plasma levels were generally >5 mcg/mL. Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
If metformin-associated lactic acidosis is suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of metformin hydrochloride tablets. In metformin hydrochloride tablets treated patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct the acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable with a clearance of up to 170 mL/min under good hemodynamic conditions). Hemodialysis has often resulted in reversal of symptoms and recovery.
Educate patients and their families about the symptoms of lactic acidosis and, if these symptoms occur, instruct them to discontinue metformin hydrochloride tablet and report these symptoms to their healthcare provider.
For each of the known and possible risk factors for metformin-associated lactic acidosis, recommendations to reduce the risk of and manage metformin-associated lactic acidosis are provided below:
The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal impairment because metformin is substantially excreted by the kidney. Clinical recommendations based upon the patient's renal function include [see Dosage and Administration ( 2.1), Clinical Pharmacology ( 12.3)] :
In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients. Such decrease, possibly due to interference with B 12 absorption from the B 12-intrinsic factor complex, may be associated with anemia but appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin B 12 supplementation. Certain individuals (those with inadequate vitamin B 12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B 12 levels. Measure hematologic parameters on an annual basis and vitamin B 12 at 2 to 3 year intervals in patients on metformin hydrochloride tablets and manage any abnormalities [see Adverse Reactions ( 6.1) ].
Insulin and insulin secretagogues (e.g., sulfonylurea) are known to cause hypoglycemia. Metformin hydrochloride tablets may increase the risk of hypoglycemia when combined with insulin and/or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with metformin hydrochloride tablet [see Drug Interactions ( 7)].
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Metformin Hydrochloride Tablets
In a U.S. clinical trial of metformin hydrochloride tablets in patients with type 2 diabetes mellitus, a total of 141 patients received metformin hydrochloride tablets up to 2550 mg per day. Adverse reactions reported in greater than 5% of metformin hydrochloride tablets treated patients and that were more common than in placebo-treated patients, are listed in Table 1.
| Metformin Hydrochloride Tablets
| Abdominal Discomfort
Diarrhea led to discontinuation of metformin hydrochloride tablets in 6% of patients. Additionally, the following adverse reactions were reported in ≥1 % to ≤5% of metformin hydrochloride tablets treated patients and were more commonly reported with metformin hydrochloride tablets than placebo: abnormal stools, hypoglycemia, myalgia, lightheaded, dyspnea, nail disorder, rash, sweating increased, taste disorder, chest discomfort, chills, flu syndrome, flushing, palpitation.
In metformin hydrochloride tablets clinical trials of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B 12 levels was observed in approximately 7% of patients.
In clinical trials with metformin hydrochloride tablets in pediatric patients with type 2 diabetes mellitus, the profile of adverse reactions was similar to that observed in adults.
The following adverse reactions have been identified during post approval use of metformin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cholestatic, hepatocellular, and mixed hepatocellular liver injury have been reported with postmarketing use of metformin.
| Carbonic Anhydrase Inhibitors
|| Carbonic anhydrase inhibitors frequently cause a decrease in serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin hydrochloride tablets may increase the risk for lactic acidosis.
|| Consider more frequent monitoring of these patients.
|| Topiramate, zonisamide, acetazolamide or dichlorphenamide.
| Drugs that Reduce metformin hydrochloride tablet Clearance
|| Concomitant use of drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin (e.g., organic cationic transporter-2 [OCT2] / multidrug and toxin extrusion [MATE] inhibitors) could increase systemic exposure to metformin and may increase the risk for lactic acidosis
[see Clinical Pharmacology (
|| Consider the benefits and risks of concomitant use with metformin hydrochloride tablets.
|| Ranolazine, vandetanib, dolutegravir, and cimetidine.
|| Alcohol is known to potentiate the effect of metformin on lactate metabolism.
|| Warn patients against excessive alcohol intake while receiving metformin hydrochloride tablets.
| Insulin Secretagogues or Insulin
|| Coadministration of metformin hydrochloride tablets with an insulin secretagogue (e.g., sulfonylurea) or insulin may increase the risk of hypoglycemia.
|| Patients receiving an insulin secretagogue or insulin may require lower doses of the insulin secretagogue or insulin.
| Drugs Affecting Glycemic Control
|| Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control.
|| When such drugs are administered to a patient receiving metformin hydrochloride tablets, observe the patient closely for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin hydrochloride tablets, observe the patient closely for hypoglycemia.
|| Thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid.
Limited data with metformin hydrochloride tablets in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. Published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes mellitus in pregnancy [see Clinical Considerations] .
No adverse developmental effects were observed when metformin was administered to pregnant Sprague Dawley rats and rabbits during the period of organogenesis at doses up to 2- and 5-times, respectively, a 2550 mg clinical dose, based on body surface area [see Data] .
The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes mellitus with an HbA1C >7 and has been reported to be as high as 20 to 25% in women with a HbA1C > 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Disease-associated maternal and/or embryo/fetal risk
Poorly-controlled diabetes mellitus in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.
Published data from post-marketing studies have not reported a clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when metformin was used during pregnancy. However, these studies cannot definitely establish the absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups.
Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Limited published studies report that metformin is present in human milk [see Data] . However, there is insufficient information to determine the effects of metformin on the breastfed infant and no available information on the effects of metformin on milk production. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for metformin hydrochloride tablets and any potential adverse effects on the breastfed child from metformin hydrochloride tablets or from the underlying maternal condition.
Published clinical lactation studies report that metformin is present in human milk which resulted in infant doses approximately 0.11 % to 1% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.13 and 1. However, the studies were not designed to definitely establish the risk of use of metformin during lactation because of small sample size and limited adverse event data collected in infants.
The safety and effectiveness of metformin hydrochloride tablets for the treatment of type 2 diabetes mellitus have been established in pediatric patients 10 to 16 years old. Safety and effectiveness of metformin hydrochloride tablets have not been established in pediatric patients less than 10 years old.
Use of metformin hydrochloride tablets in pediatric patients 10 to 16 years old for the treatment of type 2 diabetes mellitus is supported by evidence from adequate and well-controlled studies of metformin hydrochloride tablets in adults with additional data from a controlled clinical study in pediatric patients 10 to 16 years old with type 2 diabetes mellitus, which demonstrated a similar response in glycemic control to that seen in adults [see Clinical Studies ( 14.1) ] . In this study, adverse reactions were similar to those described in adults. A maximum daily dose of 2000 mg of metformin hydrochloride tablets is recommended. [see Dosage and Administration ( 2.2). ]
Controlled clinical studies of metformin hydrochloride tablets did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy and the higher risk of lactic acidosis. Assess renal function more frequently in elderly patients [see Warnings and Precautions ( 5.1) ] .
Metformin is substantially excreted by the kidney, and the risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Metformin hydrochloride tablets are contraindicated in severe renal impairment, patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m 2 [see Dosage and Administration ( 2.3), Contraindications ( 4), Warnings and Precautions ( 5.1), and Clinical Pharmacology ( 12.3) ] .
Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis. Metformin hydrochloride tablets are not recommended in patients with hepatic impairment. [see Warnings and Precautions ( 5.1)].
Overdose of metformin hydrochloride has occurred, including ingestion of amounts greater than 50 grams. Hypoglycemia was reported in approximately 10% of cases, but no causal association with metformin has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases [see Warnings and Precautions ( 5.1) ] . 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 tablets, USP contain the antihyperglycemic agent metformin, which is a biguanide, in the form of monohydrochloride. The chemical name of metformin hydrochloride is N,N-dimethylimidodicarbonimidic diamide hydrochloride. The structural formula is as shown below:
Metformin hydrochloride, 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 hydrochloride is freely soluble in water, slightly soluble in alcohol, practically insoluble in acetone and in methylene chloride. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin hydrochloride is 6.68.
Metformin hydrochloride tablets, USP contain 500 mg, 850 mg, or 1000 mg of metformin hydrochloride. Each tablet contains the inactive ingredients povidone (K-30), Povidone (K-90), pregelatinized starch, and magnesium stearate. In addition, the coating for the tablet contains artificial blackberry flavor, hypromellose, macrogol and titanium dioxide.
Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes mellitus, lowering both basal and postprandial plasma glucose. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may decrease.
The absolute bioavailability of a metformin hydrochloride tablets 500 mg given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of metformin hydrochloride tablets 500 to 1500 mg and 850 to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination. At usual clinical doses and dosing schedules of metformin hydrochloride tablets, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 μg/mL.
Following a single oral dose of metformin hydrochloride extended-release tablets, C max is achieved with a median value of 7 hours and a range of 4 to 8 hours. Peak plasma levels are approximately 20% lower compared to the same dose of metformin hydrochloride tablets, however, the extent of absorption (as measured by AUC) is comparable to metformin hydrochloride tablets.
At steady state, the AUC and C max are less than dose proportional for metformin hydrochloride extended-release tablets within the range of 500 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. The extent of metformin absorption (as measured by AUC) from metformin hydrochloride extended-release tablets at a 2000 mg once-daily dose is similar to the same total daily dose administered as metformin hydrochloride tablets 1000 mg twice daily. After repeated administration of metformin hydrochloride extended-release tablets, metformin did not accumulate in plasma.
Effect of food: Food decreases the extent of absorption and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (C max), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35-minute prolongation of time to peak plasma concentration (T max) following administration of a single 850 mg tablet of metformin hydrochloride tablets with food, compared to the same tablet strength administered fasting.
The apparent volume of distribution (V/F) of metformin following single oral doses of metformin hydrochloride tablets 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins. Metformin partitions into erythrocytes, most likely as a function of time.
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 (see Table 4) 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.
In patients with decreased renal function the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased (see Table 3 ) [see Dosage and Administration ( 2.3), Contraindications ( 4), Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.6) ].
No pharmacokinetic studies of metformin have been conducted in patients with hepatic impairment [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.7) ].
Limited data from controlled pharmacokinetic studies of metformin hydrochloride tablets in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and C max is increased, compared to healthy young subjects. It appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 4 ). [see Warnings and Precautions ( 5.1) and Use in Specific Populations ( 8.5) ].
Table 4: Select Mean (±S.D.) Metformin Pharmacokinetic Parameters Following Single or Multiple Oral Doses of Metformin Hydrochloride Tablets
aAll doses given fasting except the first 18 doses of the multiple dose studies
bPeak plasma concentration
cTime to peak plasma concentration
dCombined results (average means) of five studies: mean age 32 years (range 23 to 59 years)
eKinetic study done following dose 19, given fasting
fElderly subjects, mean age 71 years (range 65 to 81 years)
gCL cr = creatinine clearance normalized to body surface area of 1.73 m 2
Subject Groups: Metformin Hydrochloride Tablet dose a
(number of subjects)
C max b
T max c
Healthy, nondiabetic adults:
500 mg single dose (24)
850 mg single dose (74) d
850 mg three times daily for 19 doses e (9)
Adults with type 2 diabetes mellitus:
850 mg single dose (23)
850 mg three times daily for 19 doses e (9)
Elderly f, healthy nondiabetic adults:
850 mg single dose (12)
850 mg single dose
Mild (CLcr g 61 to 90 mL/min) (5)
Moderate (CLcr 31 to 60 mL/min) (4)
Severe (CLcr 10 to 30 mL/min) (6)
After administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin C max and AUC differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function.
Metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes mellitus when analyzed according to gender (males=19, females=16).
No studies of metformin pharmacokinetic parameters according to race have been performed.
In Vivo Assessment of Drug Interactions
Table 5: Effect of Coadministered Drug on Plasma Metformin Systemic Exposure
Dose of Coadministered Drug 1
Dose of Metformin 1
Geometric Mean Ratio (ratio with/without coadministered drug) No Effect= 1.00
No dosing adjustments required for the following:
Cationic drugs eliminated by renal tubular secretion may reduce metformin elimination [see Warnings and Precautions ( 5.9) and Drug Interactions ( 7.2).]
Carbonic anhydrase inhibitors may cause metabolic acidosis [see Warnings and Precautions (5.1) and Drug Interactions (7.1).]
100 mg 4
500 mg 4
Table 6: Effect of Metformin on Coadministered Drug Systemic Exposure
Dose of Coadministered Drug 5
Dose of Metformin 5
Geometric Mean Ratio (ratio with/without metformin) No Effect= 1.00
No dosing adjustments required for the following:
1 - All metformin and coadministered drugs were given as single doses
2 - AUC = AUC (INF)
3 - Ratio of arithmetic means
4 - At steady state with topiramate 100 mg every 12 hours and metformin 500 mg every 12 hours;
5 - All metformin and coadministered drugs were given as single doses
6 - AUC = AUC(INF) unless otherwise noted
7 - Ratio of arithmetic means, p-value of difference <0.05
8 - AUC(0-24 hr) reported
9 - Ratio of arithmetic means
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 900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are both approximately 3 times the maximum recommended human daily dose of 2550 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 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 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 2 times the maximum recommended human daily dose of 2550 mg based on body surface area comparisons.
A double-blind, placebo-controlled, multicenter US clinical trial involving obese patients with type 2 diabetes mellitus whose hyperglycemia was not adequately controlled with dietary management alone (baseline fasting plasma glucose [FPG] of approximately 240 mg/dL) was conducted. Patients were treated with metformin hydrochloride tablets (up to 2550 mg/day) or placebo for 29 weeks. The results are presented in Table 7.
*Not statistically significant
| Metformin Hydrochloride Tablets (n=141)
| FPG (mg/dL)
| Change at FINAL VISIT
| Hemoglobin A1c (%)
| Change at FINAL VISIT
Mean baseline body weight was 201 lbs and 206 lbs in the metformin hydrochloride tablets and placebo arms, respectively. Mean change in body weight from baseline to week 29 was -1.4 lbs and -2.4 lbs in the metformin hydrochloride tablets and placebo arms, respectively. A 29-week, double -blind, placebo-controlled study of metformin hydrochloride tablets and glyburide, alone and in combination, was conducted in obese patients with type 2 diabetes mellitus who had failed to achieve adequate glycemic control while on maximum doses of glyburide (baseline FPG of approximately 250 mg/dL). Patients randomized to the combination arm started therapy with metformin hydrochloride tablets 500 mg and glyburide 20 mg. At the end of each week of the first 4 weeks of the trial, these patients had their dosages of metformin hydrochloride tablets increased by 500 mg if they had failed to reach target fasting plasma glucose. After week 4, such dosage adjustments were made monthly, although no patient was allowed to exceed metformin hydrochloride tablets 2500 mg. Patients in the metformin hydrochloride tablets only arm (metformin plus placebo) discontinued glyburide and followed the same titration schedule. Patients in the glyburide arm continued the same dose of glyburide. At the end of the trial, approximately 70% of the patients in the combination group were taking metformin hydrochloride tablets 2000 mg/glyburide 20 mg or metformin hydrochloride tablets 2500 mg/glyburide 20 mg. The results are displayed in Table 8.
| Comb (n=213)
| Glyb vs Comb
|| MET vs Comb
|| MET vs Glyb
| Fasting Plasma Glucose (mg/dL)
| Change at FINAL VISIT
| Hemoglobin A1c (%)
| Change at FINAL VISIT
Mean baseline body weight was 202 lbs, 203 lbs, and 204 lbs in the metformin hydrochloride tablets /glyburide, glyburide, and metformin hydrochloride tablets arms, respectively. Mean change in body weight from baseline to week 29 was 0.9 lbs, -0.7 lbs, and -8.4 lbs in the metformin hydrochloride tablets /glyburide, glyburide, and metformin hydrochloride tablets arms, respectively.
Pediatric Clinical Studies
A double-blind, placebo-controlled study in pediatric patients aged 10 to 16 years with type 2 diabetes mellitus (mean FPG 182.2 mg/dL), treatment with metformin hydrochloride tablets (up to 2000 mg/day) for up to 16 weeks (mean duration of treatment 11 weeks) was conducted. The results are displayed in Table 9.
a Pediatric patients mean age 13.8 years (range 10 to 16 years)
|| Metformin Hydrochloride
| FPG (mg/dL)
| Change at FINAL VISIT
Mean baseline body weight was 205 lbs and 189 lbs in the metformin hydrochloride tablets and placebo arms, respectively. Mean change in body weight from baseline to week 16 was -3.3 lbs and -2.0 lbs in the metformin hydrochloride tablets and placebo arms, respectively.
A 24-week, double-blind, randomized study of metformin hydrochloride extended-release tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes mellitus who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. The results are shown in Table 11.
Hydrochloride Tablets 500 mg
| Metformin Hydrochloride Extended – release Tablets
| 1000 mg Once Daily
|| 1500 mg Once Daily
| Hemoglobin A
Change at FINAL VISIT (95% CI)
| (–0.04, 0.31)
|| (0.11, 0.43)
|| (–0.02, 0.28)
| FPG (mg/dL)
Change at FINAL VISIT (95% CI)
| (7.0, 21.0)
|| (4.4, 18.6)
|| (1.0, 14.2)
Mean baseline body weight was 210 lbs, 203 lbs and 193 lbs in the metformin hydrochloride tablets 500 mg twice daily, and metformin hydrochloride extended-release tablets 1000 mg and 1500 mg once daily arms, respectively. Mean change in body weight from baseline to week 24 was 0.9 lbs, 1.1 lbs and 0.9 lbs, respectively.
1000 mg White to off-white, oval, biconvex, film coated tablets debossing "H/104" on one side with score line between H and 104 and plain on the other side.
PACKAGING: 30 in 1 BLISTER PACK
Store at 20º to 25º C (68º to 77º F); excursions permitted to 15º to 30º C (59º to 86º F). [see USP Controlled Room Temperature.]
Dispense in tight, light-resistant containers with child-resistant closure.
Repackaged and Distributed By:
Remedy Repack, Inc.
625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Explain the risks of lactic acidosis, its symptoms, and conditions that predispose to its development. Advise patients to discontinue metformin hydrochloride tablets immediately and to promptly notify their healthcare provider if unexplained hyperventilation, myalgias, malaise, unusual somnolence or other nonspecific symptoms occur. Counsel patients against excessive alcohol intake and inform patients about importance of regular testing of renal function while receiving metformin hydrochloride tablets. Instruct patients to inform their doctor that they are taking metformin hydrochloride tablets prior to any surgical or radiological procedure, as temporary discontinuation may be required [see Warnings and Precautions ( 5.1) ].
Inform patients that hypoglycemia may occur when metformin hydrochloride tablets is coadministered with oral sulfonylureas and insulin. Explain to patients receiving concomitant therapy the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development [see Warnings and Precautions (5.3)].
Vitamin B12 Deficiency:
Inform patients about importance of regular hematological parameters while receiving metformin hydrochloride tablets [see Warnings and Precautions ( 5.2) ].
Females of Reproductive Age:
Inform females that treatment with metformin hydrochloride tablets may result in ovulation in some premenopausal anovulatory women which may lead to unintended pregnancy [see Use in Specific Populations ( 8.3) ].
Metformin Hydrochloride Tablets
Read the Patient Information that comes with metformin hydrochloride tablets before you start taking it and each time you get a refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your medical condition or treatment.
What is the most important information I should know about metformin hydrochloride tablets?
Serious side effects can happen in people taking metformin hydrochloride tablets, including:
Lactic Acidosis. Metformin hydrochloride, the medicine in metformin hydrochloride tablets, can cause a rare, but serious, side effect called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is a medical emergency and must be treated in a hospital.
Stop taking metformin hydrochloride tablets and call your healthcare provider right away if you get any of the following symptoms of lactic acidosis:
You have a higher chance of getting lactic acidosis if you:
What are metformin hydrochloride tablets?
Metformin hydrochloride tablets help control your blood sugar in a number of ways. These include helping your body respond better to the insulin it makes naturally, decreasing the amount of sugar your liver makes, and decreasing the amount of sugar your intestines absorb. Metformin hydrochloride tablets do not cause your body to make more insulin.
Who should not take metformin hydrochloride tablets?
Some conditions increase your chance of getting lactic acidosis, or cause other problems if you take either of these medicines. Most of the conditions listed below can increase your chance of getting lactic acidosis.
Do not take metformin hydrochloride tablets if you:
What should I tell my healthcare provider before taking metformin hydrochloride tablets?
Before taking metformin hydrochloride Tablets, tell your healthcare provider if you:
Tell your healthcare provider about all the medicines you take, including prescription and nonprescription medicines, vitamins, and herbal supplements. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
Can metformin hydrochloride tablets be used in children?
Metformin hydrochloride tablets has been shown to effectively lower glucose levels in children (ages 10 to16 years) with type 2 diabetes. Metformin hydrochloride tablets has not been studied in children younger than 10 years old. Metformin hydrochloride tablets has not been studied in combination with other oral glucose-control medicines or insulin in children. If you have any questions about the use of metformin hydrochloride tablets in children, talk with your doctor or other healthcare provider.
How should I take metformin hydrochloride tablets?
What should I avoid while taking metformin hydrochloride tablets?
Do not drink a lot of alcoholic drinks while taking metformin hydrochloride tablets. This means you should not binge drink for short periods, and you should not drink a lot of alcohol on a regular basis. Alcohol can increase the chance of getting lactic acidosis.
What are the side effects of metformin hydrochloride tablets?
Call your doctor right away if you have any of the following symptoms, which could be signs of lactic acidosis:
Most people who have had lactic acidosis with metformin have other things that, combined with the metformin, led to the lactic acidosis. Tell your doctor if you have any of the following, because you have a higher chance for getting lactic acidosis with metformin hydrochloride tablets if you:
Common side effects of metformin hydrochloride tablets include diarrhea, nausea, and upset stomach. These side effects generally go away after you take the medicine for a while. Taking your medicine with meals can help reduce these side effects. Tell your doctor if the side effects bother you a lot, last for more than a few weeks, come back after they've gone away, or start later in therapy. You may need a lower dose or need to stop taking the medicine for a short period or for good.
About 3 out of every 100 people who take metformin hydrochloride tablets have an unpleasant metallic taste when they start taking the medicine. It lasts for a short time.
Metformin hydrochloride tablets rarely cause hypoglycemia (low blood sugar) by themselves. However, hypoglycemia can happen if you do not eat enough, if you drink alcohol, or if you take other medicines to lower blood sugar.
How should I store metformin hydrochloride tablets?
Store metformin hydrochloride tablets at 68ºF to 77ºF (20ºC to 25ºC).
Keep metformin hydrochloride tablets and all medicines out of the reach of children.
General information about the use of metformin hydrochloride tablets.
If you have questions or problems, talk with your doctor or other healthcare provider. You can ask your doctor or pharmacist for the information about metformin hydrochloride tablets that is written for healthcare professionals. Medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. Do not use metformin hydrochloride tablets for a condition for which it was not prescribed. Do not share your medicine with other people.
What are the ingredients of metformin hydrochloride tablets?
Active ingredients of Metformin hydrochloride tablets: metformin hydrochloride.
Inactive ingredients in each tablet of metformin hydrochloride tablets: Povidone (k-30), Povidone (k-90), pregelatinized starch, and magnesium stearate. In addition, the coating for the tablet contains artificial blackberry flavor, hypromellose, macrogol and titanium dioxide.
What is type 2 diabetes?
Type 2 diabetes is a condition in which your body does not make enough insulin, and the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.
The main goal of treating diabetes is to lower your blood sugar to a normal level.
High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.
Talk to your healthcare provider about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and problems you have because of your diabetes.
Repackaged By / Distributed By: RemedyRepack Inc.
625 Kolter Drive, Indiana, PA 15701
DRUG: metformin hydrochloride
GENERIC: metformin hydrochloride
SCORE: Two even pieces
SIZE: 19 mm
PACKAGING: 30 in 1 BLISTER PACK
metformin hydrochloride tablet
|Labeler - REMEDYREPACK INC. (829572556)|