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Metformin ER 500 mg
Overview
What is Metformin ER 500 mg?
Metformin Hydrochloride Extended-Release Tablets, USP
Metformin hydrochloride extended-release tablets, USP are oral antihyperglycemic drugs used in the management of type 2 diabetes. Metformin hydrochloride, USP (N,N-dimethyl-monohydrochloride,Imidodicarbonimidic diamide) is not chemically or pharmacologically related to any other classes of oral antihyperglycemic agents. The structural formula is as shown:
Metformin hydrochloride, USP is a white or almost white, crystalline powder with a molecular formula of C4H11N5•HCl and a molecular weight of 165.62. 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 6.35.
Metformin hydrochloride extended-release tablets, USP contain 500 mg or 750 mg of metformin hydrochloride as the active ingredient.
Metformin hydrochloride extended-release tablets, USP 500 mg and 750 mg tablets contain the inactive ingredients hypromellose, magnesium stearate, and polyvinyl pyrrolidone.
Dissolution Method: Test 10
- Metformin hydrochloride extended-release tablets, USP comprises a dual hydrophilic polymer matrix system. Metformin hydrochloride, 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.
What does Metformin ER 500 mg look like?
What are the available doses of Metformin ER 500 mg?
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What should I talk to my health care provider before I take Metformin ER 500 mg?
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How should I use Metformin ER 500 mg?
Metformin hydrochloride 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 hydrochloride extended-release tablets, USP or any other pharmacologic agent. Dosage of metformin hydrochloride 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 hydrochloride extended-release tablets, USP in adults is 2000 mg.
Metformin hydrochloride extended-release tablets, USP should generally be given once daily with the evening meal. Metformin hydrochloride 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 hydrochloride extended-release tablets, USP and identify the minimum effective dose for the patient. Thereafter, glycosylated hemoglobin should be measured at intervals of approximately 3 months.
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 hydrochloride extended-release tablets, USP may be sufficient during periods of transient loss of control in patients usually well-controlled on diet alone.
Metformin hydrochloride extended-release tablets, USP must be swallowed whole and never crushed or chewed.
What interacts with Metformin ER 500 mg?
Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with:
1. Severe Renal Impairment (eGFR below 30mL/min/1.73m2) (see and ).
2.Known hypersensitivity to metformin hydrochloride, USP.
3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
What are the warnings of Metformin ER 500 mg?
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What are the precautions of Metformin ER 500 mg?
General Precautions
•
–There have been post marketing 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 or
metformin hydrochloride extend release tablets. In metformin hydrochloride extend release 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 extend release
tablets 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 post marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment.
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
,
):
o Before initiating metformin hydrochloride extend release tablets, obtain an estimated glomerular filtration rate (eGFR)
o Metformin hydrochloride extend release tablets is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see
).
o Initiation of metformin hydrochloride extend release tablets is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2.
o Obtain an eGFR at least annually in all patients taking metformin hydrochloride extend release tablets. In patients at risk for the development of renal impairment (e.g., the
elderly), renal function should be assessed more frequently.
o In patients taking metformin hydrochloride extend release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy.
•
– The concomitant use of metformin hydrochloride extend release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis:
those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent
monitoring of patients.
•
—The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal,
or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients.
•
—Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the
occurrence of lactic acidosis. Stop metformin hydrochloride extended release 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 m2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated
contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended release tablets if renal function is stable.
•
—withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment.
Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake.
•
— several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when
accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been
associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended release tablets.
• Excessive alcohol intake
•
—Patients with hepatic impairment have developed cases of metformin associated lactic acidosis. This may be due to impaired lactate clearance resulting in
higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended release tablets in patients with clinical or laboratory evidence of hepatic disease.
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Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3- year intervals may be useful.
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Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Macrovascular Outcomes
Information for Patients
Patients should be informed of the potential risks and benefits of metformin hydrochloride extended-release tablets 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
Array
and
sections, should be explained to patients. Patients should be advised to discontinue metformin hydrochloride extended-release tablets 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 metformin hydrochloride extended-release tablets, 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 counselled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride extended-release tablets.
Metformin hydrochloride extended-release tablets alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride extended-release tablets 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
Array
printed below.)
Patients should be informed that metformin hydrochloride extended-release tablets must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.
Laboratory Tests
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 metformin hydrochloride therapy, if this is suspected, vitamin B12 deficiency should be excluded.
Instruct patients to inform their doctor that they are taking metformin hydrochloride extended-release tablets prior to any surgical or radiological procedure, as temporary discontinuation of metformin hydrochloride extended-release tablets may be required until renal function has been confirmed to be normal (see
).
Drug Interactions (Clinical Evaluation of Drug Interactions Conducted with Metformin hydrochloride)
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Furosemide
Nifedipine
Drugs that reduce metformin 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 such as ranolazine, vandetanib, dolutegravir, and cimetidine) could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Consider the benefits and risks of concomitant use. Such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin AUC. There was no change in elimination half-life in the single-dose study. Metformin had no effect on cimetidine pharmacokinetics. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended-release tablets and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.
Other
Carbonic anhydrase inhibitors
Alcohol
Carcinogenesis, Mutagenesis, Impairment of Fertility
Long-term carcinogenicity studies have been performed in rats (dosing duration of 104 weeks) and mice (dosing duration of 91 weeks) at doses up to and including 900 mg/kg/day and 1500 mg/kg/day, respectively.
These doses are both approximately 4 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 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 3 times the maximum recommended human daily dose based on body surface area comparisons.
Pregnancy
Teratogenic Effects: Pregnancy Category B
Recent information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities. Most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Because animal reproduction studies are not always predictive of human response, metformin hydrochloride extended-release tablets should not be used during pregnancy unless clearly needed.
There are no adequate and well-controlled studies in pregnant women with metformin hydrochloride extended-release tablets. Metformin was not teratogenic in rats and rabbits at doses up to 600 mg/kg/day. This represents an exposure of about 2 and 6 times the maximum recommended human daily dose of 2000 mg based on body surface area comparisons for rats and rabbits, respectively. Determination of fetal concentrations demonstrated a partial placental barrier to metformin.
Nursing Mothers
Studies in lactating rats show that metformin is excreted into milk and reaches levels comparable to those in plasma. Similar studies have not been conducted in nursing mothers. Because the potential for hypoglycemia in nursing infants may exist, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If metformin hydrochloride extended-release tablets is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.
Pediatric Use
Safety and effectiveness of metformin hydrochloride extended-release tablets in pediatric patients have not been established.
Geriatric Use
Controlled clinical studies of metformin hydrochloride extended-release tablets 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. 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
,
, and
)
What are the side effects of Metformin ER 500 mg?
In a US double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablets patients, and that were more common in metformin hydrochloride tablets - than placebo-treated patients, are listed in
* Reactions that were more common in metformin hydrochloride tablets-than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥1 -≤5% of metformin hydrochloride tablets 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 worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients, are listed in
*
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
| Diarrhea | 53.2 | 11.7 |
| Nausea/Vomiting | 25.5 | 8.3 |
| Flatulence | 12.1 | 5.5 |
| Asthenia | 9.2 | 5.5 |
| Indigestion | 7.1 | 4.1 |
| Abdominal Discomfort | 6.4 | 4.8 |
| Headache | 5.7 | 4.8 |
| Diarrhea | 9.6 | 2.6 |
| Nausea/Vomiting | 6.5 | 1.5 |
What should I look out for while using Metformin ER 500 mg?
Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with:
1. Severe Renal Impairment (eGFR below 30mL/min/1.73m2) (see
and
).
2.Known hypersensitivity to metformin hydrochloride, USP.
3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
LACTIC ACIDOSIS:
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 evidenceof ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see
).
Drug Interactions
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WARNINGS
What might happen if I take too much Metformin ER 500 mg?
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 hydrochloride has been established. Lactic acidosis has been reported in approximately 32% of metformin overdose cases (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 overdosage is suspected.
How should I store and handle Metformin ER 500 mg?
Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017 Metformin Hydrochloride Extended-Release Tablets, USP500 mg Bottles of 30 NDC 62207-491-54500 mg Bottles of 1000 NDC 62207-491-49750 mg Bottles of 30 NDC 62207-492-54750 mg Bottles of 1000 NDC 62207-492-49Metformin Hydrochloride Extended-Release Tablets, USP 500 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G7” on one side and plain on the other side.Metformin Hydrochloride Extended-Release Tablets, USP 750 mg tablets are white to off-white uncoated, modified capsule shaped tablets debossed with “G8” on one side and plain on the other side. Store at 20° to 25° C (68° to 77° F); excursions permitted within 15° to 30° C (59° to 86° F). [See USP Controlled Room Temperature.]Dispense in light-resistant containers. Manufactured by: Granules India Limited Hyderabad-500 081, India Manufactured for: Granules USA, Inc.Parsipanny, NJ 07054Toll-free: 1-877-770-3183 May 2017
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
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
) 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.
Non-Clinical Toxicology
Metformin hydrochloride extended-release tablets, USP are contraindicated in patients with:1. Severe Renal Impairment (eGFR below 30mL/min/1.73m2) (see and ).
2.Known hypersensitivity to metformin hydrochloride, USP.
3.Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. Diabetic ketoacidosis should be treated with insulin.
LACTIC ACIDOSIS:
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 evidenceof ketonuria or ketonemia), an increased lactate/pyruvate ratio; and metformin plasma levels generally >5 mcg/mL (see
).
Array
• –There have been post marketing 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 or metformin hydrochloride extend release tablets. In metformin hydrochloride extend release 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 extend release tablets 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 post marketing metformin-associated lactic acidosis cases primarily occurred in patients with significant renal impairment. 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 , ): o Before initiating metformin hydrochloride extend release tablets, obtain an estimated glomerular filtration rate (eGFR) o Metformin hydrochloride extend release tablets is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2 (see ). o Initiation of metformin hydrochloride extend release tablets is not recommended in patients with eGFR between 30-45 mL/min/1.73 m2. o Obtain an eGFR at least annually in all patients taking metformin hydrochloride extend release tablets. In patients at risk for the development of renal impairment (e.g., the elderly), renal function should be assessed more frequently. o In patients taking metformin hydrochloride extend release tablets whose eGFR falls below 45 mL/min/1.73 m2, assess the benefit and risk of continuing therapy. • – The concomitant use of metformin hydrochloride extend release tablets with specific drugs may increase the risk of metformin-associated lactic acidosis: those that impair renal function, result in significant hemodynamic change, interfere with acid-base balance, or increase metformin accumulation. Consider more frequent monitoring of patients. • —The risk of metformin-associated lactic acidosis increases with the patient’s age because elderly patients have a greater likelihood of having hepatic, renal, or cardiac impairment than younger patients. Assess renal function more frequently in elderly patients. • —Administration of intravascular iodinated contrast agents in metformin-treated patients has led to an acute decrease in renal function and the occurrence of lactic acidosis. Stop metformin hydrochloride extended release 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 m2; in patients with a history of hepatic impairment, alcoholism or heart failure; or in patients who will be administered intra-arterial iodinated contrast. Re-evaluate eGFR 48 hours after the imaging procedure, and restart metformin hydrochloride extended release tablets if renal function is stable. • —withholding of food and fluids during surgical or other procedures may increase the risk for volume depletion, hypotension, and renal impairment. Metformin hydrochloride extended-release tablets should be temporarily discontinued while patients have restricted food and fluid intake. • — several of the postmarketing cases of metformin-associated lactic acidosis occurred in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may cause prerenal azotemia. When such an event occurs, discontinue metformin hydrochloride extended release tablets.
• Excessive alcohol intake
• —Patients with hepatic impairment have developed cases of metformin associated lactic acidosis. This may be due to impaired lactate clearance resulting in higher lactate blood levels. Therefore, avoid use of metformin hydrochloride extended release tablets in patients with clinical or laboratory evidence of hepatic disease.
Vitamin B12 levels—
:
Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurements at 2- to 3- year intervals may be useful.
Change in clinical status of patients with previously controlled type 2 diabetes—
Hypogly
c
emia
—
Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs.
Macrovascular Outcomes
In a US double-blind clinical study of metformin hydrochloride tablets in patients with type 2 diabetes, a total of 141 patients received metformin hydrochloride tablets therapy (up to 2550 mg per day) and 145 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride tablets patients, and that were more common in metformin hydrochloride tablets - than placebo-treated patients, are listed in
* Reactions that were more common in metformin hydrochloride tablets-than placebo-treated patients.
Diarrhea led to discontinuation of study medication in 6% of patients treated with metformin hydrochloride tablets. Additionally, the following adverse reactions were reported in ≥1 -≤5% of metformin hydrochloride tablets 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 worldwide clinical trials over 900 patients with type 2 diabetes have been treated with metformin hydrochloride extended-release tablets in placebo- and active-controlled studies. In placebo-controlled trials, 781 patients were administered metformin hydrochloride extended-release tablets and 195 patients received placebo. Adverse reactions reported in greater than 5% of the metformin hydrochloride extended-release tablets patients, and that were more common in metformin hydrochloride extended-release tablets- than placebo-treated patients, are listed in
*
Diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended-release tablets. Additionally, the following adverse reactions were reported in ≥1% to ≤5% of metformin hydrochloride extended-release tablets patients and were more commonly reported with metformin hydrochloride extended-release tablets than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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