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Black Box Warning
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Overview
Metformin is a hypoglycemic agent that is FDA approved for the treatment of type 2 diabetes mellitus. There is a Black Box Warning for this drug as shown here. Common adverse reactions include cobalamin deficiency, diarrhea, flatulence, indigestion, malabsorption syndrome, nausea, vomiting, asthenia, headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Type 2 diabetes mellitus
Dosing Information
Dosage
Off-Label Use and Dosage (Adult)
Non–Guideline-Supported Use
Hyperinsulinar obesity
Dosing Information
Dosage
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
There is limited information regarding Metformin FDA-Labeled Indications and Dosage (Pediatric) in the drug label.
Off-Label Use and Dosage (Pediatric)
Contraindications
Metformin Hydrochloride (HCl) Tablets, USP is an oral antihyperglycemic drug 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:
17bd7b7d-figure-01
Metformin HCl, USP is a white to off-white crystalline compound with a molecular formula of C4H11N5 • HCl and a molecular weight of 165.62. Metformin HCl, USP is freely soluble in water and is practically insoluble in acetone, ether, and chloroform. The pKa of metformin is 12.4. The pH of a 1% aqueous solution of metformin HCl, USP is 6.68.
Metformin HCl Tablets, USP, contains 500 mg, 850 mg, or 1000 mg of metformin HCl, USP. Each tablet contains the inactive ingredients povidone, microcrystalline cellulose, croscarmellose sodium and magnesium stearate. In addition, the coating for the 500 mg, 850 mg and 1000 mg tablets contain polyethylene glycol, polyvinyl alcohol, titanium dioxide, talc, gum acacia, maltodextrin, propylene glycol and natural flavors.
Warnings
Title
See full prescribing information for complete Boxed Warning.
ConditionName:
Content
Description
Precautions
Description
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Metformin in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Metformin in the drug label.
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metformin in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Metformin during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Metformin with respect to nursing mothers.
Pediatric Use
There is no FDA guidance on the use of Metformin with respect to pediatric patients.
Geriatic Use
There is no FDA guidance on the use of Metformin with respect to geriatric patients.
Gender
There is no FDA guidance on the use of Metformin with respect to specific gender populations.
Race
There is no FDA guidance on the use of Metformin with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Metformin in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Metformin in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Metformin in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Metformin in patients who are immunocompromised.
Administration and Monitoring
Administration
Oral
Intravenous
Monitoring
There is limited information regarding Monitoring of Metformin in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Metformin in the drug label.
Overdosage
Acute Overdose
Signs and Symptoms
Description
Management
Description
Chronic Overdose
There is limited information regarding Chronic Overdose of Metformin in the drug label.
Pharmacology
There is limited information regarding Metformin Pharmacology in the drug label.
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.
There is limited information regarding Pharmacodynamics of Metformin in the drug label.
Pharmacokinetics
Absorption and Bioavailability
The absolute bioavailability of a Metformin HCl 500 mg tablet given under fasting conditions is approximately 50% to 60%. Studies using single oral doses of Metformin HCl 500 mg to 1500 mg, and 850 mg 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. Food decreases the extent of and slightly delays the absorption of metformin, as shown by approximately a 40% lower mean peak plasma concentration (Cmax), a 25% lower area under the plasma concentration versus time curve (AUC), and a 35 minute prolongation of time to peak plasma concentration (Tmax) following administration of a single 850 mg tablet of metformin with food, compared to the same tablet strength administered fasting. The clinical relevance of these decreases is unknown.
Distribution
The apparent volume of distribution (V/F) of metformin following single oral doses of Metformin HCl 850 mg averaged 654 ± 358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of Metformin HCl, steady-state plasma concentrations of metformin are reached within 24 to 48 hours and are generally <1 mcg/mL. During controlled clinical trials of Metformin HCl, maximum metformin plasma levels did not exceed 5 mcg/mL, even at maximum doses.
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 (see Table 1) 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 (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.
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 Table 1; also see WARNINGS).
Hepatic Insufficiency
No pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency.
Geriatrics
Limited data from controlled pharmacokinetic studies of Metformin HCl in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and Cmax is increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin HCl 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).
Nonclinical Toxicology
There is limited information regarding Nonclinical Toxicology of Metformin in the drug label.
Clinical Studies
There is limited information regarding Clinical Studies of Metformin in the drug label.
How Supplied
Storage
There is limited information regarding Metformin Storage in the drug label.
Images
Drug Images
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