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Metformin tablets for oral use

Summary about Metformin

Metformin is an antihyperglycemic agent of the biguanide class, used for the management of type II diabetes). Currently, metformin is the first drug of choice for the management of type II diabetes and is prescribed to at least 120 million people worldwide

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) and should not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease. Metformin is sometimes used together with insulin or other medications, but it is not for treating type 1 diabetes.

 

 

Moreover, data from controlled trials and meta-analyses indicate that metformin may improve menstrual patterns in some women with polycystic ovary syndrome (PCOS) and oligomenorrhea due to PCOS, but metformin is less effective than combination oral contraceptives. It is unknown whether the improvement in ovulation rate from metformin is associated with a risk reduction for endometrial carcinoma. Additional trials may be necessary to further define the role of metformin in this condition.

Endocrine Society clinical guidelines on PCOS consider metformin a second-line therapy for menstrual irregularities in women who cannot take or tolerate hormonal contraception.

Controlled trials and meta-analyses indicate that metformin significantly reduces the risk of ovarian hyperstimulation syndrome (OHSS) in women with polycystic ovary syndrome (PCOS) receiving a gonadotropin during in vitro fertilization. Additional trials may be necessary to further define the role of metformin in this condition.

 

 

Metformin Hydrochloride

Active Ingredient

Metformin Hydrochloride

Administration Route

Oral

Alcohol Warning

Avoid! Alcohol may potentiate the effects of metformin on lactate metabolism. Patients should be advised to avoid excessive alcohol consumption while taking metformin and to promptly notify their physician if they experience possible signs of lactic acidosis such as malaise, myalgia, respiratory distress, hyperventilation, slow or irregular heartbeat, somnolence, abdominal upset, or other unusual symptoms. Other antihyperglycemic agents may be more appropriate for alcoholic patients.

Available Strength

500mg, 850mg and 1000 mg

Breastfeeding Warning

Benefit should outweigh risk

Excreted into human milk: Yes

Comments:
-Available data have not reported adverse effects in breastfed infants, however, this data is limited.
-Due to this limited data, product manufacturers recommend a decision should be made to discontinue nursing or discontinue the drug, considering the importance of the drug to the mother.
-Published data suggest this drug is compatible with breastfeeding; they recommend caution when nursing a newborn or premature infant, and those with renal impairment.Drug levels are expected to be 0.5% (range 0.11% to 1%) of the mother’s weight-adjusted dosage and milk/plasma ratio range between 0.13 and 1. Since milk levels are expected to be relatively constant, timing of breastfeeding with drug administration is expected to be of little benefit. One large prospective study found no adverse effects in breastfed infants. Low detectable serum levels were found in some breastfed infants.

Clinical Pharmacology

Pharmacodynamics

Insulin is an important hormone that regulates blood glucose levels. Type II diabetes is characterized by a decrease in sensitivity to insulin, resulting in eventual elevations in blood glucose when the pancreas can no longer compensate. In patients diagnosed with type 2 diabetes, insulin no longer exerts adequate effects on tissues and cells (called insulin resistance) and insulin deficiency may also be present.

Metformin reduces liver (hepatic) production of glucose, decreases the intestinal absorption of glucose, and enhances insulin sensitivity by increasing both peripheral glucose uptake and utilization. In contrast with drugs of the sulfonylurea class, which lead to hyperinsulinemia, the secretion of insulin is unchanged with metformin use.

Effect on fasting plasma glucose (FPG) and Glycosylated hemoglobin (HbA1c)

HbA1c is an important periodic measure of glycemic control that is used to monitor diabetic patients. Fasting plasma glucose is also a useful and important measure of glycemic control. In a 29-week clinical trial of subjects diagnosed with type II diabetes, metformin decreased the fasting plasma glucose levels by an average of 59 mg/dL from baseline, compared to an average increase of 6.3 mg/dL from baseline in subjects taking a placebo. Glycosylated hemoglobin (HbA1c) was decreased by about 1.4% in subjects receiving metformin, and increased by 0.4% in subjects receiving placebo only

Pharmacokinetics 

Onset of action: Within days; maximum effects up to 2 weeks

Distribution: Vd: 654 ± 358 L; partitions into erythrocytes; concentrates in liver, kidney, and GI tract

Protein binding: Negligible

Metabolism: Not metabolized by the liver

Bioavailability: Absolute: Fasting: 50% to 60%

Half-life elimination: Plasma: 4 to 9 hours; Blood ~17.6 hours

Time to peak, serum: Immediate release: 2 to 3 hours; Extended release: 7 hours (range: 4 to 8 hours)

Excretion: Urine (90% as unchanged drug; active secretion)

Cost

Tablets (metfomrin):
  • 500 mg (per each): $0.04 – $0.71
  • 850 mg (per each): $0.07 – $1.21
  • 1000 mg (per each): $0.07 – $1.45

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer’s AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Form

Tablets  of 500mg, 850mg and 1000mg for oral use

Dose Schedule

Dosing Adults:

Diabetes mellitus, type 2, treatment: Note: For patients who are not meeting glycemic targets despite diet, exercise, and metformin, combination therapy is necessary to achieve optimal results 

Immediate release: Oral:

Initial: 500 mg once or twice daily or 850 mg once daily 

Dosage adjustments: The dose should be increased gradually to minimize GI adverse effects. Titration strategies vary widely, but usually done in 500 mg or 850 mg increments every 7 days (range: 5 days to 1 month).

Usual maintenance dosage: 1 g twice daily or 850 mg twice daily 

Maximum: 2.55 g/day. Modest additional benefit has been observed with doses up to ~2.5 g/day; however, GI adverse effects may limit use. If doses >2 g/day are needed, consider administering in 3 divided doses to minimize GI adverse effects.

Gestational diabetes mellitus, treatment (alternative agent) (off-label use): Immediate release: Oral: Initial: 500 mg once or twice daily; increase dosage to meet glycemic targets, typically over 1 to 2 weeks, up to a maximum of 2 to 2.5 g daily in 2 to 3 divided doses. If targets not achieved with metformin alone, insulin may be added. Note: Insulin is the preferred medication for gestational diabetes as it does not cross the placenta to a measurable extent; all oral agents lack long-term safety data

Oligomenorrhea due to PCOS, treatment (alternative agent) (off-label use): Immediate release: Oral: Dosage range studied in trials: 1.5 to 2 g daily in 2 to 3 divided doses; to minimize GI adverse effects, most trials initiated therapy with 500 mg once or twice daily and gradually increased the dose in 500 mg increments every 7 days. Note: Cyclic progestin therapy may be added for the first 6 months of metformin treatment, until regular cycles are established.

Ovarian hyperstimulation syndrome (OHSS) in women with PCOS due to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI), prevention (alternative agent) (off-label use): Immediate release: Oral: Dosage range studied in trials: 1 to 2.55 g daily in 2 to 3 divided doses. Note: In most trials, metformin was used as a pretreatment and coadministered with gonadotropins; one trial coadministered metformin with gonadotropins only. Metformin was given until oocyte retrieval, hCG administration, or embryo transfer in most trials; in some trials, it was given until pregnancy test or 12 weeks’ gestation.

Pediatric dosing

Diabetes mellitus, type 2; treatment: Note: Allow 1 to 2 weeks between dose titrations. Generally, clinically significant responses are not seen at doses less than 1,500 to 2,000 mg/day; however, a lower recommended starting dose with a gradual increase in dosage is recommended to minimize gastrointestinal symptoms.

Immediate-release tablet or solution: Children ≥10 years and Adolescents: Oral: Initial: 500 to 1,000 mg once daily or 500 mg twice daily; increase dose every 1 to 2 weeks as tolerated in 500 to 1,000 mg increments; maximum dose: 1,000 mg twice daily or 850 mg 3 times daily

Drug Class

A10BA — Biguanides

Drug Unit

mg 

Food Warning

Food decreases the extent and slightly delays the absorption. Management: Administer with a meal,

Included In
Health Insurance Plan

100% of Medicare Part D and Medicare Advantage plans cover this drug.

Interacting Drugs

Carbonic Anhydrase Inhibitors: Topiramate or other carbonic anhydrase inhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequently decrease serum bicarbonate and induce non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs may induce metabolic acidosis. Use these drugs with caution in patients treated with metformin, as the risk of lactic acidosis may increase.

Cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. Although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system.

Drugs Affecting Glycemic Control. Certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blockers, and isoniazid. When such drugs are administered to a patient receiving metformin, the patient should be closely observed for loss of blood glucose control. When such drugs are withdrawn from a patient receiving metformin, the patient should be observed closely for hypoglycemia.

Is Available Generically

Yes. 

Is Proprietary

No

Label Details

https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=98c4b9a5-b8da-4bf0-bd52-7fc79152e414&type=pdf 

Legal Status

Legal.

Is not subject to the Controlled Substances Act.

Manufacturer

Heritage Pharmaceuticals Inc.

Maximum Intake

2.55 g/day.

Mechanism of Action

Metformin’s mechanisms of action are unique from other classes of oral antihyperglycemic drugs. Metformin decreases blood glucose levels by decreasing hepatic glucose production (gluconeogenesis), decreasing the intestinal absorption of glucose, and increasing insulin sensitivity by increasing peripheral glucose uptake and utilization. It is well established that metformin inhibits mitochondrial complex I activity, and it has since been generally postulated that its potent antidiabetic effects occur through this mechanism. The above processes lead to a decrease in blood glucose, managing type II diabetes and exerting positive effects on glycemic control.

After ingestion, the organic cation transporter-1 (OCT1) is responsible for the uptake of metformin into hepatocytes (liver cells). As this drug is positively charged, it accumulates in cells and in the mitochondria because of the membrane potentials across the plasma membrane as well as the mitochondrial inner membrane. Metformin inhibits mitochondrial complex I, preventing the production of mitochondrial ATP leading to increased cytoplasmic ADP:ATP and AMP:ATP ratios. These changes activate AMP-activated protein kinase (AMPK), an enzyme that plays an important role in the regulation of glucose metabolism. Aside from this mechanism, AMPK can be activated by a lysosomal mechanism involving other activators. Following this process, increases in AMP:ATP ratio also inhibit fructose-1,6-bisphosphatase enzyme, resulting in the inhibition of gluconeogenesis, while also inhibiting adenylate cyclase and decreasing the production of cyclic adenosine monophosphate (cAMP), a derivative of ATP used for cell signaling. Activated AMPK phosphorylates two isoforms of acetyl-CoA carboxylase enzyme, thereby inhibiting fat synthesis and leading to fat oxidation, reducing hepatic lipid stores and increasing liver sensitivity to insulin.

In the intestines, metformin increases anaerobic glucose metabolism in enterocytes (intestinal cells), leading to reduced net glucose uptake and increased delivery of lactate to the liver. Recent studies have also implicated the gut as a primary site of action of metformin and suggest that the liver may not be as important for metformin action in patients with type 2 diabetes. Some of the ways metformin may play a role on the intestines is by promoting the metabolism of glucose by increasing glucagon-like peptide I (GLP-1) as well as increasing gut utilization of glucose.

In addition to the above pathway, the mechanism of action of metformin may be explained by other ways, and its exact mechanism of action has been under extensive study in recent years

Non Proprietary Name

Metformin Hydrochloride

Overdosage

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 casesMetformin 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.

Pregnancy Category


Benefit should outweigh risk

AU TGA pregnancy category: C
US FDA pregnancy category: Not assignedAU TGA pregnancy category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

US FDA pregnancy category Not Assigned: The US FDA has amended the pregnancy labeling rule for prescription drug products to require labeling that includes a summary of risk, a discussion of the data supporting that summary, and relevant information to help health care providers make prescribing decisions and counsel women about the use of drugs during pregnancy. Pregnancy categories A, B, C, D, and X are being phased out.

Pregnancy Warning

Risk Summary: Data are not sufficient to inform a drug-associated risk for major birth defects or miscarriage; published studies have not reported an increased risk. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy.

Comments:
-Maternal glucose levels should be well controlled prior to conception and throughout pregnancy to avoid maternal and fetal diabetes-associated risks.
-Premenopausal women should understand the potential for unintended pregnancy with use of this drug as ovulation may occur in some anovulatory womenAnimal studies do not indicate harmful effects with respect to pregnancy, embryo or fetal development, birth or postnatal development. Poorly-controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications. Poorly controlled maternal diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Published evidence suggests this drug has a good safety profile in women with no increased long-term effects in offspring up to 18 months; however, much of the evidence is from observational, small, and/or nonrandomized studies, and therefore data must be interpreted cautiously.

Many experts continue to recommend insulin as the drug of choice for type 1, type 2, and gestational diabetes when diet alone is unsuccessful in controlling blood sugars. The estimated background risk for major birth defects in women with pre-gestational diabetes mellitus with an HbA1C greater than 7 is 6% to 10% and for women with a HbA1C greater than 10, this risk has been reported to be as high as 20% to 25%. In the US, the estimated risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The estimated risk of miscarriage for pregnant women with diabetes is unknown. There are no adequate and well-controlled studies in pregnant women.

Prescribing Info

https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=98c4b9a5-b8da-4bf0-bd52-7fc79152e414&type=pdf 

Prescription Status

Prescription only

Proprietary Name

Provera, depo-subQ provera 104

Related Drugs

Fortamet, Glucophage, Glucophage XR, Glumetza, Riomet, Riomet ER

RxCUI

238088

219495

6809

Warning


Lactic Acidosis:Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment with Metformin Hydrochloride Tablets USP; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels >5 mcg/mL are generally found.
 
The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low (approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, in particular those with unstable or acute congestive heart failure who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient’s age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking Metformin Hydrochloride Tablets USP and by use of the minimum effective dose of Metformin Hydrochloride Tablets USP. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin Hydrochloride Tablets USP treatment should not be initiated in patients ≥80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition, Metformin Hydrochloride Tablets USP should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, Metformin Hydrochloride Tablets USP should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when taking Metformin Hydrochloride Tablets USP, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism. In addition, Metformin Hydrochloride Tablets USP should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure.

The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked acidosis. The patient and the patient’s physician must be aware of the possible importance of such symptoms and the patient should be instructed to notify the physician immediately if they occur.Metformin Hydrochloride Tablets USP should be withdrawn until the situation is clarified. Serum electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin levels may be useful. Once a patient is stabilized on any dose level of Metformin Hydrochloride Tablets USP, gastrointestinal symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease.
 
Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in patients taking Metformin Hydrochloride Tablets USP do not necessarily indicate impending lactic acidosis and may be explainable by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.
 
Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia).
 
Lactic acidosis is a medical emergency that must be treated in a hospital setting. In a patient with lactic acidosis who is taking Metformin Hydrochloride Tablets USP, the drug should be discontinued immediately and general supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to correct the acidosis and remove the accumulated metformin. Such management often results in prompt reversal of symptoms and recovery. 

 

References:

Drugs.com [Internet]. Metformin Information from Drugs.com; c1996-2019 [Updated: 6 December 2018, Cited: 7 December 2019]. Available from: https://www.drugs.com/metformin.html

Drugbank.ca [Internet]. Metformin Information from Drugbank.ca; c1996-2019 [Updated: 6 December 2019, Cited: 7 December 2019]. Available from: https://www.drugbank.ca/drugs/DB00331

Uptodate.com [Internet]. Metformin Information from Uptodate.com; c1996-2019 [Topic 9621 Version 383.0, Cited: 7 December 2019]. Available from https://www.uptodate.com/contents/metformin-drug-information#F193854 

Meng X, Xu S, Chen G, Derwahl M, Liu C. Metformin and thyroid disease. J Endocrinol. 2017;233(1):R43-R51. doi: 10.1530/JOE-16-0450.

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