Metformin

Metformin is an Antidiabetic Agent belonging to pharmacology class of biguanide.

Metformin can be used in the treatment of Diabetes mellitus, type 2, treatment.

Metformin is Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release) and get distributed in and concentrates in liver, kidney and gastrointestinal tract. Crosses the placenta and enters breast milk (small amounts). Volume of distribution: 654 ± 358 L and get excreted Via urine (approx 90%, as unchanged drug). Elimination half-life: 4-9 hours (plasma); approx 17.6 hours (blood).

The common side effects associated with Metformin include Vitamin B12 deficiency, Loss of Appetite

Metformin is available in the form of Solution, Suspension, Tablet.

The molecule is available in India, USA, Japan, Germany.

Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization).

The onset of action of Metformin was upto 2 weeks.

Metformin is available in Solution, Suspension, Tablet.

Metformin can be used in the treatment of Diabetes mellitus, type 2, treatment. It is also used as Antipsychotic-induced weight gain; Diabetes mellitus, type 2 (prevention); Gestational diabetes mellitus (treatment); Ovarian hyperstimulation syndrome prevention in patients with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection.

Metformin is a biguanide antihyperglycemic agent which improves glucose tolerance by lowering both basal and postprandial plasma glucose. It exerts its effect by decreasing hepatic glucose production through inhibition of gluconeogenesis and glycogenolysis, delaying intestinal absorption of glucose, and improving insulin sensitivity by increasing peripheral glucose uptake and utilization.

Metformin is approved for use in the following clinical indications

Diabetes mellitus, type 2, treatment: Management of type 2 diabetes mellitus when hyperglycemia cannot be managed with diet and exercise alone.

Although not approved there have been certain off labelled uses documented for Metformin which includes:

Antipsychotic-induced weight gain, treatment (off-label use):

Immediate release: Oral: Dosage range studied in trials: 750 mg to 2 g daily in 2 to 3 divided doses. Doses up to 2.55 g/day have also been used. To minimize GI adverse effects, most trials initiated therapy with 250 mg or 500 mg twice daily or 850 mg once daily, and increased the dose gradually based on tolerability.

Extended release: Oral: Maintenance dosage range in trials: 1 to 2 g once daily. To minimize GI adverse effects, trials initiated therapy with 500 mg once daily and titrated dosage upwards in 500 mg increments every 2 to 6 weeks based on tolerability.

Diabetes mellitus, type 2, prevention (off-label use):

Note: For select patients with prediabetes, particularly for those with BMI ≥35 kg/m², age <60 years, and patients with prior gestational diabetes mellitus, in whom lifestyle interventions fail to improve glycemic indices.

Immediate release: Oral: Initial: 850 mg once daily for 1 month, then increase to 850 mg twice daily; unless GI adverse effects warrant a longer titration period.

Diabetes mellitus, type 2, treatment:

Note: In patients in whom glycemic targets are not met despite diet, exercise, and metformin, combination therapy is necessary to achieve optimal results .

Immediate release:

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

Dosage adjustments: Oral: 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: Oral: 1 g twice daily or 850 mg twice daily.

Maximum: Oral: 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.

Extended release:

Initial: Oral: 500 mg to 1 g once daily

Dosage adjustments: Oral: The dose should be increased gradually to minimize GI adverse effects. Titration strategies vary widely, but usually done in 500 mg increments every 7 days (range: 7 days to 6 weeks).

Maximum: Oral: 2 g/day. If glycemic control is not achieved at maximum dose given once daily, may divide maximum dose and administer twice daily.

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.

Ovarian hyperstimulation syndrome prevention in patients with polycystic ovary syndrome undergoing in vitro fertilization/intracytoplasmic sperm injection (alternative agent) (off-label use ):

Note: For use prior to and/or during ovarian stimulation in patients undergoing a gonadotropin-releasing hormone agonist protocol.

Immediate release: Oral: Initial: 500 mg once daily; increase dose gradually as tolerated up to 2 g/day in divided doses. Dosage range studied in trials: 1 to 2.55 g/day in 2 or 3 divided doses; use of ER products may reduce GI adverse effects . Discontinue metformin with a positive pregnancy test.

Solution, Suspension, Tablet.

500mg, 750 mg, 1000 mg, 500mg/ml, 625 mg, 850 mg.

Solution, Suspension, Tablet.

• Dose Adjustment in Kidney impairment patient:

eGFR ≥60 mL/minute/1.73 m²: No dosage adjustment necessary. Monitor renal function at least annually.

eGFR >45 to <60 mL/minute/1.73 m²: No dosage adjustment necessary. Metformin plasma concentrations may be higher compared to patients with an eGFR ≥60 mL/minute/1.73 m²; increase monitoring of renal function (eg, every 3 to 6 months).

eGFR 30 to 45 mL/minute/1.73 m²:

Initiation of therapy: Use generally not recommended; however, initial therapy with 500 mg once daily with the evening meal titrated to 500 mg twice daily, if tolerated, with close monitoring of kidney function has been recommended by some experts.

Continuation of existing therapy: May continue at a reduced dose up to a maximum of 500 mg twice daily with close monitoring of kidney function.

eGFR <30 mL/minute/1.73 m²: Use is contraindicated.

Acute kidney injury during therapy: If acute kidney injury occurs or if risk factors are present (eg, severe vomiting or diarrhea), instruct patient to temporarily hold metformin

• Dose Adjustment in Hepatic Patient:

Hepatic impairment prior to treatment initiation:

Initial or dose titration in patients with preexisting liver cirrhosis:

Note: In patients with concurrent kidney impairment, eGFR ≤45 mL/minute/1.73 m² and Child-Turcotte-Pugh A or B, defer to dosing in altered kidney function in adults. Monitor kidney function frequently (eg, every 1 to 3 months) (expert opinion) during continuation of therapy.

Child-Turcotte-Pugh class A : No dosage adjustment necessary.

Child-Turcotte-Pugh class B : 500 mg once daily; may increase by ≤500 mg/day increments every 30 days based on tolerability and response (expert opinion); consider slower titration (eg, every 60 days) in patients on concurrent agents that cause diarrhea (eg, lactulose) or fluid loss (eg, diuretics) (expert opinion); maximum dose: 1.5 g/day . Note: Do not initiate in patients at risk for lactic acid–producing events (eg, active alcohol consumption, dehydration, hypotension, sepsis, reduced cardiac function, reduced kidney function).

Child-Turcotte-Pugh class C: Avoid use .

Dosage adjustment in patients with chronic, worsening hepatic function during treatment (eg, progression from Child-Turcotte-Pugh class A to B):

Note: In patients with concurrent kidney impairment, eGFR ≤45 mL/minute/1.73 m² and Child-Turcotte-Pugh A or B, defer to dosing in altered kidney function in adults . Monitor kidney function frequently (eg, every 1 to 3 months) during continuation of therapy.

Progression from baseline to Child-Turcotte-Pugh class A: No dosage adjustment necessary

Progression from Child-Turcotte-Pugh class A to B: No dosage adjustment necessary; however, a dose reduction may be required in patients at risk for lactic acid–producing events (eg, active alcohol consumption, dehydration, hypotension, sepsis, reduced cardiac function, reduced kidney function).

Progression from Child-Turcotte-Pugh class B to C: If tolerating with appropriate clinical endpoints, use with caution; discontinue metformin therapy in patients at risk for or who experienced a lactic acid–producing event (eg, active alcohol consumption, dehydration, hypotension, sepsis, reduced cardiac function, reduced kidney function).

Acute hepatotoxicity during treatment:

Acute worsening of hepatic function (eg, requiring hospitalization): Discontinue metformin during the acute event. Once the acute event has resolved, may resume metformin at pre-event doses (expert opinion). Permanent discontinuation should be considered for patients who recently experienced lactic acidosis, are at high risk of recurrent decompensation, or at risk of lactic acid–producing events .

Metformin-induced hepatotoxicity: Permanently discontinue metformin therapy. Although metformin is not metabolized by the liver, rare cases of metformin-induced hepatotoxicity have been reported within weeks of initiation, but concurrent use of other hepatotoxic medications is common. Most patients present with jaundice, fatigue, and elevated AST/ALT. Upon discontinuation of metformin, LFTs normalize over days to weeks and reoccurs upon rechallenge

• Dose Adjustment in Pediatric Patient:

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 .

Extended-release: Note: Fewer gastrointestinal effects may be seen with extended-release products; however, no pediatric studies have compared extended-release products to standard metformin.

Children ≥10 years and Adolescents:

Oral suspension: Oral: 500 mg once daily in the evening; titrate dose in 500 mg increments at weekly intervals as tolerated; maximum daily dose: 2,000 mg/day once daily with evening meal.

Tablets: Limited data available: Oral: Initial: 500 to 1,000 mg once daily for 7 to 14 days; may increase dose in 500 to 1,000 mg increments every 1 to 2 weeks as tolerated; maximum daily dose: 2,000 mg/day . Note: If glycemic control is not achieved at maximum dose, may divide dose and administer twice daily.

Surgical patients :

Minor surgeries: Discontinue metformin the day of surgery; monitor glucose closely; rapid-acting SUBQ insulin may be required. Continue to withhold metformin for 48 hours following surgery and until normal renal function has been confirmed.

Major surgeries (eg, lasting >2 hours): Discontinue metformin 24 hours prior to surgery; monitor glucose closely; IV insulin infusion may be needed for hyperglycemia during surgery. Continue to withhold metformin for 48 hours following surgery and until normal renal function has been confirmed.

Obesity; severe, adjunct therapy with lifestyle interventions: Limited data available; data has shown modest efficacy; reported mean BMI reduction −0.86 to −1.16 kg/m², although reported efficacy endpoints/outcomes in trials are variable. Overall, due to limited efficacy, some experts do not consider metformin a weight loss treatment option for pediatric obesity. Optimal treatment duration not established; duration in trials varied from 3 to 12 months. Daily multivitamin supplement may be considered with therapy.

Immediate release: Dosing regimens variable: Children ≥6 years and Adolescents: Oral: Initial: 500 mg once or twice daily, may titrate upward at weekly intervals by 500 mg/day increments; reported final doses: 1,000 to 2,000 mg/day in 2 divided doses; a meta-analysis showed that metformin 2,000 mg/day intervention was most identified as most effective relative to lower doses or lifestyle modifications in adolescents without diabetes . Age-dependent efficacy findings are conflicting; some data suggests that metformin may have greater efficacy in prepubertal children and others have shown a greater effect in pubertal subjects (11 to 17 years). A low dose (850 mg/day) over a prolonged period (24 months) showed positive effects on body composition (weight and BMI standard deviation scores) and other metabolic and inflammatory markers (eg, fat mass, liver fat, leptin, highly sensitive C-reactive protein) in a small, placebo-controlled trial of 22 subjects (metformin=13; age range: 6 to 13 years).

Extended release: Metformin XR: Adolescents: Oral: Initial: 500 mg once daily with dinner for 2 weeks; increase to 1,000 mg once daily for 2 weeks, and then 2,000 mg once daily; may slow titration if adverse gastrointestinal effects.

Weight gain, atypical antipsychotic-induced; treatment: Limited data available:

Immediate release: Note: In trials, all patients were diagnosed with autism spectrum disorder; trials used metformin oral solution and slowly titrated the dose to minimize GI effects and maximize tolerability. After 16 weeks of therapy, patients receiving metformin had a statistically significant decrease in BMI z-scores (primary efficacy outcome) as well as other secondary outcomes (eg, raw weight, BMI) compared to placebo. A 16-week, open-label extension study showed results achieved in the treatment group were maintained without further decreases .

6 to 9 years: Oral: Initial: 250 mg with evening meal for 1 week, then 250 mg twice daily for 1 week, then 500 mg twice daily.

10 to 17 years: Oral: Initial: 250 mg with evening meal for 1 week, then 250 mg twice daily for 1 week, then 500 mg twice daily for 1 week, then 850 mg twice daily.

Food decreases the extent and slightly delays the absorption.

Management: Administer with a meal.

Metformin may be contraindicated in the following conditions:

Hypersensitivity to metformin or any component of the formulation; severe renal dysfunction (eGFR <30 mL/minute/1.73 m²); acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis).

Disease-related concerns:

Bariatric surgery: Altered absorption: Use IR tablets or solution after surgery. ER tablets (Glucophage XR [hydrophilic polymer matrix], Fortamet [osmotic technology], Glumetza [gastric-retentive technology]) may have a reduced effect after gastric bypass or sleeve gastrectomy due to the direct bypass of the stomach and proximal small bowel with gastric bypass or a more rapid gastric emptying and proximal small bowel transit with sleeve gastrectomy. After gastric bypass (Roux-en-Y gastric bypass [RYGB]), administration of IR tablets led to increased absorption (AUC_{0- ∞} increased by 21%) and bioavailability (increased by 50%) . Lactate levels decrease after gastric bypass (RYGB)-induced weight loss irrespective of the use of metformin. Routinely lowering metformin dose after gastric bypass is not necessary as long as normal renal function is preserved .

Heart failure: Metformin may be used in patients with stable heart failure . Use cautiously or avoid in hypoperfusion.

Hepatic impairment: Use cautiously in patients at risk for lactic acidosis . An increased risk of mortality has been observed with higher metformin doses (eg, >1 g) and more severe liver dysfunction (eg, Child-Turcotte-Pugh C>B>>>A) Cases of metformin-induced hepatotoxicity have also been reported.

Renal impairment: Metformin is substantially excreted by the kidney; dosing adjustments may be required.

Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

There is no sufficient scientific evidence traceable regarding use and safety of Metformin in concurrent use with alcohol.

Metformin is present in breast milk.

Pregnancy Category (FDA): 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 HCl should not be used during pregnancy unless clearly needed.

The adverse reactions related to Metformin can be categorized as

• Common Adverse effects:

Vitamin B12 deficiency, Loss of Appetite

• Less Common Adverse effects:

Asthenia.

• Rare Adverse effects:

Lactic acidosis.

The clinically relevant drug interactions of Metformin is briefly summarized here:

Increased risk of lactic acidosis with carbonic anhydrase inhibitors (e.g. acetazolamide, dichlorphenamide, topiramate, zonisamide), NSAIDs, including cyclo-oxygenase (COX) II inhibitors; ACE inhibitors, angiotensin II receptor antagonists, and loop diuretics. Increased risk of hypoglycaemia with other antidiabetic agents (e.g. sulfonylurea, meglitinides, insulin). Increased plasma concentration with organic cation transporters (OCT)2 inhibitors (e.g. cimetidine, dolutegravir, ranolazine, trimethoprim, vandetanib, isavuconazole).

Reduced efficacy with OCT1 inhibitors (e.g. verapamil). Increased gastrointestinal absorption and efficacy with OCT1 inducers (e.g. rifampicin). Altered efficacy and renal elimination with OCT1 and OCT2 inhibitors (e.g. crizotinib, olaparib).

May produce hyperglycemia with corticosteroids, thiazide diuretics, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, Ca channel blockers, and isoniazid. May diminish the therapeutic effect of anticoagulants (e.g. warfarin).

The most common side effects of Metformin includes: Vitamin B12 deficiency, Loss of Appetite.

Pregnancy Category (FDA): 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 HCl should not be used during pregnancy unless clearly needed.

Labor and Delivery

There is no FDA guidance on use of Metformin during labor and delivery.

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 HCl is discontinued, and if diet alone is inadequate for controlling blood glucose, insulin therapy should be considered.

Pediatric Use

The safety and effectiveness of Metformin HCl for the treatment of type 2 diabetes have been established in pediatric patients ages 10 to 16 years (studies have not been conducted in pediatric patients below the age of 10 years). Use of Metformin HCl in this age group is supported by evidence from adequate and well-controlled studies of Metformin HCl in adults with additional data from a controlled clinical study in pediatric patients ages 10 to 16 years with type 2 diabetes, which demonstrated a similar response in glycemic control to that seen in adults. In this study, adverse effects were similar to those described in adults. A maximum daily dose of 2000 mg is recommended.

Geriatic Use

Controlled clinical studies of Metformin HCl 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. Metformin is known to be substantially excreted by the kidney and because the risk of serious adverse reactions to the drug is greater in patients with impaired renal function, Metformin HCl should only be used in patients with normal renal function. Because aging is associated with reduced renal function, Metformin HCl should be used with caution as age increases. Care should be taken in dose selection and should be based on careful and regular monitoring of renal function. Generally, elderly patients should not be titrated to the maximum dose of Metformin HCl.

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.

Symptoms: Lactic acidosis manifested as malaise, myalgia, respiratory distress, increasing somnolence and abdominal distress. Hypothermia, hypotension and resistant bradyarrhythmia may be associated with more marked acidosis.

Management: Perform hemodialysis to remove lactate and metformin in the blood.

Pharmacodynamics:

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 and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.

Pharmacokinetics:

Absorption: Slowly and incompletely absorbed from the gastrointestinal tract. Food slightly delays and decreases the extent of absorption. Absolute bioavailability: 50-60%. Time to peak plasma concentration: 2-3 hours (immediate-release); 7 hours, range: 4-8 hours (extended-release).

Distribution: Concentrates in liver, kidney and gastrointestinal tract. Crosses the placenta and enters breast milk (small amounts). Volume of distribution: 654 ± 358 L.

Metabolism: Not metabolized.

Excretion: Via urine (approx 90%, as unchanged drug).

Elimination half-life: 4-9 hours (plasma); approx 17.6 hours (blood).

1. https://www.uptodate.com/contents/Metformin -drug-information?search=Metformin &source=panel_search_result&selectedTitle=1~148&usage_type=panel&kp_tab=drug_general&display_rank=1#F154338
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022352s017lbl.pdf
3. https://www.medicaid.nv.gov/Downloads/provider/Metformin _2015-1215.pdf
4. https://www.mims.com/india/drug/info/Metformin ?type=full&mtype=generic#mechanism-of-action