metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)

Dosing and uses of metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

tablet, immediate-release

• 500mg
• 850mg
• 1000mg

tablet, extended-release

• 500mg
• 750mg
• 1000mg

oral solution

• 100mg/mL

 

Type 2 Diabetes Mellitus

Monotherapy or with sulfonylurea

Immediate-release tablet or solution

• Initial: 500 mg PO q12hr or 850 mg PO qDay with meals; increase q2Weeks
• Maintenance: 1500-2550 mg/day PO divided q8-12hr with meal
• Not to exceed 2550 mg/day

Extended-release

• Glucophage XR: 500 mg PO qDay with dinner; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day
• Fortamet: 500-1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2500 mg/day
• Glumetza: 1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day

 

Type 2 Diabetes Prevention (Off-label)

850 mg PO qDay

Target dosing: 850 mg PO q12hr

 

Dosage modifications

Hepatic impairment: Avoid use; risk of lactic acidosis

Renal impairment

• Obtain eGFR before starting metformin
• eGFR <30 mL/min/1.73 m²: Contraindicated
• eGFR 30-45 mL/min/1.73 m²: Not recommended to initiate treatment
• Monitor eGFR at least annually or more often for those at risk for renal impairment (eg, elderly)
• If eGFR falls below 45mL/min/1.73 m² while taking metformin, risks and benefits of continuing therapy should be evaluated
• If eGFR falls below 30 mL/min/1.73 m²: while taking metformin, discontinue the drug

 

Polycystic Ovary Syndrome (Orphan)

Orphan designation for treatment of pediatric polycystic ovary syndrome

Sponsor

• EffRx Pharmaceuticals SA; Wolleraustrass 41 B; 8807 Freienbach (SZ); SWITZERLAND

 

Pediatric dosage forms and strengths

tablet, immediate-release

• 500mg
• 850mg
• 1000mg

tablet, extended-release

• 500mg
• 750mg
• 1000mg

oral solution

• 100mg/mL

 

Type 2 Diabetes Mellitus

Immediate-release (10-16 years)

• Initial: 500 mg PO q12hr
• Maintenance: Titrate qWeek by 500 mg; no more than 2000 mg/day in divided doses

Immediate-release (≥17 years)

• Initial: 500 mg PO q12hr or 850 mg PO qDay with meals; increase q2Weeks
• Maintenance: 1500-2550 mg/day PO divided q8-12hr with meal
• No more than 2550 mg/day

Extended-release (<17 years)

• Safety and efficacy not established

Extended-release (≥17 years)

• Glucophage XR: 500 mg PO qDay with dinner; titrate by 500 mg/day qWeek; not to exceed 2000 mg/day
• Fortamet: 500-1000 mg PO qDay; titrate by 500 mg/day qWeek; not to exceed 2500 mg/day

 

Dosage modifications

Renal impairment

• Obtain eGFR before initiating metformin
• eGFR <30 mL/min/1.73 m²: Contraindicated
• eGFR 30-45 mL/min/1.73 m²: Initiating not recommended
• Obtain GFR at least annually in all patients taking metformin; assess eGFR more frequently in patients at increased risk for renal impairment (eg, elderly)
• If eGFR falls to <45 mL/min/1.73 m² during treatment: Assess the benefits and risks of continuing treatment
• If eGFR falls to <30 mL/min/1.73 m² during treatment: Discontinue

 

Geriatric dosage forms and strengths

Elderly patients are more likely to have decreased renal function; contraindicated in patients with renal impairment, carefully monitor renal function in the elderly and use with caution as age increases

Not for use in patients >80 years unless normal renal function establishedInitial and maintenance dosing of metformin should be conservative in patients with advanced age due to the potential for decreased renal function in this population

Controlled clinical studies of metformin did not include sufficient numbers of elderly patients to determine whether they respond differently from younger patients

 

metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet) adverse (side) effects

Frequency not defined

Asthenia

Diarrhea

Flatulence

Weakness

Myalgia

Upper respiratory tract infection

Hypoglycemia

GI complaints

Lactic acidosis (rare)

Low serum vitamin B-12

Nausea/vomiting

Chest discomfort

Chills

Dizziness

Abdominal distention

Constipation

Heartburn

Dyspepsia

 

Warnings

Black box warnings

Lactic acidosis is a rare, but potentially severe, consequence of therapy with metformin; it 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 concentrations >5 mcg/mL are generally found

Patients with CHF requiring pharmacologic management, in particular those with unstable or acute CHF who are at risk for hypoperfusion and hypoxemia, are at an increased risk for lactic acidosis; the risk for lactic acidosis increases with the degree of renal dysfunction and the patient’s age

Do not start in patients aged 80 years or older unless CrCl demonstrates that renal function is not reduced, because these patients are more susceptible to developing lactic acidosis; metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis

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, during metformin therapy because alcohol potentiates the effects of metformin on lactate metabolism

Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast

The onset of lactic acidosis often is subtle and accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, increasing somnolence, nonspecific abdominal distress); with marked acidosis, hypothermia, hypotension, and resistant bradyarrhythmias may occur; patients should be instructed regarding recognition of these symptoms and told to notify their physician immediately if the symptoms occur; metformin 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, GI symptoms, which are common during initiation of therapy, are unlikely to be drug related; later occurrences of GI symptoms could be due to lactic acidosis or other serious disease

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis who is 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, the drug should be discontinued immediately and general supportive care measures promptly instituted; metformin is highly dialyzable (clearance up to 170 mL/min under good hemodynamic conditions); prompt hemodialysis is recommended to correct the acidosis and to remove the accumulated metformin; such management often results in prompt reversal of symptoms and recovery

 

Contraindications

Hypersensitivity to metformin

CHF

Metabolic acidosis with or without coma

DKA

Severe renal disease: eGFR <30 mL/min/1.73 m²

Abnormal creatinine clearance resulting from shock, septicemia, or myocardial infarction

Lactation

 

Cautions

Use with caution in patients with congestive heart failure, fever, trauma, surgery, the elderly, renal impairment, or hepatic impairment

Instruct patients to avoid heavy alcohol use

Suspend therapy prior to any type of surgery

Rare, but serious, lactic acidosis can occur due to accumulation

Possible increased risk of CV mortality

May cause ovulation in anovulatory and premenopausal PCOS patients

May be necessary to discontinue therapy with metformin and administer insulin if patient is exposed to stress (fever, trauma, infection)

Ethanol may potentiate metformin’s effect on lactate metabolism

May impair vitamin B12 or calcium intake/absorption; monitor B12 serum concentrations periodically with long-term therapy

Not indicated for use in patients with type 1 diabetes mellitus that are insulin dependent due to lack of efficacy

Withhold in patients with dehydration and/or prerenal azotemia

Iodinated contrast imaging procedures

• Discontinue metformin at the time of or before an iodinated contrast imaging procedure in patients with an eGFR between 30-60 mL/minute/1.73 m²; in patients with a history of liver disease, alcoholism, or heart failure; or in patients who will be administered intra-arterial iodinate contrast
• Reevaluate eGFR 48 hr after the imaging procedure; restart metformin if renal function is stable

 

Pregnancy and lactation

Pregnancy category: B

Lactation: Enters breast milk; not recommended

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of metformin (Glucophage, Glucophage XR, Fortamet, Glumetza, Riomet)

Mechanism of action

Decreases hepatic glucose production; decreases GI glucose absorption; increases target cell insulin sensitivity

 

Absorption

Bioavailability: 50-60%

Peak plasma time

• Regular-release: 2-3 hr
• Extended-release: 4-8 hr

 

Distribution

Protein bound: MinimaL

Vd: 650 L (regular-release)

 

Metabolism

Metabolism: Not by liver

 

Elimination

Half-Life: 4-9 hr

Dialyzable: Yes (hemodialysis)

Renal clearance: 450-540 mL/min (regular-release)

Excretion: Urine (90%, by tubular secretion)