metformin (Rx) - Glucophage, Glucophage XR, more..Fortamet, Glumetza, Riomet

Dosing Forms & Strengths

Type 2 Diabetes Mellitus (Monotherapy or with Sulfonylurea)

Protease Inhibitor-Induced Hyperglycemia

850 mg PO qDay

Polycystic Ovarian Syndrome (Off-label)

500-850 mg PO q8hr

Hepatic Impairment

Liver Disease: Avoid use, risk for development of lactic acidosis

Renal Impairment

Males: Scr >1.5 mg/dL avoid use

Females: Scr >1.4 mg/dL avoid use

Geriatric Dosing

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.

Initial 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.

Other Indications & Uses

May be used to control hyperglycemia/hyperlipidemia in HIV patients taking protease inhibitors

Dosing Forms & Strengths

Type 2 Diabetes Mellitus (>10 Years Old) Immediate Release

Initial: 500 mg PO q12hr

Maintenance: Titrate qWeek by 500 mg, no more than 2000 mg/day in divided doses

Type 2 Diabetes Mellitus (>17 Years Old) Extended Release

Initial: 500 mg qDay

Maintenance: 1000-2000 mg qDay, no more than 2000 mg/day

Other Information

Not recommended <10 years old

Potential toxic dose <6 years old: 30 mg/kg

Safety & efficacy of extended-release Fortamet or Glumetza in pediatric patients, and Glucophage XR in children younger than 17 years are not established

Frequency Not Defined

Asthenia

Diarrhea

Flatulence

Weakness

Myalgia

Upper respiratory tract infection

Hypoglycemia

GI complaints

Lactic acidosis (rare)

Low serum vitB12

Nausea/vomiting

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 of hypoperfusion and hypoxemia, are at an increased risk of lactic acidosis. The risk of 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.

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 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 to notify their physician immediately if they 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 GIl symptoms could be due to lactic acidosis or other serious disease.

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, 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, DKA

Renal disease (serum creatinine >1.5 mg/dL [132.6 umol/L])

Radiologic contrast study for 48 hr after

Lactation

Cautions

Dehydration, debilitation, malnutrition, heavy alcohol use, hypoxic states, hepatic impairment, infection-induced stress, fever, trauma, surgery, elderly

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

Mechanism of Action

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

Pharmacokinetics

Toxic range: >5mcg/mL (Regular release)

Half-Life: 1.5-6.2 hr (Regular release)

Bioavailability: 50-60%

Vd: 650 L (regular release)

Protein Bound: Minimal

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

Metabolism: Not by liver

Excretion: urine: 90% by tubular secretion

Dialyzable: HD: yes