metformin (Rx)

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

Contraindications

Hypersensitivity to metformin

CHF

Diabetic ketoacidosis with or without coma

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

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

Lactation

Cautions

Increased risk of severe hypoglycemia especially in elderly, debilitated or malnourished, adrenal or pituitary insufficiency, dehydration, heavy alcohol use, hypoxic states, hepatic/renal impairment, stress due to infection, fever, trauma, or surgery

Concomitant administration of insulin and insulin secretagogues (e.g., sulfonylurea) may increase risk of hypoglycemia; therefore, a lower dose of insulin or insulin secretagogue may be required to minimize risk of hypoglycemia when used in combination with metformin

Withholding of food and fluids during surgical or other procedures may increase risk for volume depletion, hypotension, and renal impairment; therapy should be temporarily discontinued while patients have restricted food and fluid intake

Rare lactic acidosis may occur due to metformin accumulation; fatal in approximately 50% of cases; risk increases with age, degree of renal dysfunction, and with unstable or acute CHF; if metformin-associated lactic acidosis suspected, general supportive measures should be instituted promptly in a hospital setting, along with immediate discontinuation of therapy; in patients with a diagnosis or strong suspicion of lactic acidosis, prompt hemodialysis is recommended to correct acidosis and remove accumulated metformin (metformin hydrochloride is dialyzable, with a clearance of up to170 mL/minute under good hemodynamic conditions); hemodialysis has often resulted in reversal of symptoms and recovery

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), or experiences diabetic ketoacidosis

Several of the postmarketing cases of metformin-associated lactic acidosis occurred in setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia); cardiovascular collapse (shock) acute myocardial infarction, sepsis, and other conditions associated with hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia; discontinue therapy when such events occur

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

Conclusive evidence of macrovascular risk reduction with metformin not established

Clinical recommendations based upon the patient’s renal function

• Before initiating therapy, obtain an eGFR
• Initiation of therapy is not recommended in patients with eGFR between 30 –45 mL/minute/1.73 m²
• Obtain an eGFR at least annually in all patients receiving therapy
• In patients at increased risk for development of renal impairment (e.g., the elderly), renal function should be assessed more frequently
• If eGFR later falls below 45 mL/minute/1.73 m², assess benefit and risk of continuing therapy

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

Limited data with in pregnant women are not sufficient to determine drug-associated risk for major birth defects or miscarriage; published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk; poorly-controlled diabetes mellitus in pregnancy increases maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications; poorly controlled diabetes mellitus increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity

Human data

• Published data from post-marketing studies have not reported clear association with metformin and major birth defects, miscarriage, or adverse maternal or fetal outcomes when used during pregnancy; however, these studies cannot definitely establish absence of any metformin-associated risk because of methodological limitations, including small sample size and inconsistent comparator groups

Animal data

• Metformin hydrochloride did not adversely affect development outcomes when administered to pregnant rats and rabbits at doses up to 600 mg/kg/day; this represents exposure of about 2 and 5 times a 2550 mg clinical dose based on body surface area comparisons for rats and rabbits, respectively; determination of fetal concentrations demonstrated a partial placental barrier to metformin

Reproduction potential

• Discuss potential for unintended pregnancy with premenopausal women as therapy may result in ovulation in some anovulatory women

Lactation

Limited published studies report that metformin is present in human milk; however, there is insufficient information to determine effects of metformin on breastfed infant and no available information on effects of metformin on milk production; therefore, developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed child from therapy or from the underlying maternal condition

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.

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)