Usual Adult Dose for Diabetes Type 2

Immediate-release:
Initial dose: 500 mg orally twice a day or 850 mg orally once a day

• Dose titration: Increase in 500 mg increments weekly or 850 mg every 2 weeks as tolerated

Maintenance dose: 2000 mg/day in divided doses
Maximum dose: 2550 mg/day

Extended-release:
Initial dose: 500 to 1000 mg orally once a day
Dose titration: Increase in 500 mg increments weekly as tolerated
Maximum dose: 2000 mg/day

Switching to Extended-Release:

• Patients receiving immediate-release may switch to extended-release once a day at same total daily dose (up to 2000 mg/day)

Comments:

• Metformin, if not contraindicated, should be considered first line-therapy for the management of type 2 diabetes mellitus.
• Immediate-release: Take in divided doses 2 to 3 times a day with meals; titrate slowly to minimis gastrointestinal side effects. In general, significant responses are not observed with doses less than 1500 mg/day and doses above 2000 mg are generally associated with little additional efficacy and poorer tolerability.
• Extended-release (ER): Take with the evening meal; if glycemic control is not achieved with ER 2000 mg once a day, may consider splitting daily dose to ER 1000 mg twice a day; if glycemic control is still not achieve, consider switch to immediate-release product.

Use: To improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise.

Usual Pediatric Dose for Diabetes Type 2

10 years or older:
Immediate-release:
Initial dose: 500 mg orally twice a day

• Dose titration: Increase in 500 mg increments weekly as tolerated; daily dose should be taken in divided doses 2 to 3 times a day with meals

Maximum dose: 2000 mg/day

Extended-release oral suspension:
Initial dose: 500 mg orally once a day with evening meal

• Dose titration: Increase in 500 mg increments weekly based on glycemic control and tolerability

Maximum dose: 2000 mg/day

Comments:

• Titrate slowly to minimize gastrointestinal side effects.

Use: To improve glycemic control in children with type 2 diabetes mellitus as an adjunct to diet and exercise.

Renal Dose Adjustments

Obtain eGFR prior to initiating therapy:

• eGFR less than 30 mL/min/1.73 m2: Use is contraindicated
• eGFR 30 to 45 mL/min/1.73 m2: Initiating therapy is not recommended
• eGFR that falls below 30 mL/min/1.73 m2 during therapy: Discontinue therapy
• eGFR that falls below 45 mL/min/1.73 m2 during therapy: Assess risks versus benefit of continued therapy
• eGFR greater than 45 mL/min/1.73 m2: No dose adjustments recommended

IODINATED CONTRAST PROCEDURE: See Dosage Adjustment Section

Liver Dose Adjustments

Not recommended in patients with liver impairment

IODINATED CONTRAST PROCEDURE: See Dosage Adjustment Section

Dose Adjustments

Elderly, debilitated, and malnourished patients: Titration to the maximum dose is generally not recommended.

IODINATED CONTRAST PROCEDURE:
Stop this drug at the time of, or before imaging procedure:

• In patients with an eGFR between 30 and 60 mL/min/1.73 m2
• In patients with a history of hepatic impairment, alcoholism, or heart failure
• In patients receiving intra-arterial iodinated contrast

Re-evaluate eGFR 48 hours after procedure; restart therapy only if renal function is stable.

Concomitant use with Insulin or Insulin Secretagogues:

• A lower dose of insulin or insulin secretagogues may be required to minimize the risk of hypoglycemia.

Concomitant Insulin Therapy:

• When initiating therapy in patients currently receiving insulin, metformin should be started at 500 mg orally once a day and titrated in 500 mg increments weekly.
• When fasting blood glucose levels decrease to less than 120 mg/dL, consider decreasing the insulin dose by 10% to 25%.

Therapeutic drug monitoring/range: Steady-state plasma concentrations are achieved within 24 to 48 hours and are generally less than 1 mcg/mL. Metformin levels greater than 5 mcg/mL have been implicated as the cause of lactic acidosis.

Precautions

US BOXED WARNING: LACTIC ACIDOSIS

• Postmarketing case of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis has been characterized by elevated blood lactate levels (greater than 5 mmol/L) anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally greater than 5 mcg/mL.
• Risk factors for metformin-associated lactic acidosis include with renal impairment, concomitant use of certain drugs (e.g., carbonic anhydrase inhibitors such as topiramate), age 65 years old or greater, having a radiological study with contrast, surgery, and other procedures, hypoxic states (e.g., acute congestive heart failure), excessive alcohol intake, and hepatic impairment; recommendations are provided in the full prescribing guidelines to reduce the risks.
• If acidosis is suspected, immediately discontinue drug and hospitalize patient. Prompt hemodialysis is recommended.

CONTRAINDICATIONS:

• Hypersensitivity to active substance
• Severe renal impairment (eGFR less than 30 mL/min/1.73 m2)
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma

Safety and efficacy have not been established in patients younger than 10 years.

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Take orally with meals
• Gastrointestinal tolerability may be improved by slowly increasing dose; doses above 2000 mg per day may be better tolerated given 3 times a day with meals

EXTENDED-RELEASE (ER): Take with evening meal

• ER tablets: Swallow whole; do not crush, cut, dissolve, or chew
• ER oral suspension: Measure dose in supplied dose cup; shake bottle well for at least 10 seconds before each use

Reconstitution/preparation techniques:

• ER oral suspension should be reconstituted with accompanying diluent prior to dispensing; both powder and diluent contain active drug
• To reconstitute, pour contents containing drug pellets into the drug diluent bottle; shake continuously in up/down direction for at least 2 minutes; dispense in diluent bottle (do not repackage)

Storage:

• ER oral suspension: Store between 20C and 25C (68F to 77F)
• Discard reconstituted suspension after 100 days

General:

• If patients do not respond to therapy after 3 to 4 months, consider intensifying treatment as outlined in accepted diabetes management algorithms and diabetes standards of care.
• Not for use in patients with type 1 diabetes or diabetic ketoacidosis.
• Therapy should be temporarily stopped when restricted food or fluid intake is expected such as surgical procedures; see dosage adjustment section for recommendations on radiologic studies with contrast.

Monitoring:

• Renal: Obtain eGFR at baseline and repeat at least annually; assess renal function more often in patients at risk for developing renal impairment (e.g., elderly)
• Hematologic: Measure hematologic parameters annually; periodically asses Vitamin B-12 levels, especially in patients with peripheral neuropathy or anemia.
• Monitor glycemic control

Patient advice:

• Patients should be instructed to read the US FDA-approved patient labeling (Patient Information and Instructions for Use).
• Extended-release tablet shells may appear in faeces, and this should not cause alarm.
• Inform patients about the risk of lactic acidosis, conditions that might predispose them to its occurrence, and symptoms to watch for and report.
• Patients should understand the signs and symptoms, risks, and treatment of low blood sugar, especially if using this drug in combination with insulin or other drugs that may lower blood sugar.
• Advise patient that this drug may need to be temporarily stopped if undergoing radiologic studies with iodinated contrast materials or surgical procedures that will limit food or fluid intake.
• Advise patients on the risks of excessive alcohol intake.
• Tell patients that while gastrointestinal symptoms might be common when initiating treatment, gastrointestinal problems after initiation should be reported.
• Advise premenopausal anovulatory females that this drug may result in an unintended pregnancy due to its effect on ovulation.

Frequently asked questions

• What is the safest diabetes medication?
• Does metformin cause weight loss?
• When is the best time to take metformin?
• Can you take metformin without food?
• Does metformin lower A1C, if so how much?
• How long does metformin take to work?
• What are the symptoms of lactic acidosis caused by metformin?
• Why does Metformin smell like fish?
• Does metformin cause hypoglycemia?
• How does metformin work?
• Is Invokana the same as metformin?
• How long does glucophage/Metformin stay in your system?
• Can Diabetes go away with diet and exercise?
• What are the ingredient drugs contained in Qternmet XR?