DrugindexOnline^{2nd edition}

Pronouncation: (met-FORE-min HIGH-droe-KLOR-ide)
Class: Biguanide

Trade Names:
Glucophage
- Tablets 500 mg
- Tablets 850 mg
- Tablets 1,000 mg

Trade Names:
Glucophage XR
- Tablets, extended-release 500 mg
- Tablets, extended-release 750 mg
- Tablets, extended-release 1,000 mg
- Oral solution 500 mg per 5 mL

Trade Names:
Fortamet
- Tablets, extended-release 500 mg
- Tablets, extended-release 1,000 mg

Trade Names:
Riomet
- Oral solution 500 mg per 5 mL

Apo-Metformin (Canada)
Gen-Metformin (Canada)
Novo-Metformin (Canada)
Nu-Metformin (Canada)
PMS-Metformin (Canada)
ratio-Metformin (Canada)
Rhoxal-metformin (Canada)
Rhoxal-metformin FC (Canada)

Mechanism of Action

Pharmacology

Decreases blood glucose by decreasing hepatic glucose production. May also decrease intestinal absorption of glucose and increase response to insulin.

Pharmacokinetics

Absorption

Absolute bioavailability is approximately 50% to 60%. T _max is 4 to 8 h; C _max is approximately 0.6 to 1.8 mcg/mL (extended-release [ER]). Food decreases the extent of absorption and increases the T _max (IR).

Distribution

The apparent Vd is approximately 654 L; protein binding is negligible.

Elimination

The major route for excretion is renal via tubular secretion as unchanged. The plasma t _½ is 6.2 h; t _½ in blood is 17.6 h.

Indications and Usage

Adjunct to diet and exercise to lower blood glucose in patients with type 2 diabetes mellitus. Metformin IR tablets and oral solution are indicated in patients 10 yr of age and older. The ER tablets are indicated in patients 17 yr of age and older. In combination with a sulfonylurea or insulin to improve glycemic control, metformin is indicated in patients 17 yr of age and older.

Contraindications

Renal disease or dysfunction as suggested by serum creatinine of 1.5 mg/dL or higher in men or 1.4 mg/dL or higher in women or abnormal Ccr; conditions that predispose to renal dysfunction (eg, CV collapse, acute MI, septicemia); in patients undergoing radiologic studies involving parenteral administration of iodinated contrast material (potential to acutely alter renal function); acute or chronic metabolic acidosis, including diabetic ketoacidosis; CHF requiring pharmacologic treatment.

Dosage and Administration

Concomitant Sulfonylurea Therapy Adults

PO If patient has not responded to 4 wk of max metformin monotherapy, consider gradual addition of an oral sulfonylurea while continuing the max metformin dose.

Concomitant insulin therapy Adults

PO Initiate metformin IR or ER therapy at 500 mg once daily in patients receiving insulin therapy. The metformin dose may be increased 500 mg after 1 wk and by 500 mg every wk thereafter until adequate glycemic control is achieved (max, 2,500 mg/day metformin IR and 2,000 mg/day metformin ER (2,500 mg/day Fortamet ). It is recommended that the insulin dose be decreased by 10 to 25% when fasting plasma glucose decreases to less than 120 mg/dL in patients receiving metformin IR or ER.

Glucophage (Metformin IR)
Adults Initial dose

PO 500 mg twice daily given with meals, increase by 500 mg weekly (max, 2,000 mg/day in divided doses). Patients also can be titrated from 500 mg twice daily to 850 mg twice daily after 2 weeks. For patients requiring additional glycemic control, Glucophage may be given up to a max dose of 2,550 mg/day.

Adults Initial dose

PO 850 mg once daily given with meals, increase by 850 mg q 2 wk (max, 2,550 mg/day in divided doses). Doses more than 2,000 mg may be better tolerated given tid with meals.

Fortamet
Adults

PO 1,000 mg once daily with evening meal, increase by 500 mg weekly (max, 2,500 mg once daily).

Glucophage XR
Adults Initial dose

PO 500 mg once daily with evening meal, increase by 500 mg every wk (max, 2,000 mg once daily). If glycemic control is not achieved on Glucophage XR 2,000 mg once daily, a trial of Glucophage XR 1,000 mg twice daily should be considered. If higher doses of metformin are required, administer at total daily dose up to 2,500 mg in divided daily doses as described above.

Glucophage , Riomet (Metformin IR)
Children 10 yr of age and older IR tablet or oral solution

PO 500 mg twice daily with meals. Dosage may be increased in weekly 500 mg increments to a max of 2,000 mg/day in divided doses.

Storage/Stability

Store tablets and oral solution at controlled room temperature (59° to 86°F).

Drug Interactions

Alcohol

Potentiates effect of metformin on lactate metabolism.

Cationic drugs (eg, amiloride, digoxin, quinidine)

May increase metformin serum concentration by competing for tubular secretion.

Cimetidine

Increases metformin serum concentration.

Furosemide

May increase metformin serum concentration; metformin may reduce furosemide serum concentration.

Iodinated contrast material

May cause acute renal failure and has been associated with lactic acidosis in patients receiving metformin.

Nifedipine

Increases metformin serum concentration.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Metformin IR

Palpitation (1% to 5%).

CNS

Metformin IR

Asthenia, headache (at least 5%); lightheadedness (1% to 5%).

Metformin ER

Dizziness, headache (1% to 5%).

Dermatologic

Metformin IR

Flushing, nail disorder, rash, increased sweating (1% to 5%).

GI

Metformin IR

Abdominal discomfort, diarrhea, flatulence, indigestion, nausea/vomiting (at least 5%); abnormal stools, taste disorder (1% to 5%).

Metformin ER

Diarrhea, nausea/vomiting (at least 5%); abdominal distention, abdominal pain, constipation, dyspepsia/heartburn, flatulence, taste disturbance (1% to 5%).

Metabolic-Nutritional

Metformin IR

Hypoglycemia (1% to 5%).

Musculoskeletal

Metformin IR

Myalgia (1% to 5%).

Respiratory

Metformin IR

Dyspnea (1% to 5%).

Metformin ER

Upper respiratory tract infection (1% to 5%).

Miscellaneous

Metformin IR

Chest discomfort, chills, flu syndrome (1% to 5%).

Precautions

Warnings Lactic acidosis Can occur and be fatal in approximately 50% of cases, as a result of metformin accumulation (eg, renal impairment) or with pathophysiologic conditions associated with tissue hypoperfusion and hypoxia. The risk of lactic acidosis increases with the degree of renal dysfunction and the patient's age.

Pregnancy

Category B . Insulin is recommended to maintain blood glucose levels during pregnancy.

Lactation

Undetermined.

Children

Metformin ER

Safety and efficacy not established.

Metformin IR

Safety and efficacy not established in children younger than 10 yr of age.

Elderly

Use with caution. Max doses are generally not used because of age-related decreases in renal function.

Renal Function

Decreased renal function results in decreased renal Cl and prolongation of the metformin t _{1/ 2} in patients with renal impairment. Comedications that affect renal function result in significant hemodynamic changes or interfere with disposition of metformin (eg, cationic drugs eliminated by renal tubular secretion) should be used with caution.

Hepatic Function

Avoid metformin in patients with clinical or laboratory evidence of hepatic disease.

GI symptoms

GI symptoms occurring after a patient is stabilized on metformin are unlikely to be drug related but could be because of lactic acidosis or other serious disease.

Iodinated contrast media

Withhold metformin therapy at the time of or prior to the procedure, and withhold for 48 h subsequent to the procedure and reinstate only after renal function has been re-evaluated and found to be normal.

Overdosage

Symptoms

Lactic acidosis

Malaise, myalgia, respiratory distress, increased somnolence, abdominal distress.

Patient Information

• Explain name, action, and potential side effects of drug, including risk of developing lactic acidosis.
• Advise patient or caregiver to read patient information leaflet before using the first time and with each refill.
• Advise patient to take prescribed dose with food to decrease GI side effects.
• Advise patient using ER tablets to swallow tablets whole. Caution patient not to crush, chew, or break the tablets.
• Inform patient using ER tablets that the inactive ingredients in the tablet may be eliminated in the feces as a soft mass that may look like the original tablet. Advise patient that the active medication will have already been absorbed into the body.
• Advise patient that medication will be started at a low dose that may be gradually increased until max benefit is obtained.
• Educate patient or caregiver regarding type 2 diabetes and its management, including target ranges for blood sugar control. Instruct patient that metformin is not a substitute for diet and exercise and to continue to follow prescribed regimens.
• Educate patient or caregiver regarding potential long-term complications of uncontrolled diabetes and the need for regular general physical and eye examinations.
• Emphasize the importance of regular daily blood glucose monitoring and periodic hemoglobin A _1c (HbA _1c ) tests.
• Advise patient to keep a log of measured blood sugars and to take to each visit with their health care provider.
• Advise patient to carry medical identification of diabetes (eg, card, bracelet).
• Caution patient to avoid excessive alcohol intake to reduce risk of developing lactic acidosis.
• Inform patient that medication may cause an unpleasant metallic taste when it is first started but that this usually goes away with continued treatment. Advise patient to inform health care provider if this occurs and does not go away.
• Advise patient that GI symptoms (eg, diarrhea, nausea, gas, abdominal discomfort, indigestion) are common when metformin is first started and during dose adjustments, but that they are temporary and go away. Caution patient that onset of GI symptoms developing late in therapy may indicate a serious condition (eg, lactic acidosis) and should be reported to health care provider immediately.
• Instruct patient to report any of the following to health care provider immediately: general body discomfort; feeling very weak, tired or uncomfortable; unexplained muscle aches; unexplained rapid breathing or shortness of breath; unusual or unexpected stomach discomfort; feeling cold, dizzy, or lightheaded; slow or irregular heartbeat.
• Review symptoms of hypoglycemia and hyperglycemia and action plans to undertake in the event either occur.
• Instruct patient to notify health care provider if experiencing hypoglycemic episodes or if measured blood sugars are outside target range.