Glipizide and Metformin

Pronunciation

(GLIP i zide & met FOR min)

U.S. Brand Names

Metaglip™

Synonyms

Glipizide and Metformin Hydrochloride; Metformin and Glipizide

Generic Available

No

Use

Initial therapy for management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) when hyperglycemia cannot be managed with diet and exercise alone. Second-line therapy for management of type 2 diabetes (NIDDM) when hyperglycemia cannot be managed with a sulfonylurea or metformin along with diet and exercise.

Pregnancy Risk Factor

C

Pregnancy Implications

Abnormal blood glucose levels during pregnancy may be associated with an increased incidence of congenital abnormalities. Insulin is the drug of choice for the control of diabetes mellitus during pregnancy. Glipizide and metformin both cross the placenta; use during pregnancy only if clearly needed.

Severe prolonged hypoglycemia has been reported in neonates whose mothers were taking sulfonylureas at the time of delivery. If the decision has been made to use Metaglip™ during pregnancy, it should be discontinued at least 1 month prior to delivery.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to glipizide, other sulfonamides, metformin, or any component of the formulation; renal disease or renal dysfunction (serum creatinine 1.5 mg/dL in males or 1.4 mg/dL in females, or abnormal creatinine clearance which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia); acute or chronic metabolic acidosis with or without coma (including diabetic ketoacidosis); congestive heart failure requiring pharmacologic treatment

Note: Temporarily discontinue in patients undergoing radiologic studies in which intravascular iodinated contrast materials are utilized.

Warnings/Precautions

Age, hepatic and renal impairment are independent risk factors for hypoglycemia. Use with caution in patients with hepatic impairment, malnourished or debilitated conditions, or adrenal or pituitary insufficiency. Use caution in patients with renal impairment. Use caution in the elderly and patients taking beta-blockers; signs and symptoms of hypoglycemia may be masked. Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin. Withhold therapy in hypoxemia, dehydration, or sepsis. The risk of lactic acidosis is increased in any patient with CHF requiring pharmacologic management. This risk is particularly high during acute or unstable CHF because of the risk of hypoperfusion and hypoxemia.

Metformin is substantially excreted by the kidney. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function. Patients with renal function below the limit of normal for their age should not receive metformin. In elderly patients, renal function should be monitored regularly; should not be used in any patient 80 years of age unless measurement of creatinine clearance verifies normal renal function. Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be suspended in patients with dehydration and/or prerenal azotemia. Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified).Intravascular iodinated contrast materials used for radiologic studies are associated with alteration of renal function and may increase risk of lactic acidosis. Discontinue Metaglip™ at the time of or prior to the procedure and withhold for 48 hours subsequent to the procedure; reinstitute only after renal function has been re-evaluated and found to be normal.

Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe.

Product labeling states oral hypoglycemic drugs may be associated with an increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. Data to support this association are limited, and several studies, including a large prospective trial (UKPDS), have not supported an association.

Adverse Reactions

Also see individual agents.

>10%:

Central nervous system: Headache (12%)

Endocrine & metabolic: Hypoglycemia (8% to 13%)

Gastrointestinal: Diarrhea (2% to 18%)

1% to 10%:

Cardiovascular: Hypertension (3%)

Central nervous system: Dizziness (2% to 5%)

Gastrointestinal: Nausea/vomiting (<1% to 8%), abdominal pain (6%)

Neuromuscular & skeletal: Musculoskeletal pain (8%)

Renal: Urinary tract infection (1%)

Respiratory: Upper respiratory tract infection (8% to 10%)

Overdosage/Toxicology

Glyburide: Symptoms of overdose include severe hypoglycemia, seizures, cerebral damage, tingling of lips and tongue, nausea, yawning, confusion, agitation, tachycardia, sweating, convulsions, stupor, and coma. Intoxications with sulfonylureas can cause hypoglycemia and are best managed with glucose administration (orally for milder hypoglycemia or by injection in more severe forms).

Metformin: Lactic acidosis may occur. Hemodialysis may be used in suspected cases of overdose.

Drug Interactions

Glipizide: Substrate of 2C8/9 (major)

Also see individual agents.

Ethanol/Nutrition/Herb Interactions

See individual agents.

Stability

Store at room temperature of 15°C to 30°C (59°F to 86°F).

Mechanism of Action

The combination of glipizide and metformin is used to improve glycemic control in patients with type 2 diabetes mellitus (noninsulin dependent, NIDDM) by using two different, but complementary, mechanisms of action:

Glipizide: Stimulates insulin release from the pancreatic beta cells; reduces glucose output from the liver; insulin sensitivity is increased at peripheral target sites

Metformin: Decreases hepatic glucose production, decreasing intestinal absorption of glucose and improves insulin sensitivity (increases peripheral glucose uptake and utilization)

Pharmacodynamics/Kinetics

See individual agents.

Dosage

Oral:

Adults:

Type 2 diabetes, first-line therapy: Initial: Glipizide 2.5 mg/metformin 250 mg once daily with a meal. Dose adjustment: Increase dose by 1 tablet/day every 2 weeks, up to a maximum of glipizide 10 mg/metformin 1000 mg daily

Patients with fasting plasma glucose (FPG) 280-320 mg/dL: Consider glipizide 2.5 mg/metformin 500 mg twice daily. Dose adjustment: Increase dose by 1 tablet/day every 2 weeks, up to a maximum of glipizide 10 mg/metformin 2000 mg daily in divided doses

Type 2 diabetes, second-line therapy: Glipizide 2.5 mg/metformin 500 mg or glipizide 5 mg/metformin 500 mg twice daily with morning and evening meals; starting dose should not exceed current daily dose of glipizide (or sulfonylurea equivalent) or metformin. Dose adjustment: Titrate dose in increments of no more than glipizide 5 mg/metformin 500 mg, up to a maximum dose of glipizide 20 mg/metformin 2000 mg daily.

Elderly: Conservative doses are recommended in the elderly due to potentially decreased renal function; do not titrate to maximum dose; should not be used in patients 80 years unless renal function is verified as normal

Dosage adjustment in renal impairment: Risk of lactic acidosis increases with degree of renal impairment; contraindicated in renal disease or renal dysfunction (see Contraindications)

Dosage adjustment in hepatic impairment: Use should be avoided; liver disease is a risk factor for the development of lactic acidosis during metformin therapy.

Administration

All doses should be administered with a meal. Twice-daily dosing should be administered with the morning and evening meals. Patients who are anorexic or NPO may need to have their dose held to avoid hypoglycemia.

Monitoring Parameters

Signs and symptoms of hypoglycemia, urine (glucose and ketones), FPG, Hb A1c, and fructosamine. Initial and periodic monitoring of hematologic parameters (eg, hemoglobin/hematocrit and red blood cell indices) and renal function should be performed. Monitor at least annually once patient is on maintenance therapy. While megaloblastic anemia has been rarely seen with metformin, if suspected, vitamin B12 deficiency should be excluded.

Reference Range

Target range: Adults: Fasting blood glucose: <120 mg/dL; glycosylated hemoglobin: <7%

Dietary Considerations

May cause GI upset; should be taken with food to decrease GI upset. Dietary modification based on ADA recommendations is a part of therapy. Decreases blood glucose concentration. Hypoglycemia may occur. Must be able to recognize symptoms of hypoglycemia (palpitations, sweaty palms, lightheadedness). Monitor for signs and symptoms of vitamin B12 deficiency. Monitor for signs and symptoms of folic acid deficiency.

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication is used to control diabetes; it is not a cure. Monitor glucose as recommended by prescriber. Other important components of treatment plan may include prescribed diet and exercise regimen (consult prescriber or diabetic educator). Always carry quick source of sugar with you. Take exactly as directed. All doses should be administered with a meal. Twice-daily dosing should be taken with the morning and evening meals. Do not change dose or discontinue without consulting prescriber. Avoid overuse of alcohol while taking this medication (could cause severe reaction). Do not take other medication within 2 hours of this medication unless advised by prescriber. If you experience hypoglycemic reaction, contact prescriber immediately. You may experience more sensitivity to sunlight (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight); drowsiness, dizziness, or headache (use caution driving or engaging in potentially hazardous tasks until response to drug is known); nausea or vomiting (taking with meals, eating small, frequent meals, frequent mouth care, or sucking lozenges may help). Report severe or persistent side effects (eg, hypoglycemia; palpitations, sweaty palms, lightheadedness; extended vomiting; diarrhea or constipation; flu-like symptoms; skin rash; easy bruising or bleeding; or change in color of urine or stool, sudden chest discomfort, slow or irregular heartbeat, or other adverse reactions). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Upper respiratory tract infection (8% to 10%). Dependent diabetics (noninsulin dependent, type 2) should be appointed for dental treatment in the morning in order to minimize chance of stress-induced hypoglycemia.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness

Mental Health: Effects on Psychiatric Treatment

Diarrhea is common; use caution with SSRIs. May rarely cause agranulocytosis; use caution with clozapine and carbamazepine. Phenothiazines and TCAs may antagonize glipizide hypoglycemic effects; MAO inhibitors and TCAs may enhance hypoglycemic effects.

Dosage Forms

Tablet [film coated]:

2.5/250: Glipizide 2.5 mg and metformin 250 mg

2.5/500: Glipizide 2.5 mg and metformin 500 mg

5/500: Glipizide 5 mg and metformin 500 mg

References

"Effect of Intensive Blood-Glucose Control With Metformin on Complications in Overweight Patients With Type 2 Diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group,"Lancet, 1998, 352(9131):854-65.