Repaglinide / Metformin Hydrochloride

Pronunciation: re-PAG-li-nide/met-FOR-min HYE-droe-KLOR-ide
Class: Antidiabetic combination

Trade Names

PrandiMet
- Tablets, oral repaglinide 1 mg/metformin 500 mg
- Tablets, oral repaglinide 2 mg/metformin 500 mg

Pharmacology

Repaglinide

Stimulates release of insulin from the pancreas.

Metformin

Decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

Slideshow: 2013 Drug News Round-Up: Top 20 Stories

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes who are already treated with a meglitinide (eg, repaglinide) and metformin or who have inadequate glycemic control on a meglitinide or metformin alone.

Contraindications

Renal function impairment (eg, serum creatinine levels of 1.5 mg/dL or higher in men, 1.4 mg/dL or higher in women, abnormal CrCl); acute or chronic metabolic acidosis, including diabetic ketoacidosis; coadministration of both gemfibrozil and itraconazole; known hypersensitivity to any component of the product.

Dosage and Administration

Starting dose is based on the patient's current regimen, drug effectiveness, and tolerability.

Patients Inadequately Controlled With Metformin Monotherapy
Adults

PO Start with repaglinide 1 mg/metformin 500 mg twice daily with meals and gradually increase the dose (based on glycemic control) to reduce the risk of hypoglycemia with repaglinide.

Patients Inadequately Controlled With Meglitinide Monotherapy
Adults

PO Start with 500 mg of the metformin component of repaglinide/metformin twice daily and gradually increase the dose (based on glycemic control) to reduce the risk of GI adverse reactions associated with metformin.

Patients Currently Taking Repaglinide and Metformin Concomitantly
Adults

PO Start with doses of repaglinide and metformin that are similar to, but not exceeding, the current doses, then titrate to the max daily dose necessary to achieve glycemic control.

General Advice

  • May be administered 2 to 3 times daily up to a max daily dose of repaglinide 10 mg/metformin 2,500 mg.
  • No more than repaglinide 4 mg/metformin 1,000 mg should be taken per meal.
  • The timing of the dose may vary from immediately preceding the meal to up to 30 min before the meal; however, within 15 min prior to the meal is preferable.

Storage/Stability

Do not store above 77°F. Protect from moisture.

Drug Interactions

ACE inhibitors (eg, enalapril)

Risk of hypoglycemia may be increased. Monitor for signs or symptoms of hypoglycemia when starting an ACE inhibitor. Adjust the repaglinide dose as needed.

Alcohol

The effect of metformin on lactate metabolism may be potentiated. Warn patients against excessive alcohol intake, acute or chronic, while receiving repaglinide/metformin.

Beta-adrenergic blockers (eg, propranolol)

Repaglinide hypoglycemic effects may be increased and certain clinical manifestations of hypoglycemia (eg, tachycardia) may be blunted. Monitor blood glucose when starting or stopping the beta-adrenergic blocker and adjust the repaglinide dose as needed.

Cationic drugs (eg, amiloride, cimetidine, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, vancomycin)

May increase metformin serum concentrations by competing for tubular secretion. Closely monitor and adjust the dose of repaglinide/metformin and/or the interfering drug in patients who are taking cationic medications excreted via the proximal renal tubular secretory system.

CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, rifampin)

Repaglinide serum concentrations may be reduced, decreasing the efficacy. Monitor blood glucose and adjust the repaglinide dose as needed.

CYP2C8 inhibitors (eg, deferasirox, gemfibrozil, trimethoprim), CYP3A4 inhibitors (eg, clarithromycin, cyclosporine, grapefruit juice, itraconazole, ketoconazole, telithromycin)

Repaglinide serum concentrations may be elevated, increasing the pharmacologic effect and risk of adverse reactions. Monitor blood glucose and adjust repaglinide dose as needed. Repaglinide is contraindicated in patients taking gemfibrozil and both gemfibrozil and itraconazole.

Drugs that cause hyperglycemia (eg, corticosteroids, diazoxide, diuretics, phenothiazines, phenytoin)

May increase blood glucose, interfering with glycemic control. Monitor blood glucose and adjust the repaglinide dose as needed.

Drugs that cause hypoglycemia (eg, aspirin)

May decrease blood glucose, interfering with glycemic control. Monitor blood glucose and adjust the repaglinide dose as needed.

Fenofibrate

Coadministration increased the fenofibrate and repaglinide C max . A clinically important interaction is unlikely; however, monitor blood glucose. If an interaction is suspected, adjust the repaglinide dose as needed.

Food

When given with food, mean C max and AUC of repaglinide were decreased. Food decreases the extent and slightly delays the absorption of metformin. The clinical importance of these decreases is unknown. Repaglinide/metformin should usually be taken 15 min before the meal, but timing can vary from immediately preceding the meal up to 30 min before the meal.

Furosemide

Furosemide increased metformin C max . In addition, the repaglinide/metformin combination decreased the C max and AUC of furosemide. Monitor the clinical response. If an interaction is suspected, adjust treatment as needed.

Insulin

Repaglinide is not indicated for use in combination with isophane (NPH) insulin.

Levonorgestrel/ethinyl estradiol

Coadministration of levonorgestrel/ethinyl estradiol resulted in increases in repaglinide and ethinyl estradiol C max . Monitor blood glucose when starting or stopping levonorgestrel/ethinyl estradiol and adjust the repaglinide dose as needed.

Nifedipine

Coadministration increased plasma metformin C max and AUC, and decreased repaglinide C max and AUC. Monitor the clinical response. If an interaction is suspected, it may be necessary to adjust the repaglinide/metformin dose.

NSAIDs

Coadministration may increase the risk of acute renal failure and lactic acidosis. Use with caution. Closely monitor for changes in renal function and/or lactic acidosis. If an interaction is suspected, consider discontinuation of the NSAID.

Parenteral iodinated contrast material

Because of the increased risk of metformin-induced lactic acidosis, discontinue repaglinide/metformin at the time of or prior to the procedure, and withhold repaglinide/metformin for 48 h subsequent to the procedure. Reinstate treatment only after renal function has been evaluated and found to be healthy.

Simvastatin

Coadministration resulted in an increase in repaglinide C max . Monitor blood glucose and adjust the repaglinide dose as needed.

Adverse Reactions

Except for postmarketing reactions, which were reported with repaglinide, the following adverse reactions were reported with combined use of repaglinide plus metformin.

CNS

Headache (22%).

Dermatologic

Alopecia, Stevens-Johnson syndrome (postmarketing).

GI

GI system disorder (33%); diarrhea (19%); nausea (15%); pancreatitis (postmarketing).

Hematologic-Lymphatic

Hemolytic anemia, severe hepatic function impairment including hepatitis and jaundice (postmarketing).

Metabolic-Nutritional

Hypoglycemia (33%).

Respiratory

Respiratory tract infection (11%).

Precautions

Warnings

Lactic acidosis

Although rare, lactic acidosis can occur and is fatal in approximately 50% of cases as a result of metformin accumulation (eg, renal function impairment) or with pathophysiologic conditions associated with tissue hypoperfusion and hypoxia. The risk of lactic acidosis increases with the degree of renal function impairment and the patient's age. If lactic acidosis is suspected, discontinue medication and hospitalize the patient immediately.


Monitor

Perform periodic fasting blood glucose and HbA 1c measurements to monitor therapeutic response. Monitor vitamin B 12 levels at 2- to 3-year intervals in patients at risk of deficiency. Initial and periodic monitoring of hematologic parameters, including hemoglobin, hematocrit, and RBC, and monitoring of renal function should be done annually. Assess renal function before initiation of therapy and at least annually thereafter.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Elderly

Because aging is associated with reduced renal function, use with caution, titrating to establish the minimum dose for adequate glycemic control.

Renal Function

Risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment.

Hepatic Function

Hepatic impairment has been associated with cases of lactic acidosis.

Clinical status changes

Promptly evaluate patients who develop laboratory abnormalities or clinical illness for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones, blood glucose, and, if indicated, blood pH, lactate, pyruvate, and metformin levels.

Hypoxic states

Promptly discontinue treatment in patients experiencing hypoxic states, which may result from CV collapse (shock) from events such as acute CHF or acute MI.

Loss of glucose control

Consider temporarily withholding therapy and administering insulin in patients who lose glycemic control as a result of fever, trauma, infection, or surgery.

Surgical procedures

Temporarily suspend therapy for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids). Do not restart until oral intake has resumed and renal function has been evaluated as normal.

Vitamin B 12 levels

Metformin may interfere with vitamin B 12 absorption from the B 12 -intrinsic factor complex.

Overdosage

Symptoms

Metformin

Hypoglycemia, lactic acidosis.

Repaglinide

Diarrhea; dizziness; headache; severe hypoglycemic reactions with coma, seizures, or other neurological impairment.

Patient Information

  • Instruct patients to take repaglinide/metformin with meals, usually within 15 min prior to the meal, but the timing can vary from immediately preceding the meal to up to 30 min before the meal.
  • Instruct patients that if a meal is skipped, to skip the dose of repaglinide/metformin for that missed meal.
  • Advise patients to immediately contact health care provider if unexplained hyperventilation, myalgia, malaise, unusual somnolence, or other nonspecific symptoms occur.
  • Advise patients to avoid excessive acute or chronic alcohol use.

Copyright © 2009 Wolters Kluwer Health.

Hide
(web1)