Sitagliptin / Metformin Hydrochloride

Pronunciation: (SYE-ta-GLIP-tin/met-FOR-min HYE-droe-KLOR-ide)
Class: Antidiabetic combination

Trade Names

Janumet
- Tablets sitagliptin 50 mg/metformin hydrochloride 500 mg
- Tablets sitagliptin 50 mg/metformin hydrochloride 1,000 mg

Pharmacology

Sitagliptin

Slows the inactivation of incretin hormones.

Metformin

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

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both sitagliptin and metformin is appropriate.

Contraindications

Renal disease or renal function impairment (eg, serum creatinine levels at least 1.5 mg/dL [males] and at least 1.4 mg/dL [females]); acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma; history of a serious hypersensitivity reaction, such as anaphylaxis or angioedema, to any component of the product.

Dosage and Administration

Base dosage selection of sitagliptin/metformin on the patient's current dose of these agents (max, sitagliptin 100 mg/metformin 2,000 mg daily).

Patients Inadequately Controlled on Metformin Monotherapy
Adults

PO Start with sitagliptin 50 mg twice daily plus the current dose of metformin. For patients taking metformin 850 mg twice daily, the recommended starting dosage is sitagliptin 50 mg/metformin 1,000 mg twice daily.

Patients Inadequately Controlled on Sitagliptin Monotherapy
Adults

PO Start with sitagliptin 50 mg/metformin 500 mg twice daily. Titrate patient up to sitagliptin 50 mg/metformin 1,000 mg twice daily. Patients taking sitagliptin monotherapy whose dose has been adjusted for renal function impairment should not be switched to sitagliptin plus metformin.

Patients Inadequately Controlled on Dual Combination Therapy With Any 2 of the Following Antihyperglycemic Agents: Sitagliptin, Metformin, or a Sulfonylurea
Adults

PO The usual starting dosage should provide sitagliptin dosed as 50 mg twice daily. In determining the starting dose of metformin, the patient's level of glycemic control and current dose, if any, of metformin should be considered. Gradual dose escalation to reduce the GI adverse reactions associated with metformin should be considered. Patients currently receiving or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of hypoglycemia.

Patients Inadequately Controlled With Diet and Exercise Alone
Adults

PO Start with sitagliptin 50 mg/metformin 500 mg twice daily. Patients with inadequate glycemic control on this dosage can be titrated up to sitagliptin 50 mg/metformin 1,000 mg twice daily.

Patients Switching From Sitagliptin Coadministered With Metformin
Adults

PO Initiate therapy with the dose of sitagliptin and metformin already being taken.

General Advice

• In general, administer twice daily with meals.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

Alcohol

Hypoglycemic effects and the effects of metformin on lactic acidosis may be potentiated. Warn patients against excessive alcohol intake, acute or chronic, while receiving sitagliptin/metformin.

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

May compete with metformin for renal tubular transport. Although such interactions remain theoretical, careful patient monitoring and dose adjustment of sitagliptin/metformin and/or the interfering drug is recommended in patients who are taking cationic medications excreted via the proximal renal tubular secretory system.

Cimetidine

Metformin plasma levels may be increased. Metformin pharmacologic effects and risk of adverse reactions may be increased. Monitor renal function closely. Dosage reduction may be needed during coadministration of cimetidine.

Cyclosporine

Coadministration of a single oral dose of sitagliptin 100 mg and cyclosporine 600 mg increased the AUC and C _max of sitagliptin, AUC and C _max may be increased. However, the magnitude of the change is not expected to be clinically important.

Digoxin

Digoxin AUC and C _max may be slightly increased. These increases are not likely to be clinically important.

Drugs that produce hyperglycemia (eg, calcium channel blockers, corticosteroids, diuretics [eg, thiazides], estrogens, hormonal contraceptives, isoniazid, nicotinic acid, phenothiazines, phenytoin, sympathomimetics, thyroid products)

Closely monitor patient to maintain adequate glycemic control.

Food

Food may decrease the extent and slightly delay the absorption of metformin, as shown by a decrease in C _max and AUC, and a prolongation of T _max . Sitagliptin/metformin should be taken with food.

Furosemide

Metformin AUC and C _max may be increased, while the AUC and C _max of furosemide may be decreased. The renal clearance of furosemide and metformin are not changed.

Glyburide

Glyburide AUC and C _max may be decreased. The clinical importance of this interaction is uncertain. Monitor blood glucose and, if an interaction is suspected, adjust the glyburide dose as needed.

Meglitinides (eg, nateglinide, repaglinide)

May increase risk of hypoglycemia. A lower dose of the meglitinide may be needed to reduce the risk of hypoglycemia.

Nifedipine

Metformin AUC and C _max may be increased.

NSAIDs (eg, indomethacin, rofecoxib)

NSAIDs may decrease glomerular filtration, increasing metformin concentrations and the risk of lactic acidosis. Use with caution. Closely monitor renal function and for lactic acidosis. Lactic acidosis is a medical emergency that must be treated in a hospital setting. If an interaction is suspected, consider discontinuing the NSAID.

Parenteral iodinated contrast media

Risk of metformin-induced lactic acidosis may be increased. Temporarily discontinue metformin at the time of or prior to the procedure and withhold for 48 h subsequent to the procedure; reinstitute only after renal function has been reevaluated and found to be healthy.

Sulfonylureas

May increase risk of hypoglycemia. A lower dose of the sulfonylurea may be needed to reduce the risk of hypoglycemia.

Adverse Reactions

The following adverse reactions were reported with sitagliptin/metformin combination therapy.

CNS

Headache (6%).

GI

Diarrhea (8%); nausea (5%); abdominal pain (3%); vomiting (2%); acute pancreatitis, including fatal and nonfatal hemorrhagic and necrotizing pancreatitis (postmarketing).

Hypersensitivity

Angioedema, cutaneous vasculitis, exfoliative skin conditions (including Stevens-Johnson syndrome), hypersensitivity (including anaphylaxis, rash, urticaria) (postmarketing).

Metabolic-Nutritional

Hypoglycemia (2%).

Respiratory

Upper respiratory tract infection (6%).

Miscellaneous

Hepatic enzyme elevations (postmarketing).

Precautions

Warnings Lactic acidosis, which is fatal in about 50% of cases, can occur. The risk increases with conditions such as acute CHF, dehydration, excess alcohol intake, hepatic and renal function impairment, and sepsis. Symptoms include increasing somnolence, malaise, myalgia, nonspecific abdominal distress, and respiratory distress. Abnormal laboratory findings include elevated blood lactate, increased anion gap, and low pH. If acidosis is suspected, discontinue drug and hospitalize the patient immediately.

Monitor Measure blood glucose and glycosated hemoglobin (HbA 1c ) levels periodically; monitor hematologic parameters and renal function initially and at least annually thereafter.

Pregnancy

Category B .

Lactation

Metformin is excreted, but is considered compatible with breast-feeding; undetermined for sitagliptin.

Children

Safety and efficacy not established.

Elderly

Use with caution because of possible age-related reduction in renal function.

Hypersensitivity

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin. Reactions include anaphylaxis, angioedema, and exfoliative skin conditions, including Stevens-Johnson syndrome.

Renal Function

Contraindicated in patients with renal dysfunction. Metformin accumulation and lactic acidosis risk increases with the degree of renal function impairment.

Hepatic Function

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

Special Risk Patients

Debilitated, malnourished, or elderly patients, and patients with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in elderly patients, and in people who are taking beta-blocking agents.

Changes in clinical status

Promptly evaluate patients with previously well-controlled type 2 diabetes who develop laboratory abnormalities or clinical illness for ketoacidosis or lactic acidosis.

Hypoxic states

Immediately discontinue therapy in any condition characterized by hypoxemia (eg, acute CHF, MI).

Loss of blood glucose control

Patients exposed to stress (eg, fever, infection, surgery, trauma) may experience a loss in glycemic control. It may be necessary to withhold sitagliptin/metformin and temporarily administer insulin until an acute episode has been resolved.

Pancreatitis

If pancreatitis is suspected, promptly discontinue sitagliptin/metformin and initiate appropriate management.

Surgical patients

Temporarily suspend treatment for any surgical procedure, except in procedures not associated with restricted intake of food and fluids, and do not restart treatment until oral intake has resumed and renal function has been evaluated as healthy.

Vitamin B ₁₂ levels

Metformin may decrease vitamin B ₁₂ levels.

Overdosage

Symptoms

Sitagliptin

Increased QTc interval 8 msec (not considered clinically important).

Metformin

Hypoglycemia, lactic acidosis.

Patient Information

• Advise patient to read the patient information leaflet before using product the first time and with each refill.
• Advise patient or caregiver to take prescribed dose with meals.
• Counsel patient against excessive alcohol intake, either acute or chronic.
• Educate patient, family, or caregiver about symptoms of lactic acidosis.
• Educate patient, family, or caregiver regarding type 2 diabetes and its management.
• Instruct patient that this drug is not a substitute for diet and exercise, and to follow prescribed regimens.
• Emphasize the importance of regular daily blood glucose monitoring and periodic HbA _1c tests.
• Review symptoms of hypoglycemia and hyperglycemia, and action plans to undertake in the event either occurs.
• Instruct patients to report hypoglycemic or hyperglycemic episodes to health care provider.
• Advise patients that, during periods of stress (eg, fever, infection, surgery, trauma), medication requirements may change and to seek medical advice promptly.
• Advise patients that severe abdominal pain, sometimes radiating to the back and accompanied by vomiting, is a hallmark symptom of acute pancreatitis and to contact their health care provider immediately.

Copyright © 2009 Wolters Kluwer Health.