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Sitagliptin / Metformin Hydrochloride

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

Trade Names

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

Janumet XR
- Tablets, ER, oral sitagliptin 50 mg/metformin hydrochloride 500 mg ER
- Tablets, ER, oral sitagliptin 50 mg/metformin hydrochloride 1,000 mg ER
- Tablets, ER, oral sitagliptin 100 mg/metformin hydrochloride 1,000 mg ER



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


Slows the inactivation of incretin hormones.

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.


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

Dosage and Administration

Base dosage selection of sitagliptin/metformin on the patient's current dose of these agents. May gradually titrate dose to reduce GI adverse reactions (max, sitagliptin 100 mg/metformin 2,000 mg daily [immediate release and ER]).

Patients Already on Metformin
Adults Immediate release

PO Start with a sitagliptin 50 mg twice daily dose 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.


PO Start with sitagliptin 100 mg/day plus the current dose of metformin. For patients taking metformin 850 mg immediate release twice daily or 1,000 mg twice daily, the recommended starting dosage is sitagliptin 100 mg/metformin 2,000 mg ER once daily.

Patients Not on Metformin
Adults Immediate release

PO Start with sitagliptin 50 mg/metformin 500 mg twice daily.


PO Start with sitagliptin 100 mg/metformin 1,000 mg ER once daily.

General Advice

  • Administer with food.
  • ER tablets must not be split, broken, crushed, or chewed before swallowing.
  • Coadministration with an insulin secretagogue (eg, sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia.
  • Maintain the same total daily dose of sitagliptin and metformin when changing between sitagliptin and metformin immediate release and sitagliptin and metformin ER.


Store between 59° and 86°F.

Drug Interactions


Hypoglycemic effects and the effects of metformin on lactic acidosis may be potentiated. Avoid excessive alcohol intake.

Carbonic anhydrase inhibitors (eg, acetazolamide, topiramate, zonisamide)

Risk of metformin-induced lactic acidosis may be increased. Lactic acidosis is a medical emergency that must be treated in a hospital setting. Use with caution.

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.


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.


Coadministration of a single oral dose of sitagliptin 100 mg and cyclosporine 600 mg increased the AUC and C max of sitagliptin by approximately 29% and 68%, respectively. However, the magnitude of the change is not expected to be clinically important.


Digoxin AUC and C max may be slightly increased. Patients should be monitored appropriately. No dosage adjustment is recommended.

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 patients to maintain adequate glycemic control.


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 .


Metformin AUC and C max may be increased, while the AUC and C max of furosemide may be decreased. The renal Cl of furosemide and metformin are not changed. No dosage adjustments are required.

Insulin, sulfonylureas (eg, glyburide)

May increase risk of hypoglycemia. A lower dose of insulin or sulfonylurea may be needed to reduce the risk of hypoglycemia. Glyburide AUC and C max may be decreased. The clinical importance of this interaction is uncertain.


Metformin AUC and C max may be increased. However, no dosage adjustments are required.

NSAIDs (eg, celecoxib, indomethacin)

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.

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.

Adverse Reactions

The following adverse reactions were reported with sitagliptin/metformin combination therapy. Postmarketing reactions occurred during postapproval use of sitagliptin with or without metformin and/or in combination with other antidiabetic medications.


Headache (6%).


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


Worsening renal function, including acute renal failure (sometimes requiring dialysis) (postmarketing).


Anaphylaxis, angioedema, cutaneous vasculitis, exfoliative skin conditions (including Stevens-Johnson syndrome), rash, urticaria (postmarketing).


Hypoglycemia (2%).


Upper respiratory tract infection (6%).


Hepatic enzyme elevations (postmarketing).



Lactic acidosis is a rare but serious complication that can occur because of metformin accumulation. The risk increases with conditions such as acute CHF, dehydration, excess alcohol intake, hepatic and/or renal 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 the drug and hospitalize the patient immediately.


Measure blood glucose and hemoglobin A 1c (HbA 1c ) levels periodically; monitor hematologic parameters (eg, Hgb/Hct, red blood cell indices) and renal function (serum creatinine) initially and at least annually thereafter. Megaloblastic anemia has rarely been seen with metformin therapy; if suspected, exclude vitamin B 12 deficiency. Carefully observe patients for signs and symptoms of pancreatitis after initiation of therapy.


Category B . To prevent maternal and fetal adverse reactions resulting from high maternal glucose levels, most experts, including the American College of Obstetricians and Gynecologists, recommend that insulin be used for types 1 and 2 diabetes during pregnancy.


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


Safety and efficacy not established.


Use with caution because of possible age-related reduction in renal function. Do not initiate therapy in patients 80 y and older unless measurement of CrCl demonstrates that renal function is not reduced.


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. Use with caution in patients with a history of angioedema.

Renal Function

Contraindicated in patients with renal dysfunction. Metformin accumulation and lactic acidosis risk increases with the degree of renal impairment. Do not administer to patients with serum creatinine levels higher than the ULN for their age.

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 patients 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

CV collapse (shock) from whatever cause (eg, acute CHF, acute MI) has been associated with lactic acidosis and may also cause azotemia. Promptly discontinue therapy when such events occur.

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.


Acute pancreatitis, including fatal and nonfatal hemorrhage or necrotizing pancreatitis, has been reported.

Renal effects

Worsening of renal function, including acute renal failure sometimes requiring dialysis, has been reported.

Surgical patients

Temporarily suspend treatment for any surgical procedure, except in minor 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.




Hypoglycemia, lactic acidosis.


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

Patient Information

  • Advise patients to read the Medication Guide before using product the first time and with each refill.
  • Advise patients or caregivers to take or administer the prescribed dose with meals.
  • Inform patients that the ER tablets must be swallowed whole and never split, crushed, or chewed.
  • Counsel patients against excessive alcohol intake, either short or long term.
  • Educate patients, families, or caregivers about symptoms of lactic acidosis (eg, dizziness, malaise, myalgia, sensation of feeling cold, slow or irregular heartbeat) and advise them to promptly notify their health care provider if these symptoms occur.
  • Educate patients, families, or caregivers about symptoms of lactic acidosis.
  • Educate patient, families, or caregivers regarding type 2 diabetes and its management.
  • Instruct patients 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 their 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.
  • Inform patients that severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis; patients should promptly discontinue sitagliptin/metformin and contact their health care provider if persistent severe abdominal pain occurs.
  • Instruct patients to stop taking sitagliptin/metformin and promptly seek medical advice if symptoms of allergic reactions (eg, rash, hives, and swelling of the face, lips, tongue, or throat that may cause difficulty in breathing or swallowing) occur.

Copyright © 2009 Wolters Kluwer Health.