Skip to Content

Sitagliptin and Metformin

Pronunciation

(sit a GLIP tin & met FOR min)

Index Terms

  • Metformin and Sitagliptin
  • Sitagliptin Phos/Metformin HCl
  • Sitagliptin Phosphate and Metformin Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral:

Janumet 50/500: Sitagliptin 50 mg and metformin hydrochloride 500 mg

Janumet 50/1000: Sitagliptin 50 mg and metformin hydrochloride 1000 mg

Tablet, extended release, oral:

Janumet XR: 50/500: Sitagliptin 50 mg [immediate release] and metformin hydrochloride 500 mg [extended release]

Janumet XR: 50/1000: Sitagliptin 50 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

Janumet XR: 100/1000: Sitagliptin 100 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

Brand Names: U.S.

  • Janumet
  • Janumet XR

Pharmacologic Category

  • Antidiabetic Agent, Biguanide
  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor

Pharmacology

Sitagliptin inhibits dipeptidyl peptidase IV (DPP-IV) enzymes resulting in prolonged active incretin levels. Incretin hormones [eg, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic beta cells and decreasing glucagon secretion from pancreatic alpha cells. Decreased glucagon secretion results in decreased hepatic glucose production. Under normal physiologic circumstances, incretin hormones are released by the intestine throughout the day and levels are increased in response to a meal; incretin hormones are rapidly inactivated by DPP-IV enzymes.

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

Use: Labeled Indications

Diabetes mellitus, type 2: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate

Contraindications

Note: The manufacturer recommends to temporarily discontinue metformin in patients undergoing radiologic studies in which intravascular iodinated contrast media are utilized.

US labeling: Hypersensitivity to sitagliptin, metformin, or any component of the formulation; renal impairment (serum creatinine ≥1.5 mg/dL in men or ≥1.4 mg/dL in women, or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; acute or chronic metabolic acidosis including diabetic ketoacidosis.

Canadian labeling: Hypersensitivity to sitagliptin, metformin, or any component of the formulation; renal function unknown, renal impairment, and serum creatinine levels above the upper limit of normal range; renal disease or renal dysfunction (serum creatinine ≥136 micromole/L in males or ≥124 micromole/L in females or abnormal creatinine clearance <60 mL/minute) which may result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia; unstable and/or insulin-dependent (type 1) diabetes mellitus (IDDM); acute or chronic metabolic acidosis including diabetic ketoacidosis (with or without coma), history of ketoacidosis (with or without coma); history of lactic acidosis, regardless of precipitating factors; acute or chronic excessive alcohol intake; severe hepatic disease; cardiovascular collapse and disease states associated with hypoxemia (eg, cardiorespiratory insufficiency) which are often associated with hyperlactacidemia; use during stress conditions (eg, severe infection, trauma, surgery) and the recovery phase thereafter; severe dehydration; breast-feeding; pregnancy

Dosing: Adult

Note: Patients receiving concomitant insulin and/or insulin secretagogues (eg, sulfonylureas) may require dosage adjustments of these agents.

Diabetes mellitus, type 2: Oral: Initial doses should be based on current dose of sitagliptin and metformin.

Patients inadequately controlled on metformin alone: Initial dose:

Immediate release: Sitagliptin 100 mg daily plus current daily dose of metformin given in 2 equally divided doses; maximum: sitagliptin 100 mg/metformin 2000 mg daily. Note: Patients currently receiving metformin 850 mg twice daily should receive an initial dose of sitagliptin 50 mg and metformin 1000 mg twice daily.

Extended release: Sitagliptin 100 mg daily plus current daily dose of metformin given once daily; maximum: sitagliptin 100 mg/metformin 2000 mg daily. Note: Patients currently receiving immediate release metformin 850 to 1000 mg twice daily should receive sitagliptin/metformin extended release at an initial dose of sitagliptin 100 mg and metformin 2000 mg once daily.

Patients inadequately controlled on sitagliptin alone: Initial dose: Note: Patients currently receiving a renally-adjusted dose of sitagliptin should not be switched to a combination product.

Immediate release: Metformin 1000 mg daily plus sitagliptin 100 mg daily given in 2 equally divided doses

Extended release: Metformin 1000 mg and sitagliptin 100 mg once daily

Conversion from immediate release to extended release: Convert using same total daily dose (up to the maximum recommended dose), but adjust frequency as indicated for immediate (twice daily) or extended (once daily) release products.

Alternative recommendations:

Patients inadequately controlled on combination metformin and either pioglitazone, a sulfonylurea, or insulin: Sitagliptin 100 mg daily plus current daily dose of metformin. If taking insulin or a sulfonylurea concomitantly with sitagliptin/metformin, the dosage of insulin or sulfonylurea may need adjusted (Janumet/Janumet XR Canadian product labeling 2016).

Patients inadequately controlled on combination therapy with sitagliptin and insulin: Sitagliptin 100 mg daily plus metformin (dose based on glycemic control). Insulin dose may need adjusted (Janumet/Janumet XR Canadian product labeling 2016).

Dosing adjustment: Metformin component may be gradually increased up to the maximum dose. Maximum dose: Sitagliptin 100 mg/metformin 2000 mg daily

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor). Do not use in patients ≥80 years of age unless normal renal function has been established.

Dosing: Renal Impairment

Serum creatinine (SCr) ≥1.5 mg/dL [≥136 micromol/L] (males) or ≥1.4 mg/dL [≥124 micromol/L] (females) or abnormal CrCl: Use is contraindicated.

Alternate recommendations: Note: The United Kingdom National Institute for Health and Clinical Excellence (NICE) Guidelines recommend prescribing metformin with caution in those patients who are at risk of sudden deterioration in renal function and at risk of an estimated glomerular filtration rate (eGFR) <45 mL/minute/1.73 m2 (NICE, 2008). Some evidence suggests that use of metformin is unsafe when eGFR <30 mL/minute/1.73 m2 (calculated using MDRD) (Shaw, 2007). A review of the available data by members of the American Diabetes Association proposed the following recommendations based on eGFR (Lipska, 2011):

eGFR ≥60 mL/minute/1.73 m2: No contraindications, monitor renal function annually

eGFR ≥45 to <60 mL/minute/1.73 m2: Continue use; monitor renal function every 3 to 6 months. Note: The manufacturer’s labeling for sitagliptin recommends a maximum dose of 50 mg once daily in patients with CrCl 30 to <50 mL/minute.

eGFR ≥30 to <45 mL/minute/1.73 m2: In patients currently receiving metformin, use with caution, consider dosage reduction (eg, 50% reduction or 50% of maximal dose), monitor renal function every 3 months. Do not initiate therapy in patients with eGFR <45 mL/minute/1.73 m2. Note: The manufacturer’s labeling for sitagliptin recommends a maximum dose of 50 mg once daily in patients with CrCl 30 to <50 mL/minute.

eGFR <30 mL/minute/1.73 m2: Discontinue use

Dosing: Hepatic Impairment

The manufacturer recommends to avoid metformin since liver disease is considered a risk factor for the development of lactic acidosis during metformin therapy. However, continued use of metformin in diabetics with liver dysfunction, including cirrhosis, has been used successfully and may be associated with a survival benefit in carefully selected patients; use cautiously in patients at risk for lactic acidosis (eg, renal impairment, alcohol use) (Brackett, 2010; Zhang, 2014). Use of sitagliptin in patients with severe hepatic impairment has not been studied.

Administration

Administer with meals, at the same time each day (evening meal preferable for extended release tablets). Swallow extended release tablets whole; do not split, crush, or chew; do not split or divide regular release tablets.

Dietary Considerations

Should be taken with meals (to decrease GI upset). Take at the same time each day. Individualized medical nutrition therapy (MNT) based on ADA recommendations is an integral part of therapy. Monitor for signs and symptoms of vitamin B12 and/or folic acid deficiency; supplementation may be required.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of MetFORMIN. Specifically, alcohol may potentiate the risk of lactic acidosis Avoid combination

Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Monitor therapy

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

BuPROPion: May increase the serum concentration of OCT2 Substrates. Monitor therapy

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk of developing lactic acidosis may be increased. Exceptions: Brinzolamide; Dorzolamide. Monitor therapy

Cephalexin: May increase the serum concentration of MetFORMIN. Monitor therapy

Cimetidine: May increase the serum concentration of MetFORMIN. Management: Consider alternatives to cimetidine in patients receiving metformin due to a potential for increased metformin concentrations and toxicity (including lactic acidosis). Consider therapy modification

Dalfampridine: MetFORMIN may increase the serum concentration of Dalfampridine. Dalfampridine may increase the serum concentration of MetFORMIN. Monitor therapy

Digoxin: SITagliptin may increase the serum concentration of Digoxin. Monitor therapy

Dofetilide: MetFORMIN may increase the serum concentration of Dofetilide. Monitor therapy

Dolutegravir: May increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. Consider therapy modification

Glycopyrrolate (Systemic): May increase the serum concentration of MetFORMIN. Monitor therapy

Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Insulin: DPP-IV Inhibitors may enhance the hypoglycemic effect of Insulin. Management: Consider a decrease in insulin dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Iodinated Contrast Agents: May enhance the adverse/toxic effect of MetFORMIN. Renal dysfunction that may be caused by iodinated contrast agents may lead to metformin-associated lactic acidosis. Management: Management advice varies. Refer to the full drug interaction monograph content for details. Exceptions: Diatrizoate Meglumine; Ethiodized Oil. Consider therapy modification

Isavuconazonium Sulfate: May increase the serum concentration of MetFORMIN. Monitor therapy

LamoTRIgine: May increase the serum concentration of MetFORMIN. Management: The lamotrigine Canadian product monograph states that coadministration of these drugs is not recommended. Monitor therapy

Lumacaftor: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. Lumacaftor may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. Monitor therapy

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Ombitasvir, Paritaprevir, and Ritonavir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: May enhance the adverse/toxic effect of MetFORMIN. Specifically, the risk for lactic acidosis may be increased. Monitor therapy

Ondansetron: May increase the serum concentration of MetFORMIN. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

P-glycoprotein/ABCB1 Inducers: May decrease the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inducers may also further limit the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ranolazine: May increase the serum concentration of MetFORMIN. Management: Limit the metformin dose to a maximum of 1700 mg/day when used together with ranolazine 1000 mg twice daily. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sulfonylureas: DPP-IV Inhibitors may enhance the hypoglycemic effect of Sulfonylureas. Management: Consider a decrease in sulfonylurea dose when initiating therapy with a dipeptidyl peptidase-IV inhibitor and monitor patients for hypoglycemia. Consider therapy modification

Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Topiramate: May enhance the adverse/toxic effect of MetFORMIN. Monitor therapy

Trimethoprim: May increase the serum concentration of MetFORMIN. Monitor therapy

Trospium: MetFORMIN may decrease the serum concentration of Trospium. Monitor therapy

Vandetanib: May increase the serum concentration of MetFORMIN. Monitor therapy

Verapamil: May diminish the therapeutic effect of MetFORMIN. Monitor therapy

Adverse Reactions

Also see individual agents.

1% to 10%:

Central nervous system: Headache (6%)

Gastrointestinal: Diarrhea (8%), nausea (5%), abdominal pain (3%), vomiting (2%)

Respiratory: Upper respiratory tract infection (6%)

<1% (Limited to important or life-threatening): Hypersensitivity reaction (including anaphylaxis, angioedema, skin rash, urticaria, hypersensitivity angiitis, exfoliative skin conditions [including Stevens-Johnson syndrome]), lactic acidosis, pancreatitis (including hemorrhagic or necrotizing), pemphigoid, renal failure, renal insufficiency, severe arthralgia (FDA Safety Alert, Aug 28, 2015)

ALERT: U.S. Boxed Warning

Lactic acidosis:

Lactic acidosis is a rare, but serious, complication that can occur because of metformin accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol intake, hepatic impairment, renal impairment, and acute congestive heart failure (CHF).

The onset of lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.

If acidosis is suspected, discontinue sitagliptin/metformin and hospitalize the patient immediately.

Warnings/Precautions

Concerns related to adverse effects:

• Arthralgia: Severe and disabling arthralgia has been reported with DPP-IV inhibitor use; onset may occur within one day to years after treatment initiation and may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-IV inhibitor therapy resumed.

• Hematologic: Dose-related decrease in lymphocyte count has been observed with other dipeptidyl peptidase-4 inhibitors; clinical significance is not known. Monitoring of lymphocyte counts may be warranted in patients with unusual or persistent infection.

• Hypersensitivity reactions: Rare hypersensitivity reactions (including anaphylaxis, angioedema and/or severe dermatologic reactions, such as Stevens-Johnson syndrome) have been reported in postmarketing surveillance; discontinue if signs/symptoms of hypersensitivity reactions occur. Events have generally been noted within the first 3 months of therapy, and may occur with the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use.

• Lactic acidosis: [US Boxed Warning]: Lactic acidosis is a rare, but potentially severe consequence of therapy with metformin that requires urgent care and hospitalization. The risk is increased in patients with acute congestive heart failure, dehydration, excessive alcohol intake, hepatic or renal impairment, or sepsis. Symptoms may be nonspecific (eg, abdominal distress, malaise, myalgia, respiratory distress, somnolence); low pH, increased anion gap and elevated blood lactate may be observed. Discontinue immediately if acidosis is suspected. Lactic acidosis should be suspected in any patient with diabetes receiving metformin with evidence of acidosis but without evidence of ketoacidosis. Discontinue metformin in patients with conditions associated with dehydration, sepsis, or hypoxemia. The risk of accumulation and lactic acidosis increases with the degree of impairment of renal function.

• Pancreatitis: Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities) have been reported with use. Monitor for signs/symptoms of pancreatitis; discontinue use immediately if pancreatitis is suspected and initiate appropriate management. Use with caution in patients with a history of pancreatitis as it is not known if this population is at greater risk.

Disease-related concerns:

• Diabetic ketoacidosis: Not indicated for use in patients with diabetic ketoacidosis (DKA) due to lack of efficacy in this patient population.

• Diabetes mellitus (type 1): Not indicated for use in patients with insulin-dependent diabetes mellitus (IDDM) (type 1) due to lack of efficacy in this population.

• Heart failure: Use with caution in patients with congestive heart failure requiring pharmacologic management, particularly in patients with unstable acute heart failure; risk of lactic acidosis may be increased secondary to hypoperfusion.

• Hepatic impairment: Use with caution in patients with hepatic impairment due to potential for lactic acidosis.

• Renal impairment: Metformin is substantially excreted by the kidney; use with caution in patients with renal impairment (use is contraindicated in some patients; refer to contraindications). Monitor renal function; may assess more frequently in patients at increased risk of developing renal impairment (eg, elderly). Use of concomitant medications that may affect renal function (ie, affect tubular secretion) may also affect metformin disposition. Metformin should be withheld in patients with dehydration and/or prerenal azotemia.

• Stress-related states: It may be necessary to discontinue metformin and administer insulin if the patient is exposed to stress (fever, trauma, infection, surgery).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage forms specific issues:

• Extended release tablet: Incompletely dissolved tablets passed in stool have been reported; assess the adequacy of glycemic control in patients who repeatedly observe tablets in their stool.

Special populations:

• Elderly: Metformin should not be initiated in patients ≥80 years of age unless normal renal function is confirmed.

Other warnings/precautions:

• Ethanol use: Instruct patients to avoid excessive acute or chronic ethanol use; ethanol may potentiate metformin's effect on lactate metabolism.

• Iodinated contrast: The FDA recommends temporary discontinuation of metformin at the time of or before iodinated contrast imaging procedures in patients with an eGFR 30 to 60 mL/minute/1.73 m2; or with a history of hepatic disease, alcoholism, or heart failure; or in patients who will receive intra-arterial iodinated contrast. Alternatively, the American College of Radiology (ACR) guidelines recommend that metformin may be used prior to or following administration of iodinated contrast media in patients with no evidence of acute kidney injury (AKI) and with an eGFR ≥30 mL/minute/1.73 m2; ACR guidelines recommend temporary discontinuation of metformin in patients with known AKI or severe chronic kidney disease ([stage IV or V [ie, eGFR <30 mL/minute/1.73 m2]) or who are undergoing arterial catheter studies (ACR 2015). Temporary discontinuation of metformin should occur at the time of or prior to the procedure, withheld for 48 hours following the procedure, and then resumed only when normal renal function is confirmed.

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of therapy.

• Surgical procedures: Therapy should be suspended for any surgical procedures (resume only after normal intake resumed and normal renal function is verified).

• Vitamin B12 concentrations: May impair vitamin B12 absorption, particularly in those with inadequate vitamin B12 or calcium intake/absorption; very rarely associated with anemia. Rapid reversal of vitamin B12 deficiency may be observed with discontinuation of therapy or supplementation. Monitor vitamin B12serum concentrations periodically with long-term therapy.

Monitoring Parameters

HbA1c (at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; quarterly in patients not meeting treatment goals or with therapy change [ADA 2016a]), serum glucose, hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) at least annually; lymphocyte counts if unusual or persistent infection; hepatic function, renal function (prior to initiation of therapy then annually or more frequent if necessary); vitamin B12 (periodically with long-term treatment) and folate (if megaloblastic anemia is suspected)

Pregnancy Risk Factor

B

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual agents.

Health professionals are encouraged to report any prenatal exposure to Janumet by contacting Merck’s pregnancy registry (1-800-986-8999).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, nausea, vomiting, diarrhea, flatulence, loss of strength and energy, headache, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of too much lactic acid in the blood (lactic acidosis; fast breathing, fast heartbeat, abnormal heartbeat, vomiting, drowsiness, shortness of breath, feeling very tired or weak, severe dizziness, feeling cold, muscle pain, or cramps), angina, chills, pharyngitis, urinary retention, change in amount of urine passed, signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of a pancreas problem (pancreatitis; severe abdominal pain, severe back pain, severe nausea, vomiting), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), severe joint pain, or tablet shell in stool (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Hide