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

Hypersensitivity to sitagliptin, metformin, or any component of the formulation; severe renal impairment (estimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m2); acute or chronic metabolic acidosis including diabetic ketoacidosis.

Canadian labeling: Additional contraindications (not in the US labeling): 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); 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

Diabetes mellitus, type 2: Oral: Initial doses should be based on the current dose of sitagliptin and metformin; titrate gradually per glycemic response. Total daily dose should be administered in 2 equally divided doses (immediate-release tablets) or once daily (extended-release tablets). Maximum dose: Sitagliptin 100 mg/metformin 2,000 mg per day.

Patients already on metformin: Initial: Sitagliptin 100 mg/day plus current daily dose of metformin. Patients currently on metformin 1,700 mg/day (eg, 850 mg twice daily) may receive an initial dose of sitagliptin 100 mg/metformin 2,000 mg per day.

Patients not on metformin: Initial: Sitagliptin 100 mg/metformin 1,000 mg per day.

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.

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

Dosing: Geriatric

Refer to adult dosing. The initial and maintenance dosing should be conservative, due to the potential for decreased renal function (monitor).

Dosing: Renal Impairment

eGFR >45 mL/minute/1.73 m2: No dosage adjustment necessary; monitor renal function at least annually.

eGFR 30 to 45 mL/minute/1.73 m2: Use is not recommended for initiation of therapy; if eGFR falls to <45 mL/minute/1.73 m2 during therapy, consider benefits/risks of continuing therapy and limit sitagliptin dose to 50 mg once daily (immediate-release products available will not accommodate this dose and are not recommended).

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

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

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

Patiromer: May decrease the serum concentration of MetFORMIN. Management: Administer metformin at least 3 hours before or 3 hours after patiromer. Consider therapy modification

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

Prothionamide: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. 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:

Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, somnolence, and abdominal pain. Metformin-associated lactic acidosis was characterized by elevated blood lactate levels (>5 mmol/L), anion gap acidosis (without evidence of ketonuria or ketonemia), an increased lactate/pyruvate ratio, and metformin plasma levels generally >5 mcg/mL.

Risk factors for metformin-associated lactic acidosis include renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age ≥65 years, having a radiological study with contrast, surgery and other procedures, hypoxic states (eg, acute congestive heart failure), excessive alcohol intake, and hepatic impairment.

Steps to reduce the risk of and manage metformin-associated lactic acidosis in these high risk groups are provided in the full prescribing information.

If metformin-associated lactic acidosis is suspected, immediately discontinue sitagliptin/metformin and institute general supportive measures in a hospital setting. Prompt hemodialysis is recommended.

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.

• Bullous pemphigoid: DPP-4 inhibitor use has been associated with development of bullous pemphigoid; cases have typically resolved with topical or systemic immunosuppressive therapy and discontinuation of DPP-4 inhibitor therapy. Advise patients to report development of blisters or erosions. Discontinue therapy if bullous pemphigoid is suspected and consider referral to a dermatologist.

• 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]: Postmarketing cases of metformin-associated lactic acidosis have resulted in death, hypothermia, hypotension, and resistant bradyarrhythmias. The onset is often subtle, accompanied by nonspecific symptoms (eg, malaise, myalgias, respiratory distress, somnolence, abdominal pain); elevated blood lactate levels (>5 mmol/L); anion gap acidosis (without evidence of ketonuria or ketonemia); increased lactate:pyruvate ratio; metformin plasma levels generally >5 mcg/mL. Risk factors for lactic acidosis include patients with renal impairment, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), ≥65 years, having a radiologic study with contrast, surgery and other procedures, hypoxic states (eg, acute heart failure), excessive alcohol intake, and hepatic impairment. Discontinue immediately if acidosis is suspected; prompt hemodialysis is recommended. 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, hypoperfusion, sepsis, or hypoxemia. Temporarily discontinue therapy in patients with restricted food and fluid intake. 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.

• Vitamin B12 concentrations: Long-term metformin use is associated with vitamin B12 deficiency; monitor vitamin B12 serum concentrations periodically with long-term therapy. Monitoring of B12 serum concentrations should be considered in all patients receiving metformin and in particular those with peripheral neuropathy or anemia (ADA 2017c).

Disease-related concerns:

• Cardiovascular disease: 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. In one large randomized, double-blinded trial in patients with type 2 diabetes and established cardiovascular disease (history of major CAD, ischemic cerebrovascular disease, or atherosclerotic peripheral arterial disease), the occurrence of the primary composite cardiovascular outcome (cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina) with sitagliptin was found to be noninferior to placebo. In addition, the rate of hospitalization for heart failure did not differ between the two groups (Green 2015). In a scientific statement from the American Heart Association, sitagliptin has been determined to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (AHA [Page 2016]).

• Hepatic impairment: Use is not recommended in patients with hepatic impairment due to potential for lactic acidosis.

• Renal impairment: Metformin is substantially excreted by the kidney; use is contraindicated in patients with eGFR <30 mL/minute/1.73 m2. 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: Use with caution; risk of metformin associated lactic acidosis increases with age.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with insulin-dependent diabetes mellitus (IDDM) (type 1) or in patients with diabetic ketoacidosis (DKA).

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

• Iodinated contrast: Discontinue 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. Reevaluate eGFR 48 hours after imaging procedure; restart if renal function is stable. 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).

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

• Surgical procedures: Metformin should be withheld 24 hours before surgery (all other oral hypoglycemic agents should be withheld the morning of surgery or procedure) (ADA 2017d). Resume only after normal intake resumed and normal renal function is verified.

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 2017a]), serum glucose, hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices) at least annually; hepatic function, renal function (eGFR) should be performed prior to initiation of therapy and at least annually (more often in patients at risk of developing renal impairment; every 3 to 6 months if eGFR 45 to <60 mL/minute/1.73 m2; every 3 months if eGFR 30 to <45 mL/minute/1.73 m2 [Lipska 2011]); 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 sitagliptin/metformin combination 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