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Saxagliptin and Metformin

Pronunciation

(sax a GLIP tin & met FOR min)

Index Terms

  • Metformin and Saxagliptin
  • Metformin Hydrochloride and Saxagliptin
  • Saxagliptin and Metformin Hydrochloride
  • Saxagliptin HCl/Metformin HCl

Dosage Forms

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

Tablet, variable release, oral:

Kombiglyze XR 2.5/1000: Saxagliptin 2.5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

Kombiglyze XR 5/500: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 500 mg [extended release]

Kombiglyze XR 5/1000: Saxagliptin 5 mg [immediate release] and metformin hydrochloride 1000 mg [extended release]

Brand Names: U.S.

  • Kombiglyze XR

Pharmacologic Category

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

Pharmacology

Saxagliptin inhibits dipeptidyl peptidase IV (DPP-IV) enzyme 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 the DPP-IV enzyme.

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: Management of type 2 diabetes mellitus (noninsulin dependent, NIDDM) as an adjunct to diet and exercise when treatment with both saxagliptin 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 saxagliptin, metformin, or any component of the formulation; renal impairment (eg, serum creatinine ≥1.5 mg/dL [≥136 micromole/L] in males or ≥1.4 mg/dL [≥124 micromole/L] in females or abnormal creatinine clearance [CrCl]) that may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia; acute or chronic metabolic acidosis including diabetic ketoacidosis

Canadian labeling: Hypersensitivity to saxagliptin, another dipeptidyl peptidase-4 inhibitor, metformin, or any component of the formulation; unstable and/or insulin-dependent (Type 1) diabetes mellitus; 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); presence of renal disease or impairment and patients with serum creatinine levels above the upper limit of normal range or abnormal creatinine clearance (<60 mL/minute), which may also result from conditions such as cardiovascular collapse, acute myocardial infarction, and septicemia or when renal function is unknown; excessive ethanol intake (acute or chronic); moderate and severe hepatic impairment; cases of cardiovascular collapse and disease states associated with hypoxemia such as cardiorespiratory insufficiency which are often associated with hyperlactacidemia; during stress conditions (eg, severe infection, trauma, surgery and postoperative recovery phase); severe dehydration; pregnancy; breast-feeding

Dosing: Adult

Diabetes mellitus, type 2: Oral:

US labeling: Initial doses should be based on current dose of saxagliptin and metformin; daily doses should be given once daily with the evening meal. Maximum: Saxagliptin 5 mg/metformin 2000 mg daily

Patients inadequately controlled on metformin alone: Initial dose: Saxagliptin 2.5-5 mg daily plus current dose of metformin. Note: Patients who require saxagliptin 2.5 mg (eg, dose adjusted for concomitant use of strong CYP3A4/5 inhibitors) and metformin >1000 mg should not be switched to the combination product.

Patients inadequately controlled on saxagliptin alone: Initial dose: Metformin 500 mg daily plus saxagliptin 5 mg daily. Note: Metformin-naive patients currently receiving saxagliptin 2.5 mg daily (eg, dose adjusted for concomitant use of strong CYP3A4/5 inhibitors) should not be switched to the combination product.

Concomitant use with strong CYP3A4/5 inhibitors: Maximum: Saxagliptin 2.5 mg/metformin 1000 mg daily

Concomitant use with insulin or insulin secretagogues: Reduced dose of insulin or insulin secretagogues (eg, sulfonylureas) may be needed.

Canadian labeling: Initial doses should be based on current dose of saxagliptin and metformin; daily dose should be divided into 2 equal doses given with meals. Maximum: Saxagliptin 5 mg/metformin 2000 mg daily

Patients inadequately controlled on metformin alone: Initial dose: Saxagliptin 2.5 mg twice daily plus current dose of metformin.

Concomitant use with insulin: Reduced dose of insulin may be needed.

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

Manufacturer's labeling: Serum creatinine (SCr) ≥1.5 mg/dL (males) or ≥1.4 mg/dL (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

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.

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).

Administration

Oral: Administer once daily with the evening meal. Swallow whole; do not crush, cut, or chew tablets.

Komboglyze immediate release formulation [Canadian product; not available in the US] should be administered twice daily with meals (eg, breakfast and dinner).

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 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

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. 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

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers: May decrease the serum concentration of SAXagliptin. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of SAXagliptin. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

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

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. 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

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. 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

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

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

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. 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

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

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

See individual agents.

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 saxagliptin/metformin extended release (ER) and immediately hospitalize the patient.

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 saxagliptin; 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 exfoliative dermatologic reactions have been reported with saxagliptin use; discontinue if signs/symptoms of severe hypersensitivity reaction 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 have been reported with saxagliptin 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 (DKA): Saxagliptin should not be used in patients with DKA due to lack of efficacy in this patient population.

• Heart failure: Heart failure that may require hospitalization has been reported with saxagliptin in a multi-center, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history of, or at risk for, cardiovascular events; risk was increased in patients with preexisting heart failure or renal impairment and during the first 12 months of therapy (Scirica 2013; Scirica 2014). However, a population-based retrospective study in an ambulatory setting with relatively lower baseline cardiovascular risk factors failed to demonstrate increased risk in patients on saxagliptin compared to other agents (eg, sitagliptin, pioglitazone, sulfonylureas, insulin) (Toh 2016). Monitor for signs and symptoms of heart failure during therapy and consider discontinuation if condition develops.

• Hepatic impairment: Use metformin 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). 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).

• Type 1 diabetes mellitus: Saxagliptin should not be used in patients with type 1 diabetes mellitus (insulin dependent, IDDM) due to lack of efficacy in this patient population

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.

Special populations:

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

Dosage form specific issues:

• Extended release tablet: The inactive ingredients may appear in the stool as a soft mass resembling the tablet.

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 B12 serum concentrations periodically with long-term therapy.

Monitoring Parameters

Plasma glucose; 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]); hematologic parameters (eg, hemoglobin/hematocrit, red blood cell indices, and 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); signs/symptoms of pancreatitis and/or heart failure

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies conducted with this combination. Also see individual agents.

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 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, or muscle pain or cramps), angina, chills, pharyngitis, pain with urination, difficult urination, foul-smelling urine, 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), or severe joint pain (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.

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