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Saxagliptin

Pronunciation

(sax a GLIP tin)

Index Terms

  • BMS-477118
  • Saxagliptin HCl

Dosage Forms

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

Tablet, Oral:

Onglyza: 2.5 mg, 5 mg

Brand Names: U.S.

  • Onglyza

Pharmacologic Category

  • 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.

Metabolism

Hepatic via CYP3A4/5 to 5-hydroxy saxagliptin (active; ~50% potency of the parent compound)

Excretion

Urine (75%, 24% of the total dose as saxagliptin, 36% of the total dose as 5-hydroxy saxagliptin); feces (22%)

Time to Peak

Plasma: Saxagliptin: 2 hours; 5-hydroxy saxagliptin: 4 hours

Duration of Action

24 hours

Half-Life Elimination

Saxagliptin: 2.5 hours; 5-hydroxy saxagliptin: 3.1 hours

Protein Binding

Negligible

Special Populations: Renal Function Impairment

AUC was up to 2.1- and 4.5-fold higher in patients with moderate or severe renal impairment. Dosage adjustment is required. In patients with mild renal impairment, AUC for saxagliptin and its active metabolite were 20% and 70% higher, respectively, which is not considered significant.

Special Populations: Hepatic Function Impairment

Cmax and AUC were 8% and 77% higher, respectively, in patients with hepatic impairment (Child-Pugh class A, B, and C). The corresponding Cmax and AUC of the active metabolite were 59% and 33% lower, respectively.

Special Populations: Elderly

Elderly patients had 23% and 59% higher Cmax and AUC values, respectively, compared with younger subjects.

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 (noninsulin dependent, NIDDM) as monotherapy or in combination therapy.

Contraindications

Hypersensitivity (eg, anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Diabetic ketoacidosis, diabetic coma/precoma, type 1 diabetes mellitus

Dosing: Adult

Diabetes mellitus, type 2: Oral: 2.5 to 5 mg once daily (US labeling) or 5 mg once daily (Canadian labeling)

Concomitant use with strong CYP3A4/5 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin):

US labeling: 2.5 mg once daily

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; concurrent administration of single dose saxagliptin (100 mg) and ketoconazole increased saxagliptin systemic exposure 145% and decreased exposure to saxagliptin’s major metabolite by 88%.

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

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

Note: Renal function may be estimated using the Cockcroft-Gault formula or the MDRD formula for dosage adjustment purposes.

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl ≤50 mL/minute: 2.5 mg once daily.

ESRD requiring hemodialysis:

U.S. labeling: 2.5 mg once daily; administer postdialysis

Canadian labeling: Use is not recommended.

Peritoneal dialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Dosing: Hepatic Impairment

U.S. labeling: Mild-to-severe impairment: No dosage adjustment necessary.

Canadian labeling:

Mild impairment: There are no dosage adjustments provided in manufacturer’s labeling.

Moderate to severe impairment: Use is not recommended (lack of clinical experience).

Administration

May be administered without regard to meals. Swallow whole; do not split or cut tablets.

Dietary Considerations

Individualized medical nutrition therapy (MNT) is an integral part of therapy (ADA 2013).

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

ACE Inhibitors: DPP-IV Inhibitors may enhance the adverse/toxic effect of ACE Inhibitors. Specifically, the risk of angioedema may be increased. Monitor therapy

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

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

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

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

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

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

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. 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

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 P-glycoprotein/ABCB1 Substrates. Monitor therapy

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

Adverse Reactions

Frequencies and adverse reactions reported with monotherapy unless otherwise noted.

1% to 10%:

Cardiovascular: Peripheral edema (≤4%; incidence increased in conjunction with thiazolidinediones: ≤8%)

Central nervous system: Headache (7%)

Endocrine & metabolic: Hypoglycemia (≤6%; incidence increased in conjunction with insulin secretagogues: ≤15%)

Gastrointestinal: Abdominal pain (2%), gastroenteritis (2%), vomiting (2%)

Genitourinary: Urinary tract infection (7%)

Hematologic: Lymphocytopenia (≤2%; dose related)

Hypersensitivity: Hypersensitivity reaction (2%; including facial edema and urticaria)

Respiratory: Sinusitis (3%)

<1% (important or life-threatening): Acute pancreatitis, anaphylaxis, angioedema, exfoliative dermatitis, immune thrombocytopenia, increased creatine phosphokinase, increased serum creatinine, severe arthralgia (FDA Safety Alert, Aug 28, 2015), skin rash

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.

• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, angioedema, and exfoliative dermatologic reactions have been reported; discontinue if signs/symptoms of severe hypersensitivity reaction occur. Events have generally occurred within the first 3 months of therapy, and may occur after the initial dose. Use with caution if patient has experienced angioedema with other DPP-IV inhibitor use.

• Pancreatitis: Cases of acute pancreatitis 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 the treatment of diabetic ketoacidosis (DKA) due to lack of efficacy in this patient population.

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

• Heart failure: Heart failure that may require hospitalization has been reported 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.

• Renal impairment: Use with caution in patients with moderate-to-severe renal dysfunction and end-stage renal disease (ESRD) requiring hemodialysis; dosing adjustment required.

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:

• Lactose: May contain lactose; Canadian labeling recommends avoiding use in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndromes.

Other warnings/precautions:

• Patient education: Diabetes self-management education (DSME) is essential to maximize the effectiveness of 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]), renal function (prior to initiation of therapy and periodically thereafter); signs/symptoms of pancreatitis and/or heart failure

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies, except with doses that were also maternally toxic. In women with diabetes, maternal hyperglycemia can be associated with congenital malformations as well as adverse effects in the fetus, neonate, and the mother (ACOG 2005; ADA 2015; Kitzmiller 2008; Metzger 2007). To prevent adverse outcomes, prior to conception and throughout pregnancy maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ACOG 2013; ADA 2015; Blumer 2013; Kitzmiller 2008). Prior to pregnancy, effective contraception should be used until glycemic control is achieved (Kitzmiller 2008). Other agents are currently recommended to treat diabetes in pregnant women (ACOG 2013; Blumer 2013).

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 headache, rhinitis, rhinorrhea, or pharyngitis. Have patient report immediately to prescriber signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), signs of heart problems (cough or shortness of breath that is new or worse, swelling of the ankles or legs, abnormal heartbeat, weight gain of more than five pounds in 24 hours, dizziness, or passing out), painful urination, difficult urination, foul-smelling urine, 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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