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Saxagliptin: Drug information

Saxagliptin: Drug information
(For additional information see "Saxagliptin: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Brand Names: US
  • Onglyza
Brand Names: Canada
  • APO-Saxagliptin;
  • Onglyza;
  • SANDOZ Saxagliptin
Pharmacologic Category
  • Antidiabetic Agent, Dipeptidyl Peptidase 4 (DPP-4) Inhibitor
Dosing: Adult

Note: Due to lack of additive glycemic benefit, use in combination with a glucagon-like peptide-1 receptor agonist should be avoided (ADA/EASD [Davies 2018]). May require a dose reduction of insulin and/or insulin secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (AACE/ACE [Garber 2020]).

Diabetes mellitus, type 2, treatment

Diabetes mellitus, type 2, treatment:

Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin. May be preferred in patients close to glycemic goals when avoidance of hypoglycemia and/or weight gain is desirable. Use has not been associated with improved cardiovascular (CV) or renal outcomes; use has been associated with an increased risk of heart failure hospitalization in patients with CV disease or multiple CV risk factors (AACE/ACE [Garber 2020]; ADA 2021; Scirica 2013).

Oral: 2.5 to 5 mg once daily.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR ≥45 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <45 mL/minute/1.73 m2: 2.5 mg once daily.

ESRD requiring hemodialysis: 2.5 mg once daily; administer postdialysis

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

Dosing: Hepatic Impairment: Adult

Mild to severe impairment: No dosage adjustment necessary.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

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

Tablet, Oral:

Onglyza: 2.5 mg, 5 mg

Generic Equivalent Available: US

No

Dosage Forms: Canada

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

Tablet, Oral:

Onglyza: 2.5 mg, 5 mg [contains fd&c blue #2 (indigotine)]

Generic: 2.5 mg, 5 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and at http://www.azpicentral.com/onglyza/onglyza_med.pdf#page=1, must be dispensed with this medication.

Administration: Adult

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

Use: Labeled Indications

Diabetes mellitus, type 2, treatment: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus as monotherapy or combination therapy.

Medication Safety Issues
Sound-alike/look-alike issues:

SAXagliptin may be confused with SITagliptin, SUMAtriptan

Adverse Reactions (Significant): Considerations
Arthralgia

Arthralgia, including severe and disabling cases, has been reported with dipeptidyl peptidase-4 (DPP-4) inhibitors, including saxagliptin (Ref). Specific inflammatory joint complications with DPP-4 inhibitors may include polyarthritis, polyarthropathy, rheumatoid arthritis, and severe synovitis (Ref). Patients may or may not exhibit an increase in rheumatoid factors (Ref).

Mechanism: Not well established; one hypothesis includes cytokine-induced inflammation (Ref).

Onset: Varied; onset may occur within 1 day to years after treatment initiation. Symptoms may resolve with discontinuation of therapy. Some patients may experience a recurrence of symptoms if DPP-4 inhibitor therapy resumes (Ref).

In one study, most patients who reported arthralgias did so within 3 months of initiation of DPP-4 inhibitors and symptoms resolved within 1 month after discontinuation (Ref).

Risk factors:

• Longer duration of therapy; data are conflicting (Ref)

Dermatologic reactions

Dipeptidyl peptidase-4 (DPP-4) inhibitor use, including saxagliptin, has been associated with development or exacerbation of bullous pemphigoid (Ref). Although most DPP-4 inhibitors have been associated with the development of bullous pemphigoid, vildagliptin is associated with a higher risk (Ref). In addition, severe cutaneous adverse reactions (SCARs) (eg, exfoliative skin conditions) have been reported with saxagliptin (Ref).

Mechanism: Non–dose-related; immunologic

Bullous pemphigoid: Exact mechanism unknown (Ref). Some skin cells (including keratinocytes) express DPP-4, leading to an increase in cytokine production, tissue differentiation, and collagen metabolism; whether this leads to an alteration in the properties of the epidermal basement membrane is unknown.

Delayed hypersensitivity reactions (including SCARs): Mediated by T-cells (Ref).

Onset:

Bullous pemphigoid: Delayed; median onset of ~6 months (range: 6 to 1,751 days) (Ref). Most cases of bullous pemphigoid typically resolve following discontinuation; some require symptomatic treatment (Ref).

Delayed hypersensitivity reactions: Varied; typically occur days to weeks after drug exposure (Ref)

Risk factors:

• Age; although older age may be a risk factor for the development of bullous pemphigoid (Ref), some studies have not shown age to be a factor (Ref)

• Males; some studies have suggested that male patients with diabetes may be at higher risk than female patients (Ref), although a meta-analysis of case-controlled studies did not find sex to be a predisposing risk factor (Ref)

Heart failure

An increased risk of hospitalization due to heart failure (HF) was identified as a potential issue with dipeptidyl peptidase-4 (DPP-4) inhibitors, specifically saxagliptin and alogliptin, following results from the SAVOR TIMI 53 and EXAMINE trials, respectively (Ref). The SAVOR TIMI 53 trial showed that the overall incidence of hospitalization for HF was greater in the saxagliptin arm compared to placebo (3.5% vs 2.8%; p=0.007); in a multivariable analysis of the data, the strongest association with hospitalization for HF regardless of treatment group was previous HF and preexisting kidney impairment (Ref). In contrast, the TECOS and CARMELINA trials showed no increased risk of hospitalization due to HF with sitagliptin or linagliptin, respectively (Ref). A meta-analysis of 182 trials found that, overall, use of a DPP-4 inhibitor was not associated with an increased risk of HF (OR: 1.05; 95% CI: 0.96 to 1.15; I2 = 0%); however, a significantly higher risk of HF was seen with saxagliptin (OR: 1.22; 95% CI: 1.03 to 1.45), but not for other DPP-4 inhibitors (Ref). The American Diabetes Association recommends avoiding use of saxagliptin in patients with HF (Ref); the American Heart Association (AHA) considers saxagliptin to be an agent that may exacerbate underlying myocardial dysfunction (magnitude: major) (Ref).

Mechanism: Unknown (Ref)

Onset: Variable; the AHA suggests the impact of DPP-4 inhibitors on myocardial dysfunction may be seen within weeks to ≥1 year (Ref).

Risk factors:

• Presence of risk factors for HF or preexisting HF (Ref)

• Kidney impairment (Ref)

Hypersensitivity reactions

Anaphylaxis and angioedema have been reported (Ref). Vildagliptin may be associated with higher risk of angioedema than other DPP-4 inhibitors (Ref).

Mechanism: Non–dose-related; immunologic

Angioedema: Considered a non–mast-cell-mediated process involving impaired catabolism of bradykinin (Ref). Saxagliptin and other dipeptidyl peptidase-4 (DPP-4) inhibitors can inactivate substance P and bradykinin (Ref).

Anaphylaxis: Considered to be an IgE-mediated reaction (Ref)

Onset: Varied; events have generally been noted within the first 3 months of therapy and may occur with the initial dose.

Risk factors:

• Concomitant use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (Ref)

• Hereditary angioedema (Ref)

• History of angioedema with other DPP-4 inhibitors

Pancreatic events

Cases of acute pancreatitis (including hemorrhagic and necrotizing with some fatalities), chronic pancreatitis, and pancreatic cancer have been reported with use of incretin-based therapies (eg, dipeptidyl peptidase-4 [DPP-4] inhibitors, glucagon-like peptide 1 [GLP-1] receptor agonists), including saxagliptin (Ref).

Mechanism: Causality has not been firmly established (Ref). DPP-4 inhibitors indirectly stimulate GLP-1 receptors in pancreatic islet beta cells and exocrine duct cells, which may cause an overgrowth of the cells that cover the smaller ducts, thereby resulting in hyperplasia, increased pancreatic weight, duct occlusion, back pressure, and subsequent acute or chronic pancreatic inflammation (Ref).

Risk factors:

• Patients with a prior history of pancreatitis may be at an increased risk for acute pancreatitis.

• Patients with acute pancreatitis due to any cause are at an increased risk for progression to recurrent acute pancreatitis and then to chronic pancreatitis; patients with chronic pancreatitis are at an increased risk for pancreatic cancer (Ref)

• Risk factors for pancreatitis due to any cause include, but are not limited to, hypertriglyceridemia, cholelithiasis, alcohol use, and obesity.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

1% to 10%:

Cardiovascular: Peripheral edema (4%)

Endocrine & metabolic: Hypoglycemia (6%)

Genitourinary: Urinary tract infection (7%)

Hematologic & oncologic: Lymphocytopenia (≤2%)

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

Nervous system: Headache (7%)

Frequency not defined:

Dermatologic: Skin rash

Hematologic & oncologic: Thrombocytopenia

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen

Renal: Increased serum creatinine

Postmarketing:

Cardiovascular: Heart failure (FDA 2018a)

Dermatologic: Bullous pemphigoid (García-Díez 2018), exfoliative dermatitis

Gastrointestinal: Pancreatitis (including acute pancreatitis) (Lee 2014)

Hepatic: Hepatotoxicity (Thalha 2018)

Hypersensitivity: Anaphylaxis, angioedema (Hahn 2017)

Neuromuscular & skeletal: Arthralgia (including severe arthralgia) (Chaica-Brom 2013), rhabdomyolysis

Contraindications

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

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to another DPP-4 inhibitor; diabetic ketoacidosis, diabetic coma/precoma, type 1 diabetes mellitus

Warnings/Precautions

Disease-related concerns:

• Bariatric surgery:

– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Melissas 2013).

– Glucagon-like peptide-1 exposure and therapeutic efficacy: Closely monitor for signs and symptoms of pancreatitis; gastric bypass and sleeve gastrectomy may increase endogenous secretion of glucagon-like peptide-1 (Korner 2009; Peterli 2012). A single-dose, placebo-controlled study evaluated short-term therapy (4 weeks) with sitagliptin in gastric bypass patients having persistent or recurrent type 2 diabetes and found it to be well tolerated and provided a small but significant reduction in postprandial blood glucose (Shah 2018).

• Renal impairment: Use with caution in patients with moderate to severe renal dysfunction (eGFR <45 mL/minute/1.73 m2) including end-stage renal disease requiring hemodialysis; dosing adjustment required.

Other warnings/precautions:

• Appropriate use: Not indicated for use in patients with type 1 diabetes mellitus or with diabetic ketoacidosis.

Metabolism/Transport Effects

Substrate of CYP3A4 (major), P-glycoprotein/ABCB1 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.

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

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Angiotensin-Converting Enzyme Inhibitors: Dipeptidyl Peptidase-IV Inhibitors may enhance the adverse/toxic effect of Angiotensin-Converting Enzyme Inhibitors. Specifically, the risk of angioedema may be increased. Risk C: Monitor therapy

Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of SAXagliptin. Risk C: Monitor therapy

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

CYP3A4 Inhibitors (Strong): May increase the serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors. Risk D: Consider therapy modification

Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy

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

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

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

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

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

Sulfonylureas: Dipeptidyl Peptidase-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. Risk D: Consider therapy modification

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

Reproductive Considerations

Dipeptidyl peptidase 4 (DPP-4) inhibitors are not recommended for patients with type 2 diabetes mellitus planning to become pregnant. Patients who could become pregnant should use effective contraception during therapy. Transition to a preferred therapy should be initiated prior to conception and contraception should be continued until glycemic control is achieved (ADA 2021; Alexopoulos 2019; Egan 2020)

Pregnancy Considerations

Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia. 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 (ADA 2021; Blumer 2013).

Agents other than saxagliptin are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).

Breastfeeding Considerations

It is not known if saxagliptin is present in breast milk.

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and benefits of treatment to the mother.

Dietary Considerations

Individualized medical nutrition therapy based on American Diabetes Association recommendations is an integral part of therapy.

Monitoring Parameters

Plasma glucose; renal function (prior to initiation of therapy and periodically thereafter); lymphocyte counts (if unusual or persistent infection); signs/symptoms of pancreatitis, heart failure, and/or bullous pemphigoid (eg, blisters or erosions).

HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).

Reference Range

Recommendations for glycemic control in patients with diabetes:

Nonpregnant adults (ADA 2021):

HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.

Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).

Older adults (≥65 years of age) (ADA 2021):

Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).

HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.

Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 80 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).

Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).

Classification of hypoglycemia (ADA 2021):

Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.

Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.

Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.

Mechanism of Action

Saxagliptin inhibits dipeptidyl peptidase 4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones (eg, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide) 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-4 enzyme.

Pharmacokinetics

Duration: 24 hours

Protein binding: Negligible

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

Half-life elimination: Saxagliptin: 2.5 hours; 5-hydroxy saxagliptin: 3.1 hours

Time to peak, plasma: Saxagliptin: 2 hours; 5-hydroxy saxagliptin: 4 hours

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

Pharmacokinetics: Additional Considerations

Altered kidney function: 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.

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.

Pricing: US

Tablets (Onglyza Oral)

2.5 mg (per each): $18.84

5 mg (per each): $18.84

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Formigliptin (EG);
  • Glipitrose (EG);
  • Glyza (BD);
  • Ongliza (UA);
  • Onglyza (AE, AR, AT, AU, BB, BE, BH, BR, CH, CL, CN, CO, CR, CY, CZ, DE, DK, DO, EE, EG, ES, ET, FR, GB, GR, GT, HK, HN, HR, ID, IE, IL, IN, JO, JP, KR, KW, LB, LK, LT, LU, LV, MT, MY, NI, NL, NO, NZ, PA, PH, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, SV, TH, TR, TW, VN, ZA);
  • Sixtin (BD)


For country code abbreviations (show table)
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