Saxagliptin

Pronunciation: SAX-a-GLIP-tin
Class: Antidiabetic agent

Trade Names

Onglyza
- Tablets, oral 2.5 mg
- Tablets, oral 5 mg

Pharmacology

Competitive dipeptidyl peptidase-4 (DPP4) inhibitor that slows the inactivation of incretin hormones, thereby reducing fasting and postprandial glucose concentrations.

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Pharmacokinetics

Absorption

Following a 5 mg oral dose, mean AUC was 78 ng•h/mL for saxagliptin and 214 ng•h/mL for its active metabolite. C _max and T _max were 24 ng/mL and 2 h for saxagliptin and 47 ng/mL and 4 h for the active metabolite, respectively. Administration with a high-fat meal increased T _max by 20 min and AUC by 27%.

Distribution

Protein binding is negligible.

Metabolism

Metabolized by CYP3A4/5. The major metabolite is also a DPP4 inhibitor, which is one-half as potent as saxagliptin.

Elimination

Terminal half-life is 2.5 h for saxagliptin and 3.1 h for its active metabolite. Average renal Cl is approximately 230 mL/min. Approximately 22% is excreted in feces with 24% and 36% excreted in urine as saxagliptin and its active metabolite, respectively.

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. No dosage adjustment is required in patients with mild renal impairment.

Hepatic Function Impairment

C _max and AUC were 8% and 77% higher, respectively, in patients with hepatic impairment (Child-Pugh class A, B, and C). The corresponding C _max and AUC of the active metabolite were 59% and 33% lower, respectively. No dosage is adjustment required.

Elderly

Elderly patients had 23% and 59% higher C _max and AUC values, respectively, compared with younger subjects. Dosage adjustment based on age alone is not required.

Gender

Women had approximately 25% higher exposure values for the active metabolite compared with men.

Race

No significant differences in pharmacokinetics of saxagliptin were seen among different races.

Indications and Usage

Adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.

Contraindications

Hypersensitivity to saxagliptin, such as anaphylaxis, angioedema, or exfoliative skin conditions.

Dosage and Administration

Adults

PO 2.5 or 5 mg once daily.

Renal Function Impairment
Adults

PO

Moderate to severe renal impairment (CrCl 50 mL/min or less)

Do not exceed 2.5 mg once daily.

ESRD requiring hemodialysis

Do not exceed 2.5 mg once daily after hemodialysis.

Strong CYP3A4/5 Inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)
Adults

PO 2.5 mg once daily.

General Advice

• May be taken with or without food.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Aluminum hydroxide/magnesium hydroxide/simethicone, metformin

Saxagliptin plasma concentrations may be reduced slightly. No dosage adjustment is required.

Antidiabetic agents (eg, sulfonylureas)

The risk of hypoglycemia may be increased when used with other antidiabetic agents. A lower dose of the antidiabetic agent may be needed.

Digoxin

Digoxin concentrations may be elevated slightly. No dosage adjustment is required.

Diltiazem, pioglitazone

Plasma concentrations of diltiazem, pioglitazone, and saxagliptin may be elevated slightly. No dosage adjustment is required.

Ethinyl estradiol/norgestimate

Ethinyl estradiol, norelgestromin, and norgestrel concentrations may be elevated slightly. No dosage adjustment is required.

Famotidine

Saxagliptin plasma concentrations may be elevated slightly. No dosage adjustment is required.

Food

High-fat meals increase saxagliptin T _max approximately 20 minutes compared with fasting. Compared with fasting, giving saxagliptin with a meal increases the AUC by 27%. Saxagliptin may be administered without regard to food.

Glyburide

Glyburide and saxagliptin plasma concentrations may be elevated slightly. No dosage adjustment is required.

Ketoconazole

Ketoconazole plasma concentrations may be decreased slightly by saxagliptin. No ketoconazole dosage adjustment is required. However, the saxagliptin dosage should be limited to 2.5 mg once daily. See Strong CY3A4/5 Inhibitors.

Omeprazole

Saxagliptin AUC may be increased slightly. No dosage adjustment is required.

Rifampin

Saxagliptin C _max and AUC may be reduced; however, dosage adjustment is not recommended. Monitor the clinical response of the patient. If an interaction is suspected, adjust treatment as needed.

Simvastatin

Saxagliptin plasma concentrations may be elevated slightly and simvastatin concentrations may be decreased slightly. No dosage adjustment is required.

Strong CYP3A4/5 inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)

Saxagliptin C _max and AUC may be increased, increasing the pharmacologic effects and risk of adverse reactions. The dosage of saxagliptin should be limited to 2.5 mg once daily when administered with a strong CYP3A4/5 inhibitor. Monitor the clinical response of the patient.

Adverse Reactions

CNS

Headache (7%).

EENT

Nasopharyngitis (7%); sinusitis (3%).

GI

Abdominal pain, gastroenteritis, vomiting (2%); pancreatitis (postmarketing).

Genitourinary

UTI (7%).

Hematologic

Decreased absolute lymphocyte count (2%); lymphopenia (1%).

Metabolic-Nutritional

Hypoglycemia (6%); peripheral edema (4%).

Respiratory

Upper respiratory tract infection (8%).

Miscellaneous

Hypersensitivity reactions (eg, urticaria, facial edema) (2%); other hypersensitivity reactions (eg, anaphylaxis, angioedema, exfoliative skin conditions) (postmarketing).

Precautions

Monitor Assess renal function prior to initiation of therapy and periodically thereafter. Periodically measure blood glucose and HbA 1c . Measure lymphocyte count when clinically indicated (eg, unusual or prolonged infection).

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy have not been established.

Elderly

Take care in dose selection based on renal function.

Renal Function

Dosage adjustments are required in patients with moderate or severe renal impairment.

Pancreatitis

There have been postmarketing reports of acute pancreatitis. If suspected, promptly discontinue saxagliptin.

Type 1 diabetes mellitus/diabetic ketoacidosis

Do not use in these settings, as it would not be effective.

Patient Information

• Instruct patients that this drug is not a substitute for diet and exercise and to follow their prescribed regimen.
• Emphasize the importance of regular daily blood glucose monitoring and periodic glycosylated Hgb tests.
• Review symptoms and management of hypoglycemia and hyperglycemia.
• Instruct patients to report hypoglycemic or hyperglycemic episodes to their health care provider.
• Advise patients that during periods of stress (eg, fever, trauma, infection, surgery), medication requirements may change and to seek medical advice promptly.
• Inform patients of the potential need to adjust their dose based on changes in renal function tests over time.
• Inform patients that there have been reports of pancreatitis in patients taking saxagliptin and symptoms, such as persistent severe abdominal pain sometimes radiating to the back that may be accompanied by vomiting, can indicate pancreatitis. Instruct patients to stop taking saxagliptin and contact their health care provider immediately if these symptoms occur.
• Inform patients that serious allergic reactions have been reported. Instruct patients to immediately contact their health care provider if symptoms such as rash; skin flaking, peeling, or swelling; itching; or swelling of the face, lips tongue, and throat that may cause difficulty in breathing and swallowing occur. Instruct patients to stop taking saxagliptin and seek medical attention immediately if these symptoms occur.

Copyright © 2009 Wolters Kluwer Health.