Saxagliptin Hydrochloride

Class: Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
VA Class: HS502
Chemical Name: (1S,3S,5S) - 2 - [(2S) - Amino(3 - hydroxytricyclo(3.3.1.13,7)dec - 1 - yl)acetyl]2 - azabicyclo(3.1.0)hexane - 3 - carbonitrile
Molecular Formula: C₁₈H₂₅N₃O₂•H₂O
CAS Number: 945667-22-1
Brands: Onglyza, Kombiglyze XR

Introduction

Antidiabetic agent; dipeptidyl peptidase-4 (DPP-4) inhibitor.^{1 3}

Uses for Saxagliptin Hydrochloride

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Diabetes Mellitus

Used as monotherapy as an adjunct to diet and exercise for management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone.^{1 2 3 10 25 31}

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Used in combination with metformin, a sulfonylurea, or a thiazolidinedione (e.g., a peroxisome proliferator-activated receptor-_γ [PPAR-_γ] agonist) for management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and metformin, sulfonylurea, or thiazolidinedione monotherapy.^{1 4 5 6 7 25 29 30} Patients initially receiving an oral antidiabetic agent will eventually require multiple oral antidiabetic agents of different therapeutic classes and/or insulin for adequate glycemic control because of declining β₂-cell function with disease progression.^{15 16 17 18 19 20}

Not indicated for type 1 diabetes mellitus or diabetic ketoacidosis; insulin is required in these conditions.^{1 2}

Saxagliptin Hydrochloride Dosage and Administration

General

• Individualize dosage of saxagliptin in fixed combination with extended-release metformin hydrochloride based on patient’s current antidiabetic regimen, clinical response, and tolerability.²⁷ Undertake any change in therapy with care and appropriate monitoring because changes in glycemic control can occur.²⁷

Administration

Oral Administration

Saxagliptin Monotherapy

Administer once daily without regard to meals.^{1 2 21}

Saxagliptin/Metformin Hydrochloride Fixed Combination

Administer once daily with the evening meal, increasing dosage gradually to minimize adverse GI effects of extended-release metformin hydrochloride component.²⁷

Swallow whole; do not cut, chew, or crush.^{27 28}

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as saxagliptin hydrochloride; dosage expressed in terms of saxagliptin.¹

Adults

Diabetes Mellitus

Previously Untreated Patients

Oral

Monotherapy: 2.5 or 5 mg once daily.¹ Higher dosages did not provide additional benefit in clinical trials and are not recommended by manufacturer.^{1 5 27 32}

If used with a potent CYP3A4/5 inhibitor, limit dosage to 2.5 mg daily.¹ (See Interactions.)

Saxagliptin/Metformin Hydrochloride Fixed-combination Therapy

Oral

Patients inadequately controlled on saxagliptin 5 mg daily as monotherapy: Initially, 5 mg of saxagliptin and 500 mg of extended-release metformin hydrochloride once daily; increase metformin dosage gradually to minimize adverse GI effects of metformin.²⁷

Patients inadequately controlled on monotherapy with extended-release metformin hydrochloride: Dosage should provide metformin hydrochloride at the patient’s current dosage, or the nearest therapeutically appropriate dosage.²⁷ Following a switch from immediate-release to extended-release metformin, closely monitor glycemic control and adjust dosage accordingly.²⁷

Patients inadequately controlled on saxagliptin 2.5 mg daily as monotherapy: Initially, 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride daily. ²⁷ Use the individual components in patients who require 2.5 mg of saxagliptin and are either metformin naive or require a metformin hydrochloride dose >1 g.²⁷

If used with a potent CYP3A4/5 inhibitor, limit dosage to 2.5 mg of saxagliptin and 1 g of extended-release metformin hydrochloride.²⁷ (See Interactions.)

Prescribing Limits

Adults

Diabetes Mellitus

Oral

Saxagliptin dosages >5 mg daily did not provide additional benefit in clinical trials and are not recommended by manufacturer.^{1 5 27 32}

Fixed combination with extended-release metformin hydrochloride: Maximum 5 mg of saxagliptin and 2 g of metformin hydrochloride daily.²⁷

Special Populations

Hepatic Impairment

No dosage adjustment recommended.¹

Renal Impairment

Mild renal impairment: No saxagliptin dosage adjustment recommended.¹

Moderate or severe renal impairment (Cl_cr ≤50 mL/minute): 2.5 mg once daily.¹

End-stage renal disease requiring hemodialysis: 2.5 mg once daily, following hemodialysis.¹

Peritoneal dialysis: Not studied.¹

Fixed combination of saxagliptin and extended-release metformin hydrochloride contraindicated in patients with renal impairment.²⁷

Geriatric Patients

Because of the greater frequency of decreased renal function in geriatric patients, select dosage with caution.¹

Cautions for Saxagliptin Hydrochloride

Contraindications

• No contraindications according to the manufacturer.¹

Warnings/Precautions

Concomitant Therapy with Hypoglycemic Agents

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

When adding saxagliptin to therapy with insulin secretagogues (e.g., a sulfonylurea), consider reducing the dosage of the insulin secretagogue to reduce the risk of hypoglycemia.¹

Macrovascular Outcomes

Evidence of macrovascular risk reduction with saxagliptin or any other antidiabetic agent has not been conclusively demonstrated in clinical trials.¹

Use of Fixed Combinations

When saxagliptin is used in fixed combination with metformin hydrochloride, consider the cautions, precautions, and contraindications associated with metformin.²⁷

Reduction in Lymphocyte Counts

Dose-related mean decreases in absolute lymphocyte count reported with saxagliptin dosages of 5 and 10 mg daily;¹ clinical importance not known.¹ When clinically indicated (i.e., settings of unusual or prolonged infection), measure lymphocyte count.¹

Sensitivity Reactions

Generalized urticaria and facial edema reported during postmarketing experience; not reported as life-threatening or resulting in hospitalization.¹

Specific Populations

Pregnancy

Category B.¹

Lactation

Distributed into milk in rats; not known whether distributed into human milk.¹ Use caution.¹

Pediatric Use

Safety and efficacy not established in children <18 years of age.¹

Geriatric Use

No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.¹

Eliminated in part by kidneys; assess renal function periodically since geriatric patients are more likely to have decreased renal function.¹

Renal Impairment

Renal impairment increases exposure to saxagliptin and its active metabolite.¹ (See Special Populations under Pharmacokinetics.) Dosage adjustment recommended for patients with moderate or severe renal impairment or end-stage renal disease requiring hemodialysis.¹ (See Renal Impairment under Dosage and Administration.)

Fixed combination of saxagliptin and metformin hydrochloride contraindicated in patients with renal impairment.²⁷

Assess renal function prior to initiation of therapy and periodically thereafter.^{1 27}

Common Adverse Effects

Saxagliptin monotherapy: Upper respiratory infection, urinary tract infection, headache.¹

Saxagliptin and extended-release metformin hydrochloride fixed-combination therapy: Headache, nasopharyngitis.^{1 27 28}

Interactions for Saxagliptin Hydrochloride

Metabolized principally via CYP3A4 and CYP3A5.¹

Saxagliptin and its active metabolite do not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro and do not induce CYP isoenzymes 1A2, 2B6, 2C9, or 3A4 in vitro.¹

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4/5 inhibitors: Substantial increases in saxagliptin plasma concentrations and AUC are expected.¹ Limit saxagliptin dosage to 2.5 mg daily when used concomitantly with a potent CYP3A4/5 inhibitor.¹

Drugs Metabolized by Hepatic Microsomal Enzymes

Drugs metabolized by CYP isoenzymes 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1, or 3A4: Pharmacokinetic interactions unlikely.¹

Specific Drugs

Drug	Interaction	Comments
Antacids (aluminum-, magnesium-, and simethicone-containing)	Decreased peak concentration of saxagliptin; AUC unchanged12	No dosage adjustment required1
Antifungals, azoles (e.g., itraconazole, ketoconazole)	Ketoconazole: Decreased peak concentration and AUC of ketoconazole; increased peak concentration and AUC of saxagliptin1 12 24 Itraconazole: Substantial increase in plasma concentrations and AUC of saxagliptin expected1	Limit saxagliptin dosage to 2.5 mg daily1
Digoxin	Pharmacokinetic interaction unlikely1	No dosage adjustment required1
Diltiazem	Increased peak concentration of diltiazem; increased peak concentration and AUC of saxagliptin and 5-hydroxy saxagliptin12	No dosage adjustment required1
Famotidine	Increased peak concentration of saxagliptin12	No dosage adjustment required1
HIV protease inhibitors (e.g., atazanavir, indinavir, nelfinavir, ritonavir, saquinavir)	Substantial increase in plasma concentrations and AUC of saxagliptin expected1	Limit saxagliptin dosage to 2.5 mg daily1
Hormonal contraceptives	Ethinyl estradiol/norgestimate: No appreciable effect on ethinyl estradiol or norgestimate pharmacokinetics	No dosage adjustment required1
Macrolide antibiotics (e.g., clarithromycin, telithromycin)	Substantial increase in plasma concentrations and AUC of saxagliptin expected1	Limit saxagliptin dosage to 2.5 mg daily1
Metformin	Decreased peak concentration of saxagliptin; no effect on saxagliptin AUC or metformin pharmacokinetics12	No dosage adjustment required1
Nefazodone	Substantial increase in plasma concentrations and AUC of saxagliptin expected1	Limit saxagliptin dosage to 2.5 mg daily1
Omeprazole	Saxagliptin pharmacokinetics not substantially altered1 12	No dosage adjustment required1
Pioglitazone	Increased peak concentration of pioglitazone; AUC not appreciably altered12	No dosage adjustment required1
Rifampin	Decreased peak concentration and AUC of saxagliptin12	No dosage adjustment required1
Simvastatin	Increased peak concentration and AUC of saxagliptin12	No dosage adjustment required1 22
Sulfonylureas (e.g., glyburide)	Glyburide: Increased peak concentrations of glyburide and saxagliptin	May need to decrease sulfonylurea dosage to reduce risk of hypoglycemia1

Saxagliptin Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Estimated oral bioavailability is 67%.¹¹

Onset

Rapidly absorbed following oral administration;¹¹ peak plasma concentrations generally attained in 2 hours following administration of recommended doses.¹

Food

Food does not appear to affect absorption. ^{1 21}

Distribution

Extent

Distributed into milk in rats; not known whether distributed into human milk.¹

Plasma Protein Binding

Negligible.^{1 11}

Elimination

Metabolism

Metabolized principally via CYP3A4 and CYP3A5 to active metabolite 5-hydroxy saxagliptin.^{1 11}

Elimination Route

saxagliptin and its metabolites excreted in urine and feces.¹

Half-life

2.5 hours.^{1 11}

Special Populations

Hepatic impairment increases peak concentrations and AUC of saxagliptin by ≤8 and ≤77%, respectively, and increases peak concentrations and AUC of active metabolite by ≤59 and ≤33%, respectively.¹ Not considered clinically important.¹

Mild renal impairment increase AUC of saxagliptin and its active metabolite by 20 and 70%, respectively; not considered clinically important.¹ However, moderate or severe renal impairment increases AUC of saxagliptin and its active metabolite by 2.1- and 4.5-fold, respectively.¹

Removed by hemodialysis.¹

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).^{1 27}

Actions

• Inhibits dipeptidyl peptidase-4 (DPP-4), an enzyme that inactivates incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).^{1 8 9 25 26}

• More selective for inhibition of DPP-4 than for DPP-8 or DDP-9.¹⁴

• Increases circulating concentrations of GIP and GLP-1 in a glucose-dependent manner.^{1 8}

• GIP and GLP-1 stimulate insulin synthesis and release from pancreatic β-cells in a glucose-dependent manner (i.e., when glucose concentrations are normal or elevated).^{1 8 9 25}

• GLP-1 also decreases glucagon secretion from pancreatic α-cells in a glucose-dependent manner, leading to reduced hepatic glucose production.^{1 9 25}

• Lowers fasting plasma glucose concentrations and reduces glucose excursions following glucose load or meal in patients with type 2 diabetes mellitus.^{1 25}

• Saxagliptin usually not associated with hypoglycemia or substantial changes in body weight.^{2 3 4 10 25}

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

• Importance of patient reading patient information leaflet before initiating therapy and each time drug is dispensed.¹

• Importance of informing patients of the potential risks and benefits of saxagliptin and of alternative therapies.¹

• Importance of informing patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA_1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment of diabetes complications.¹

• Importance of seeking medical advice promptly during periods of stress such as fever, trauma, infection, or surgery as medication requirements may change.¹

  Importance of informing patients that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1c, with a goal of decreasing these levels toward the normal range.¹

  Importance of informing patients of the potential need to adjust their dosage based on changes in renal function over time.¹

• Importance of informing clinician if any unusual symptom develops or if any existing symptom persists or worsens.¹

• Importance of informing patients to contact their clinician immediately if allergic (hypersensitivity) reaction (e.g., rash, hives, swelling of the face, lips, and throat) occurs.²

• Importance of women informing their clinicians if they are or plan to become pregnant or plan to breast-feed.^{1 2}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., allergies, kidney disease).²

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Saxagliptin Hydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	2.5 mg (of saxagliptin)	Onglyza	Bristol-Myers Squibb
		5 mg (of saxagliptin)	Onglyza	Bristol-Myers Squibb

Saxagliptin Hydrochloride Combinations

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	2.5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g	Kombiglyze XR	Bristol-Myers Squibb
		5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 500 mg	Kombiglyze XR	Bristol-Myers Squibb
		5 mg (of saxagliptin) with Metformin Hydrochloride extended-release 1 g	Kombiglyze XR	Bristol-Myers Squibb

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 04/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Kombiglyze XR 2.5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$119.99 or 90/$344.98

Kombiglyze XR 5-1000MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$236.98 or 90/$679.00

Kombiglyze XR 5-500MG 24-hr Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$240.00 or 90/$699.98

Onglyza 2.5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$240.00 or 90/$658.98

Onglyza 5MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$235.98 or 90/$635.96