Saxagliptin

FDA Drug Information • Also known as: Onglyza, Saxagliptin

Brand Names: Onglyza, Saxagliptin
Dosage Form: POWDER
Product Type: BULK INGREDIENT

Description

11 DESCRIPTION Saxagliptin is an orally-active inhibitor of the DPP-4 enzyme. Saxagliptin monohydrate is described chemically as (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3-hydroxytricyclo[3.3.1.1 3,7 ]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile, monohydrate or (1 S ,3 S ,5 S )-2-[(2 S )-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C 18 H 25 N 3 O 2

H 2 O and the molecular weight is 333.43. The structural formula is: Saxagliptin monohydrate is a white to off-white powder. It is soluble in methanol, ethanol; sparingly soluble in water. Each film-coated tablet of saxagliptin for oral use contains either 2.79 mg saxagliptin hydrochloride equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride equivalent to 5 mg saxagliptin and the following inactive ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose. In addition, the film coating contains the following inactive ingredients: hypromellose, iron oxide yellow (2.5 mg tablet only), iron oxide red (5 mg tablet only), polyethylene glycol and titanium dioxide. The imprinting ink contains the following: ammonium hydroxide, n-butyl alcohol, FD&C blue #2, isopropyl alcohol, propylene glycol and shellac. saxagliptistructure

What Is Saxagliptin Used For?

1 INDICATIONS AND USAGE Saxagliptin tablets are a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1.1 ) Limitations of use:

Not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. ( 1.2 ) 1.1 Monotherapy and Combination Therapy Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [ see Clinical Studies ( 14 ) ]. 1.2 Limitation of Use Saxagliptin tablets are not recommended for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis. 1.1 Monotherapy and Combination Therapy Saxagliptin tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [ see Clinical Studies ( 14 ) ].

Dosage and Administration

2 DOSAGE AND ADMINISTRATION

Recommended dosage is 2.5 mg or 5 mg orally once daily taken regardless of meals. ( 2.1 )

Patients with an eGFR < 45 mL/min/1.73 m 2 (moderate or severe renal impairment, or end-stage renal disease): Recommended dosage is 2.5 mg once daily regardless of meals. ( 2.2 )

Assess renal function before starting saxagliptin tablets and periodically thereafter. ( 2.2 )

Limit the dosage of Saxagliptin tablets to 2.5 mg daily for patients also taking strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). ( 2.3 ) 2.1 Recommended Dosage The recommended dosage of saxagliptin tablets is 2.5 mg or 5 mg orally once daily taken regardless of meals. Do not cut, crush, or chew Saxagliptin tablets. If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose 2.2 Dosage in Patients with Renal Impairment Assess renal function prior to initiation of saxagliptin tablets and then as clinically indicated [see Use in Specific Populations ( 8.6 )]. The recommended dosage of saxagliptin tablets in patients with an eGFR greater than or equal to 45 mL/ minute /1.73 m 2 is the same as the recommended dosage in patients with normal renal function [see Dosage and Administration ( 2.1 )]. The dosage of saxagliptin tablets is 2.5 mg orally once daily for patients with eGFR < 45 mL/min/1.73 m 2 w[hich includes a subset of moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis] [ see Clinical Pharmacology (12.3) and Clinical Studies (14.2) ]. Saxagliptin tablets should be administered following hemodialysis. Saxagliptin tablets have not been studied in patients undergoing peritoneal dialysis. 2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors The dosage of saxagliptin tablets is 2.5 mg orally once daily when used concomitantly with strong cytochrome P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) [ see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ].

Side Effects (Adverse Reactions)

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information:

Pancreatitis [ see Warnings and Precautions (5.1) ]

Heart Failure [ see Warnings and Precautions (5.2) ]

Hypoglycemia with Concomitant Use of Insulin or Insulin Secretagogues [ see Warnings and Precautions ( 5.3 ) ]

Hypersensitivity Reactions [ see Warnings and Precautions ( 5.4 ) ]

Severe and disabling arthralgia [ see Warnings and Precautions (5.5) ]

Bullous pemphigoid [ see Warnings and Precautions (5.6) ]

Most common adverse reactions (incidence ≥ 5% and more often than placebo) are upper respiratory tract infection, urinary tract infection, and headache. ( 6.1 )

Peripheral edema was reported more commonly in patients treated with the combination of saxagliptin and a thiazolidinedione (TZD) than in patients treated with the combination of placebo and TZD. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Efficacy Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions in Placebo-Controlled Trials in Adults with Type 2 Diabetes Mellitus The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [ see Clinical Studies (14) ]. These data shown in the table reflect exposure of 882 patients to saxagliptin and a mean duration of exposure to saxagliptin of 21 weeks. The mean age of these patients was 55 years, 1.4% were 75 years of age or older and 48.4% were male. The population was 67.5% White, 4.6% Black or African American, 17.4% Asian, other races 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population had type 2 diabetes mellitus for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline estimated renal function was normal or mildly impaired (eGFR ≥ 60mL/min/1.73 m 2 ) in 91% of these patients. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of saxagliptin. These adverse reactions occurred more commonly on saxagliptin than on placebo and occurred in at least 5% of patients treated with saxagliptin. Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥ 5% of Patients Treated with Saxagliptin 5 mg and More Commonly than in Patients Treated with Placebo % of Patients Saxagliptin 5 mg N=882 Placebo N=799 Upper respiratory tract infection 7.7 7.6 Urinary tract infection 6.8 6.1 Headache 6.5 5.9 In patients treated with saxagliptin 2.5 mg, headache (6.5%) was the only adverse reaction reported at a rate ≥ 5% and more commonly than in patients treated with placebo. In the add-on to TZD trial, the incidence of peripheral edema was higher for saxagliptin 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for saxagliptin 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in trial drug discontinuation. Rates of peripheral edema for saxagliptin 2.5 mg and saxagliptin 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1% versus 2.2% given as add-on therapy to metformin HCl, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide. The incidence rate of fractures was 1 and 0.6 per 100 patient-years, respectively, for saxagliptin (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The...

Drug Interactions

7 DRUG INTERACTIONS

Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with saxagliptin significantly increases saxagliptin concentrations. Limit saxagliptin dosage to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor. ( 7.1 ) 7.1 Strong Inhibitors of CYP3A4/5 Enzymes Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). The dosage of saxagliptin should be limited to 2.5 mg when coadministered with a strong CYP3A4/5 inhibitor [ see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ]. 7.2 Insulin or Insulin Secretagogues Insulin and insulin secretagogues are known to cause hypoglycemia. Concomitant use of saxagliptin tablets with insulin or an insulin secretagogue may require lower dosages of insulin or the insulin secretagogue to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].

Contraindications

4 CONTRAINDICATIONS Saxagliptin tablets are contraindicated in patients with a history of a serious hypersensitivity reaction to saxagliptin or any of the ingredients in saxagliptin tablets. Reactions such as anaphylaxis, angioedema, or exfoliative skin conditions have been reported with saxagliptin tablets [ see Warnings and Precautions ( 5.4 ) and Adverse Reactions (6.2) ].

History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema, exfoliative skin conditions) to saxagliptin or any of the ingredients in saxagliptin. ( 4 )

Pregnancy and Breastfeeding

8.1 Pregnancy Risk Summary Limited data with saxagliptin in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriages. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . No adverse developmental effects independent of maternal toxicity were observed when saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis and in pregnant and lactating rats during the pre- and postnatal period [see Data] . The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with an HbA1c greater than 7 and has been reported to be as high as 20 to 25% in women with an HbA1c greater than 10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, still birth and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Animal Data In embryo-fetal development studies, saxagliptin was administered to pregnant rats and rabbits during the period of organogenesis, corresponding to the first trimester of human pregnancy. No adverse developmental effects were observed in either species at exposures 1503- and 152-times the 5 mg clinical dose in rats and rabbits, respectively, based on AUC. Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats. In a prenatal and postnatal development study, no adverse developmental effects were observed in...

Overdosage

10 OVERDOSAGE In a controlled clinical trial, once-daily, orally-administered saxagliptin in healthy patients at doses up to 400 mg daily for 2 weeks (80-times the MRHD) had no dose-related clinical adverse reactions and no clinically meaningful effect on QTc interval or heart rate. In the event of an overdose, initiate appropriate supportive treatment as dictated by the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis (23% of dose over 4 hours). Contact the Poison Help Line, (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Saxagliptin Tablets are available in the strengths and packages listed in Table 16 Table 16: Saxagliptin Tablet Presentations Tablet Strength Film-Coated Tablet Color/Shape Tablet Markings Package Size NDC Code 2.5 mg pale yellow to yellow, biconvex, round, film-coated “G74” printed on one side in blue ink Bottles of 30 Bottles of 90 Bottles of 500 68462-726-30 68462-726-90 68462-726-05 5 mg pink, biconvex, round, film-coated “G75” printed on one side in blue ink Bottles of 30 Bottles of 90 Bottles of 500 Carton of 100 (10x10 unit-dose) 68462-727-30 68462-727-90 68462-727-05 68462-727-14 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.