ONGLYZA

ONGLYZA- saxagliptin hydrochloride tablet, film coated
E.R. Squibb & Sons, L.L.C.

1 INDICATIONS AND USAGE

1.1 Monotherapy and Combination Therapy

ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus in multiple clinical settings. [See Clinical Studies (14).]

1.2 Limitations of Use

ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

ONGLYZA has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at an increased risk for the development of pancreatitis while using ONGLYZA. [See Warnings and Precautions (5.1).]

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosage

The recommended dosage of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals.

ONGLYZA tablets must not be split or cut.

2.2 Dosage in Patients with Renal Impairment

No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment (creatinine clearance [CrCl] >50 mL/min).

The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min) [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. ONGLYZA should be administered following hemodialysis. ONGLYZA has not been studied in patients undergoing peritoneal dialysis.

Because the dosage of ONGLYZA should be limited to 2.5 mg based upon renal function, assessment of renal function is recommended prior to initiation of ONGLYZA and periodically thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault formula or Modification of Diet in Renal Disease formula. [See Clinical Pharmacology (12.3).]

2.3 Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors

The dosage of ONGLYZA is 2.5 mg once daily when coadministered 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).]

2.4 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with insulin, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia. [See Warnings and Precautions (5.2).]

3 DOSAGE FORMS AND STRENGTHS

  • ONGLYZA (saxagliptin) 5 mg tablets are pink, biconvex, round, film-coated tablets with “5” printed on one side and “4215” printed on the reverse side, in blue ink.
  • ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow, biconvex, round, film-coated tablets with “2.5” printed on one side and “4214” printed on the reverse side, in blue ink.

4 CONTRAINDICATIONS

ONGLYZA is contraindicated in patients with a history of a serious hypersensitivity reaction to ONGLYZA, such as anaphylaxis, angioedema, or exfoliative skin conditions. [See Warnings and Precautions (5.3) and Adverse Reactions (6.2).]

5 WARNINGS AND PRECAUTIONS

5.1 Pancreatitis

There have been postmarketing reports of acute pancreatitis in patients taking ONGLYZA. After initiation of ONGLYZA, patients should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected, ONGLYZA should promptly be discontinued and appropriate management should be initiated. It is unknown whether patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using ONGLYZA.

5.2 Hypoglycemia with Cocomitant Use of Sulfonylurea or Insulin

When ONGLYZA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of confirmed hypoglycemia was increased over that of placebo used in combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of the insulin secretagogue or insulin may be required to minimize the risk of hypoglycemia when used in combination with ONGLYZA. [See Dosage and Administration (2.4).]

5.3 Hypersensitivity Reactions

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with ONGLYZA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first 3 months after initiation of treatment with ONGLYZA, with some reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions (6.2).]

Use caution in a patient with a history of angioedema to another dipeptidyl peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be predisposed to angioedema with ONGLYZA.

5.4 Macrovascular Outcomes

There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with ONGLYZA or any other antidiabetic drug.

6 ADVERSE REACTIONS

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 with Monotherapy and with Add-On Combination Therapy

In two placebo-controlled monotherapy trials of 24-weeks duration, patients were treated with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo. Three 24-week, placebo-controlled, add-on combination therapy trials were also conducted: one with metformin, one with a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials, patients were randomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy trials and in the add-on combination trial with metformin. The 10 mg dosage is not an approved dosage.

In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the two monotherapy trials, the add-on to metformin trial, the add-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated with ONGLYZA 2.5 mg and ONGLYZA 5 mg was similar to placebo (72% and 72.2% versus 70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%, and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively. The most common adverse events (reported in at least 2 patients treated with ONGLYZA 2.5 mg or at least 2 patients treated with ONGLYZA 5 mg) associated with premature discontinuation of therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated with ONGLYZA 5 mg, and more commonly than in patients treated with placebo are shown in Table 1.

Table 1: Adverse Reactions in Placebo-Controlled Trials* Reported in ≥5% of Patients Treated with ONGLYZA 5 mg and More Commonly than in Patients Treated with Placebo
Number (%) of Patients
ONGLYZA 5 mgN=882 PlaceboN=799
* The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of glycemic rescue.
Upper respiratory tract infection 68 (7.7) 61 (7.6)
Urinary tract infection 60 (6.8) 49 (6.1)
Headache 57 (6.5) 47 (5.9)

In patients treated with ONGLYZA 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 this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequently compared to placebo included: sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).

In the add-on to TZD trial, the incidence of peripheral edema was higher for ONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema resulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 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, and 2.4% and 1.2% versus 2.2% given as add-on therapy to glyburide.

The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The 10 mg dosage is not an approved dosage. The incidence rate of fracture events in patients who received ONGLYZA did not increase over time. Causality has not been established and nonclinical studies have not demonstrated adverse effects of ONGLYZA on bone.

An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is not known.

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