Pharmacy & Therapeutics - January 2009 - (Page 18) Brief Summary of Prescribing Information JANUVIA® (sitagliptin) Tablets INDICATIONS AND USAGE Important Limitations of Use. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. JANUVIA has not been studied in combination with insulin. DOSAGE AND ADMINISTRATION Recommended Dosing. The recommended dose of JANUVIA is 100 mg once daily. JANUVIA can be taken with or without food. Patients with Renal Insufficiency. For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥50 mL/min, approximately corresponding to serum creatinine levels of ≤1.7 mg/dL in men and ≤1.5 mg/dL in women), no dosage adjustment for JANUVIA is required. For patients with moderate renal insufficiency (CrCl ≥30 to 1.7 to ≤3.0 mg/dL in men and >1.5 to ≤2.5 mg/dL in women), the dose of JANUVIA is 50 mg once daily. For patients with severe renal insufficiency (CrCl 3.0 mg/dL in men and >2.5 mg/dL in women) or with end-stage renal disease (ESRD) requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis. Because there is a need for dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter. Creatinine clearance can be estimated from serum creatinine using the Cockcroft-Gault formula. Concomitant Use with a Sulfonylurea. When JANUVIA is used in combination with a sulfonylurea, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. [See Warnings and Precautions.] CONTRAINDICATIONS History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. [See Warnings and Precautions and Adverse Reactions.] WARNINGS AND PRECAUTIONS Use in Patients with Renal Insufficiency. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency and in patients with ESRD requiring hemodialysis or peritoneal dialysis. [See Dosage and Administration.] Use with Medications Known to Cause Hypoglycemia. As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA was used in combination with a sulfonylurea, a class of medications known to cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo. [See Adverse Reactions.] Therefore, a lower dose of sulfonylurea may be required to reduce the risk of hypoglycemia. [See Dosage and Administration.] Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes. [See Adverse Reactions.] Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with JANUVIA or any other anti-diabetic drug. ADVERSE REACTIONS 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. In controlled clinical studies as both monotherapy and combination therapy with metformin or pioglitazone, the overall incidence of adverse reactions, hypoglycemia, and discontinuation of therapy due to clinical adverse reactions with JANUVIA were similar to placebo. In combination with glimepiride, with or without metformin, the overall incidence of clinical adverse reactions with JANUVIA was higher than with placebo, in part related to a higher incidence of hypoglycemia (see Table 1); the incidence of discontinuation due to clinical adverse reactions was similar to placebo. Two placebo-controlled monotherapy studies, one of 18- and one of 24-week duration, included patients treated with JANUVIA 100 mg daily, JANUVIA 200 mg daily, and placebo. Three 24-week, placebo-controlled add-on combination therapy studies, one with metformin, one with pioglitazone, and one with glimepiride with or without metformin, were also conducted. In addition to a stable dose of metformin, pioglitazone, glimepiride, or glimepiride and metformin, patients whose diabetes was not adequately controlled were given either JANUVIA 100 mg daily or placebo. The adverse reactions, reported regardless of investigator assessment of causality in ≥5% of patients treated with JANUVIA 100 mg daily as monotherapy, JANUVIA in combination with pioglitazone, or JANUVIA in combination with glimepiride, with or without metformin, and more commonly than in patients treated with placebo, are shown in Table 1. Table 1. Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with Pioglitazone or Glimepiride +/- Metformin: Adverse Reactions Reported in ≥5% of Patients and More Commonly than in Patients Given Placebo, Regardless of Investigator Assessment of Causalitya Number of Patients (%) Monotherapy JANUVIA 100 mg Placebo N=443 N=363 Nasopharyngitis 23 (5.2) 12 (3.3) Combination with Pioglitazone JANUVIA 100 mg + Placebo + Pioglitazone Pioglitazone N=175 N=178 Upper Respiratory Tract Infection 11 (6.3) 6 (3.4) Headache 9 (5.1) 7 (3.9) Combination with Glimepiride JANUVIA 100 mg + Placebo + Glimepiride (+/- Metformin) Glimepiride (+/- Metformin) (+/- Metformin) N=222 N=219 Hypoglycemia 27 (12.2) 4 (1.8) Nasopharyngitis 14 (6.3) 10 (4.6) Headache 13 (5.9) 5 (2.3) In the prespecified pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia in patients treated with JANUVIA 100 mg was similar to placebo (1.2% vs 0.9%). Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidence of selected gastrointestinal adverse reactions in patients treated with JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), and diarrhea (3.0%, 2.3%). In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in combination with metformin, the adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients are shown in Table 2. The incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in patients given sitagliptin in combination with metformin. Table 2. Initial Therapy with Combination of Sitagliptin and Metformin: Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin alone, and Placebo)a Number of Patients (%) Placebo Sitagliptin Metformin 500 Sitagliptin 50 mg bid (JANUVIA) or 1000 mg bidb + Metformin 500 or 100 mg qd 1000 mg bidb N=176 N=179 N=364b N=372b Upper Respiratory Infection 9 (5.1) 8 (4.5) 19 (5.2) 23 (6.2) Headache 5 (2.8) 2 (1.1) 14 (3.8) 22 (5.9) a b Intent-to-treat population. Data pooled for the patients given the lower and higher doses of metformin. No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA. Laboratory Tests Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell (WBC) count was observed due to an increase in neutrophils. This increase in WBC (of approximately 200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline WBC count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of 91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA [0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of this added increase in serum creatinine relative to placebo is not known. Postmarketing Experience. The following additional adverse reactions have been identified during postapproval use of JANUVIA. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions]; hepatic enzyme elevations. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B: Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg (approximately 12 times the human exposure at the maximum recommended human dose) did not impair fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant women. Because animal rep
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