Each film-coated tablet of JANUVIA contains 32.13, 64.25, or 128.5 mg of sitagliptin phosphate monohydrate, which is equivalent to 25, 50, or 100 mg, respectively, of free base.
Excipients/Inactive Ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate (calcium hydrogen phosphate, anhydrous), croscarmellose sodium, magnesium stearate, and sodium stearyl fumarate. In addition, the film coating contains the following inactive ingredients: polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide, red iron oxide, and yellow iron oxide.
JANUVIA (sitagliptin phosphate) is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme for the treatment of type 2 diabetes. Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. By inhibiting the DPP-4 enzyme, sitagliptin increases the levels of two known active incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretins are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. When blood glucose concentrations are normal or elevated, GLP-1 and GIP increase insulin synthesis and release from pancreatic beta cells. GLP-1 also lowers glucagon secretion from pancreatic alpha cells, leading to reduced hepatic glucose production. Sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4 and does not inhibit the closely-related enzymes DPP-8 or DPP-9 at therapeutic concentrations. In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.
Monotherapy: JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus.
Combination with Metformin: JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin as initial therapy or when the single agent alone, with diet and exercise, does not provide adequate glycemic control.
Combination with a Sulfonylurea: JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with a sulfonylurea when treatment with the maximal tolerated dose of a single agent alone, with diet and exercise, does not provide adequate glycemic control and when metformin is inappropriate due to contraindications or intolerance.
Combination with a PPARγ agonist: JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with a PPARγ agonist (i.e., thiazolidinediones) as initial therapy or when the single agent alone, with diet and exercise, does not provide adequate glycemic control.
Combination with Metformin and a Sulfonylurea: JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin and a sulfonylurea when dual therapy with these agents, with diet and exercise, does not provide adequate glycemic control.
Combination with Metformin and a PPARγ agonist: JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin and a PPARγ agonist (i.e., thiazolidinediones) when dual therapy with these agents, with diet and exercise, does not provide adequate glycemic control.
Combination with Insulin: JANUVIA is indicated in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in combination with insulin (with or without metformin).
The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination therapy with metformin, a sulfonylurea, insulin (with or without metformin), a PPARγ agonist (i.e., thiazolidinediones), metformin plus a sulfonylurea, or metformin plus a PPARγ agonist. JANUVIA can be taken with or without food.
When JANUVIA is used in combination with a sulfonylurea or with insulin, a lower dose of sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia. (See Hypoglycemia in Combination with a Sulfonylurea or with Insulin under Precautions).
Patients with Renal Impairment: Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter.
For patients with mild renal impairment (glomerular filtration rate [GFR] ≥60 mL/min to 90 mL/min,), no dosage adjustment for JANUVIA is required.
For patients with moderate renal impairment (GFR ≥ 45 mL/min to < 60 mL/min), no dosage adjustment for JANUVIA is required.
For patients with moderate renal impairment (GFR ≥30 mL/min to <45 mL/min), the dose of JANUVIA is 50 mg once daily.
For patients with severe renal impairment (GFR ≥ 15 mL/min to <30 mL/min,) or with end-stage renal disease (ESRD) (GFR < 15 mL/min), including those requiring hemodialysis or peritoneal dialysis, the dose of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of dialysis.
Patients with Hepatic Impairment: In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and Cmax of sitagliptin increased approximately 21% and 13%, respectively, compared to healthy matched controls following administration of a single 100-mg dose of JANUVIA. These differences are not considered to be clinically meaningful. No dosage adjustment for JANUVIA is necessary for patients with mild to moderate hepatic impairment. JANUVIA has not been studied in patients with severe hepatic impairment (Child-Pugh score >9).
During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were administered. Maximal mean increases in QTc of 8.0 msec, a mean effect that is not considered to be clinically important, were observed in one study at a dose of 800 mg JANUVIA. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose studies, there were no dose-related clinical adverse reactions observed with JANUVIA with doses of up to 600 mg per day for periods of up to 10 days and 400 mg per day for periods of up to 28 days.
In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required.
Sitagliptin is modestly dialyzable. In clinical studies, approximately 13.5% of the dose was removed over a 3- to 4-hour hemodialysis session. Prolonged hemodialysis may be considered if clinically appropriate. It is not known if sitagliptin is dialyzable by peritoneal dialysis.
JANUVIA is contraindicated in patients who are hypersensitive to any components of this product. (See Hypersensitivity Reactions under Precautions and Postmarketing Experience under Side Effects.)
General: JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.
Pancreatitis: There have been reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis (see Side Effects), in patients taking sitagliptin. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin. If pancreatitis is suspected, JANUVIA and other potentially suspect medicinal products should be discontinued.
Use in Patients with Renal Impairment: JANUVIA is renally excreted. To achieve plasma concentrations of JANUVIA similar to those in patients with normal renal function, lower dosages are recommended in patients with GFR < 45 mL/min, as well as in ESRD patients requiring hemodialysis or peritoneal dialysis. (See Patients with Renal Impairment under Dosage & Administration.)
Hypoglycemia in Combination with a Sulfonylurea or with Insulin: In clinical trials of JANUVIA as monotherapy and JANUVIA as part of combination therapy with agents not known to cause hypoglycemia (i.e. metformin or a PPARγ agonist (thiazolidinedione)), rates of hypoglycemia reported with JANUVIA were similar to rates in patients taking placebo. As is typical with other antihyperglycemic agents, hypoglycemia has been observed when JANUVIA was used in combination with insulin or a sulfonylurea (see Side Effects). Therefore, to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered (see Dosage & 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 Contraindications and Postmarketing Experience under Side Effects.)
Bullous Pemphigoid: Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor.
Tell patients to report development of blisters or erosions while receiving JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be discontinued and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
Use in Children: Safety and effectiveness of JANUVIA in pediatric patients under 18 years have not been established.
Use in the Elderly: In clinical studies, the safety and effectiveness of JANUVIA in the elderly (≥65 years) were comparable to those seen in younger patients (<65 years). No dosage adjustment is required based on age. Elderly patients are more likely to have renal impairment; as with other patients, dosage adjustment may be required in the presence of significant renal impairment (see Patients with Renal Impairment under Dosage & Administration).
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 reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20 (organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of 100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in offspring of rats.
Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and 80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was approximately 66% at 2 hours and 30% at 24 hours.
Nursing Mothers: Sitagliptin is secreted in the milk of lactating rats. It is not known whether sitagliptin is secreted in human milk. Therefore, JANUVIA should not be used by a woman who is nursing.
JANUVIA was generally well tolerated in controlled clinical studies as both monotherapy and combination therapy. 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 four placebo-controlled clinical studies as both monotherapy (one study of 18- and one of 24-week duration) and add-on combination therapy with metformin or pioglitazone (both of 24-week duration), there were 1082 patients treated with JANUVIA 100 mg once daily and 778 patients given placebo. (Two of these studies also included 456 patients treated with JANUVIA 200 mg daily, two times the recommended daily dose.) There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving JANUVIA 100 mg. Overall, the safety profile of the 200-mg daily dose was similar to that of the 100-mg daily dose.
In a prespecified pooled analysis of the above studies, the overall incidence of adverse experiences of hypoglycemia in patients treated with JANUVIA 100 mg was similar to placebo (1.2% vs. 0.9%). The incidences of selected gastrointestinal adverse experiences in patients treated with JANUVIA or placebo were: abdominal pain (JANUVIA, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), vomiting (0.8%, 0.9%), and diarrhea (3.0%, 2.3%).
In all studies, adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose measurement was not required.
Add-on Combination with a Sulfonylurea: In a 24-week placebo-controlled study of JANUVIA 100 mg in combination with glimepiride or with glimepiride and metformin (JANUVIA, N=222; placebo, N=219), the drug-related adverse reaction reported in ≥1% of patients treated with JANUVIA and more commonly than in patients treated with placebo was hypoglycemia (JANUVIA, 9.5%; placebo, 0.9%).
Add-on Combination with Metformin and a PPARγ Agonist: In a placebo-controlled study of JANUVIA 100 mg in combination with metformin and rosiglitazone (JANUVIA, N=170; placebo, N=92), the drug-related adverse reactions reported through the primary time point at Week 18 in ≥1% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: headache (JANUVIA, 2.4%; placebo, 0.0%), diarrhea (1.8%, 1.1%), nausea (1.2%, 1.1%), hypoglycemia (1.2%, 0.0%), and vomiting (1.2%, 0.0%). Through Week 54, the drug-related adverse reactions reported in ≥1% of patients treated with JANUVIA and more commonly than in patients treated with placebo were: headache (2.4%, 0.0%), hypoglycemia (2.4%, 0.0%), upper respiratory tract infection (1.8%, 0.0%), nausea (1.2%, 1.1%), cough (1.2%, 0.0%), fungal skin infection (1.2%, 0.0%), peripheral edema (1.2%, 0.0%), and vomiting (1.2%, 0.0%).
Initial Combination Therapy with Metformin: In a 24-week placebo-controlled factorial study of initial therapy with sitagliptin 100 mg in combination with metformin at 1000 mg or 2000 mg per day (administered as sitagliptin 50 mg/metformin 500 mg or 1000 mg twice daily), the drug-related adverse reactions reported in ≥1% of patients treated with sitagliptin plus metformin (N=372) and more commonly than in patients treated with metformin alone (N=364) were: diarrhea (sitagliptin plus metformin, 3.5%; metformin, 3.3%), dyspepsia (1.3%; 1.1%), flatulence (1.3%; 0.5%), vomiting (1.1%; 0.3%), and headache (1.3%; 1.1%). The incidence of hypoglycemia was 1.1% in patients given sitagliptin in combination with metformin and 0.5% in patients given metformin alone.
Initial Combination Therapy with a PPARγ Agonist: In a 24-week study of initial therapy with JANUVIA at 100 mg/day in combination with pioglitazone at 30 mg/day, the only drug-related adverse reaction reported in ≥1% of patients treated with JANUVIA with pioglitazone (N=261) and more commonly than in patients treated with pioglitazone alone (N=259) was (asymptomatic) decreased blood glucose (JANUVIA with pioglitazone, 1.1%; pioglitazone, 0.0%). The incidence of (symptomatic) hypoglycemia was 0.4% in patients given JANUVIA in combination with pioglitazone and 0.8% in patients given pioglitazone.
Add-on Combination with Insulin: In a 24-week placebo-controlled study of JANUVIA 100 mg in combination with stable-dose insulin (with or without metformin), the drug-related adverse reactions reported in ≥1% of patients treated with JANUVIA (N=322) and more commonly than in patients treated with placebo (N=319) were: hypoglycemia (JANUVIA, 9.6%; placebo, 5.3%), influenza (1.2%, 0.3%), and headache (1.2%, 0.0%). In another 24-week study of patients receiving JANUVIA as add-on therapy while undergoing insulin intensification (with or without metformin), there were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients treated with JANUVIA 100mg and more commonly than in patients treated with placebo.
Pancreatitis: In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control (N=4817), the incidence of non-adjudicated acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control). See also TECOS Cardiovascular Safety Study, as follows. (See Pancreatitis under Precautions.)
No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in patients treated with JANUVIA.
TECOS Cardiovascular Safety Study: The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline estimated glomerular filtration rate (eGFR) was ≥30 and <50 mL/min/1.73m2), and 7,339 patients treated with placebo in the intention-to-treat population. Both treatments were added to usual care targeting regional standards for HbA1c and CV risk factors. The overall incidence of serious adverse events in patients receiving sitagliptin was similar to that in patients receiving placebo.
In the intention-to-treat population, among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycemia 1.0% in sitagliptin-treated patients and 0.7% in placebo-treated patients. The incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo-treated patients.
Postmarketing Experience: Additional adverse reactions have been identified during postmarketing use of JANUVIA as monotherapy and/or in combination with other antihyperglycemic agents. 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 including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications and Hypersensitivity Reactions under Precautions); acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis (see Pancreatitis under Precautions); worsening renal function, including acute renal failure (sometimes requiring dialysis); bullous pemphigoid (see Bullous Pemphigoid under Precautions); upper respiratory tract infection; nasopharyngitis; constipation; vomiting; headache; arthralgia; myalgia; pain in extremity; back pain; pruritus.
Laboratory Test Findings: The incidence of laboratory adverse experiences was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. Across clinical studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs. placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to an increase in neutrophils. This observation was seen in most but not all studies. This change in laboratory parameters 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.
In Vitro Assessment of Drug Interactions: Sitagliptin is not an inhibitor of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19 or 2B6, and is not an inducer of CYP3A4. Sitagliptin is a p-glycoprotein substrate, but does not inhibit p-glycoprotein mediated transport of digoxin. Based on these results, sitagliptin is considered unlikely to cause interactions with other drugs that utilize these pathways.
Sitagliptin is not extensively bound to plasma proteins. Therefore, the propensity of sitagliptin to be involved in clinically meaningful drug-drug interactions mediated by plasma protein binding displacement is very low.
In Vivo Assessment of Drug Interactions: Effects of Sitagliptin on Other Drugs: In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of the following: metformin, rosiglitazone, glyburide, simvastatin, warfarin, and oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, 2C8, or 2C9, and organic cationic transporter (OCT).
Digoxin: There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug concentration (Cmax, 18%) of digoxin with the co-administration of 0.25mg digoxin and 100mg sitagliptin for 10 days. Patients receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is recommended.
Metformin: Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.
Sulfonylureas: Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, was not meaningfully altered in subjects receiving multiple doses of sitagliptin. Clinically meaningful interactions would not be expected with other sulfonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, like glyburide, are primarily eliminated by CYP2C9.
Simvastatin: Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.
Thiazolidinediones: Single-dose pharmacokinetics of rosiglitazone was not meaningfully altered in subjects receiving multiple daily doses of sitagliptin, indicating that JANUVIA is not an inhibitor of CYP2C8-mediated metabolism. Clinically meaningful interactions with pioglitazone are not expected because pioglitazone predominantly undergoes CYP2C8- or CYP3A4-mediated metabolism.
Warfarin: Multiple daily doses of sitagliptin did not meaningfully alter the pharmacokinetics, as assessed by measurement of S(-) or R(+) warfarin enantiomers, or pharmacodynamics (as assessed by measurement of prothrombin INR) of a single dose of warfarin. Because S(-) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.
Oral Contraceptives: Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.
Effects of Other Drugs on Sitagliptin: Clinical data described as follows suggest that sitagliptin is not susceptible to clinically meaningful interactions by co-administered medications: Metformin: Co-administration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with type 2 diabetes.
Cyclosporine: The AUC and Cmax of sitagliptin were increased approximately 29% and 68%, respectively, in subjects with co-administration of a single 100-mg oral dose of JANUVIA and a single 600-mg oral dose of cyclosporine, a potent probe inhibitor of p-glycoprotein. The observed changes in sitagliptin pharmacokinetics are not considered likely to be clinically meaningful. The renal clearance of sitagliptin was also not meaningfully altered. Therefore, meaningful interactions would not be expected with other p-glycoprotein inhibitors.
Population Pharmacokinetics: Population pharmacokinetic analyses have been conducted in patients with type 2 diabetes. Concomitant medications did not have a clinically meaningful effect on the pharmacokinetics of sitagliptin. Medications assessed were those that are commonly administered to patients with type 2 diabetes including cholesterol-lowering agents (e.g., statins, fibrates, ezetimibe), anti-platelet agents (e.g., clopidogrel), antihypertensives (e.g., ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium channel blockers, hydrochlorothiazide), analgesics and non-steroidal anti-inflammatory agents (e.g., naproxen, diclofenac, celecoxib), anti-depressants (e.g., bupropion, fluoxetine, sertraline), antihistamines (e.g., cetirizine), proton-pump inhibitors (e.g., omeprazole, lansoprazole), and medications for erectile dysfunction (e.g., sildenafil).
A10BH01 - sitagliptin ; Belongs to the class of dipeptidyl peptidase 4 (DPP-4) inhibitors. Used in the treatment of diabetes.
Tab 25 mg x 28's. 50 mg x 28's. 100 mg x 28's.