Januvia

Single-dose pharmacokinetics of rosiglitazone were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin 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. The effect of thiazolidinediones on the pharmacokinetics of sitagliptin was not assessed.

There are no known interactions with food.

A study was conducted to assess the effect of cyclosporine, a potent inhibitor of p-glycoprotein, on the pharmacokinetics of sitagliptin. Coadministration of a single 100-mg oral dose of JANUVIA and a single 600 mg oral dose of cyclosporine increased the AUC and C_max of sitagliptin by approximately 29% and 68%, respectively. These modest changes in sitagliptin pharmacokinetics were not considered 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. No dosage adjustment for JANUVIA is recommended when co-administered with cyclosporine or other p-glycoprotein inhibitors (e.g., ketoconazole).

Co-administration with sitagliptin did not meaningfully alter the steady-state pharmacokinetics of norethindrone or ethinyl estradiol.

Interactions with laboratory tests have not been established.

Single-dose pharmacokinetics of simvastatin, a CYP3A4 substrate, were not meaningfully altered in subjects receiving multiple daily doses of sitagliptin. Therefore, sitagliptin is not an inhibitor of CYP3A4-mediated metabolism.

Interactions with herbal products have not been established.

No studies of the effects of JANUVIA on the ability to drive and use machines have been performed. However, JANUVIA is not expected to affect the ability to drive and use machines.

In clinical studies, as described below, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives, providing in vivo evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C8, CYP2C9, and organic cationic transporter (OCT).

Single-dose pharmacokinetics of glyburide, a CYP2C9 substrate, were 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. The effect of sulfonylureas on the pharmacokinetics of sitagliptin was not assessed.

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. Since S(−) warfarin is primarily metabolized by CYP2C9, these data also support the conclusion that sitagliptin is not a CYP2C9 inhibitor.

Sitagliptin had a minimal effect on the pharmacokinetics of digoxin. Following administration of 0.25 mg digoxin concomitantly with 100 mg of JANUVIA daily for 10 days, the plasma AUC of digoxin was increased by 11%, and the plasma C_max by 18%. These increases are not considered likely to be clinically meaningful. No dosage adjustment of digoxin or JANUVIA is recommended.

Co-administration of multiple twice-daily doses of sitagliptin with metformin, an OCT substrate, did not meaningfully alter the pharmacokinetics of metformin or JANUVIA in patients with type 2 diabetes. Therefore, sitagliptin is not an inhibitor of OCT-mediated transport.

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.

No dosage adjustment is necessary for geriatric patients.

Use of sitagliptin in patients with moderate or severe renal insufficiency including those with ESRD is not recommended.

JANUVIA can be taken with or without food.

Use of sitagliptin in patients with severe hepatic insufficiency is not recommended.

The recommended dose of JANUVIA is 100 mg once daily.

There are no data available on the use of JANUVIA in patients younger than 18 years of age. Therefore, use of JANUVIA in pediatric patients is not recommended.

If a dose of JANUVIA is missed, it should be taken as soon as the patient remembers. A double dose of JANUVIA should not be taken on the same day.

dysmenorrhea, erectile dysfunction.

The following additional adverse reactions have been identified during post-marketing 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, cutaneous vasculitis and exfoliative skin conditions, including Stevens-Johnson syndrome (see Contraindications and Warnings and Precautions, Hypersensitivity Reactions); pancreatitis.

The incidence of laboratory adverse experiences was similar in patients treated with JANUVIA 100 mg compared to patients treated with placebo. In most clinical studies, a slight decrease in alkaline phosphatase and small increases in uric acid and white blood cell count (due to an increase in neutrophils) were observed. In active comparator studies versus a sulfonylurea agent (glipizide) similar changes were seen in alkaline phosphatase and uric acid.

decreased appetite, hypoglycemia.

face edema, malaise, peripheral edema, pain.

bundle branch block.

cough.

migraine, neuropathy peripheral, parosmia, somnolence.

exanthem, rash, urticaria.

muscle tightness.

gastric ulcer helicobacter, helicobacter gastritis, upper respiratory tract infection.

hepatic steatosis.

orthostatic hypotension.

Nausea was the only drug-related adverse reaction reported by the investigator that occurred with an incidence ≥1% in patients receiving JANUVIA (1.1%) and greater than in patients receiving placebo (0.4%).

JANUVIA was generally well tolerated in controlled clinical studies as a combination therapy with metformin, with the overall incidence of side effects similar to that reported with placebo.

The incidences of serious adverse experiences and discontinuation of therapy due to clinical adverse experiences were also similar to placebo. The most frequent adverse reaction in trials of JANUVIA as add-on combination therapy with metformin (reported regardless of causality, and more common with JANUVIA than other treatments) was nasopharyngitis.

blood glucose decreased.

Adverse Reactions ≥1% in Any Treatment Group (regardless of causality) Reported in Patients From Double-Blind Clinical Trials of JANUVIA in Add-On Combination Use with Metformin in Studies Up to One Year Compared to a Sulfonylurea Agent (Glipizide)

abdominal discomfort, abdominal pain upper, diarrhea, dyspepsia, flatulence, reflux esophagitis disease, retching.

Safety and effectiveness of JANUVIA in pediatric patients have not been established. Therefore, JANUVIA should not be used in this population.

No dosage adjustment is required base on age however, greater sensitivity of some older individuals cannot be ruled out (see Warnings and Precautions, Dosage and Administration and Action and Clinical Pharmacology).

There are limited clinical experiences in patients with moderate hepatic insufficiency and no clinical experience in patients with severe hepatic insufficiency. Use in patients with severe hepatic insufficiency is not recommended (see Action and Clinical Pharmacology).

There have been post-marketing reports of serious hypersensitivity reactions in patients treated with JANUVIA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. 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 Adverse Reactions, Post-Market Adverse Drug Reactions).

JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

Clinical study experience with JANUVIA in patients with moderate or severe renal insufficiency including those with ESRD is limited. Use in these patients is not recommended (see Action and Clinical Pharmacology).

Response to all diabetic therapies should be monitored by periodic measurements of blood glucose and HbA_1c levels, with a goal of decreasing these levels towards the normal range. HbA_1c is especially useful for evaluating long-term glycemic control. Sitagliptin is substantially excreted by the kidney. Renal function should be assessed prior to initiating dosing and periodically thereafter.

A limited number of patients with congestive heart failure participated in clinical studies of sitagliptin. In studies of sitagliptin in combination with metformin, patients with congestive heart failure requiring pharmacological therapy or NYHA Class III or IV congestive heart failure were excluded. Patients with Classes I and II were included in small number. Use in this population is not recommended.

Safety and effectiveness of JANUVIA in pediatric patients have not been established. Therefore, JANUVIA should not be used in this population.

There are no adequate and well-controlled studies in pregnant women; therefore, the safety of JANUVIA in pregnant women is not known. JANUVIA is not recommended for use in pregnancy.

In clinical studies, no overall differences in safety or effectiveness were observed between subjects 65 years and over and younger subjects. While this and other reported clinical experience have not identified differences in responses between the geriatric and younger patients, greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney. Renal function should be assessed prior to initiating dosing and periodically thereafter in geriatric patients because they are more likely to have decreased renal function (see Dosage and Administration and Action and Clinical Pharmacology).

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.

The mean volume of distribution at steady state following a single 100-mg intravenous dose of sitagliptin to healthy subjects is approximately 198 liters. The fraction of sitagliptin reversibly bound to plasma proteins is low (38%).

In a randomized, placebo-controlled crossover study, 79 healthy subjects were administered a single oral dose of JANUVIA 100 mg, JANUVIA 800 mg (8 times the recommended dose), and placebo. At the recommended dose of 100 mg, there was no effect on the QTc interval obtained at the peak plasma concentration, or at any other time during the study. Following the 800-mg dose, the maximum increase in the placebo-corrected mean change in QTc from baseline at 3 hours postdose was 8.0 msec. This small increase was not considered to be clinically significant. At the 800-mg dose, peak sitagliptin plasma concentrations were approximately 11-fold higher than the peak concentrations following a 100-mg dose.

In patients with type 2 diabetes administered JANUVIA 100 mg (N=81) or JANUVIA 200 mg (N=63) daily, there were no meaningful changes in QTc interval based on ECG data obtained at the time of expected peak plasma concentration.

The absolute bioavailability of sitagliptin is approximately 87%. Since coadministration of a high-fat meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or without food.

Following administration of an oral [¹⁴C] sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. The apparent terminal t_1/2 following a 100-mg oral dose of sitagliptin was approximately 12.4 hours and renal clearance was approximately 350 mL/min.

Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3 (hOAT-3), which may be involved in the renal elimination of sitagliptin. The clinical relevance of hOAT-3 in sitagliptin transport has not been established. Sitagliptin is also a substrate of p-glycoprotein, which may also be involved in mediating the renal elimination of sitagliptin. However, cyclosporine, a p-glycoprotein inhibitor, did not reduce the renal clearance of sitagliptin.

In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia, suggesting that the insulinotropic and glucagon suppressive actions of the drug are glucose dependent.

No dosage adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data.

Sitagliptin is primarily eliminated unchanged in urine, and metabolism is a minor pathway. Approximately 79% of sitagliptin is excreted unchanged in the urine.

Following a [¹⁴C] sitagliptin oral dose, approximately 16% of the radioactivity was excreted as metabolites of sitagliptin. Six metabolites were detected at trace levels and are not expected to contribute to the plasma DPP-4 inhibitory activity of sitagliptin. In vitro studies indicated that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4, with contribution from CYP2C8.

In patients with type 2 diabetes, administration of single oral doses of JANUVIA leads to inhibition of DPP-4 enzyme activity for a 24-hour period, resulting in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, increased plasma levels of insulin and C-peptide, decreased glucagon concentrations, reduced fasting glucose, and reduced glucose excursion following an oral glucose load or a meal.

In a study of patients with type 2 diabetes inadequately controlled on metformin monotherapy (N=26), glucose levels monitored throughout the day were significantly lower (p<0.001) in patients who received JANUVIA 100 mg per day in combination with metformin compared with patients who received placebo with metformin (see Figure 1).

No studies with JANUVIA have been performed in pediatric patients.

No dosage adjustment is required based on age. Age did not have a clinically meaningful impact on the pharmacokinetics of sitagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data. Elderly subjects (65 to 80 years) had approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.

In patients with moderate hepatic insufficiency (Child-Pugh score 7 to 9), mean AUC and C_max of sitagliptin increased approximately 21% (90% CI: 1%, 46%) and 13% (90% CI: −9%, 42%), respectively, compared to healthy matched controls following administration of a single 100-mg dose of JANUVIA.

JANUVIA is an orally-active, potent, and highly selective inhibitor of the dipeptidyl peptidase 4 (DPP-4) enzyme that enhances incretin hormones. The DPP-4 inhibitors are a novel class of agents.

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. 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, by intracellular signaling pathways involving cyclic AMP. Progressive beta-cell failure is a feature characterizing the pathogenesis of type 2 diabetes. Treatment with GLP-1 or with DPP-4 inhibitors in animal models of type 2 diabetes has been demonstrated to improve beta cell responsiveness to glucose and stimulate insulin biosynthesis and release. With higher insulin levels, tissue glucose uptake is enhanced.

In addition, GLP-1 lowers glucagon secretion from pancreatic alpha cells. Decreased glucagon concentrations, along with higher insulin levels, lead to reduced hepatic glucose production, resulting in a decrease in blood glucose levels. When blood glucose concentrations are low, stimulation of insulin release and suppression of glucagon secretion by GLP-1 are not observed. GLP-1 does not impair the normal glucagon response to hypoglycemia.

The activity of GLP-1 and GIP is limited by the DPP-4 enzyme, which rapidly hydrolyzes the incretin hormones to produce inactive products. Sitagliptin prevents the hydrolysis of incretin hormones by DPP-4, thereby increasing plasma concentrations of the active forms of GLP-1 and GIP. By enhancing active incretin levels, sitagliptin increases insulin release and decreases glucagon levels in a glucose-dependent manner. In patients with type 2 diabetes with hyperglycemia, these changes in insulin and glucagon levels lead to lower hemoglobin A_1c (HbA_1c) and lower fasting and postprandial glucose concentrations. While sitagliptin is a potent and highly selective inhibitor of the enzyme DPP-4, it does not inhibit the closely-related enzymes DPP-8 or DPP-9. Inhibition of DPP-8 or DPP-9, but not DPP-4, is associated with toxicity in preclinical animal models and alteration of immune function in vitro.

No dosage adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of sitagliptin based on a composite analysis of Phase I pharmacokinetic data and on a population pharmacokinetic analysis of Phase I and Phase II data, including subjects of white, Hispanic, black and Asian racial groups.

An approximately 2-fold increase in the plasma AUC of sitagliptin was observed in patients with moderate renal insufficiency, and an approximately 4-fold increase was observed in patients with severe renal insufficiency and in patients with ESRD on hemodialysis, as compared to normal healthy control subjects.

The pharmacokinetics of sitagliptin have been extensively characterized in healthy subjects and patients with type 2 diabetes. After oral administration of a 100-mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations (median T_max) occurring 1 to 4 hours post-dose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100-mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52 µM·hr, C_max was 950 nM, and apparent terminal half-life (t_1/2) was 12.4 hours. Plasma AUC of sitagliptin increased approximately 14% following 100-mg doses at steady-state compared to the first dose. The intra-subject and inter-subject coefficients of variation for sitagliptin AUC were small (5.8% and 15.1%). The pharmacokinetics of sitagliptin were generally similar in healthy subjects and in patients with type 2 diabetes.