HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`JANUVIA safely and effectively. See full prescribing information
`for JANUVIA.
`
`JANUVIA™ (sitagliptin phosphate) Tablets
`Initial U.S. Approval: 2006
`----------------------------INDICATIONS AND USAGE ----------------------------
`JANUVIA is indicated as an adjunct to diet and exercise to improve
`glycemic control in patients with type 2 diabetes mellitus (type 2
`diabetes). JANUVIA is indicated for:
`• Monotherapy (1.1)
`• Combination therapy with metformin or a peroxisome proliferator-
`activated receptor gamma (PPARγ) agonist (e.g., thiazolidinediones)
`when the single agent does not provide adequate glycemic control.
`(1.2)
`Important Limitations of Use: JANUVIA should not be used in patients
`with type 1 diabetes mellitus (type 1 diabetes) or for the treatment of
`diabetic ketoacidosis. (1.3)
`----------------------- DOSAGE AND ADMINISTRATION------------------------
`The recommended dose of JANUVIA is 100 mg once daily as
`monotherapy or as combination therapy with metformin or a PPARγ
`agonist (e.g., thiazolidinediones). (2.1)
`
`JANUVIA can be taken with or without food. (2.1)
`
`Dosage Adjustment in Patients With Moderate, Severe and End Stage
`Renal Disease (ESRD) (2.2)
`50 mg once daily
`25 mg once daily
`Moderate
`Severe and ESRD
`
`
`CrCl <30 mL/min
`CrCl ≥30 to <50 mL/min
`~Serum Cr levels [mg/dL]
`~Serum Cr levels [mg/dL]
`Men: >3.0;
`Men: >1.7– ≤3.0;
`Women: >2.5;
` Women: >1.5– ≤2.5
`or on dialysis
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Monotherapy
`1.2 Combination Therapy
`1.3
`Important Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Patients with Renal Insufficiency
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`7 DRUG INTERACTIONS
`7.1 Digoxin
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
`8.4 Pediatric Use
`8.5 Geriatric Use
`
`FULL PRESCRIBING INFORMATION
`
`9762700
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets: 100 mg, 50 mg, and 25 mg (3)
`-------------------------------CONTRAINDICATIONS-------------------------------
`None. (4)
`------------------------WARNINGS AND PRECAUTIONS------------------------
`A dosage adjustment is recommended in patients with moderate renal
`insufficiency and in patients with severe renal insufficiency or with
`ESRD requiring hemodialysis or peritoneal dialysis. 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. (2.2, 5)
`------------------------------ ADVERSE REACTIONS-------------------------------
`The most common adverse reactions, reported in ≥5% of patients
`treated with JANUVIA and more commonly than in patients treated with
`placebo are: upper respiratory tract infection, nasopharyngitis, and
`headache. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck &
`Co.,
`Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`----------------------- USE IN SPECIFIC POPULATIONS -----------------------
`Safety and effectiveness of JANUVIA in children under 18 years have
`not been established. (8.4)
`
`for PATIENT COUNSELING
`See 17
`FDA-approved patient labeling.
`
`INFORMATION and
`
`
`
`Revised: 10/2006
`
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Monotherapy
`14.2 Combination Therapy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions
`17.2 Laboratory Tests
`17.3 FDA-Approved Patient Labeling
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`INDICATIONS AND USAGE
`1
`1.1 Monotherapy
`JANUVIA1 is indicated as an adjunct to diet and exercise to improve glycemic control in patients with
`type 2 diabetes mellitus.
`
`Mylan EX 1006, Page 1
`
`

`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`1.2 Combination Therapy
`JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in
`combination with metformin or a PPARγ agonist (e.g., thiazolidinediones) when the single agent alone,
`with diet and exercise, does not provide adequate glycemic control.
`1.3
`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.
`
`9762700
`
`
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The recommended dose of JANUVIA is 100 mg once daily as monotherapy or as combination
`therapy with metformin or a PPARγ agonist (e.g., thiazolidinediones). JANUVIA can be taken with or
`without food.
`2.2 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 <50 mL/min, approximately corresponding
`to serum creatinine levels of >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 <30 mL/min, approximately corresponding to serum
`creatinine levels of >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. [See Clinical Pharmacology
`(12.3).]
`
`DOSAGE FORMS AND STRENGTHS
`3
`• 100 mg tablets are beige, round, film-coated tablets with “277” on one side.
`• 50 mg tablets are light beige, round, film-coated tablets with “112” on one side.
`• 25 mg tablets are pink, round, film-coated tablets with “221” on one side.
`
`4
`
`CONTRAINDICATIONS
`None.
`
`5 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 (2.2); Clinical Pharmacology (12.3).]
`Use with Medications Known to Cause Hypoglycemia: In clinical trials of JANUVIA as monotherapy
`and JANUVIA as part of combination therapy with metformin or pioglitazone, rates of hypoglycemia
`reported with JANUVIA were similar to rates in patients taking placebo. The use of JANUVIA in
`combination with medications known to cause hypoglycemia, such as sulfonylureas or insulin, has not
`been adequately studied.
`
`6
`
`ADVERSE REACTIONS
`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.
`
`2
`
`Mylan EX 1006, Page 2
`
`

`
`
`
`9762700
`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`6.1 Clinical Trials Experience
`In controlled clinical studies as both monotherapy and combination therapy, the overall incidence of
`adverse reactions with JANUVIA was similar to that reported with placebo. Discontinuation of therapy due
`to clinical adverse reactions was also 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. Two 24-week,
`placebo-controlled combination studies, one with metformin and one with pioglitazone, were also
`conducted. In addition to a stable dose of metformin or pioglitazone, 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 or in combination with pioglitazone and more commonly than in patients
`treated with placebo, are shown in Table 1.
`
`
`
`Monotherapy
`
`
`Nasopharyngitis
`
`Placebo
`N = 363
`12 (3.3)
`Placebo +
`Pioglitazone
`N = 178
`6 (3.4)
`7 (3.9)
`
`Table 1
`Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Combination with Pioglitazone:
`Adverse Reactions Reported in ≥5% of Patients and More Commonly than in Patients
`Given Placebo, Regardless of Investigator Assessment of Causality†
`Number of Patients (%)
`JANUVIA, 100 mg
`N = 443
`23 (5.2)
`JANUVIA 100 mg +
`Pioglitazone
`N = 175
`11 (6.3)
`9 (5.1)
`
`Combination with Pioglitazone
`
`Upper Respiratory Tract Infection
`Headache
`† Intent to treat population
`In patients receiving JANUVIA in combination with metformin, there were no adverse reactions
`reported regardless of investigator assessment of causality in ≥5% of patients and more commonly than
`in patients given placebo.
`The overall incidence of hypoglycemia in patients treated with JANUVIA 100 mg was similar to
`placebo (1.2% vs 0.9%). 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%).
`No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in
`patients treated with JANUVIA.
`Laboratory Tests
`The incidence of laboratory adverse reactions in patients treated with JANUVIA 100 mg was 8.2%
`compared to 9.8% in 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.
`
`
`
`7 DRUG INTERACTIONS
`7.1 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 100 mg sitagliptin for 10 days. Patients
`receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is
`recommended.
`
`3
`
`Mylan EX 1006, Page 3
`
`

`
`
`
`9762700
`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 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. Merck & Co., Inc. maintains a registry to monitor
`the pregnancy outcomes of women exposed to JANUVIA while pregnant. Health care providers are
`encouraged to report any prenatal exposure to JANUVIA by calling the Pregnancy Registry at (800) 986-
`8999.
`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.
`8.3 Nursing Mothers
`Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known
`whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution
`should be exercised when JANUVIA is administered to a nursing woman.
`8.4 Pediatric Use
`Safety and effectiveness of JANUVIA in pediatric patients have not been established.
`8.5 Geriatric Use
`Of the total number of subjects (N=3884) in clinical safety and efficacy studies of JANUVIA, 725
`patients were 65 years and over, while 61 patients were 75 years and over. 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
`elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
`This drug is known to be substantially excreted by the kidney. Because elderly patients are more
`likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may
`be useful to assess renal function in these patients prior to initiating dosing and periodically thereafter
`[see Dosage and Administration (2.2); Clinical Pharmacology (12.3)].
`
`10 OVERDOSAGE
`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 were observed in one study at a dose of
`800 mg JANUVIA, a mean effect that is not considered clinically important [see Clinical Pharmacology
`(12.2)]. There is no experience with doses above 800 mg in humans.
`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 as dictated by the patient's clinical status.
`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.
`
`11 DESCRIPTION
`JANUVIA Tablets contain sitagliptin phosphate, an orally-active inhibitor of the dipeptidyl peptidase-4
`(DPP-4) enzyme.
`
`4
`
`Mylan EX 1006, Page 4
`
`

`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`
`
`
`9762700
`
`Sitagliptin phosphate is described chemically as 7-[(3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl]-
`5,6,7,8-tetrahydro-3-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyrazine phosphate (1:1) monohydrate.
`The empirical formula is C16H15F6N5O•H3PO4•H2O and the molecular weight is 523.32. The structural
`formula is:
`
`F
`
`F
`
`H
`
`NH2
`
`O
`
`F
`
`N
`
`N
`
`N
`
`N
`
`. H3PO4
`
`. H2O
`
`CF3
`
`
`
`
`Sitagliptin phosphate is a white to off-white, crystalline, non-hygroscopic powder. It is soluble in water
`and N,N-dimethyl formamide; slightly soluble in methanol; very slightly soluble in ethanol, acetone, and
`acetonitrile; and insoluble in isopropanol and isopropyl acetate.
`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 and the following
`inactive ingredients: microcrystalline cellulose, anhydrous dibasic calcium phosphate, 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.
`
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`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. Concentrations of the active intact hormones are increased
`by JANUVIA, thereby increasing and prolonging the action of these hormones. Incretin hormones,
`including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are
`released by the intestine throughout the day, and levels are increased in response to a meal. These
`hormones are rapidly inactivated by the enzyme, DPP-4. 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. GLP-1 also lowers glucagon secretion from
`pancreatic alpha cells, leading to reduced hepatic glucose production. By increasing and prolonging
`active incretin levels, JANUVIA increases insulin release and decreases glucagon levels in the circulation
`in a glucose-dependent manner. Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit
`DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses.
`12.2 Pharmacodynamics
`General
`In patients with type 2 diabetes, administration of JANUVIA led to inhibition of DPP-4 enzyme activity
`for a 24-hour period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a 2- to 3-fold
`increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and
`increased responsiveness of insulin release to glucose, resulting in higher C-peptide and insulin
`concentrations. The rise in insulin with the decrease in glucagon was associated with lower fasting
`glucose concentrations and reduced glucose excursion following an oral glucose load or a meal.
`In studies with healthy subjects, JANUVIA did not lower blood glucose or cause hypoglycemia.
`Cardiac Electrophysiology
`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 was observed at 3 hours postdose and was
`8.0 msec. This increase is 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.
`
`5
`
`Mylan EX 1006, Page 5
`
`

`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`
`
`
`9762700
`
`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.
`12.3 Pharmacokinetics
`The pharmacokinetics of sitagliptin has 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 Tmax) occurring 1 to 4 hours postdose.
`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, Cmax was 950 nM, and apparent
`terminal half-life (t1/2) 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 was
`generally similar in healthy subjects and in patients with type 2 diabetes.
`Absorption
`The absolute bioavailability of sitagliptin is approximately 87%. Because coadministration of a high-fat
`meal with JANUVIA had no effect on the pharmacokinetics, JANUVIA may be administered with or
`without food.
`Distribution
`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%).
`Metabolism
`Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor
`pathway of elimination.
`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.
`Excretion
`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 t1/2 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.
`Special Populations
`Renal Insufficiency
`A single-dose, open-label study was conducted to evaluate the pharmacokinetics of JANUVIA (50 mg
`dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control
`subjects. The study included patients with renal insufficiency classified on the basis of creatinine
`clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min), as well as
`patients with ESRD on hemodialysis. In addition, the effects of renal insufficiency on sitagliptin
`pharmacokinetics in patients with type 2 diabetes and mild or moderate renal insufficiency were assessed
`using population pharmacokinetic analyses. Creatinine clearance was measured by 24-hour urinary
`creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault
`formula:
`
`
`CrCl =
`
`
`[140 - age (years)] x weight (kg) {x 0.85 for female patients}
`[72 x serum creatinine (mg/dL)]
`
`
`Compared to normal healthy control subjects, an approximate 1.1- to 1.6-fold increase in plasma
`AUC of sitagliptin was observed in patients with mild renal insufficiency. Because increases of this
`
`6
`
`Mylan EX 1006, Page 6
`
`

`
`
`
`9762700
`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`magnitude are not clinically relevant, dosage adjustment in patients with mild renal insufficiency is not
`necessary. Plasma AUC levels of sitagliptin were increased approximately 2-fold and 4-fold in patients
`with moderate renal insufficiency and in patients with severe renal insufficiency, including patients with
`ESRD on hemodialysis, respectively. Sitagliptin was modestly removed by hemodialysis (13.5% over a 3-
`to 4-hour hemodialysis session starting 4 hours postdose). To achieve plasma concentrations of
`sitagliptin similar to those in patients with normal renal function, lower dosages are recommended in
`patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring
`hemodialysis. [See Dosage and Administration (2.2).]
`Hepatic Insufficiency
`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 or moderate
`hepatic insufficiency.
`There is no clinical experience in patients with severe hepatic insufficiency (Child-Pugh score >9).
`Body Mass Index (BMI)
`No dosage adjustment is necessary based on BMI. Body mass index 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.
`Gender
`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.
`Geriatric
`No dosage adjustment is required based solely on age. When the effects of age on renal function are
`taken into account, age alone did not have a clinically meaningful impact on the pharmacokinetics of
`sitagliptin based on a population pharmacokinetic analysis. Elderly subjects (65 to 80 years) had
`approximately 19% higher plasma concentrations of sitagliptin compared to younger subjects.
`Pediatric
`Studies characterizing the pharmacokinetics of sitagliptin in pediatric patients have not been
`performed.
`Race
`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 available pharmacokinetic data,
`including subjects of white, Hispanic, black, Asian, and other racial groups.
`Drug Interactions
`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
`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).
`Digoxin: 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 Cmax by 18%.
`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.
`
`7
`
`Mylan EX 1006, Page 7
`
`

`
`JANUVIA
`(sitagliptin phosphate) Tablets
`
`
`
`
`9762700
`
`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. However, the risk of hypoglycemia from the
`co-administration of sitagliptin and sulfonylureas is unknown.
`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.
`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 below 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: A study was conducted to assess the effect of cyclosporine, a potent inhibitor of
`p-glycoprotein, on the pharmacokinetics of sitagliptin. Co-administration of a single 100 mg oral dose of
`JANUVIA and a single 600 mg oral dose of cyclosporine increased the AUC and Cmax 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.
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`A two-year carcinogenicity study was conducted in male and female rats given oral doses of
`sitagliptin of 50, 150, and 500 mg/kg/day. There was an increased incidence of combined liver
`adenoma/carcinoma in males and females and of liver carcinoma in females at 500 mg/kg. This dose
`results in exposures approximately 60 times the human exposure at the maximum recommended daily
`adult human dose (MRHD) of 100 mg/day based on AUC comparisons. Liver tumors were not observed
`at 150 mg/kg, approximately 20 times the human exposure at the MRHD. A two-year carcinogenicity
`study was conducted in male and female mice given oral doses of sitagliptin of 50, 125, 250, and
`500 mg/kg/day. There was no increase in the incidence of tumors in any organ up to 500 mg/kg,
`approximately 70 times human exposure at the MRHD. Sitagliptin was not mutagenic or clastogenic with
`or without metabolic activation in the Ames bacterial mutagenicity assay, a Chinese hamster ovary (CHO)
`chromosome aberration assay, an in vitro cytogenetics assay in CHO, an in vitro rat hepatocyte DNA
`alkaline elution assay, and an in vivo micronucleus assay.
`In rat fertility studies with oral gavage doses of 125, 250, and 1000 mg/kg, males were treated for 4
`weeks prior to mating, during mating, up to scheduled termination (approximately 8 weeks total) and
`females were treated 2 weeks prior to mating through gestation day 7. No adverse effect on fertility was
`observed at 125 mg/kg (approximately 12 times human exposure at the MRHD of 100 mg/day based on
`AU