`
`
`
`
`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) Tablets
`Initial U.S. Approval: 2006
`---------------------------RECENT MAJOR CHANGES ---------------------------
`Indications and Usage
`xx/20xx
`Important Limitations of Use (1.2)
`
`Warnings and Precautions
`xx/20xx
`Pancreatitis (5.1)
`----------------------------INDICATIONS AND USAGE ----------------------------
`
`JANUVIA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an
`adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus. (1.1)
`
`Important Limitations of Use:
`• JANUVIA should not be used in patients with type 1 diabetes or for
`
`the treatment of diabetic ketoacidosis. (1.2)
`• JANUVIA has not been studied in combination with insulin. (1.2)
`
`• JANUVIA has not been studied in patients with a history of
`
`pancreatitis. (1.2, 5.1)
`----------------------- DOSAGE AND ADMINISTRATION------------------------
`
`The recommended dose of JANUVIA is 100 mg once daily. JANUVIA
`can be taken with or without food. (2.1)
`
`Dosage adjustment is recommended for patients with moderate or
`severe renal insufficiency or end-stage renal disease. (2.2)
`
`Dosage Adjustment in Patients With Moderate, Severe and End Stage
`Renal Disease (ESRD) (2.2)
`50 mg once daily
`25 mg once daily
`
`
`Severe and ESRD
`Moderate
`
`
`CrCl ≥30 to <50 mL/min
`CrCl <30 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
`
`
`
`97627XX
`
`
`
`
`--------------------- DOSAGE FORMS AND STRENGTHS ---------------------
`Tablets: 100 mg, 50 mg, and 25 mg (3)
`-------------------------------CONTRAINDICATIONS -------------------------------
`
`History of a serious hypersensitivity reaction to sitagliptin, such as
`
`anaphylaxis or angioedema (5.4, 6.2)
`------------------------WARNINGS AND PRECAUTIONS------------------------
`
`• There have been postmarketing reports of acute pancreatitis,
`
`including fatal and non-fatal hemorrhagic or necrotizing pancreatitis.
`If pancreatitis is suspected, promptly discontinue JANUVIA. (5.1)
`
`• Dosage adjustment is recommended in patients with moderate or
`
`severe renal insufficiency and in patients with ESRD. Assessment of
`
`renal function is recommended prior to initiating JANUVIA and
`periodically thereafter. (2.2, 5.2)
`• When used with a sulfonylurea, a lower dose of sulfonylurea may be
`
`
`required to reduce the risk of hypoglycemia. (2.3, 5.3)
`• There have been postmarketing reports of serious allergic and
`
`hypersensitivity reactions in patients treated with JANUVIA such as
`anaphylaxis, angioedema, and exfoliative skin conditions including
`Stevens-Johnson syndrome.
`In such cases, promptly stop
`JANUVIA, assess for other potential causes, institute appropriate
`monitoring and treatment, and initiate alternative treatment for
`diabetes. (5.4, 6.2)
`• There have been no clinical studies establishing conclusive
`
`evidence of macrovascular risk reduction with JANUVIA or any
`
`other anti-diabetic drug. (5.5)
`------------------------------ ADVERSE REACTIONS-------------------------------
`
`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.
`Hypoglycemia was also reported more commonly in patients treated
`with the combination of JANUVIA and sulfonylurea, with or without
`metformin, than in patients given the combination of placebo and
`sulfonylurea, with or without metformin. (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)
`• There are no adequate and well-controlled studies in pregnant
`
`women. To report drug exposure during pregnancy call 1-800-986­
`8999. (8.1)
`
`
`for PATIENT COUNSELING
`See 17
`
`FDA-approved Medication Guide.
`
`
`
`INFORMATION and
`
`Revised: xx/20xx
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`1
`INDICATIONS AND USAGE
`1.1 Monotherapy and Combination Therapy
`
`1.2
`Important Limitations of Use
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Patients with Renal Insufficiency
`
`2.3 Concomitant Use with a Sulfonylurea
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Use in Patients with Renal Insufficiency
`
`5.3 Use with Medications Known to Cause Hypoglycemia
`5.4 Hypersensitivity Reactions
`
`5.5 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Postmarketing 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
`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
`
`
`
`
`

`

` JANUVIA™
`
`
`(sitagliptin) Tablets
`
` *Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`
`97627XX
`
`
`INDICATIONS AND USAGE
`1
`1.1 Monotherapy and Combination Therapy
`
`JANUVIA1 is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`
`type 2 diabetes mellitus. [See Clinical Studies (14).]
`1.2
`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.
`JANUVIA has not been studied in patients with a history of pancreatitis. It is unknown whether
`patients with a history of pancreatitis are at increased risk for the development of pancreatitis while using
`
`JANUVIA. [See Warnings and Precautions (5.1).]
`
`DOSAGE AND ADMINISTRATION
`2
`2.1 Recommended Dosing
`The recommended dose of JANUVIA is 100 mg once daily. 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).]
`2.3 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 (5.3).]
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`• 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
`History of a serious hypersensitivity reaction to sitagliptin, such as anaphylaxis or angioedema. [See
`
`Warnings and Precautions (5.4) and Adverse Reactions (6.2).]
`
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal
`hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. After initiation of JANUVIA, patients
`should be observed carefully for signs and symptoms of pancreatitis. If pancreatitis is suspected,
`
`2
`
`
`

`

`
`
` 97627XX
`
`
`
` JANUVIA™
`
`
`(sitagliptin) Tablets
`
`JANUVIA 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 JANUVIA.
`
`5.2 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).]
`5.3 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 (6.1).] Therefore, a lower dose of sulfonylurea may be required to reduce the risk of
`
`
`hypoglycemia. [See Dosage and Administration (2.3).]
`5.4 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 (6.2).]
`5.5 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
`6
`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.
`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.
`
`
`3
`
`
`

`

` JANUVIA™
`
`
`(sitagliptin) Tablets
`
`
`
`Monotherapy
`
`
`
`Nasopharyngitis
`
`Combination with Pioglitazone
`
`Upper Respiratory Tract Infection
`Headache
`
` 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 Causality†
`
`
`Number of Patients (%)
`
`JANUVIA 100 mg
`N = 443
`23 (5.2)
`JANUVIA 100 mg +
`Pioglitazone
`N = 175
`11 (6.3)
`9 (5.1)
`JANUVIA 100 mg
`+ Glimepiride
`(+/- Metformin)
`N = 222
`27 (12.2)
`14 (6.3)
`13 (5.9)
`
`
`
`
`97627XX
`
`
`Placebo
`N = 363
`12 (3.3)
`Placebo +
`
`Pioglitazone
`N = 178
`6 (3.4)
`7 (3.9)
`Placebo
`
`+ Glimepiride
`(+/- Metformin)
`N = 219
`4 (1.8)
`10 (4.6)
`5 (2.3)
`
`Combination with Glimepiride
`(+/- Metformin)
`
`Hypoglycemia
`Nasopharyngitis
`Headache
`† Intent to treat population
`In the study of patients receiving JANUVIA as add-on combination therapy 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.
`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)†
`
`
`Number of Patients (%)
`
`Metformin
`500 or 1000 mg bid ††
`
`
`
`
`
`
`
`
`Placebo
`
`Sitagliptin
`(JANUVIA)
`100 mg QD
`
`Sitagliptin
`50 mg bid +
`Metformin
`500 or 1000 mg bid ††
`
`
` N = 372††
`23 (6.2)
`22 (5.9)
`
`N = 176
`9 (5.1)
`5 (2.8)
`
`N = 179
`8 (4.5)
`2 (1.1)
`
`
` N = 364††
`19 (5.2)
`14 (3.8)
`
`
`
`
`Upper Respiratory Infection
`Headache
`† 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
`count (WBC) was observed due to an increase in neutrophils. This increase in WBC (of approximately
`
`4
`
`
`

`

`
`
`
`97627XX
`
`
`
`JANUVIA™
`
`(sitagliptin) Tablets
`
`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.
`6.2 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, cutaneous vasculitis, and
`exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions (5.4)];
`hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing
`pancreatitis [see Limitations of Use (1.2); Warnings and Precautions (5.1)].
`
`DRUG INTERACTIONS
`7
`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.
`
`8
`USE IN SPECIFIC POPULATIONS
`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 under 18 years of age have not been
`established.
`8.5 Geriatric Use
`Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of
`JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall
`
`5
`
`
`

`

`JANUVIA™
`
`
`(sitagliptin) Tablets
`
`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)].
`
`
`97627XX
`
`
`
`
`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 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 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 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.
`Sitagliptin phosphate monohydrate 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 monohydrate 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,
`
`6
`
`
`

`

`
`
`
`97627XX
`
`
`JANUVIA™
`
`(sitagliptin) Tablets
`
`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 a two-day study in healthy subjects, sitagliptin alone increased active GLP-1 concentrations,
`whereas metformin alone increased active and total GLP-1 concentrations to similar extents. Co­
`administration of sitagliptin and metformin had an additive effect on active GLP-1 concentrations.
`Sitagliptin, but not metformin, increased active GIP concentrations. It is unclear how these findings relate
`to changes in glycemic control in patients with type 2 diabetes.
`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
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`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 times 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.
`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%).
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` JANUVIA™
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`(sitagliptin) Tablets
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` Metabolism
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`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
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`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
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`creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault
`formula:
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`CrCl =
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`[140 - age (years)] x weight (kg) {x 0.85 for female patients}
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`[72 x serum creatinine (mg/dL)]
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`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
`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
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`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 adj