`------------------------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)
` There have been postmarketing reports of acute renal failure,
`sometimes requiring dialysis. 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, 6.2)
` There is an increased risk of hypoglycemia when JANUVIA is added
`to an insulin secretagogue (e.g., sulfonylurea) or insulin therapy.
`Consider lowering the dose of the sulfonylurea or insulin 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. In the add-
`on to sulfonylurea and add-on to insulin studies, hypoglycemia was
`also more commonly reported in patients treated with JANUVIA
`compared to placebo. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Merck
`Sharp & Dohme Corp., a subsidiary of 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)
`
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`approved Medication Guide.
`
`Revised: XX/XXXX
`
`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
`
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`
`
`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 ---------------------------
`Dosage and Administration
`02/2012
`Recommended Dosing (2.1)
`04/2011
`Patients with Renal Insufficiency (2.2)
`
`Warnings and Precautions
`04/2011
`Renal Impairment (5.2)
`03/2012
`Hypersensitivity Reactions (5.4)
`----------------------------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 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 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
`
`
`--------------------- 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)
`
`
`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 an
`Insulin Secretagogue (e.g.,
`Sulfonylurea) or with Insulin
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Pancreatitis
`5.2 Renal Impairment
`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
`
`Reference ID: 3105563
`
`

`

`
`
`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`1.1 Monotherapy and Combination Therapy
`JANUVIA® 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 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. JANUVIA should be swallowed whole. The tablets must not be split, crushed, or chewed before
`swallowing.
`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).] There have been postmarketing reports of worsening renal function in patients with renal
`insufficiency, some of whom were prescribed inappropriate doses of sitagliptin.
`2.3 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin
`When JANUVIA is used in combination with an insulin secretagogue (e.g., sulfonylurea) or with
`insulin, a lower dose of the insulin secretagogue or insulin 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); Adverse Reactions (6.2).]
`
`Reference ID: 3105563
`
`1
`
`

`

` 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,
`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 Renal Impairment
`Assessment of renal function is recommended prior to initiating JANUVIA and periodically thereafter.
`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).] Caution should be used to ensure that the correct dose of JANUVIA is
`prescribed for patients with moderate (creatinine clearance 30 to <50 mL/min) or severe (creatinine
`clearance <30 mL/min) renal impairment.
`There have been postmarketing reports of worsening renal function, including acute renal failure,
`sometimes requiring dialysis. A subset of these reports involved patients with renal insufficiency, some of
`whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal insufficiency
`has been observed with supportive treatment and discontinuation of potentially causative agents.
`Consideration can be given to cautiously reinitiating JANUVIA if another etiology is deemed likely to have
`precipitated the acute worsening of renal function.
`JANUVIA has not been found to be nephrotoxic in preclinical studies at clinically relevant doses, or in
`clinical trials.
`5.3 Use with Medications Known to Cause Hypoglycemia
`When JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to
`cause hypoglycemia, the incidence of hypoglycemia was increased over that of placebo used in
`combination with a sulfonylurea or with insulin. [See Adverse Reactions (6.1).] Therefore, a lower dose of
`sulfonylurea or insulin 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. 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).]
`Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution
`in a patient with a history of angioedema with another DPP-4 inhibitor because it is unknown whether
`such patients will be predisposed to angioedema with JANUVIA.
`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,
`pioglitazone, or rosiglitazone and metformin, 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 3); the incidence of discontinuation due to clinical adverse reactions was similar to placebo.
`
`Reference ID: 3105563
`
`2
`
`

`

`
`Monotherapy (18 or 24 weeks)
`
`
`Nasopharyngitis
`
`
`
`I
`
`Combination with Pioglitazone (24
`weeks)
`
`Upper Respiratory Tract Infection
`Headache
`
`Combination with Metformin +
`Rosiglitazone (18 weeks)
`
`Upper Respiratory Tract Infection
`Nasopharyngitis
`
`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. Five placebo-
`controlled add-on combination therapy studies were also conducted: one with metformin; one with
`pioglitazone; one with metformin and rosiglitazone; one with glimepiride (with or without metformin); and
`one with insulin (with or without metformin). In these trials, patients with inadequate glycemic control on a
`stable dose of the background therapy were randomized to add-on therapy with JANUVIA 100 mg daily
`or placebo. The adverse reactions, excluding hypoglycemia, reported regardless of investigator
`assessment of causality in 5% of patients treated with JANUVIA 100 mg daily and more commonly than
`in patients treated with placebo, are shown in Table 1 for the clinical trials of at least 18 weeks duration.
`ncidences of hypoglycemia are shown in Table 3.
`Table 1
`Placebo-Controlled Clinical Studies of JANUVIA Monotherapy or Add-on Combination Therapy with
`Pioglitazone, Metformin + Rosiglitazone, or Glimepiride +/- Metformin: Adverse Reactions (Excluding
`Hypoglycemia) 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
`+ Metformin
`+ Rosiglitazone
`N = 181
`10 (5.5)
`11 (6.1)
`JANUVIA 100 mg
`+ Glimepiride
`(+/- Metformin)
`N = 222
`14 (6.3)
`13 (5.9)
`
`Placebo
`N = 363
`12 (3.3)
`Placebo +
`Pioglitazone
`N = 178
`6 (3.4)
`7 (3.9)
`Placebo
`+ Metformin
`+ Rosiglitazone
`N = 97
`5 (5.2)
`4 (4.1)
`Placebo
`+ Glimepiride
`(+/- Metformin)
`N = 219
`10 (4.6)
`5 (2.3)
`
`Combination with Glimepiride
`(+/- Metformin) (24 weeks)
`
`Nasopharyngitis
`Headache
`† Intent-to-treat population
`In the 24-week 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 24-week study of patients receiving JANUVIA as add-on therapy to insulin (with or without
`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, except for hypoglycemia (see
`Table 3).
`In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1),
`through Week 54 the adverse reactions reported regardless of investigator assessment of causality in
`5% of patients treated with JANUVIA and more commonly than in patients treated with placebo were:
`upper respiratory tract infection (JANUVIA, 15.5%; placebo, 6.2%), nasopharyngitis (11.0%, 9.3%),
`peripheral edema (8.3%, 5.2%), and headache (5.5%, 4.1%).
`In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on
`to pioglitazone study, 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.
`
`
`
`Reference ID: 3105563
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`
`

`

`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)
`
`
`
`
`
`
`
`r
`
`
`
`N = 176
`9 (5.1)
`5 (2.8)
`
`N = 179
`8 (4.5)
`2 (1.1)
`
`N = 364††
`19 (5.2)
`14 (3.8)
`
`Add-On to Glimepiride
`(+/- Metformin) (24 weeks)
`
`Overall (%)
`Rate (episodes/patient-year)‡
`Severe (%)§
`Add-On to Insulin
`(+/- Metformin) (24 weeks)
`
`
`Upper Respiratory Infection
`Headache
`† Intent-to-treat population.
`†† Data pooled for the patients given the lower and higher doses of metformin.
`In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no
`adverse reactions reported (regardless of investigator assessment of causality) in 5% of patients and
`more commonly than in patients given pioglitazone alone.
`No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed in
`patients treated with JANUVIA.
`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 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 Warnings and Precautions (5.1).]
`Hypoglycemia
`In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic
`hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports
`of hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. When JANUVIA was
`co-administered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse
`eaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
`Table 3
`Incidence and Rate of Hypoglycemia† in Placebo-Controlled Clinical Studies when JANUVIA was used
`as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin),
`Regardless of Investigator Assessment of Causality
`Placebo
`JANUVIA 100 mg
`+ Glimepiride
`+ Glimepiride
`(+/- Metformin)
`(+/- Metformin)
`N = 219
`N = 222
`4 (1.8)
`27 (12.2)
`0.24
`0.59
`0 (0.0)
`0 (0.0)
`JANUVIA 100 mg
`Placebo
`+ Insulin
`+ Insulin
`(+/- Metformin)
`(+/- Metformin)
`N = 319
`N = 322
`
`25 (7.8)
`50 (15.5)
`Overall (%)
`Rate (episodes/patient-year)‡
`0.51
`1.06
`Severe (%)§
`1 (0.3)
`2 (0.6)
`† Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose
`measurement was not required; intent-to-treat population.
`‡ Based on total number of events (i.e., a single patient may have had multiple events).
`§ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss
`of consciousness or seizure.
`In a 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 was 1.2% in patients
`treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.
`
`Reference ID: 3105563
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`
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`

`
`
`In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the overall
`incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in patients given add-
`on placebo through Week 18. Through Week 54, the overall incidence of hypoglycemia was 3.9% in
`patients given add-on JANUVIA and 1.0% in patients given add-on placebo.
`In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with
`metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given
`JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in
`combination with metformin.
`In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA experienced
`a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in other
`studies except in the study involving co-administration with insulin.
`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
`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
`Additional adverse reactions have been identified during postapproval 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 Warnings and Precautions
`(5.4)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and
`necrotizing pancreatitis [see Indications and Usage (1.2); Warnings and Precautions (5.1)]; worsening
`renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions
`(5.2)]; constipation; vomiting; headache.
`
`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.
`
`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 Sharp & Dohme Corp., a subsidiary of
`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 1-800-986-8999.
`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
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`Reference ID: 3105563
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`

`
`
`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
`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 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 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:
`
`Reference ID: 3105563
`
`6
`
`

`

`
`
`F
`
`F
`
`F
`
`H
`
`NH2
`
`O
`
`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,
`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
`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 t