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, for oral use
`Initial U.S. Approval: 2006
`----------------------------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)
`
`Limitations of Use:
` JANUVIA should not be used in patients with type 1 diabetes or for
`the treatment of diabetic ketoacidosis. (1)
` JANUVIA has not been studied in patients with a history of
`pancreatitis. (1, 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 eGFR less than
`45 mL/min/1.73 m2. (2.2)
`Dosage Adjustment in Patients with Renal Impairment (2.2)
`
`eGFR greater than or equal to
`30 mL/min/1.73 m2 to less than
`45 mL/min/1.73 m2
`
`eGFR less than
`30 mL/min/1.73 m2 (including
`patients with end stage renal
`disease [ESRD] on dialysis)
`
`50 mg once daily
`
`25 mg once daily
`
`--------------------- 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 (5.5, 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)
` Heart failure has been observed with two other members of the
`DPP-4 inhibitor class. Consider risks and benefits of JANUVIA in
`patients who have known risk factors for heart failure. Monitor
`patients for signs and symptoms. (5.2)
` There have been postmarketing reports of acute renal failure,
`sometimes requiring dialysis. Dosage adjustment is recommended
`in patients with moderate or severe renal impairment and in patients
`with ESRD. Assessment of renal function is recommended prior to
`initiating JANUVIA and periodically thereafter. (2.2, 5.3, 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. (5.4, 7.2)
` 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. (5.5, 6.2)
` Severe and disabling arthralgia has been reported in patients taking
`DPP-4 inhibitors. Consider as a poss ble cause for severe joint pain
`and discontinue drug if appropriate. (5.6)
` There have been postmarketing reports of bullous pemphigoid
`requiring hospitalization in patients taking DPP-4 inh bitors. Tell
`patients to report development of blisters or erosions. If bullous
`pemphigoid is suspected, discontinue JANUVIA. (5.7)
` There have been no clinical studies establishing conclusive
`evidence of macrovascular risk reduction with JANUVIA. (5.8)
`------------------------------ 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 -----------------------
` 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 Medication
`Guide.
`
`Revised: 8/2019
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`INDICATIONS AND USAGE
`1
`2 DOSAGE AND ADMINISTRATION
`2.1 Recommended Dosing
`2.2 Recommendations for Use in Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Pancreatitis
`5.2 Heart Failure
`5.3
`Assessment of Renal Function
`5.4 Use with Medications Known to Cause Hypoglycemia
`5.5 Hypersensitivity Reactions
`5.6
`Severe and Disabling Arthralgia
`5.7
`Bullous Pemphigoid
`5.8 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`Postmarketing Experience
`6.2
`7 DRUG INTERACTIONS
`7.1 Digoxin
`7.2
`Insulin Secretagogues or Insulin
`8 USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Lactation
`8.4
`Pediatric Use
`8.5 Geriatric Use
`8.6 Renal Impairment
`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
`
`DRL Ex. 1014, p. 001
`
`

`

`14.1 Monotherapy
`14.2 Combination Therapy
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`2
`
`DRL Ex. 1014, p. 002
`
`

`

`FULL PRESCRIBING INFORMATION
`
`1
`
`INDICATIONS AND USAGE
`JANUVIA® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus.
`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.
`2.2 Recommendations for Use in Renal Impairment
`For patients with an estimated glomerular filtration rate [eGFR] greater than or equal to
`45 mL/min/1.73 m2 to less than 90 mL/min/1.73 m2, no dosage adjustment for JANUVIA is required.
`
`For patients with moderate renal impairment (eGFR greater than or equal to 30 mL/min/1.73 m2 to
`less than 45 mL/min/1.73 m2), the dose of JANUVIA is 50 mg once daily.
`
`For patients with severe renal impairment (eGFR less than 30 mL/min/1.73 m2) 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 dialysis.
`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. There have been
`postmarketing reports of worsening renal function in patients with renal impairment, some of whom were
`prescribed inappropriate doses of sitagliptin.
`
`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 (5.5); Adverse Reactions (6.2).]
`
`WARNINGS AND PRECAUTIONS
`5
`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.
`
`3
`
`DRL Ex. 1014, p. 003
`
`

`

`5.2 Heart Failure
`An association between dipeptidyl peptidase-4 (DPP-4) inhibitor treatment and heart failure has
`been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class.
`These trials evaluated patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease.
`
`Consider the risks and benefits of JANUVIA prior to initiating treatment in patients at risk for heart
`failure, such as those with a prior history of heart failure and a history of renal impairment, and observe
`these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic
`symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate
`and manage according to current standards of care and consider discontinuation of JANUVIA.
`5.3 Assessment of Renal Function
`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 impairment
`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 (eGFR 30 mL/min/1.73 m2 to <45 mL/min/1.73 m2) or severe
`(eGFR <30 mL/min/1.73 m2) 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 impairment, some of
`whom were prescribed inappropriate doses of sitagliptin. A return to baseline levels of renal impairment
`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.
`5.4 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 Drug Interactions (7.2).]
`5.5 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 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.
`5.6 Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4
`inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years.
`Patients experienced relief of symptoms upon discontinuation of the medication. A subset of patients
`experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor.
`Consider DPP-4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`5.7 Bullous Pemphigoid
`Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4
`inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive
`treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or
`erosions while receiving JANUVIA. If bullous pemphigoid is suspected, JANUVIA should be discontinued
`and referral to a dermatologist should be considered for diagnosis and appropriate treatment.
`5.8 Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`reduction with JANUVIA.
`
`4
`
`DRL Ex. 1014, p. 004
`
`

`

`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.
`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.
`Incidences of
`hypoglycemia are shown in Table 3.
`
`Monotherapy (18 or 24 weeks)
`
`Nasopharyngitis
`
`Combination with Pioglitazone (24
`weeks)
`
`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)
`
`Upper Respiratory Tract Infection
`Headache
`
`Combination with Metformin +
`Rosiglitazone (18 weeks)
`
`Upper Respiratory Tract Infection
`Nasopharyngitis
`
`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
`
`5
`
`DRL Ex. 1014, p. 005
`
`

`

`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.
`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 (%)
`
`Sitagliptin
`(JANUVIA)
`100 mg QD
`
`Metformin
`500 or 1000 mg bid†
`
`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 the above studies (N=9), 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 coadministered with a sulfonylurea or with insulin, the percentage of patients with at least
`one adverse reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
`
`Sitagliptin
`50 mg bid +
`Metformin
`500 or 1000 mg bid†
`N = 372†
`23 (6.2)
`22 (5.9)
`
`Placebo
`
`N = 176
`9 (5.1)
`5 (2.8)
`
`N = 179
`8 (4.5)
`2 (1.1)
`
`N = 364†
`19 (5.2)
`14 (3.8)
`
`6
`
`DRL Ex. 1014, p. 006
`
`

`

`Add-On to Glimepiride
`(+/- Metformin) (24 weeks)
`
`Overall (%)
`Rate (episodes/patient-year)†
`Severe (%)‡
`Add-On to Insulin
`(+/- Metformin) (24 weeks)
`
`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)
`Placebo
`JANUVIA 100 mg
`+ 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.
`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 coadministration with insulin.
`In an additional, 30-week placebo-controlled, study of patients with type 2 diabetes inadequately
`controlled with metformin comparing the maintenance of sitagliptin 100 mg versus withdrawal of sitagliptin
`when initiating basal insulin therapy,
`the event rate and incidence of documented symptomatic
`hypoglycemia (blood glucose measurement ≤70 mg/dL) did not differ between the sitagliptin and placebo
`groups.
`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
`
`7
`
`DRL Ex. 1014, p. 007
`
`

`

`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
`(5.5)]; 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
`(5.3)]; severe and disabling arthralgia [see Warnings and Precautions (5.6)]; bullous pemphigoid [see
`Warnings and Precautions (5.7)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain;
`pruritus; mouth ulceration; stomatitis; rhabdomyolysis.
`
`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 coadministration of 100 mg sitagliptin for 10 days. Patients
`receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is
`recommended.
`7.2
`Insulin Secretagogues or Insulin
`Coadministration of JANUVIA with an insulin secretagogue (e.g., sulfonylurea) or insulin may
`require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia. [See
`Warnings and Precautions (5.4).]
`
`USE IN SPECIFIC POPULATIONS
`8
`8.1 Pregnancy
`Pregnancy Exposure Registry
`There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
`JANUVIA during pregnancy. Health care providers are encouraged to report any prenatal exposure to
`JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.
`Risk Summary
`The limited available data with JANUVIA in pregnant women are not sufficient to inform a drug-
`associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated
`with poorly controlled diabetes in pregnancy [see Clinical Considerations]. No adverse developmental
`effects were observed when sitagliptin was administered to pregnant rats and rabbits during
`organogenesis at oral doses up to 30-times and 20-times, respectively, the 100 mg clinical dose, based on
`AUC [see Data].
`The estimated background risk of major birth defects is 6-10% in women with pre-gestational
`diabetes with a Hemoglobin A1c >7% and has been reported to be as high as 20-25% in women with a
`Hemoglobin A1c >10%. In the U.S. general population, the estimated background risk of major birth
`defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
`
`Clinical Considerations
`Disease-Associated Maternal and/or Embryo/Fetal Risk
`Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-
`eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled
`diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.
`
`Data
`Animal Data
`In embryo-fetal development studies, sitagliptin administered to pregnant rats and rabbits during
`organogenesis (gestation day 6 to 20) did not adversely affect developmental outcomes at oral doses up
`to 250 mg/kg (30-times the 100 mg clinical dose) and 125 mg/kg (20-times the 100 mg clinical dose),
`respectively, based on AUC. Higher doses in rats associated with maternal toxicity increased the
`incidence of rib malformations in offspring at 1000 mg/kg, or approximately 100-times the clinical dose,
`based on AUC. Placental transfer of sitagliptin was observed in pregnant rats and rabbits.
`
`8
`
`DRL Ex. 1014, p. 008
`
`

`

`Sitagliptin administered to female rats from gestation day 6 to lactation day 21 caused no functional
`or behavioral toxicity in offspring of rats at doses up to 1000 mg/kg.
`8.2
`Lactation
`Risk Summary
`There is no information regarding the presence of JANUVIA in human milk, the effects on the
`breastfed infant, or the effects on milk production. Sitagliptin is present in rat milk and therefore possibly
`present in human milk [see Data]. The developmental and health benefits of breastfeeding should be
`considered along with the mother’s clinical need for JANUVIA and any potential adverse effects on the
`breastfed infant from JANUVIA or from the underlying maternal condition.
`Data
`
`Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1.
`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.
`Because sitagliptin is substantially excreted by the kidney, and because aging can be associated
`with reduced renal function, renal function should be assessed more frequently in elderly patients [see
`Warnings and Precautions (5.3); Clinical Pharmacology (12.3)].
`8.6 Renal Impairment
`Sitagliptin is excreted by the kidney, and sitagliptin exposure is increased in patients with renal
`impairment. Lower dosages are recommended in patients with eGFR less than 45 mL/min/1.73 m2
`(moderate and severe renal impairment, as well as in ESRD patients requiring dialysis). [See Dosage and
`Administration (2.2); Clinical Pharmacology (12.3).]
`
`10
`
`OVERDOSAGE
`In the event of an overdose with JANUVIA, contact the Poison Control Center.
`
`In the event of an overdose, it is reasonable to employ 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:
`
`9
`
`DRL Ex. 1014, p. 009
`
`

`

`F
`
`F
`
`F
`
`H
`
`NH2
`
`O
`
`N
`
`N
`
`. H3PO4
`
`. H2O
`
`N
`
`N
`
`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.
`
`CLINICAL PHARMACOLOGY
`12
`12.1 Mechanism of Action
`Sitagliptin is a DPP-4 inhibitor, which is believed to exert its actions in patients with type 2 diabetes
`mellitus by slowing the inactivation of incretin hormones. Concentrations of the active intact hormones are
`increased by sitagliptin, 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