` 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 --------------------------­
`
`Warnings and Precautions
`
`
`
`
`1/2017
`Bullous Pemphigoid (5.6)
`
`
`
`
`----------------------------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)
`
` 25 mg once daily
`
`
`
` 50 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ------------------------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
`
`In such cases, promptly stop
`Stevens-Johnson syndrome.
`
`
`JANUVIA, assess for other potential causes, institute appropriate
`
`
`monitoring and treatment, and initiate alternative treatment for
`
`diabetes. (5.4, 6.2)
`
`
`
`
`• Severe and disabling arthralgia has been reported in patients taking
`
`
`
`
`
`DPP-4 inhibitors. Consider as a possible cause for severe joint pain
`
`
`
`and discontinue drug if appropriate. (5.5)
`
`
`• There have been postmarketing reports of bullous pemphigoid
`
`
`requiring hospitalization in patients taking DPP-4 inhibitors. Tell
`
`
`
`
`
`
`
`
`
`patients to report development of blisters or erosions. If bullous
`
`pemphigoid is suspected, discontinue JANUVIA. (5.6)
`
`• There have been no clinical studies establishing conclusive
`
`
`
`evidence of macrovascular risk reduction with JANUVIA or any
`
`
`other anti-diabetic drug. (5.7)
`
`
`
`
`------------------------------ 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 Medication
`
`Guide.
`
`
`
`Revised: 1/2017
`
`
`
`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 Severe and Disabling Arthralgia
`
`
`
`5.6 Bullous Pemphigoid
`
`
`
`
`5.7 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
`
`Reference ID: 4043029
`
`

`

`
`
` 14 CLINICAL STUDIES
`
`
` 14.1 Monotherapy
`
`
` 14.2 Combination Therapy
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
` Instructions
`
`
` 17.1
`
` 17.2 Laboratory Tests
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`
` are not listed.
`
`
`
` 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).]
`
`
`Important Limitations of Use
`1.2
`
`
`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 Patients with Renal Insufficiency
`
`
`
`For patients with mild renal insufficiency (creatinine clearance [CrCl] greater than or equal to
`
`50 mL/min, approximately corresponding to serum creatinine levels of less than or equal to 1.7 mg/dL in
`
`
`
`
`
`
`
`
`
`
`men and less than or equal to 1.5 mg/dL in women), no dosage adjustment for JANUVIA is required.
`
`
`For patients with moderate renal insufficiency (CrCl greater than or equal to 30 to less than
`
`
`
`50 mL/min, approximately corresponding to serum creatinine levels of greater than 1.7 to less than or
`
`
`
`equal to 3.0 mg/dL in men and greater than 1.5 to less than or equal to 2.5 mg/dL in women), the dose of
`
`
`
`JANUVIA is 50 mg once daily.
`
`
`
`For patients with severe renal insufficiency (CrCl less than 30 mL/min, approximately corresponding
`
`
`to serum creatinine levels of greater than 3.0 mg/dL in men and greater than 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 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. 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
`
`
`
`
`
`
`W hen 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: 4043029
`
`
`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,
`
`
`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 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.
`
`
`5.6 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.
`
`
`
`5.7 Macrovascular Outcomes
`
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`reduction with JANUVIA or any other anti-diabetic drug.
`
`
`
`Reference ID: 4043029
`
`
`3
`
`

`

`
`
`
`
`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.
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
` Monotherapy (18 or 24 weeks)
`
`
`
`
` Nasopharyngitis
`
`Combination with Pioglitazone (24
`
`
`weeks)
`
` Upper Respiratory Tract Infection
`
` Headache
`
`
`
`
`
`
`
` Combination with Metformin +
` Rosiglitazone (18 weeks)
`
`
`
`
`
` Upper Respiratory Tract Infection
`
` Nasopharyngitis
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4043029
`
`
`4
`
` 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).
`
`

`

`
`
`
`
`
`
` Placebo
`
`
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` Sitagliptin
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` (JANUVIA)
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` 100 mg QD
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`In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone (Table 1),
`through W eek 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:
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` 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
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`
`
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` JANUVIA was as follows: abdominal pain (JANUVIA 100 mg, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%),
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` and diarrhea (3.0%, 2.3%).
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` In an additional, 24-week, placebo-controlled factorial study of initial therapy with sitagliptin in
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` combination with metformin, the adverse reactions reported (regardless of investigator assessment of
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` causality) in ≥5% of patients are shown in Table 2.
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` Table 2:
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` Initial Therapy with Combination of Sitagliptin and Metformin:
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` Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in ≥5% of Patients
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`
`
`
`Receiving Combination Therapy (and Greater than in Patients Receiving Metformin alone, Sitagliptin
`
` alone, and Placebo)*
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`
` Number of Patients (%)
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`
` Metformin
` 500 or 1000 mg bid†
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`
`
`
`
` Sitagliptin
` 50 mg bid +
`
` Metformin
`
` 500 or 1000 mg bid†
`
`
` N = 372†
`
` 23 (6.2)
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` 22 (5.9)
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`
`
` N = 176
`
` 9 (5.1)
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` 5 (2.8)
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`
` N = 179
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` 8 (4.5)
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` 2 (1.1)
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`
` N = 364†
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` 19 (5.2)
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` 14 (3.8)
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`
` Upper Respiratory Infection
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` Headache
`* Intent-to-treat population.
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`
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` † Data pooled for the patients given the lower and higher doses of metformin.
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`In a 24-week study of initial therapy with JANUVIA in combination with pioglitazone, there were no
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`adverse reactions reported (regardless of investigator assessment of causality) in ≥5% of patients and
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`more commonly than in patients given pioglitazone alone.
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`No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
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`in patients treated with JANUVIA.
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`In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients
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`randomized to receive sitagliptin 100 mg/day (N=5429) or corresponding (active or placebo) control
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`(N=4817), the incidence of acute pancreatitis was 0.1 per 100 patient-years in each group (4 patients with
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`an event in 4708 patient-years for sitagliptin and 4 patients with an event in 3942 patient-years for control).
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`[See Warnings and Precautions (5.1).]
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`Hypoglycemia
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`In all (N=9) studies, adverse reactions of hypoglycemia were based on all reports of symptomatic
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`hypoglycemia. A concurrent blood glucose measurement was not required although most (74%) reports of
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`hypoglycemia were accompanied by a blood glucose measurement ≤70 mg/dL. W hen JANUVIA was
`coadministered with a sulfonylurea or with insulin, the percentage of patients with at least one adverse
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`reaction of hypoglycemia was higher than in the corresponding placebo group (Table 3).
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`Reference ID: 4043029
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`5
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`

`

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`Add-On to Glimepiride
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`(+/- Metformin) (24 weeks)
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` Overall (%)
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` Rate (episodes/patient-year)†
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` Severe (%)‡
`Add-On to Insulin
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` (+/- Metformin) (24 weeks)
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` Table 3:
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` Incidence and Rate of Hypoglycemia* in Placebo-Controlled Clinical Studies when JANUVIA was used
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`as Add-On Therapy to Glimepiride (with or without Metformin) or Insulin (with or without Metformin),
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`Regardless of Investigator Assessment of Causality
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`
`Placebo
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` JANUVIA 100 mg
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`
` + Glimepiride
` + Glimepiride
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` (+/- Metformin)
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` (+/- Metformin)
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` N = 219
` N = 222
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` 4 (1.8)
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` 27 (12.2)
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` 0.24
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` 0.59
` 0 (0.0)
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` 0 (0.0)
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` Placebo
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` JANUVIA 100 mg
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` + Insulin
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` + Insulin
` (+/- Metformin)
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` (+/- Metformin)
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` N = 319
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` N = 322
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`
` 25 (7.8)
` Overall (%)
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` 50 (15.5)
` Rate (episodes/patient-year)†
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` 0.51
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` 1.06
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` Severe (%)‡
` 1 (0.3)
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` 2 (0.6)
`* Adverse reactions of hypoglycemia were based on all reports of symptomatic hypoglycemia; a concurrent glucose
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` measurement was not required; intent-to-treat population.
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`† Based on total number of events (i.e., a single patient may have had multiple events).
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`‡ Severe events of hypoglycemia were defined as those events requiring medical assistance or exhibiting depressed level/loss
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`of consciousness or seizure.
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`In a pooled analysis of the two monotherapy studies, the add-on to metformin study, and the add-on
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`to pioglitazone study, the overall incidence of adverse reactions of hypoglycemia was 1.2% in patients
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`treated with JANUVIA 100 mg and 0.9% in patients treated with placebo.
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`In the study of JANUVIA as add-on combination therapy with metformin and rosiglitazone, the
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`overall incidence of hypoglycemia was 2.2% in patients given add-on JANUVIA and 0.0% in patients given
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`add-on placebo through W eek 18. Through W eek 54, the overall incidence of hypoglycemia was 3.9% in
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`patients given add-on JANUVIA and 1.0% in patients given add-on placebo.
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`In the 24-week, placebo-controlled factorial study of initial therapy with JANUVIA in combination with
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`metformin, the incidence of hypoglycemia was 0.6% in patients given placebo, 0.6% in patients given
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`JANUVIA alone, 0.8% in patients given metformin alone, and 1.6% in patients given JANUVIA in
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`combination with metformin.
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`In the study of JANUVIA as initial therapy with pioglitazone, one patient taking JANUVIA
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`experienced a severe episode of hypoglycemia. There were no severe hypoglycemia episodes reported in
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`other studies except in the study involving coadministration with insulin.
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`Laboratory Tests
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`Across clinical studies, the incidence of laboratory adverse reactions was similar in patients treated
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`with JANUVIA 100 mg compared to patients treated with placebo. A small increase in white blood cell
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`count (W BC) was observed due to an increase in neutrophils. This increase in W BC (of approximately
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`200 cells/microL vs placebo, in four pooled placebo-controlled clinical studies, with a mean baseline W BC
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`count of approximately 6600 cells/microL) is not considered to be clinically relevant. In a 12-week study of
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`91 patients with chronic renal insufficiency, 37 patients with moderate renal insufficiency were randomized
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`to JANUVIA 50 mg daily, while 14 patients with the same magnitude of renal impairment were randomized
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`to placebo. Mean (SE) increases in serum creatinine were observed in patients treated with JANUVIA
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`[0.12 mg/dL (0.04)] and in patients treated with placebo [0.07 mg/dL (0.07)]. The clinical significance of
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`this added increase in serum creatinine relative to placebo is not known.
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`6.2 Postmarketing Experience
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`Additional adverse reactions have been identified during postapproval use of JANUVIA as
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`monotherapy and/or in combination with other antihyperglycemic agents. Because these reactions are
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`reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their
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`frequency or establish a causal relationship to drug exposure.
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`Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis,
`and exfoliative skin conditions including Stevens-Johnson syndrome [see Warnings and Precautions
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`(5.4)]; hepatic enzyme elevations; acute pancreatitis, including fatal and non-fatal hemorrhagic and
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`necrotizing pancreatitis [see Indications and Usage (1.2); Warnings and Precautions (5.1)]; worsening
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`Reference ID: 4043029
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`6
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`

`

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` renal function, including acute renal failure (sometimes requiring dialysis) [see Warnings and Precautions
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` (5.2)]; severe and disabling arthralgia [see Warnings and Precautions (5.5)]; bullous pemphigoid [see
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` Warnings and Precautions (5.6)]; constipation; vomiting; headache; myalgia; pain in extremity; back pain;
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` pruritus.
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` DRUG INTERACTIONS
` 7
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` 7.1 Digoxin
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` There was a slight increase in the area under the curve (AUC, 11%) and mean peak drug
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`concentration (Cmax, 18%) of digoxin with the coadministration of 100 mg sitagliptin for 10 days. Patients
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`receiving digoxin should be monitored appropriately. No dosage adjustment of digoxin or JANUVIA is
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`recommended.
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`USE IN SPECIFIC POPULATIONS
`8
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`8.1 Pregnancy
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`Pregnancy Category B:
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`Reproduction studies have been performed in rats and rabbits. Doses of sitagliptin up to 125 mg/kg
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`(approximately 12 times the human exposure at the maximum recommended human dose) did not impair
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`fertility or harm the fetus. There are, however, no adequate and well-controlled studies in pregnant
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`women. Because animal reproduction studies are not always predictive of human response, this drug
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`should be used during pregnancy only if clearly needed. Merck Sharp & Dohme Corp., a subsidiary of
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`Merck & Co., Inc., maintains a registry to monitor the pregnancy outcomes of women exposed to
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`JANUVIA while pregnant. Health care providers are encouraged to report any prenatal exposure to
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`JANUVIA by calling the Pregnancy Registry at 1-800-986-8999.
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`Sitagliptin administered to pregnant female rats and rabbits from gestation day 6 to 20
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`(organogenesis) was not teratogenic at oral doses up to 250 mg/kg (rats) and 125 mg/kg (rabbits), or
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`approximately 30- and 20-times human exposure at the maximum recommended human dose (MRHD) of
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`100 mg/day based on AUC comparisons. Higher doses increased the incidence of rib malformations in
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`offspring at 1000 mg/kg, or approximately 100 times human exposure at the MRHD.
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`Sitagliptin administered to female rats from gestation day 6 to lactation day 21 decreased body
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`weight in male and female offspring at 1000 mg/kg. No functional or behavioral toxicity was observed in
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`offspring of rats.
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`Placental transfer of sitagliptin administered to pregnant rats was approximately 45% at 2 hours and
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`80% at 24 hours postdose. Placental transfer of sitagliptin administered to pregnant rabbits was
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`approximately 66% at 2 hours and 30% at 24 hours.
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`8.3 Nursing Mothers
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`Sitagliptin is secreted in the milk of lactating rats at a milk to plasma ratio of 4:1. It is not known
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`whether sitagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution
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`should be exercised when JANUVIA is administered to a nursing woman.
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`8.4 Pediatric Use
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`Safety and effectiveness of JANUVIA in pediatric patients under 18 years of age have not been
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`established.
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`8.5 Geriatric Use
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`Of the total number of subjects (N=3884) in pre-approval clinical safety and efficacy studies of
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`JANUVIA, 725 patients were 65 years and over, while 61 patients were 75 years and over. No overall
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`differences in safety or effectiveness were observed between subjects 65 years and over and younger
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`subjects. W hile this and other reported clinical experience have not identified differences in responses
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`between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out.
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`This drug is known to be substantially excreted by the kidney. Because elderly patients are more
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`likely to have decreased renal function, care should be taken in dose selection in the elderly, and it may be
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`useful to assess renal function in these patients prior to initiating dosing and periodically thereafter [see
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`Dosage and Administration (2.2); Clinical Pharmacology (12.3)].
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`Reference ID: 4043029
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`
`7
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`

`

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`
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`10 OVERDOSAGE
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`During controlled clinical trials in healthy subjects, single doses of up to 800 mg JANUVIA were
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`administered. Maximal mean increases in QTc of 8.0 msec were observed in one study at a dose of
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`800 mg JANUVIA, a mean effect that is not considered clinically important [see Clinical Pharmacology
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`(12.2)]. There is no experience with doses above 800 mg in clinical studies. In Phase I multiple-dose
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`studies, there were no dose-related clinical adverse reactions observed with JANUVIA with doses of up to
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`600 mg per day for periods of up to 10 days and 400 mg per day for up to 28 days.
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`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
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`electrocardiogram), and institute supportive therapy as dictated by