`
`
` 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
`
`
`
`
`
`
`
`
`
`
`
`
` ---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
`
`
`
`
`
`
` Indications and Usage
` 12/2020
`
`
` Dosage and Administration (2.2)
`
`
`
` 12/2020
`
`
`
` Warnings and Precautions (5.3, 5.4)
`
`
`
` 12/2020
`
`
`
`
`
` Warnings and Precautions (5.8) removed
`
`
`
`
`
`
` 12/2020
`
`
`
`
`
`
`
`
`
`
`
`
` ----------------------------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 (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
` eGFR less than
` 30 mL/min/1.73 m2 (including
` 30 mL/min/1.73 m2 to less than
`
`
`
`
`
`
`
`
`
`
` 45 mL/min/1.73 m2
`
`
`
`
` patients with end stage renal
`
`
`
`
`
`
` disease [ESRD] on dialysis)
`
`
`
`
` 25 mg once daily
`
`
`
` 50 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)
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`
`
`
`
`
` 1
` INDICATIONS AND USAGE
`
`
` 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 Acute Renal Failure
`
`
` 5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin
`
`
` Secretagogues
`
`
`
` 5.5 Hypersensitivity Reactions
`
`
` 5.6 Severe and Disabling Arthralgia
`
`
`
`
` 5.7 Bullous Pemphigoid
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
`
` 6.2 Postmarketing Experience
`
` 7 DRUG INTERACTIONS
`
`
` Insulin Secretagogues or Insulin
`
`
` 7.1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
`
`
`
`
`
` ----------------------- WARNINGS AND PRECAUTIONS ----------------------­
`• Pancreatitis: 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: 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)
`
`
`
`
`
`
`
`• Acute Renal Failure: Has been reported postmarketing, sometimes
`
`
`
`
`
`
`
`
` requiring dialysis. Assessment of renal function is recommended
`
`
`
`
`
`
`
`
` prior to initiating JANUVIA and periodically thereafter. (5.3)
`
`
`
`
`
`
`
`
`• Hypoglycemia with Concomitant Use with
`
`
`
` Insulin or
`
`
`
`
`
`
` Insulin
`
` Secretagogues: Increased risk of hypoglycemia when used in
`
`
`
`
`
`
`
` combination with insulin and/or an insulin secretagogue. Lower dose
`
`
`
`
`
`
`
`
`
` of insulin or insulin secretagogue may be required. (5.4, 7.1)
`
`
`
`
`
`
`
`
`
`• Hypersensitivity Reactions: 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. Promptly stop
`
`
`
`
`
`
` JANUVIA, assess for other potential causes, institute appropriate
`
`
`
`
`
`
`
`
` monitoring and treatment. (5.5, 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. (5.6)
`
`
`
`
`
`
`
`• Bullous Pemphigoid: There have been postmarketing reports
`
`
`
`
`
`
`
`
` requiring hospitalization in patients taking DPP-4 inhibitors. Tell
`
`
`
`
`
`
` patients to report development of blisters or erosions. If bullous
`
`
`
`
`
`
`
`
`
`
` pemphigoid is suspected, discontinue JANUVIA. (5.7)
`
`
`
`
`
`
`
`
`
`
`
` ------------------------------ 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.
`
`
`
`
`
`
`
`
` See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`
` Guide.
`
`
`
`
`
`
`
`
`
` Revised: 12/2020
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
` 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).]
`
`
`
`
`
`
`
`
`
`
`
`
`
` 2
`
`
`
` DOSAGE AND ADMINISTRATION
`
`
`
`
`
` 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
`
`
` Assess renal function prior to initiation of JANUVIA and periodically thereafter.
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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).]
`
`
`
`
`
`
`
`
`
`
`
` 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 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.
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 2
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 Acute Renal Failure
`
`
`
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` 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); Use in Specific Populations (8.6).]
`
`
`
`
`
`
` 5.4 Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues
`
`
`
` When JANUVIA was used in combination with insulin or insulin secretagogues (e.g., sulfonylurea),
`
`
`
`
`
`
`
` 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 (7.1).]
`
` 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
` topical or systemic
`
`
` recovered with
` reported cases, patients
`
`
`
`
`In
` typically
`inhibitor use.
`
`
` 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.
`
`
`
`
` 6
`
`
`
` ADVERSE REACTIONS
`
`
` The following adverse reactions are also discussed elsewhere in the labeling:
`• Pancreatitis [see Warnings and Precautions (5.1)]
`
`
`
`
`• Heart Failure [see Warnings and Precautions (5.2)]
`
`
`• Acute Renal Failure [see Warnings and Precautions (5.3)]
`
`
`
`• Hypoglycemia with Concomitant Use with Insulin or Insulin Secretagogues [see Warnings and
`
`
`
`
`
`
`
` Precautions (5.4)]
`
`• Hypersensitivity Reactions [see Warnings and Precautions (5.5)]
`
`
`
`
`• Severe and Disabling Arthralgia [see Warnings and Precautions (5.6)]
`
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 3
`
`

`

`
`
`
`• Bullous Pemphigoid [see Warnings and Precautions (5.7)]
`
`
`
`
`
`
`
`
`
`
` 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
`
`
` Monotherapy (18 or 24 weeks)
`
`
`
`
`
`
`
`
`
`
`
`
`
` Placebo
`
`
`
`
`
` Nasopharyngitis
`
`
`
`
`
` Combination with Pioglitazone (24
`
` weeks)
`
`
` 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
`
`
`
`
`
`
`
`
` 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)
`
`
`
`
`
`
` 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)
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`Reference ID: 4712165
`
`
`
` 4
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 (%)
`
`
`
` Metformin HCl
` 500 or 1000 mg bid†
`
`
`
`
`
`
`
`
` Placebo
`
`
`
`
` Sitagliptin
`
` (JANUVIA)
`
` 100 mg QD
`
`
`
`
`
`
`
`
` Sitagliptin
`
` 50 mg bid +
`
`
`
` Metformin HCl
`
` 500 or 1000 mg bid†
`
`
`
` N = 372†
`
`
`
`
`
`
`
`
`
` 23 (6.2)
`
`
`
`
`
` 22 (5.9)
`
`
` Upper Respiratory Infection
`
`
`
`
`
`
`
`
`
` Headache
`
`
`
`
`
` N = 176
`
`
`
` N = 179
`
`
`
`
`
`
`
` 9 (5.1)
`
`
`
`
`
` 5 (2.8)
`
`
`
` 8 (4.5)
`
`
`
`
`
` 2 (1.1)
`
`
`
`
`
` N = 364†
`
`
`
`
`
` 19 (5.2)
`
`
`
`
`
` 14 (3.8)
`
`* 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).
`
`
`
` 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).
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 5
`
`

`

`
`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
`
`
`
`
`
`
`
`
` Add-On to Glimepiride
` (+/- Metformin) (24 weeks)
`
`
`
`
`
`
`
`
`
` Overall (%)
` Rate (episodes/patient-year)†
`
` Severe (%)‡
`
`
`
`
`
`
`
`
`
`
` JANUVIA 100 mg
` + Glimepiride
`
` (+/- Metformin)
`
` N = 222
`
`
` 27 (12.2)
`
`
` 0.59
`
` 0 (0.0)
`
`
`
`
`
` Placebo
`
` + Glimepiride
`
`
` (+/- Metformin)
` N = 219
`
`
`
` 4 (1.8)
`
` 0.24
`
` 0 (0.0)
`
`
`
`
`
`
` Add-On to Insulin
` (+/- Metformin) (24 weeks)
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
`Reference ID: 4712165
`
`
`
` 6
`
`

`

`
`
`
`
`
`
`
` 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; hepatic enzyme elevations; acute
`
`
`
`
`
`
` pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis [see Indications and
`
`
`
`
`
`
`
`
`
` Usage (1.2); worsening renal function, including acute renal failure (sometimes requiring dialysis); severe
`
`
`
`
`
`
` and disabling arthralgia; bullous pemphigoid; constipation; vomiting; headache; myalgia; pain in extremity;
`
`
` back pain; pruritus; mouth ulceration; stomatitis; rhabdomyolysis.
`
`
`
`
`
`
`
`
` 7
`
`
`
` DRUG INTERACTIONS
`
` 7.1
`
`
`
`
`
` 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).]
`
`
`
`
`
`
` 8
`
`
`
` USE IN SPECIFIC POPULATIONS
`
` 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.
`
`
` 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 devel