CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-044
`
`LABELING
`
`

`

`97941 XX
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`JANUMET safely and effectively. See full prescribing information
`for JANUMET.
`
`JANUMET” (sitagliptin/metformin HCI) tablets
`Initial U.S. Approval: 2007
`
`WARNING: LACTIC ACIDOSIS
`See full prescribing information for complete boxed warning.
`
`
`
`Lactic acidosis can occur due to metformin accumulation. The
`risk increases with conditions such as sepsis, dehydration,
`excess alcohol intake, hepatic insufficiency, renal impairment,
`and acute congestive heart failure. (5.1)
`respiratory distress,
`Symptoms include malaise, myalgias,
`increasing somnolence, and nonspecific abdominal distress.
`Laboratory abnormalities include low pH, increased anion gap
`and elevated blood lactate. (5.1)
`If acidosis is suspected, discontinue JANUMET and hospitalize
`the patient immediately. (5.1)
`
`---------s--------------RECENT MAJOR CHANGES --------------------------
`Indications and Usage (1)
`2/2008
`Dosage and Administration
`Recommended Dosing (2.1)
`Contraindications (4)
`Warnings and Precautions
`2/2008
`Use with Medications Known to Cause Hypoglycemia (5.8)
`1/2008
`Hypersensitivity Reactions (5.13)
`2/2008
`Macrovascular Outcomes (5.14)
`-—--—-—------------—---lNDICATIONS AND USAGE ----------------------
`JANUMET is a dipeptidyl peptidase—4 (DPP-4) inhibitor and biguanide
`combination product indicated as an adjunct to diet and exercise to
`improve glycemic control in adults with type 2 diabetes mellitus when
`treatment with both sitagliptin and metformin is appropriate. (1)
`
`2/2008
`1/2008
`
`Important Limitations of Use:
`-
`JANUMET should not be used in patients with type 1 diabetes or for
`the treatment of diabetic ketoacidosis. (1 )
`JANUMET has not been studied in combination with insulin. (1)
`.
`------------------- DOSAGE AND ADMINISTRATION----------—-—--a------
`.
`Individualize the starting dose of JANUMET based on the patient’s
`current regimen. (2.1)
`0 May adjust the dosing based on effectiveness and tolerability while
`not exceeding the maximum recommended daily dose of 100 mg
`sitagliptin and 2000 mg metformin. (2.1)
`JANUMET should be given twice daily with meals, with gradual dose
`escalation,
`to reduce the gastrointestinal (GI) side effects due to
`metformin. (2.1)
`
`-
`
`-—--—---1--------- DOSAGE FORMS AND STRENGTHS ---—-----------—-
`Tablets:
`50 mg
`sitagliptin/500 mg metformin HCI
`and
`50 mg
`sitagliptin/1000 mg metformin HCI (3)
`----------------------- CONTRAINDICATIONS —-—----—----—---—------
`
`serum creatinine 21.5 mg/dL [males].
`0 Renal dysfunction, e.g.,
`21.4 mg/dL [females] or abnormal creatinine clearance. (4, 5.1, 5.3)
`0 Acute or chronic metabolic acidosis, including diabetic ketoacidosis,
`with or without coma. (4, 5.1)
`- History of a serious hypersensitivity reaction to JANUMET or
`sitagliptin (one of
`the components of
`JANUMET),
`such as
`anaphylaxis or angioedema. (5.13, 6.2)
`
`undergoing
`patients
`in
`JANUMET
`discontinue
`o Temporarily
`radiologic studies involving intravascular administration of iodinated
`contrast materials. (4, 5.1, 5.10)
`--------------------WARNINGS AND PRECAUTIONS---------------------
`. Do not use JANUMET in patients with hepatic disease. (5.1, 5.2)
`0 Before initiating JANUMET and at least annually thereafter, assess
`renal function and verify as normal. (4, 5.1, 5.3, 5.9)
`a Measure hematologic parameters annually. (5.4, 6.1)
`. Warn patients against excessive alcohol intake. (5.1, 5.5)
`0 May need to discontinue JANUMET and temporarily use insulin
`during periods of stress and decreased intake of fluids and food as
`may occur with fever, trauma, infection or surgery. (5.6, 5.7, 5.11,
`5.12)
`- Promptly evaluate patients previously controlled on JANUMET who
`develop laboratory abnormalities or clinical illness for evidence of
`ketoacidosis or lactic acidosis. (5.1, 5.7, 5.11, 5.12)
`sulfonylurea,
`. When used with an insulin secretagogue (e.g.,
`meglitinide), a lower dose of the insulin secretagogue may be
`required to reduce the risk of hypoglycemia. (2.1, 5.8)
`. There have been postmarketing reports of serious allergic and
`hypersensitivity reactions in patients treated with sitagliptin (one of
`the components of JANUMET), such as anaphylaxis, angioedema,
`and
`exfoliative
`skin
`conditions
`including
`Stevens-Johnson
`syndrome. In such cases, promptly stop JANUMET, assess for other
`potential causes, institute appropriate monitoring and treatment, and
`initiate alternative treatment for diabetes. (5.13, 6.2)
`- There have been no clinical
`studies establishing conclusive
`evidence of macrovascular risk reduction with JANUMET or any
`other oral anti-diabetic drug (5.14).
`-------—---------—--------- ADVERSE REACTIONS---------------------------
`o The most common adverse reactions reported in 25% of patients
`simultaneously started on sitagliptin and metformin and more
`commonly than in patients treated with placebo were diarrhea,
`upper respiratory tract infection, and headache. (6.1)
`. Adverse reactions reported in 25% of patients treated with sitagliptin
`in combination with sulfonylurea and metformin and more commonly
`than in patients
`treated with placebo in
`combination with
`sulfonylurea and metformin were hypoglycemia and headache. (6.1)
`o Nasopharyngitis was the only adverse reaction reported in 25% of
`patients treated with sitagliptin monotherapy and more commonly
`than in patients given placebo. (6.1)
`o The most common (>5%) adverse reactions due to initiation of
`metformin
`therapy are diarrhea,
`nausea/vomiting,
`flatulence,
`abdominal discomfort, indigestion, asthenia, and headache. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Merck &
`Co.,
`Inc. at 1-877-888-4231 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`--------------------------DRUG INTERACTIONS-----------------------------
`- Cationic drugs eliminated by renal
`tubular secretion: Use with
`caution. (5.9, 7.1)
`------------------—- USE IN SPECIFIC POPULATIONS —------------—------
`0 Safety and effectiveness of JANUMET 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)
`
`PATIENT COUNSELING INFORMATION and
`for
`17
`See
`FDA-approved patient labeling.
`
`Revised: 2/2008 .
`
`

`

`97941XX
`JANUMETTNI
`(sitagliptin/metformin HCI) Tablets
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`-
`
`7 DRUG INTERACTIONS
`7.1
`Cationic Drugs
`7.2
`Digoxin
`7.3
`Glyburide
`7.4
`Furosemide
`7.5
`Nifedipine
`7.6
`The Use of Metformin with Other Drugs
`8 USE IN SPECIFIC POPULATIONS
`8-1
`Pregnancy
`8-3
`Nursing Mothers
`8-4
`Pediatric Use
`8-5 Geriatric Use
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1
`Instructions
`17.2 Laboratory Tests
`
`*Sections or subsections omitted from the full prescribing information
`are not listed.
`
`WARNING - LACTIC ACIDOSIS
`1
`INDICATIONS AND USAGE
`2 DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosing
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Lactic Acidosis
`5.2
`Impaired Hepatic Function
`5.3 Assessment of Renal Function
`5.4
`Vitamin 8,; Levels
`5.5 Alcohol Intake
`5.6
`Surgical Procedures
`5.7
`Change in Clinical Status of Patients with Previously
`Controlled Type 2 Diabetes
`5.8 Use with Medications Known to Cause Hypoglycemia
`5.9
`Concomitant Medications Affecting Renal Function
`Metformin Disposition
`5.10 Radiologic Studies with Intravascular
`Materials
`5.11 Hypoxic States
`5.12 Loss of Control of Blood Glucose
`5.13 Hypersensitivity Reactions
`5.14 Macrovascular Outcomes
`6 ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`or
`
`Iodinated Contrast
`
`.
`
`.
`
`
`
`FULL PRESCRIBING INFORMATION
`WARNING: LACTIC ACIDOSIS
`
`
`
`Lactic acidosis is a rare, but serious complication that can occur due to metformin
`accumulation. The risk increases with conditions such as sepsis, dehydration, excess alcohol
`
`intake, hepatic insufficiency, renal impairment, and acute congestive heart failure.
`
`
`The onset is often subtle, accompanied only by nonspecific symptoms such as malaise,
`myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.
`Laboratory abnormalities include Iow1pH, increased anion gap and elevated blood lactate.
`
`If acidosis is suspected, JANUMET should be discontinued and the patient hospitalized
`immediately. [See Warnings and Precautions (5.1).]
`
`
`
`
`
`1
`
`INDICATIONS AND USAGE
`
`JANUMET is indicated as an adjunct to diet and exercise to improve glycemic control in adults with
`type 2 diabetes mellitus when treatment with both sitagliptin and metformin is appropriate. [See C/xh/ba/
`Studies (14).]
`Important Limitations of Use
`JANUMET 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.
`JANUMET has not been studied in combination with insulin.
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Recommended Dosing
`The dosage of antihyperglycemic therapy with JANUMET should be individualized on the basis of the
`patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended
`daily dose of 100 mg sitagliptin and 2000 mg metformin. Initial combination therapy or maintenance of
`combination therapy should be individualized and left to the discretion of the health care provider.
`JANUMET should generally be given twice daily with meals, with gradual dose escalation, to reduce
`the gastrointestinal (GI) side effects due to metformin.
`
`

`

`JANUMETTM
`(sitagliptin/metformin HCI) Tablets
`
`'
`
`97941xx
`
`The starting dose of JANUMET should be based on the patient’s current regimen. JANUMET should
`be given twice daily with meals. The following doses are available:
`50 mg sitagliptin/500 mg metformin hydrochloride
`50 mg sitagliptin/1000 mg metformin hydrochloride.
`Fella/71‘s lhao’eqz/a/e/y contra/ed Mm 0729/ andexam/Se a/one
`lf therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a
`patient with type 2 diabetes mellitus inadequately controlled with diet and exercise alone,
`the
`recommended starting dose is 50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients with
`inadequate glycemic control on this dose can be titrated up to 50 mg sitagliptin/1000 mg metformin
`hydrochloride twice daily.
`Pal/ants Managua/fly con/roiled 0/7 mew/mm mono/fierapy
`If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a
`patient inadequately controlled on metformin alone, the recommended starting dose of JANUMET should
`provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and the dose of metformin already
`being taken. For patients taking metformin 850 mg twice daily,
`the recommended starting dose of
`JANUMET is 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily.
`Pafien/s Madam/alley comm/90’0/7 stag/[017?) mono/flerapy
`If therapy with a combination tablet containing sitagliptin and metformin is considered appropriate for a
`patient inadequately controlled on sitagliptin alone, the recommended starting dose of JANUMET is
`50 mg sitagliptin/500 mg metformin hydrochloride twice daily. Patients with inadequate control on this
`dose can be titrated up to 50 mg sitagliptin/1000 mg metformin hydrochloride twice daily. Patients taking
`sitagliptin monotherapy dose-adjusted for renal insufficiency should not be switched to JANUMET [see
`Con/ra/hwbafions {4}]
`Paw/71‘s swim/fig #007 co-ao’M/h/is/raI/b” ofgray/4271777 andmeflor/n/h
`For patients switching from sitagliptin co-administrated with metformin, JANUMET may be initiated at
`the dose of sitagliptin and metformin already being taken.
`Pawn/s Madame/61V con/roiled 0/7 dua/ comb/hallo” therapy Mm any [W0 0/ [/76 f0//0M}7g
`antihyperglycemic agents: sitagliptin, metformin or a sulfonylurea
`lf therapy with a combination tablet containing sitagliptin and metformin is considered appropriate in
`this setting, the usual starting dose of JANUMET should provide sitagliptin dosed as 50 mg twice daily
`(100 mg total daily dose). In determining the starting dose of the metformin component, the patient's level
`of glycemic control and current dose (if any) of metformin should be considered. Gradual dose escalation
`to reduce the gastrointestinal (GI) side effects associated with metformin should be considered. Patients .
`currently on or initiating a sulfonylurea may require lower sulfonylurea doses to reduce the risk of
`hypoglycemia [see Mam/279.9 andPrecaz/l/bns {5 9/]
`No studies have been performed specifically examining the safety and efficacy of JANUMET in
`patients previously treated with other oral antihyperglycemic agents and switched to JANUMET. Any
`change in therapy of type 2 diabetes should be undertaken with care and appropriate monitoring as
`changes in glycemic control can occur.
`
`3
`
`DOSAGE FORMS AND STRENGTHS
`
`-
`
`0
`
`50 mg/500 mg tablets are light pink, capsule-shaped, film-coated tablets with “575" debossed
`on one side.
`
`50 mg/1000 mg tablets are red, capsule-shaped, film-coated tablets with “577" debossed on
`one side.
`.
`
`4
`
`CONTRAINDICATIONS
`JANUMET (sitagliptin/metformin HCl) is contraindicated in patients with:
`0
`Renal disease or renal dysfunction, e.g., as suggested by serum creatinine levels 21.5 mg/dL
`[males], 21.4 mg/dL [females] or abnormal creatinine clearance which may also result from
`conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia
`[see Warm/figs afldP/ecaul/bfls {.5 7/]
`0 Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma.
`
`

`

`JANUMETTM
`(sitagliptin/metformin HCI) Tablets
`
`97941 XX
`
`. History of a serious hypersensitivity reaction to JANUMET or sitagliptin (one of the components
`of JANUMET), such as anaphylaxis or angioedema. [See Warn/figs and Precautions {.5 73/ and
`Adverse Reactions (6. 2).]
`
`JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving
`intravascular administration of iodinated contrast materials, because use of such products may result in
`acute alteration of renal function [see M/arn/hgs andPrecaz/l/bfls {.5 70/]
`
`5
`
`WARNINGS AND'PRECAUTIONS
`
`5.1
`
`Lactic Acidosis
`
`Metformin hydrochloride
`Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin
`accumulation during treatment with JANUMET; when it occurs, it is fatal in approximately 50% of cases.
`Lactic acidosis may also occur in association with a number of pathophysiologic conditions,
`including
`diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis
`is characterized by elevated blood lactate levels
`(>5 mmoI/L), decreased blood pH, electrolyte
`disturbances with an increased anion gap, and an increased Iactate/pyruvate ratio. When metformin is
`implicated as the cause of lactic acidosis, metformin plasma levels >5 pg/mL are generally found.
`The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low
`(approximately 0.03 cases/1000 patient-years, with approximately 0.015 fatal cases/1000 patient-years).
`In more than 20,000 patient-years exposure to metformin in clinical trials, there Were no reports of lactic
`acidosis. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency,
`including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant
`medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure
`requiring pharmacologic management, in particular those with unstable or acute congestive heart failure
`who are at risk of hypoperfusion and hypoxemia, are at increased risk of lactic acidosis. The risk of lactic
`acidosis increases with the degree of renal dysfunction and the patient's age. The risk of lactic acidosis
`may,
`therefore, be significantly decreased by regular monitoring of renal function in patients taking
`metformin and by use of the minimum effective dose of metformin. In particular, treatment of the elderly
`should be accompanied by careful monitoring of renal function. Metformin treatment should not be
`initiated in patients 280 years of age unless measurement of creatinine clearance demonstrates that renal
`function is not reduced, as these patients are more susceptible to developing lactic acidosis. In addition,
`metformin should be promptly withheld in the presence of any condition associated with hypoxemia,
`dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear
`lactate, metformin should generally be avoided in patients with clinical or laboratory evidence of hepatic
`disease. Patients should be cautioned against excessive alcohol intake, either acute or chronic, when
`taking metformin, since alcohol potentiates the effects of metformin hydrochloride on lactate metabolism.
`In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study
`and for any surgical procedure [see Warn/279.9 andP/ecaz/l/ofls {.53, 5.5, .56} .5 70//
`The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as
`malaise, myalgias, respiratory distress,
`increasing somnolence, and nonspecific abdominal distress.
`There may be associated hypothermia, hypotension, and resistant bradyarrhythmias with more marked
`acidosis. The patient and the patient's physician must be aware of the possible importance of such
`symptoms and the patient should be instructed to notify the physician immediately if they occur [see
`Warn/figs andPrecaz/flons {5 77/] Metformin should be withdrawn until the situation is clarified. Serum
`electrolytes, ketones, blood glucose, and if indicated, blood pH, lactate levels, and even blood metformin
`levels may be useful. Once a patient is stabilized on any dose level of metformin, gastrointestinal
`symptoms, which are common during initiation of therapy, are unlikely to be drug related. Later
`occurrence of gastrointestinal symptoms could be due'to lactic acidosis or other serious disease.
`Levels of fasting venous plasma lactate above the upper limit of normal but less than 5 mmol/L in
`patients taking metformin do not necessarily indicate impending lactic acidosis and may be explainable
`by other mechanisms, such as poorly controlled diabetes or obesity, vigorous physical activity, or
`technical problems in sample handling [see 1449/0/th andPrecaz/flb/Is {.5 7, .5 72/]
`Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of
`ketoacidosis (ketonuria and ketonemia).
`
`

`

`JANUMETTM
`
`(sitagliptin/metformin HCI) Tablets
`
`'
`
`97941 XX
`
`In a patient with
`Lactic acidosis is a medical emergency that must be treated in a hospital setting.
`lactic acidosis who is taking metformin,
`the drug should be discontinued immediately and general
`supportive measures promptly instituted. Because metformin hydrochloride is dialyzable (with a clearance
`of up to 170 mL/min under good hemodynamic conditions), prompt hemodialysis is recommended to
`correct the acidosis and remove the accumulated metformin. Such management often results in prompt
`reversal of symptoms and recovery [see Conz‘ra/hmz'afims {4}; Mrn/hgs andPrecaz/flons {55, .56,“ 5.9,
`5. 70,
`.5 77/]
`5.2
`Impaired Hepatic Function
`Since impaired hepatic function has been associated with some cases of lactic acidosis, JANUMET
`should generally be avoided in patients with clinical or laboratory evidence of hepatic disease.
`5.3 Assessment of Renal Function
`
`Metformin and sitagliptin are known to be substantially excreted by the kidney. The risk of metformin
`- accumulation and lactic acidosis increases with the degree of impairment of renal function. Thus, patients
`with serum creatinine levels above the upper limit of normal for their age should not receive JANUMET. In
`the elderly, JANUMET should be carefully titrated to establish the minimum dose for adequate glycemic
`effect, because aging can be associated with reduced renal function. [See Mar/mg: andPrecaz/fions
`(.5 7/ and Use /'/7 SOHO/776‘ Papa/mans {63 5).]
`Before initiation of therapy with JANUMET and at least annually thereafter, renal function should be
`assessed and verified as normal. In patients in whom development of renal dysfunction is anticipated,
`particularly in elderly patients,
`renal function should be assessed more frequently and JANUMET
`discontinued if evidence of renal impairment is present.
`5.4 Vitamin B12 Levels
`In controlled clinical trials of metformin of 29 weeks duration, a decrease to subnormal levels of
`previously normal
`serum Vitamin B12
`levels, without clinical manifestations, was observed in
`approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the
`B12-intrinsic factor complex,
`is, however, very rarely associated with anemia and appears to be rapidly
`reversible with discontinuation of metformin or Vitamin B12 supplementation. Measurement of hematologic
`parameters on an annual basis is advised in patients on JANUMET and any apparent abnormalities
`should be appropriately investigated and managed [SeeAdI/erse Read/00.9 {6‘ 7].]
`Certain individuals (those with inadequate Vitamin B12 or calcium intake or absorption) appear to be
`predisposed to developing subnormal Vitamin B12 levels.
`In these patients, routine serum Vitamin B12
`measurements at two- to three-year intervals may be useful.
`5.5 Alcohol Intake
`
`is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore,
`Alcohol
`should be warned against excessive alcohol intake, acute or chronic, while receiving JANUMET.
`5.6
`Surgical Procedures
`Use of JANUMET should be temporarily suspended for any surgical procedure (except minor
`procedures not associated with restricted intake of food and fluids) and should not be restarted until the
`patient's oral intake has resumed and renal function has been evaluated as normal.
`5.7 Change in Clinical Status of Patients with Previously Controlled Type 2 Diabetes
`A patient with type 2 diabetes previously well controlled on JANUMET who develops laboratory
`abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly
`for evidence of ketoacidosis or lactic acidosis. Evaluation should include serum electrolytes and ketones,
`blood glucose and,
`if indicated, blood pH, lactate, pyruvate, and metformin levels.
`If acidosis of either
`form occurs, JANUMET must be stopped immediately and other appropriate corrective measures
`initiated.
`
`5.8 Use with Medications Known to Cause Hypoglycemia
`Sitagliptin
`As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when
`sitagliptin was used in combination with metformin and a sulfonylurea, a medication known to cause
`hypoglycemia, the incidence of hypoglycemia was increased over that of placebo in combination with
`metformin and a sulfonylurea [see Adi/arse Reacfl'ons {67/ Therefore, patients also receiving an insulin
`secretagogue (e.g., sulfonylurea, meglitinide) may require a lower dose of the insulin secretagogue to
`reduce the risk of hypoglycemia [see Dosage andAo’M/h/Js'lrafion /2 7/]
`
`

`

`JANUMETTM
`(sitagliptin/metformin HCI) Tablets
`
`97941 XX
`
`Mafia/mm /7y0’roc/7/0//'0’e
`Hypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use,
`but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric
`supplementation or during concomitant use with other glucose-lowering agents (such as sulfonylureas
`and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with adrenal or pituitary
`insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia
`may be difficult to recognize in the elderly, and in people who are taking B-adrenergic blocking drugs.
`5.9 Concomitant Medications Affecting Renal Function or Metformin Disposition
`Concomitant medication(s) that may affect renal function or result in significant hemodynamic change
`or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal
`tubular secretion [see DrugM/eracfians {Z 7/] should be used with caution.
`5.10 Radiologic Studies with lntravascular lodinated Contrast Materials
`lntravascular contrast studies with lodinated materials (for example, intravenous urogram, intravenous
`cholangiography, angiography, and computed tomography (CT) scans with lntravascular contrast
`materials) can lead to acute alteration of renal function and have been associated with lactic acidosis in
`patients receiving metformin [see Can/ra/hwbafi'ofls 39/ Therefore, in patients in whom any such study is
`planned, JANUMET should be temporarily discontinued at the time of or prior to the procedure, and
`withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-
`evaluated and found to be normal.
`
`5.11 Hypoxic States
`failure, acute
`from whatever cause, acute congestive heart
`Cardiovascular collapse (shock)
`myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic
`acidosis and may also cause prerenal azotemia. When such events occur in patients on JANUMET
`therapy, the drug should be promptly discontinued.
`5.12 Loss of Control of Blood Glucose
`
`trauma,
`When a patient stabilized on any diabetic regimen is exposed to stress such as fever,
`infection, or surgery, a temporary loss of glycemic control may occur. At such times, it may be necessary
`to withhold JANUMET and temporarily administer insulin. JANUMET may be reinstituted after the acute
`episode'Is resolved
`5.13 Hypersensitivity Reactions
`There have been postmarketing reports of serious hypersensitivity reactions in patients treated with
`sitagliptin, one of the components of JANUMET. These reactions include anaphylaxis, angioedema, and
`exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported
`voluntarily from a population of uncertain size,
`it
`is generally not possible to reliably estimate their
`frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within
`the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first
`dose. If a hypersensitivity reaction is suspected, discontinue JANUMET, assess for other potential causes
`for the event, and institute alternative treatment for diabetes. [SeeAdVe/se Read/ans {621/
`5.14 Macrovascular Outcomes
`_
`There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction
`with JANUMET or any other oral anti-diabetic drug.
`
`6
`
`ADVERSE REACTIONS
`
`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.
`.S‘lfagflpfih andMe/forM/h Co—ao’M/b/lslral/bfl /77 Pal/enls 1447/7 7206 20/309193 Madeqz/a/e/y Con/ro/Aao’ 0/7
`0/29] and/Exercise
`
`Table 1 summarizes the most common (25% of patients) adverse reactions reported (regardless of
`investigator assessment of causality) in a 24-week placebo-controlled factorial study in which sitagliptin
`and metformin were co-administered to patients with type 2 diabetes inadequately controlled on diet and
`exerCIse.
`
`

`

`JANUMETTM
`(sitagliptin/metformin HCI) Tablets
`
`97941XX
`
`
`
`
`
`Table 1: Sitagliptin and Metformin Co-administered to Patients with Type 2 Diabetes
`lnadequately Controlled on Diet and Exercise:
`Adverse Reactions Reported (Regardless of Investigator Assessment of Causality) in 25% of
`Patients Receiving Combination Therapy (and Greater than in Patients Receiving Placebo),r
`
`— Number of Patients %
`
`Sitagliptin
`100 mg QD
`
`Metformin 500 mg]
`Metformin 1000 mg bid”
`
`
`
`
`
`
`Sitagliptin
`50 mg bid +
`Metformin 500 mg/
`Metformin 1000 m bid "
`
`N=372”
`28 7.5
`
`23 (6.2)
`
`— N=175
`
`N=119
`
`Upper Respiratory
`Tract Infection
`
`9 (5.1)
`
`8 (4.5)
`
`28 7.7
`
`19 (5.2)
`
`
`
`Intent-to-treat population.
`”Data pooled for the patients given the lower and higher doses of metformin.
`
`14 3.8
`
`22 5.9
`
`
`
`S/i‘ag/joflb Add-0n Therapy/)7 Pal/emf: 1447/7 717,09 ZD/abe/es Madeqz/a/e/y Con/rofleo’on Mew/mm ,4/0/79
`In a 24-week placebo-controlled trial of sitagliptin 100 mg administered once daily added to a twice
`daily metformin regimen, there were no adverse reactions reported regardless of investigator assessment
`of causality in .>.5% of patients and more commonly than in patients given placebo. Discontinuation of
`therapy due to clinical adverse reactions was similar to the placebo treatment group (sitagliptin and
`metformin, 1.9%; placebo and metformin, 2.5%).
`Hypog/J/ce/II/ia
`Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose
`measurement was not required. The overall incidence of pre-specified adverse reactions of hypoglycemia
`in patients with type 2 diabetes inadequately controlled on diet and exercise was 0.6% in patients given
`placebo, 0.6% in patients given sitagliptin alone, 0.8% in patients given metformin alone, and 1.6% in
`patients given sitagliptin in combination with metformin.
`In patients with type 2 diabetes inadequately
`controlled on metformin alone, the overall incidence of adverse reactions of hypoglycemia was 1.3% in,
`patients given add-on sitagliptin and 2.1% in patients given add-on placebo.
`Gaslm/hz‘esllha/Ao’I/e/se Reacfi'ons
`
`The incidences of pre-selected gastrointestinal adverse experiences in patients treated with sitagliptin
`and metformin were similar to those reported for patients treated with metformin alone. See Table 2.
`
`Table 2: Pre-selected Gastrointestinal Adverse Reactions (Regardless of Investigator Assessment of Causality)
`Reported in Patients with Type 2 Diabetes Receiving Sitagliptin and Metformin
`
`
`Number of Patients %
`
`
`
`
`1
`Study of Sitagliptin Add-on in
`Study of Sitagliptin and Metformin in Patients lnadequately Controlled
`
`
`
`
`Patients lnadequately Controlled
`.
`on Diet and Exercise
`1
`on Metformin Alone
`
`Placebo and
`Sitagliptin 100 mg
`
`
`
`
`
`Metformin
`OD and Metformin
`Placebo Sitagliptin Metformin 500 mg/
`Sitagliptin 50 mg bid +
`
`
`
`.
`Metformin 500 mgl
`
`
`21500 mg daily
`
`"’0 "‘9 QD M°“°'":i':il°°° "‘9 Metformin 1000 mg bid1 ‘
`
`
`
`
`N=176
`:
`N=237 ”-
`N=179 m- N=372
`
`——Im 28 7.7
`28 7.5
`'m- 11 2.4
`
`
`MM?
`
`
`“mum-8.1m-
`
`
`-——-—
`
`
`PainTT
`:
`.
`Data pooled for the patients given the lower and higher doses of metformin.
`"Abdominal discomfort was included in the analysis of abdominal pain in the study of initial therapy.
`
`&7agflpflh /}7 Comb/77am” [Mi/7 Mew/mm and G/IMepl'r/b’e
`In a 24-week placebo-controlled study of sitagliptin 100 mg as add-on therapy in patients with type 2
`diabetes inadequately controlled on metformin and glimepiride (sitagliptin, N=116; placebo, N=113), the
`
`

`

`JANUMETTM
`(sitagliptin/metformin HCl) Tablets
`
`97941 XX
`
`adverse reactions reported regardless of investigator assessment of causality in 25% of patients treated
`with sitagliptin and more commonly than in patients treated with placebo were: hypoglycemia (sitagliptin,
`16.4%; placebo, 0.9%) and headache (6.9%, 2.7%).
`No clinically meaningful changes in vital signs or in ECG (including in QTc interval) were observed
`with the combination of sitagliptin and metformin.
`The most common adverse experience in sitagliptin monotherapy reported regardless of investigator
`assessment of causality in 25% of patients and more commonly than in patients given placebo was
`nasopharyngitis.
`The most common (>5%) established adverse reactions due to initiation of metformin therapy are
`diarrhea, nausea/vomiting, flatulence, abdominal discomfort, indigestion, asthenia, and headache.
`laborafoxy 7793/5
`&7ag//p//}7
`The incidence of laboratory adverse reactions was similar in patients treated with sitagliptin and
`metformin (7.6%) compared to patients treated with placebo and metformin (8.7%).
`In most but not all
`studies, a small increase in white blood cell count (approximately 200 cells/microL difference in WBC vs
`placebo; mean baseline WBC approximately 6600 cells/microL) was observed due to a small increase in
`neutrophils. This change in laboratory parameters is not considered to be clinically relevant.
`Mafia/mm flyo’rocfi/or/o’e
`In controlled