`These highlights do not include all the information needed to use
`ONGLYZA safely and effectively. See full prescribing information for
`ONGLYZA.
`ONGLYZA (saxagliptin) tablets
`Initial U.S. Approval: 2009
`---------------------------INDICATIONS AND USAGE----------------------------
`ONGLYZA is a dipeptidyl peptidase-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:
`•
`
`Should not be used for the treatment of type 1 diabetes mellitus or
`diabetic ketoacidosis. (1.2)
`
`• Has not been studied in combination with insulin. (1.2)
`
`------------------------DOSAGE AND ADMINISTRATION----------------------
`•
`
`The recommended dose is 2.5 mg or 5 mg once daily taken regardless of
`meals. (2.1)
`2.5 mg daily is recommended for patients with moderate or severe renal
`
`impairment, or end-stage renal disease (CrCl ≤50 mL/min). Assess renal
`
`function prior to initiation of ONGLYZA and periodically thereafter.
`
`(2.2)
`2.5 mg daily is recommended for patients also taking strong cytochrome
`
`P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.2)
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`•
`
`Tablets: 5 mg and 2.5 mg (3)
`
`------------------------------CONTRAINDICATIONS-------------------------------
`• None. (4)
`
`------------------------WARNINGS AND PRECAUTIONS-----------------------
`• When used with an insulin secretagogue (e.g., sulfonylurea), a lower
`
`dose of the insulin secretagogue may be required to reduce the risk of
`hypoglycemia. (5.1)
`
`
`•
`
`
`•
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`
`1
`INDICATIONS AND USAGE
`
`
`Monotherapy and Combination Therapy
`1.1
`
`
`Important Limitations of Use
`1.2
`
`DOSAGE AND ADMINISTRATION
`
`
`
`2.1
`Recommended Dosing
`
`
`Patients with Renal Impairment
`2.2
`
`
`2.3
`Strong CYP3A4/5 Inhibitors
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`
`Use with Medications Known to Cause Hypoglycemia
`5.1
`
`
`5.2
`Macrovascular Outcomes
`
`ADVERSE REACTIONS
`
`
`6.1
`Clinical Trials Experience
`
`DRUG INTERACTIONS
`
`
`7.1
`Inducers of CYP3A4/5 Enzymes
`
`
`Inhibitors of CYP3A4/5 Enzymes
`7.2
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.3
`Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`2
`
`
`3
`
`4
`
`5
`
`
`6
`
`7
`
`
`8
`
`•
`
`
`•
`
`
`There have been no clinical studies establishing conclusive evidence of
`macrovascular risk reduction with ONGLYZA or any other antidiabetic
`
`drug. (5.2)
`
`-------------------------------ADVERSE REACTIONS------------------------------
`• Adverse reactions reported in ≥5% of patients treated with ONGLYZA
`
`
`and more commonly than in patients treated with placebo are: upper
`
`respiratory tract infection, urinary tract infection, and headache. (6.1)
`Peripheral edema was reported more commonly in patients treated with
`
`the combination of ONGLYZA and a thiazolidinedione (TZD) than in
`patients treated with the combination of placebo and TZD. (6.1)
`
`• Hypoglycemia was reported more commonly in patients treated with the
`
`
`combination of ONGLYZA and sulfonylurea than in patients treated
`with the combination of placebo and sulfonylurea. (6.1)
`
`• Hypersensitivity-related events (e.g., urticaria, facial edema) were
`
`
`reported more commonly in patients treated with ONGLYZA than in
`patients treated with placebo. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers
`Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch
`
`--------------------------------DRUG INTERACTIONS-----------------------------
`• Coadministration with strong CYP3A4/5 inhibitors (e.g., ketoconazole)
`
`
`significantly increases saxagliptin concentrations. Recommend limiting
`
`ONGLYZA dose to 2.5 mg once daily. (2.3, 7.2)
`------------------------USE IN SPECIFIC POPULATIONS-----------------------
`•
`
`There are no adequate and well-controlled studies in pregnant women.
`
`(8.1)
`Safety and effectiveness of ONGLYZA in pediatric patients below the
`age of 18 have not been established. (8.4)
`
`See 17 for PATIENT COUNSELING INFORMATION and FDA-
`
`approved patient labeling
`
`•
`
`
`Revised: 07/2009
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`
`Geriatric Use
`8.5
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`12.2
`Pharmacodynamics
`
`
`12.3
`Pharmacokinetics
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`13.2
`Animal Toxicology
`
`CLINICAL STUDIES
`
`
`14.1 Monotherapy
`
`
`14.2 Combination Therapy
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`
`17.1
`Instructions
`
`
`17.2
`Laboratory Tests
`
`*Sections or subsections omitted from the full prescribing information
`are not listed
`
`
`13
`
`
`14
`
`
`16
`
`17
`
`1
`
`
`
`
`
`FULL PRESCRIBING INFORMATION
`
`1
`
`1.1
`
`INDICATIONS AND USAGE
`
`
`Monotherapy and Combination Therapy
`
`
`
` ONGLYZA is indicated as an adjunct to diet and exercise to improve glycemic control in adults
`with type 2 diabetes mellitus. [See Clinical Studies (14).]
`
`1.2
`
`Important Limitations of Use
`
`ONGLYZA should not be used for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis, as it would not be effective in these settings.
`
`ONGLYZA has not been studied in combination with insulin.
`
`2
`
`2.1
`
`DOSAGE AND ADMINISTRATION
`
`Recommended Dosing
`
`The recommended dose of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless of meals.
`
`2.2
`
`Patients with Renal Impairment
`
`No dosage adjustment for ONGLYZA is recommended for patients with mild renal impairment
`(creatinine clearance [CrCl] >50 mL/min).
`
`The dose of ONGLYZA is 2.5 mg once daily for patients with moderate or severe renal
`impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance
`
` [CrCl] ≤50 mL/min). ONGLYZA should be administered following hemodialysis. ONGLYZA
`has not been studied in patients undergoing peritoneal dialysis.
`
` Because the dose of ONGLYZA should be limited to 2.5 mg based upon renal function,
`
`assessment of renal function is recommended prior to initiation of ONGLYZA and periodically
`thereafter. Renal function can be estimated from serum creatinine using the Cockcroft-Gault
`formula or Modification of Diet in Renal Disease formula. [See Clinical Pharmacology (12.3).]
`
`2
`
`
`
`
`
`2.3
`
`
`
` Strong CYP3A4/5 Inhibitors
`
` The dose of ONGLYZA is 2.5 mg once daily when coadministered with strong cytochrome
`
`P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole, atazanavir, clarithromycin, indinavir,
`itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin). [See Drug
`
` Interactions (7.2) and Clinical Pharmacology (12.3).]
`
`DOSAGE FORMS AND STRENGTHS
`3
`• ONGLYZA (saxagliptin) 5 mg tablets are pink, biconvex, round, film-coated tablets with “5”
`
`printed on one side and “4215” printed on the reverse side, in blue ink.
`• ONGLYZA (saxagliptin) 2.5 mg tablets are pale yellow to light yellow, biconvex, round,
`
`
`film-coated tablets with “2.5” printed on one side and “4214” printed on the reverse side, in
`blue ink.
`CONTRAINDICATIONS
`
`4
`
`None.
`
`5
`
`5.1
`
`WARNINGS AND PRECAUTIONS
`
`Use with Medications Known to Cause Hypoglycemia
`
`Insulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore, a lower dose of the
`
`insulin secretagogue may be required to reduce the risk of hypoglycemia when used in
`combination with ONGLYZA. [See Adverse Reactions (6.1).]
`
`
`5.2
`
`Macrovascular Outcomes
`
`There have been no clinical studies establishing conclusive evidence of macrovascular risk
`
`reduction with ONGLYZA or any other antidiabetic drug.
`
`6
`
`6.1
`
`ADVERSE REACTIONS
`
`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.
`3
`
`
`
`
`
`
`Monotherapy and Add-On Combination Therapy
`
`In two placebo-controlled monotherapy trials of 24-weeks duration, patients were treated with
`ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo. Three 24-week, placebo-
`controlled, add-on combination therapy trials were also conducted: one with metformin, one with
`
`
`a thiazolidinedione (pioglitazone or rosiglitazone), and one with glyburide. In these three trials,
`
`patients were randomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg
`daily, or placebo. A saxagliptin 10 mg treatment arm was included in one of the monotherapy
`trials and in the add-on combination trial with metformin.
`
`
`In a prespecified pooled analysis of the 24-week data (regardless of glycemic rescue) from the
`two monotherapy trials, the add-on to metformin trial, the add-on to thiazolidinedione (TZD)
`trial, and the add-on to glyburide trial, the overall incidence of adverse events in patients treated
`
`with ONGLYZA 2.5 mg and ONGLYZA 5 mg was similar to placebo (72.0% and 72.2% versus
`70.6%, respectively). Discontinuation of therapy due to adverse events occurred in 2.2%, 3.3%,
`
`and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively.
`
`The most common adverse events (reported in at least 2 patients treated with ONGLYZA 2.5 mg
`
`or at least 2 patients treated with ONGLYZA 5 mg) associated with premature discontinuation of
`therapy included lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2% and 0.3%
`versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%), and blood creatine
`phosphokinase increased (0.1% and 0.2% versus 0%). The adverse reactions in this pooled
`
`analysis reported (regardless of investigator assessment of causality) in ≥5% of patients treated
`
`with ONGLYZA 5 mg, and more commonly than in patients treated with placebo are shown in
`Table 1.
`
`4
`
`
`
`
`
`
`
`
`
`
`Table 1:
`
`Adverse Reactions (Regardless of Investigator Assessment of
`Causality) in Placebo-Controlled Trials* Reported in ≥5% of
`
`Patients Treated with ONGLYZA 5 mg and More Commonly than
`in Patients Treated with Placebo
` Number (%) of Patients
`Placebo
`ONGLYZA 5 mg
`
` N=799
`
` N=882
`61 (7.6)
`68 (7.7)
`Upper respiratory tract infection
`49 (6.1)
`60 (6.8)
`Urinary tract infection
`47 (5.9)
`57 (6.5)
`Headache
`* The 5 placebo-controlled trials include two monotherapy trials and one add-on combination therapy trial with
`
`
`
`each of the following: metformin, thiazolidinedione, or glyburide. Table shows 24-week data regardless of
`glycemic rescue.
`
`In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction
`reported at a rate ≥5% and more commonly than in patients treated with placebo.
`
`In this pooled analysis, adverse reactions that were reported in ≥2% of patients treated with
`ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequently compared to placebo
`included: sinusitis (2.9% and 2.6% versus 1.6%, respectively), abdominal pain (2.4% and 1.7%
`
` versus 0.5%), gastroenteritis (1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus
`1.3%).
`
`In the add-on to TZD trial, the incidence of peripheral edema was higher for ONGLYZA 5 mg
`versus placebo (8.1% and 4.3%, respectively). The incidence of peripheral edema for
`
` ONGLYZA 2.5 mg was 3.1%. None of the reported adverse reactions of peripheral edema
`
` resulted in study drug discontinuation. Rates of peripheral edema for ONGLYZA 2.5 mg and
`ONGLYZA 5 mg versus placebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and
`
` 2.1% versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus 2.2% given
`as add-on therapy to glyburide.
`
`The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years, respectively, for
`
` ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) and placebo. The incidence rate of
`
` fracture events in patients who received ONGLYZA did not increase over time. Causality has
`not been established and nonclinical studies have not demonstrated adverse effects of saxagliptin
`on bone.
`
`
`5
`
`
`
`
`
`An event of thrombocytopenia, consistent with a diagnosis of idiopathic thrombocytopenic
`purpura, was observed in the clinical program. The relationship of this event to ONGLYZA is
`not known.
`
`Adverse Reactions Associated with ONGLYZA Coadministered with Metformin in
`Treatment-Naive Patients with Type 2 Diabetes
`
`Table 2 shows the adverse reactions reported (regardless of investigator assessment of causality)
`in ≥5% of patients participating in an additional 24-week, active-controlled trial of
`coadministered ONGLYZA and metformin in treatment-naive patients.
`
`Table 2:
`
`Initial Therapy with Combination of ONGLYZA and Metformin in
`Treatment-Naive Patients: Adverse Reactions Reported (Regardless
`of Investigator Assessment of Causality) in ≥5% of Patients Treated
`with Combination Therapy of ONGLYZA 5 mg Plus Metformin
`(and More Commonly than in Patients Treated with Metformin
`Alone)
`
`
`
`Number (%) of Patients
`
`Metformin*
`ONGLYZA 5 mg + Metformin*
`
`
`N=328
`N=320
`
`
`17 (5.2)
`24 (7.5)
`Headache
`13 (4.0)
`22 (6.9)
`Nasopharyngitis
`* Metformin was initiated at a starting dose of 500 mg daily and titrated up to a maximum of 2000 mg daily.
`
`
`
`
`
`Hypoglycemia
`
`Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent
`
` glucose measurement was not required. In the add-on to glyburide study, the overall incidence of
`
` reported hypoglycemia was higher for ONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and
`14.6%) versus placebo (10.1%). The incidence of confirmed hypoglycemia in this study, defined
`as symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL, was
`
` 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and 0.7% for placebo. The
`incidence of reported hypoglycemia for ONGLYZA 2.5 mg and ONGLYZA 5 mg versus
`placebo given as monotherapy was 4.0% and 5.6% versus 4.1%, respectively, 7.8% and 5.8%
`versus 5% given as add-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given as add-
`on therapy to TZD. The incidence of reported hypoglycemia was 3.4% in treatment-naive
`patients given ONGLYZA 5 mg plus metformin and 4.0% in patients given metformin alone.
`
`6
`
`
`
`
`
`Hypersensitivity Reactions
`
`Hypersensitivity-related events, such as urticaria and facial edema in the 5-study pooled analysis
`up to Week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received ONGLYZA
`2.5 mg, ONGLYZA 5 mg, and placebo, respectively. None of these events in patients who
`received ONGLYZA required hospitalization or were reported as life-threatening by the
`investigators. One saxagliptin-treated patient in this pooled analysis discontinued due to
`generalized urticaria and facial edema.
`
`Vital Signs
`
`No clinically meaningful changes in vital signs have been observed in patients treated with
`ONGLYZA.
`
`
`Laboratory Tests
`
`Absolute Lymphocyte Counts
`
`There was a dose-related mean decrease in absolute lymphocyte count observed with
`lymphocyte count of approximately
`ONGLYZA. From a baseline mean absolute
`
`
` 2200 cells/microL, mean decreases of approximately 100 and 120 cells/microL with ONGLYZA
`5 mg and 10 mg, respectively, relative to placebo were observed at 24 weeks in a pooled analysis
`
` of five placebo-controlled clinical studies. Similar effects were observed when ONGLYZA 5 mg
`was given in initial combination with metformin compared to metformin alone. There was no
`difference observed for ONGLYZA 2.5 mg relative to placebo. The proportion of patients who
`
` were reported to have a lymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4%
`in the saxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In most patients,
`recurrence was not observed with repeated exposure to ONGLYZA although some patients had
`recurrent decreases upon rechallenge that led to discontinuation of ONGLYZA. The decreases in
`lymphocyte count were not associated with clinically relevant adverse reactions.
`
`The clinical significance of this decrease in lymphocyte count relative to placebo is not known.
`When clinically indicated, such as in settings of unusual or prolonged infection, lymphocyte
`count should be measured. The effect of ONGLYZA on lymphocyte counts in patients with
`lymphocyte abnormalities (e.g., human immunodeficiency virus) is unknown.
`
`7
`
`
`
`
`
`Platelets
`
`ONGLYZA did not demonstrate a clinically meaningful or consistent effect on platelet count in
`the six, double-blind, controlled clinical safety and efficacy trials.
`
`7
`
`7.1
`
`DRUG INTERACTIONS
`
`Inducers of CYP3A4/5 Enzymes
`
`Rifampin significantly decreased saxagliptin exposure with no change in the area under the time-
`
` concentration curve (AUC) of its active metabolite, 5-hydroxy saxagliptin. The plasma
`
` dipeptidyl peptidase-4 (DPP4) activity inhibition over a 24-hour dose interval was not affected
`
` by rifampin. Therefore, dosage adjustment of ONGLYZA is not recommended. [See Clinical
`
` Pharmacology (12.3).]
`
`7.2
`
`Inhibitors of CYP3A4/5 Enzymes
`
`Moderate Inhibitors of CYP3A4/5
`
` Diltiazem increased the exposure of saxagliptin. Similar increases in plasma concentrations of
`
`saxagliptin are anticipated in the presence of other moderate CYP3A4/5 inhibitors (e.g.,
`amprenavir, aprepitant, erythromycin, fluconazole, fosamprenavir, grapefruit
`juice, and
`
` verapamil); however, dosage adjustment of ONGLYZA is not recommended. [See Clinical
`
` Pharmacology (12.3).]
`
`Strong Inhibitors of CYP3A4/5
`
`Ketoconazole significantly increased saxagliptin exposure. Similar significant increases in
`plasma concentrations of saxagliptin are anticipated with other strong CYP3A4/5 inhibitors (e.g.,
`atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir,
`and telithromycin). The dose of ONGLYZA should be limited to 2.5 mg when coadministered
`
`with a strong CYP3A4/5 inhibitor. [See Dosage and Administration (2.3) and Clinical
`Pharmacology (12.3).]
`
`
`8
`
`
`
`
`
`8
`
`USE IN SPECIFIC POPULATIONS
`
`8.1
`
`
`Pregnancy
`
`Pregnancy Category B
`
` There are no adequate and well-controlled studies in pregnant women. Because animal
`
`reproduction studies are not always predictive of human response, ONGLYZA, like other
`antidiabetic medications, should be used during pregnancy only if clearly needed.
`
` Saxagliptin was not teratogenic at any dose tested when administered to pregnant rats and rabbits
`
`during periods of organogenesis. Incomplete ossification of the pelvis, a form of developmental
`delay, occurred in rats at a dose of 240 mg/kg, or approximately 1503 and 66 times human
`exposure to saxagliptin and the active metabolite, respectively, at the maximum recommended
`human dose (MRHD) of 5 mg. Maternal toxicity and reduced fetal body weights were observed
`at 7986 and 328 times the human exposure at the MRHD for saxagliptin and the active
`
` metabolite, respectively. Minor skeletal variations in rabbits occurred at a maternally toxic dose
`of 200 mg/kg, or approximately 1432 and 992 times the MRHD. When administered to rats in
`combination with metformin, saxagliptin was not teratogenic nor embryolethal at exposures 21
`times the saxagliptin MRHD. Combination administration of metformin with a higher dose of
`saxagliptin (109 times the saxagliptin MRHD) was associated with craniorachischisis (a rare
`neural tube defect characterized by incomplete closure of the skull and spinal column) in two
`fetuses from a single dam. Metformin exposures in each combination were 4 times the human
`exposure of 2000 mg daily.
`
`Saxagliptin administered to female rats from gestation day 6 to lactation day 20 resulted in
`decreased body weights in male and female offspring only at maternally toxic doses (exposures
`≥1629 and 53 times saxagliptin and its active metabolite at the MRHD). No functional or
`behavioral toxicity was observed in offspring of rats administered saxagliptin at any dose.
`
`Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.
`
`8.3
`
`Nursing Mothers
`
` Saxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratio with plasma drug
`
`concentrations. It is not known whether saxagliptin is secreted in human milk. Because many
`
`9
`
`
`
`
`
`drugs are secreted in human milk, caution should be exercised when ONGLYZA is administered
`to a nursing woman.
`
`8.4
`
`Pediatric Use
`
`Safety and effectiveness of ONGLYZA in pediatric patients have not been established.
`
`8.5
`
`Geriatric Use
`
`In the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA, 634 (15.3%)
`of the 4148 randomized patients were 65 years and over, and 59 (1.4%) patients were 75 years
`and over. No overall differences in safety or effectiveness were observed between patients ≥65
`years old and the younger patients. While this clinical experience has not identified differences
`in responses between the elderly and younger patients, greater sensitivity of some older
`individuals cannot be ruled out.
`
`Saxagliptin and its active metabolite are eliminated in part by the kidney. Because elderly
`patients are more likely to have decreased renal function, care should be taken in dose selection
`in the elderly based on renal function. [See Dosage and Administration (2.2) and Clinical
`Pharmacology (12.3).]
`
`10
`
`OVERDOSAGE
`
`In a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthy subjects at
`
` doses up to 400 mg daily for 2 weeks (80 times the MRHD) had no dose-related clinical adverse
`reactions and no clinically meaningful effect on QTc interval or heart rate.
`
`In the event of an overdose, appropriate supportive treatment should be initiated as dictated by
`the patient’s clinical status. Saxagliptin and its active metabolite are removed by hemodialysis
`(23% of dose over 4 hours).
`
`11
`
`DESCRIPTION
`
`Saxagliptin is an orally-active inhibitor of the DPP4 enzyme.
`
`(1S,3S,5S)-2-[(2S)-2-Amino-2-(3
`is described chemically as
`Saxagliptin monohydrate
`hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile,
`(1S,3S,5S)-2-[(2S)-2-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2
`monohydrate
`or
`10
`
`
`
`
`
`azabicyclo[3.1.0]hexane-3-carbonitrile hydrate. The empirical formula is C18H25N3O2•H2O and
`the molecular weight is 333.43. The structural formula is:
`
`
`
`
`
`Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic, crystalline
`powder. It is sparingly soluble in water at 24°C ± 3°C, slightly soluble in ethyl acetate, and
`soluble in methanol, ethanol, isopropyl alcohol, acetonitrile, acetone, and polyethylene glycol
`400 (PEG 400).
`
`Each film-coated tablet of ONGLYZA for oral use contains either 2.79 mg saxagliptin
`hydrochloride (anhydrous) equivalent to 2.5 mg saxagliptin or 5.58 mg saxagliptin hydrochloride
`(anhydrous) equivalent to 5 mg saxagliptin and the following inactive ingredients: lactose
`monohydrate, microcrystalline cellulose, croscarmellose sodium, and magnesium stearate. In
`
` addition, the film coating contains the following inactive ingredients: polyvinyl alcohol,
`
` polyethylene glycol, titanium dioxide, talc, and iron oxides.
`
`12
`
`CLINICAL PHARMACOLOGY
`
`12.1
`
`Mechanism of Action
`
`Increased concentrations of the incretin hormones such as glucagon-like peptide-1 (GLP-1) and
`
` glucose-dependent insulinotropic polypeptide (GIP) are released into the bloodstream from the
`small intestine in response to meals. These hormones cause insulin release from the pancreatic
` beta cells in a glucose-dependent manner but are inactivated by the dipeptidyl peptidase-4
`
`(DPP4) enzyme within minutes. GLP-1 also lowers glucagon secretion from pancreatic alpha
`
`cells, reducing hepatic glucose production. In patients with type 2 diabetes, concentrations of
`GLP-1 are reduced but the insulin response to GLP-1 is preserved. Saxagliptin is a competitive
`DPP4 inhibitor that slows the inactivation of the incretin hormones, thereby increasing their
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`11
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`bloodstream concentrations and reducing fasting and postprandial glucose concentrations in a
`glucose-dependent manner in patients with type 2 diabetes mellitus.
`
`12.2
`
`Pharmacodynamics
`
` In patients with type 2 diabetes mellitus, administration of ONGLYZA inhibits DPP4 enzyme
`
`activity for a 24-hour period. After an oral glucose load or a meal, this DPP4 inhibition resulted
`in a 2- to 3-fold increase in circulating levels of active GLP-1 and GIP, decreased glucagon
`concentrations, and increased glucose-dependent insulin secretion from pancreatic beta cells. The
`
` rise in insulin and decrease in glucagon were associated with lower fasting glucose
`concentrations and reduced glucose excursion following an oral glucose load or a meal.
`
`
`
` Cardiac Electrophysiology
`
`
` In a randomized, double-blind, placebo-controlled, 4-way crossover, active comparator study
`
` using moxifloxacin in 40 healthy subjects, ONGLYZA was not associated with clinically
`
` meaningful prolongation of the QTc interval or heart rate at daily doses up to 40 mg (8 times the
`MRHD).
`
`12.3
`
`Pharmacokinetics
`
`The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin were
`similar in healthy subjects and in patients with type 2 diabetes mellitus. The Cmax and AUC
`
`values of saxagliptin and its active metabolite increased proportionally in the 2.5 to 400 mg dose
`
`range. Following a 5 mg single oral dose of saxagliptin to healthy subjects, the mean plasma
`AUC values for saxagliptin and its active metabolite were 78 ng•h/mL and 214 ng•h/mL,
`respectively. The corresponding plasma Cmax values were 24 ng/mL and 47 ng/mL, respectively.
`The average variability (%CV) for AUC and Cmax for both saxagliptin and its active metabolite
`was less than 25%.
`
`No appreciable accumulation of either saxagliptin or its active metabolite was observed with
`repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in
`the clearance of saxagliptin and its active metabolite over 14 days of once-daily dosing with
`saxagliptin at doses ranging from 2.5 to 400 mg.
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`Absorption
`
`The median time to maximum concentration (Tmax) following the 5 mg once daily dose was 2
`hours for saxagliptin and 4 hours for its active metabolite. Administration with a high-fat meal
`resulted in an increase in Tmax of saxagliptin by approximately 20 minutes as compared to fasted
`
`conditions. There was a 27% increase in the AUC of saxagliptin when given with a meal as
`compared to fasted conditions. ONGLYZA may be administered with or without food.
`
`Distribution
`
` The in vitro protein binding of saxagliptin and its active metabolite in human serum is negligible.
`
`Therefore, changes in blood protein levels in various disease states (e.g., renal or hepatic
`impairment) are not expected to alter the disposition of saxagliptin.
`
`Metabolism
`
`The metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5).
`The major metabolite of saxagliptin is also a DPP4 inhibitor, which is one-half as potent as
`
`
`saxagliptin. Therefore, strong CYP3A4/5 inhibitors and inducers will alter the pharmacokinetics
`
`
`of saxagliptin and its active metabolite. [See Drug Interactions (7).]
`
`Excretion
`
`Saxagliptin is eliminated by both renal and hepatic pathways. Following a single 50 mg dose of
`14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its
`active metabolite, and total radioactivity, respectively. The average renal clearance of saxagliptin
`(∼230 mL/min) was greater than the average estimated glomerular filtration rate (∼120 mL/min),
`suggesting some active renal excretion. A total of 22% of the administered radioactivity was
`
` recovered in feces representing the fraction of the saxagliptin dose excreted in bile and/or
`unabsorbed drug from the gastrointestinal tract. Following a single oral dose of ONGLYZA
`
` 5 mg to healthy subjects, the mean plasma terminal half-life (t1/2) for saxagliptin and its active
`metabolite was 2.5 and 3.1 hours, respectively.
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`Specific Populations
`
`Renal Impairment
`
`A single-dose, open-label study was conducted to evaluate the pharmacokinetics of saxagliptin
`
`(10 mg dose) in subjects with varying degrees of chronic renal impairment (N=8 per group)
`compared to subjects with normal renal function. The study included patients with renal
`impairment classified on the basis of creatinine clearance as mild (>50 to ≤80 mL/min),
`moderate (30 to ≤50 mL/min), and severe (<30 mL/min), as well as patients with end-stage renal
`disease on hemodialysis. Creatinine clearance was estimated from serum creatinine based on the
`Cockcroft-Gault formula:
`CrCl = [140 − age (years)] × weight (kg) {× 0.85 for female patients}
`[72 × serum creatinine (mg/dL)]
`
`
`The degree of renal impairment did not affect the Cmax of saxagliptin or its active metabolite. In
`
`
`
` subjects with mild renal impairment, the AUC values of saxagliptin and its active metabolite
`
` were 20% and 70% higher, respectively, than AUC values in subjects with normal renal
`function. Because increases of this magnitude are not considered to be clinically relevant, dosage
`adjustment in patients with mild renal impairment is not recommended. In subjects with
`
` moderate or severe renal impairment, the AUC values of saxagliptin and its active metabolite
`were up to 2.1- and 4.5-fold higher, respectively, than AUC values in subjects with normal renal
`function. To achieve plasma exposures of saxagliptin and its active metabolite similar to those in
`patients with normal renal function, the recommended dose is 2.5 mg once daily in patients with
`
` moderate and severe renal impairment, as well as in patients with end-stage renal disease
`requiring hemodialysis. Saxagliptin is removed by hemodialysis.
`
`Hepatic Impairment
`
`In subjects with hepatic impairment (Child-Pugh classes A, B, and C), mean Cmax and AUC of
`saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls
`
`following administration of a single 10 mg dose of saxagliptin. The corresponding Cmax and
`
`AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy
`matched controls. These differences are not considered to be clinically meaningful. No dosage
`adjustment is recommended for patients with hepatic impairment.
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`Body Mass Index
`
`No dosage adjustment is recommended based on body mass index (BMI) which was not
`identified as a significant covariate on the apparent clearance of saxagliptin or its active
`metabolite in the population pharmacokinetic analysis.
`
`Gender
`
`No dosage adjustment is recommended based on gender. There were no differences observed in
`
` saxagliptin pharmacokinetics between males and females. Compared to males, females had
`
` approximately 25% higher exposure values for the active metabolite than males, but this
`difference is unlikely to be of clinical relevance. Gender was not identified as a significant
`covariate on the apparent clearance of saxagliptin and its active metabolite in the population
`pharmacokinetic analysis.
`
`Geriatric
`
`No dosage adjustment is recommended based on age alone. Elderly subjects (65-80 years) had
`23% and 59% higher geometric mean Cmax and geometric mean AUC values, respectively, for
`saxagliptin than young subjects (18-40 years). Differences in active metabolite pharmacokinetics
`between elderly and young subjects generally reflected the differences observed in saxagliptin
`pharmacokinetics. The difference between the pharmacokinetics of saxagliptin and the active
`
`metabolite in young and elderly subjects is likely due to multiple factors including declining
`renal function and metabolic capacity with increasing age. Age was not identified as a significant
`
`covariate on the apparent clearance of saxagliptin and its active metabolite in the population
`pharmacokinetic analysis.
`
`Pediatric
`
`Studies characterizing the pharmacokinetics of saxagliptin in pediatric patients have not been
`performed.
`
`Race and Ethnicity
`
`No dosage adjustment is recommended based on race. The population pharmacokinetic analysis
`compared the pharmacokinetics of saxagliptin and its active metabolite in 309 Caucasian
`subjects with 105 non-Caucasian subjects (consisting of six racial groups). No significant
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`difference in the pharmacokinetics of saxagliptin and its active metabolite were detected be