`HIGHLIGHTS OF PRESORIBING INFORMATION
`
`These highlights do not include all the intonnation needed to use ONGLYZA
`safely and effectively. See full prescribing inionnation tor ONGLYZA.
`
`ONGLYZA” (saxagliptin) tablets, for oral use
`Initial U.S. Approval: 2009
`
`————————————————— RECENT MAJOR CHANGES—————————————————
`Warnings and Precautions
`4/2016
`Pancreatitis (5.1)
`4/2016
`Heart Failure (5.2)
`—————————————————lNDlCATlONS AND USAGE—————————————————
`ONGLYZA is a dipeptidyl peptidase-4 (DPP4) inhibitor indicated as an adjunct to diet
`and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
`(1.1, 14)
`Limitation of use:
`
`Not used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis.(1.2)
`0
`——————————————— DOSAGE AND ADMINISTRATION ———————————————
`0 Recommended dosage is 2.5 mg or 5 mg once daily taken regardless of meals. (2.1)
`0 Patients with moderate or severe renal impairment, or end-stage renal disease
`(CrC| :50 mUmin): Recommended dosage is 2.5 mg once daily regardless of
`meals. (2.2)
`
`0 Assess renal function before starting ONGLYZA and periodically thereafter. (2.2)
`0
`2.5 mg daily is
`recommended for patients also taking strong cytochrome
`P450 3A4/5 (CYP3A4/5) inhibitors (e.g., ketoconazole). (2.3, 7.1)
`——————————————— DOSAGE FORMS AND STRENGTHS ———————————————
`0 Tablets: 5 mg and 2.5 mg. (3)
`——————————————————CONTRA|ND|CAT|ONS——————————————————
`0 History of a serious hypersensitivity reaction (e.g., anaphylaxis, angioedema,
`exfoliative skin conditions) to ONGLYZA. (4)
`———————————————WARNlNGS AND PRECAUT1ONS———————————————
`0 Pancreatitis: If pancreatitis is suspected, promptly discontinue ONGLYZA. (5.1)
`0 Heart Failure: Consider the risks and benefits of ONGLYZA in patients who have
`known risk factors for heart failure. Monitor patients for signs and symptoms. (5.2)
`
`FULL PRESORIBING INFORMATION: OONTENTS*
`
`1
`
`2
`
`01-505
`
`6
`
`INDICATIONS AND USAGE
`1.1
`Monotherapy and Combination Therapy
`1.2
`Limitation of Use
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosage
`2.2
`Dosage in Patients with Renal Impairment
`2.3
`Dosage Adjustment with Concomitant Use of Strong CYP3A4/5 Inhibitors
`nsu In
`2.4
`|Conr|:_omitant Use with an Insulin secretagogue (e.g., Sulfonylurea) or with
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Pancreatitis
`5.2
`Heart Failure
`5.3
`Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`5.4
`Hypersensitivity Reactions
`5.5
`Severe and Disabling Arthralgia
`5.6 Macrovascular Outcomes
`ADVERSE REACTIONS
`6.1
`Clinical Trials Experience
`6.2
`Postmarketing Experience
`
`In add-on to sulfonylurea, add-on to insulin, and add-on to
`0 Hypoglycemia:
`metformin plus sulfonylurea trials, confirmed hypoglycemia was more common in
`patients treated with ONGLYZA compared to placebo. when used with an insulin
`secretagogue (e.g., sulfonylurea) or insulin, a lower dose of insulin secretagogue
`or insulin may be required to minimize the risk of hypoglycemia. (5.3, 6.1)
`0 Hypersensitivity-Related Events (e.g., urticaria, facial edema): More common
`in patients treated with ONGLYZA than in patients treated with placebo; and
`postmarketing reports of serious hypersensitivity reactions such as anaphylaxis,
`angioedema, and exfoliative skin conditions. Promptly discontinue ONGLYZA,
`assess for other potential causes, institute appropriate monitoring and treatment,
`and initiate alternative treatment for diabetes. (5.4, 6.1, 6.2)
`
`0 Arthralgia: Severe and disabling arthralgia has been reported in patients taking
`DPP4 inhibitors. Consider as a possible cause for severe joint pain and discontinue
`drug if appropriate. (5.5)
`
`0 Macrovascular Outcomes: There have been no clinical studies establishing
`conclusive evidence of macrovascular risk reduction with ONGLYZA or any other
`antidiabetic drug. (5.6)
`--------------- ——ADVERSE REACTIONS—————————————————
`0 Adverse reactions reported in 25% 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)
`
`0 Peripheral edema was reported more commonly in patients treated with the
`combination of ONGLYZA and a thiazolidinedione ('|'ZD) than in patients treated with
`the combination of placebo and TZD. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at
`1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
`------------------nnuc INTERACTIONS ------------------
`- Strong CYP3A4/5 inhibitors (e.g., ketoconazole): Coadministration with ONGLYZA
`significantly increases saxagliptin concentrations. Recommend limiting ONGLYZA
`dosage to 2.5 mg once daily. (2.3, 7.1)
`————————————————USE IN SPECIFIC POPULATIONS ————————————————
`0 No adequate and well-controlled studies in pregnant women. (8.1)
`See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
`
`Revised: 4/2016
`
`7
`
`8
`
`_L_L_LN-‘Q
`
`DRUG INTERACTIONS
`7.1
`Strong Inhibitors of CYP3A4/5 Enzymes
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`8.5
`Geriatric Use
`OVERDOSAGE
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3
`Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`14.1 Glycemic Efficacy Trials
`14.2 Renal Impairment
`14.3 Cardiovascular Safety Trial
`16 HOW SUPPUED/STORAGE AND HANDUNG
`17 PATIENT COUNSEUNG INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`Page 1 of 12
`
`Astraleneca Exhibit 2196
`
`Mylan v. Astraleneca
`lPR2015-01340
`
`AstraZeneca Exhibit 2196
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 12
`
`
`
`ONGLYZA® (saxagliptin)
`FULL PRESCRIBING INFORMATION
`1
`INDICATIONS AND USAGE
`1.1
`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
`limitation of Use
`ONGLYZA is not indicated for the treatment of type 1 diabetes mellitus or diabetic
`ketoacidosis, as it would not be effective in these settings.
`2
`DOSAGE AND ADMINISTRATION
`2.1
`Recommended Dosage
`The recommended dosage of ONGLYZA is 2.5 mg or 5 mg once daily taken regardless
`of meals. ONGLYZA tablets must not be split or cut.
`2.2
`Dosage in Patients with Renal lmpainnent
`No dosage adjustment for ONGLYZA is recommended for patients with mild renal
`impairment (creatinine clearance [CrCl] >50 mUmin).
`The dosage of ONGLYZA is 2.5 mg once daily (regardless of meals) for patients with
`moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring
`hemodialysis (creatinine clearance [CrCl] s50 mUmin) [see Clinical Pharmacology (12.3)
`and Clinical Studies (14.2)]. ONGLYZA should be administered following hemodialysis.
`ONGLYZA has not been studied in patients undergoing peritoneal dialysis.
`Because the dosage 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)].
`2.3
`Dosage Adjustment with Concomitant Use of Stmng CYP3A4I5 Inhibitors
`The dosage 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 (7.1) and Clinical Pharmacology (12.3)].
`2.4
`Concomitant Use with an Insulin Sccretagogue (e.g., Sulfonylurea) or
`with Insulin
`When ONGLYZA is used in combination with an insulin secretagogue (e.g., sulfonylurea)
`or with insulin, a lower dose of the insulin secretagogue or insulin may be required to
`minimize the risk of hypoglycemia [see Warnings and Precautions (5.3)].
`3
`DOSAGE FORMS AND STRENGTHS
`0 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.
`0 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
`ONGLYZA is contraindicated in patients with a history of a serious hypersensitivity
`reaction to ONGLYZA, such as anaphylaxis, angioedema, or exfoliative skin conditions
`[see Warnings and Precautions (5.4) and Adverse Reactions (6.2)].
`5
`WARNINGS AND PRECAUTIONS
`5.1
`Pancreatitis
`There have been postmarketing reports of acute pancreatitis in patients taking
`ONGLYZA. In a cardiovascular outcomes trial enrolling participants with established
`atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors for ASCVD
`(SAVOR trial), cases of definite acute pancreatitis were confirmed in 17 of 8240
`(0.2%) patients receiving ONGLYZA compared to 9 of 8173 (0.1%) receiving placebo.
`Preexisting risk factors for pancreatitis were identified in 88% (15/17) of those
`patients receiving ONGLYZA and in 100% (9/9) of those patients receiving placebo.
`After initiation of ONGLYZA, observe patients for signs and symptoms of pancreatitis.
`If pancreatitis is suspected, promptly discontinue ONGLYZA and initiate appropriate
`management. It is unknown whether patients with a history of pancreatitis are at
`increased risk for the development of pancreatitis while using ONGLYZA.
`5.2
`Heart Failure
`In a cardiovascular outcomes trial enrolling participants with established ASCVD or
`multiple risk factors for ASCVD (SAVOR trial), more patients randomized to ONGLYZA
`(289/8280, 3.5%) were hospitalized for heart failure compared to patients randomized
`to placebo (228/8212, 2.8%). In a time-to-first-event analysis the risk of hospitaliza-
`tion for heart failure was higher in the ONGLYZA group (estimated Hazard Ratio: 1.27;
`95% Cl: 1.07, 1.51). Subjects with a prior history of heart failure and subjects with
`renal impairment had a higher risk for hospitalization for heart failure, irrespective of
`treatment assignment.
`Consider the risks and benefits of ONGLYZA prior to initiating treatment in patients at a
`higher risk for heart failure. Observe 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 ONGLYZA.
`5.3
`Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin
`When ONGLYZA was used in combination with a sulfonylurea or with insulin,
`medications known to cause hypoglycemia, the incidence of confirmed 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 the insulin
`secretagogue or insulin may be required to minimize the risk of hypoglycemia when
`used in combination with ONGLYZA [see Dosage and Administration (2.4)].
`
`Page 2 of 12
`
`Hypersensitivity Reactions
`5.4
`There have been postmarketing reports of serious hypersensitivity reactions in
`patients treated with ONGLYZA. These reactions include anaphylaxis, angioedema,
`and exfoliative skin conditions. Onset of these reactions occurred within the first 3
`months after initiation of treatment with ONGLYZA, with some reports occurring after
`the first dose.
`If a serious hypersensitivity reaction is suspected, discontinue ONGLYZA, assess for
`other potential causes for the event, and institute alternative treatment for diabetes
`[see Adverse Reactions (6.2)].
`Use caution in a patient with a history of angioedema to another dipeptidyl
`peptidase-4 (DPP4) inhibitor because it is unknown whether such patients will be
`predisposed to angioedema with ONGLYZA.
`5.5
`Severe and Disabling Arthralgia
`There have been postmarketing reports of severe and disabling arthralgia in patients
`taking DPP4 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 DPP4 inhibitor. Consider DPP4
`inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`5.6
`Macrovascular Outcomes
`There have been no clinical studies establishing conclusive evidence of macrovascular
`risk reduction with ONGLYZA or any other antidiabetic drug.
`6
`ADVERSE REACTIONS
`The following serious adverse reactions are described below or elsewhere in the
`prescribing information:
`0 Pancreatitis [see Warnings and Precautions (5.1)]
`0 Heart Failure [see Warnings and Precautions (5.2)]
`0 Hypoglycemia with Concomitant Use of Sulfonylurea or Insulin [see Warnings and
`Precautions (5.3)]
`0 Hypersensitivity Reactions [see Warnings and Precautions (5.4)]
`6.1
`Clinical Trials Experience
`Because clinical trials are conducted under widely varying conditions, adverse reaction
`rates observed in the clinical trials of a dnrg cannot be directly compared to rates in the
`clinical trials of another drug and may not reflect the rates observed in practice.
`Adverse Reactions in Efficacy Trials
`The data in Table 1 are derived from a pool of 5 placebo-controlled clinical trials [see
`Clinical Studies (14)]. These data shown in the table reflect exposure of 882 patients
`to ONGLYZA and a mean duration of exposure to ONGLYZA of 21 weeks. The mean
`age of these patients was 55 years, 1.4 % were 75 years or older and 48.4% were
`male. The population was 67.5% White, 4.6% Black orAfrican American, 17.4% Asian,
`Other 10.5% and 9.8% were of Hispanic or Latino ethnicity. At baseline the population
`had diabetes for an average of 5.2 years and a mean HbA1c of 8.2%. Baseline
`estimated renal function was normal or mildly impaired (eGFR260mL/min/1.73m?) in
`91% of these patients.
`Table 1 shows common adverse reactions, excluding hypoglycemia, associated with
`the use of ONGLYZA. These adverse reactions occurred more commonly on ONGLYZA
`than on placebo and occurred in at least 5% of patients treated with ONGLYZA.
`Table 1:
`Adverse Reactions in Placebo-Controlled Trials* Reported in 25% of
`Patients Treated with ONGLYZA 5 mg and More Commonly than in
`Patients Treated with Placebo
`
`% of Patients
`
`ONGLYZA 5 mg
`N=882
`
`Placebo
`N=799
`
` “PW reSP"a*°rY "301 i"fe°*l°"
`
`Urinary tract infection n
`Headache
`11
`* 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.
`
`I
`
`In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the only adverse reaction
`reported at a rate 25% and more commonly than in patients treated with placebo.
`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 10 mg
`dosage is not an approved dosage. The incidence rate of fracture events in patients
`who received ONGLYZA did not increase overtime. Causality has not been established
`and nonclinical studies have not demonstrated adverse effects of ONGLYZA on bone.
`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.
`
`Page 2 of 12
`
`
`
`ONGLYZA® (saxagliptin)
`
`Discontinuation of therapy due to adverse reactions occurred in 2.2%, 3.3%, and 1.8%
`of subjects receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo, respectively.
`The most common adverse reactions (reported in at least 2 subjects treated with
`ONGLYZA 2.5 mg or at least 2 subjects 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%).
`Adverse Reactions with concomitant Use with Insulin
`In the add-on to insulin trial [see Clinical Studies (14.1)], the incidence of adverse
`events, including serious adverse events and discontinuations due to adverse events,
`was similar between ONGLYZA and placebo, except for confirmed hypoglycemia [see
`Adverse Reactions (6.1)].
`Hypoglycemia
`Adverse reactions of hypoglycemia were based on all reports of hypoglycemia. A
`concurrent glucose measurement was not required or was normal in some patients.
`Therefore,
`it is not possible to conclusively determine that all these reports reflect
`true hypoglycemia.
`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
`(1 0.1 %). 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
`[see Warnings and Precautions (5.3)]. The incidence of reported hypoglycemia for
`ONGLYZA 2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4%
`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% in patients given metformin alone.
`In the active-controlled trial comparing add-on therapy with ONGLYZA 5 mg to
`glipizide in patients inadequately controlled on metformin alone, the incidence of
`reported hypoglycemia was 3% (19 events in 13 patients) with ONGLYZA 5 mg
`versus 36.3% (750 events in 156 patients) with glipizide. Confirmed symptomatic
`hypoglycemia (accompanying fingerstick blood glucose :50 mg/dL) was reported
`in none of the ONGLYZA-treated patients and in 35 glipizide-treated patients (8.1%)
`(p<0.0001).
`incidence of reported hypoglycemia was
`In the add-on to insulin trial, the overall
`18.4% for ONGLYZA 5 mg and 19.9% for placebo. However,
`the incidence of
`confirmed symptomatic hypoglycemia (accompanying fingerstick blood glucose
`:50 mg/dL) was higher with ONGLYZA 5 mg (5.3%) versus placebo (3.3%).
`In the add-on to metformin plus sulfonylurea trial, the overall incidence of reported
`hypoglycemia was 10.1% for ONGLYZA 5 mg and 6.3% for placebo. Confirmed
`hypoglycemia was reported in 1.6% of the ONGLYZA-treated patients and in none of
`the placebo-treated patients [see Warnings and Precautions (5.3)].
`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 ONGLYZA-treated patient in this
`pooled analysis discontinued due to generalized urticaria and facial edema.
`Renal lmpainnent
`In the SAVOR trial, adverse reactions related to renal impairment, including laboratory
`changes (i.e., doubling of serum creatinine compared with baseline and serum
`creatinine >6 mg/dL), were reported in 5.8% (483/8280) of ONGLYZA-treated
`subjects and 5.1% (422/8212) of placebo-treated subjects. The most frequently
`reported adverse reactions included renal impairment (2.1% vs. 1.9%), acute renal
`failure (1.4% vs. 1.2%), and renal failure (0.8% vs. 0.9%),
`in the ONGLYZA versus
`placebo groups, respectively. From baseline to the end of treatment, there was a
`mean decrease in eGFR of 2.5 mUmin/1.73m2 for ONGLYZA-treated patients and a
`mean decrease of 2.4 mUmin/1.73m2 for placebo-treated patients. More subjects
`randomized to ONGLYZA (421/5227, 8.1%) compared to subjects randomized to
`placebo (344/5073, 6.8%) had downward shifts in eGFR from >50 mUmin (i.e.,
`normal or mild renal
`impairment) to :50 mUmin (i.e., moderate or severe renal
`impairment). The proportions of subjects with renal adverse reactions increased
`with worsening baseline renal function and increased age, regardless of treatment
`assignment.
`Infections
`In the unblinded, controlled, clinical trial database for ONGLYZA to date, there have
`been 6 (0.12%) reports of tuberculosis among the 4959 ONGLYZA-treated patients
`(1.1 per 1000 patient-years) compared to no reports of tuberculosis among the 2868
`comparator-treated patients. Two of these six cases were confirmed with laboratory
`testing. The remaining cases had limited information or had presumptive diagnoses
`of tuberculosis. None of the six cases occurred in the United States or in Western
`Europe. One case occurred in Canada in a patient originally from Indonesia who had
`recently visited Indonesia. The duration of treatment with ONGLYZA until report of
`tuberculosis ranged from 144 to 929 days. Post-treatment lymphocyte counts were
`consistently within the reference range for four cases. One patient had lymphopenia
`prior to initiation of ONGLYZA that remained stable throughout ONGLYZA treatment.
`The final patient had an isolated lymphocyte count below normal approximately four
`months prior to the report of tuberculosis. There have been no spontaneous reports
`of tuberculosis associated with ONGLYZA use. Causality has not been estimated
`
`Page 3 of 12
`
`3
`
`and there are too few cases to date to determine whether tuberculosis is related to
`ONGLYZA use.
`There has been one case of a potential opportunistic infection in the unblinded,
`controlled clinical trial database to date in an ONGLYZA-treated patient who developed
`suspected foodborne fatal salmonella sepsis after approximately 600 days of
`ONGLYZA therapy. There have been no spontaneous reports of opportunistic infections
`associated with ONGLYZA use.
`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 ONGLYZA. From a baseline mean absolute lymphocyte count of approximately
`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 s750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in the ONGLYZA 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
`10 mg dosage is not an approved dosage.
`In the SAVOR trial mean decreases of approximately 84 cells/microL with ONGLYZA
`relative to placebo was observed. The proportion of patients who experienced a
`decrease in lymphocyte counts to a count of $750 cells/microL was 1.6% (136/8280)
`and 1.0% (78/8212) on ONGLYZA and placebo respectively.
`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.
`
`Postmarketing Experience
`6.2
`Additional adverse reactions have been identified during post-approval use of
`ONGLYZA. 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 dnrg exposure.
`0 Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin
`conditions [see Contraindications (4) and Warnings and Precautions (5.4)].
`0 Acute pancreatitis [see Warnings and Precautions (5. 1)].
`0 Severe and disabling arthralgia [see Warnings and Precautions (5.5)].
`7
`DRUG INTERACTIONS
`7.1
`Strong Inhibitors of CYP3A4/5 Enzymes
`Ketoconazole significantly increased saxagliptin exposure. Similar significant
`increases in plasma concentrations of saxagliptin are anticipated with other
`strong CYP3A4/5 inhibitors (e.g., atazanavir, clarittrromycin,
`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
`USE IN SPECIFIC POPULATIOHS
`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 clearty 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 matemally toxic dose of
`200 mg/kg, or approximately 1432 and 992 times the MRHD.
`Coadministration of saxagliptin and metformin, to pregnant rats and rabbits during the
`period of organogenesis, was neither embryolethal nor teratogenic in either species
`when tested at doses yielding systemic exposures (AUC) up to 100 and 10 times the
`MRHD (saxagliptin 5 mg and metformin 2000 mg), respectively, in rats; and 249 and
`1.1 times the MRHDs in rabbits. In rats, minor developmental toxicity was limited to an
`increased incidence of wavy ribs; associated maternal toxicity was limited to weight
`decrements of 11% to 17% over the course of the study, and related reductions in
`maternal food consumption.
`In rabbits, coadministration was poorly tolerated in a
`subset of mothers (12 of 30), resulting in death, moribundity, or abortion. However,
`among surviving mothers with evaluable litters, matemal
`toxicity was limited to
`marginal reductions in body weight over the course of gestation days 21 to 29; and
`associated developmental toxicity in these litters was limited to fetal body weight
`decrements of 7%, and a low incidence of delayed ossification of the fetal hyoid.
`
`Page 3 of 12
`
`
`
`ONGLYZA® (saxagliptin)
`
`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 matemally
`toxic doses (exposures 21629 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 dmg concentrations. It is not known whether saxagliptin is secreted in human
`milk. Because many 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 under 18 years of age have
`not been established. Additionally, studies characterizing the pharmacokinetics of
`ONGLYZA in pediatric patients have not been performed.
`8.5
`Geriatric Use
`In the seven, double—blind, controlled clinical safety and efficacy trials of ONGLYZA, a
`total of 4751 (42.0%) of the 11301 patients randomized to ONGLYZA were 65 years
`and over, and 1210 (10.7%) were 75 years and over. No overall differences in safety or
`effectiveness were observed between subjects 265 years old and younger subjects. While
`this clinical experience has not identified differences in responses between the elderty
`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)].
`8.6
`Renal lmpainnent
`In a 12-week randomized placebo-controlled trial, ONGLYZA 2.5 mg was administered
`to 85 subjects with moderate (n=48) or severe (n=18) renal impairment or end-stage
`renal disease (ESRD) (n=19) [see Clinical Studies (14)]. The incidence of adverse
`events, including serious adverse events and discontinuations due to adverse events,
`was similar between ONGLYZA and placebo. The overall
`incidence of reported
`hypoglycemia was 20% among subjects treated with ONGLYZA 2.5 mg and 22%
`among subjects treated with placebo. Four ONGLYZA-treated subjects (4.7%) and
`three placebo-treated subjects (3.5%) reported at least one episode of confirmed
`symptomatic hypoglycemia (accompanying fingerstick glucose :50 mg/dL).
`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.
`Saxagliptin monohydrate is described chemically as (1 S,3S,5.$)-2-[(2$)-2-Amino-
`2-(3-hydroxytricyc|o[3.3.1.13~7]dec-1-y|)acety|]-2-azabicyc|o[3.1.0]hexane-
`3-carbonitrile, monohydrate or (1 3,3S56)-2-[(26)-2-Amino-2-(3-hydroxyadamantan-1-yl)
`acety|]-2-azabicyc|o[3.1.0]hexane-3-carbonitrile hydrate. The empirical
`formula is
`C18H25N302-H20 and the molecular weight is 333.43. The structural formula is:
`
`HO
`
`H2N
`
`- H20
`
`0
`
`CN
`
`Saxagliptin monohydrate is a white to light yellow or light brown, non-hygroscopic,
`crystalline powder. It is sparingly soluble in water at 24°C 1 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
`GIJNICAL 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 DPP4 enzyme within minutes. GLP-1 also lowers glucagon
`secretion from pancreatic alpha c