HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use
`
`
` NESINA safely and effectively. See full prescribing information for
`
`
` NESINA.
`
` NESINA (alogliptin) tablets
`
` Initial U.S. Approval: 2013
`
`
`
`
`
`
`
`
`
`---------------------------RECENT MAJOR CHANGES--------------------------­
`
` 8/2015
`
`
`
` Warnings and Precautions (5.5)
`
` ----------------------------INDICATIONS AND USAGE---------------------------­
`
`
`
`
` NESINA is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an
` adjunct to diet and exercise to improve glycemic control in adults with
`
`
` type 2 diabetes mellitus. (1.1, 14)
`
`
` Limitation of Use: Not for treatment of type 1 diabetes or diabetic
`
`
` ketoacidosis. (1.2)
`
`
`
`
`
`
` ------------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
` The recommended dose in patients with normal renal function or
`•
` mild renal impairment is 25 mg once daily. (2.1)
`
`
`
`
`
`
`
` Can be taken with or without food. (2.1)
` Adjust dose if moderate or severe renal impairment or end-stage
`
`
` renal disease (ESRD). (2.2)
`
`
`
`
`
`
`
`
`
`•
`
`•
`
`
`
`Degree of Renal
`
`
` Impairment
`
`
` Moderate
`
`Creatinine
`Clearance
`
` (mL/min)
`
` ≥30 to <60
`
`
`
` Severe/ESRD
`
`
`
` <30
`
`
` Recommended Dosing
`
`
` 12.5 mg once daily
`
`
`
` 6.25 mg once daily
`
`
`
`
`•
`
`
`•
`
`
`
`-----------------------W ARNINGS AND PRECAUTIONS------------------­
`
`
`
`Acute pancreatitis: There have been postmarketing reports of
`•
`
`
`
`acute pancreatitis. If pancreatitis is suspected, promptly
`
`discontinue NESINA. (5.1)
`
`
`
`Hypersensitivity: There have been postmarketing reports of
`
`
`serious hypersensitivity reactions in patients treated with NESINA
`
`
`
`such as anaphylaxis, angioedema and severe cutaneous adverse
`
`
`
`
`
`reactions. In such cases, promptly discontinue NESINA, assess
`
`for other potential causes, institute appropriate monitoring and
`
`
`treatment and initiate alternative treatment for diabetes. (5.2)
`
`
`
`Hepatic effects: Postmarketing reports of hepatic failure,
`
`
`
`
`sometimes fatal. Causality cannot be excluded. If liver injury is
`
`
`
`detected, promptly interrupt NESINA and assess patient for
`
`
`probable cause, then treat cause if possible, to resolution or
`
`
`
`
`stabilization. Do not restart NESINA if liver injury is confirmed and
`
`
`
`no alternative etiology can be found. (5.3)
`
`
`
`
`Hypoglycemia: When an insulin secretagogue (e.g., sulfonylurea)
`
`
`
`
`or insulin is used in combination with NESINA, a lower dose of the
`
`
`insulin secretagogue or insulin may be required to minimize the
`
`risk of hypoglycemia. (5.4)
`
`Arthralgia: Severe and disabling arthralgia has been reported in
`
`
`
`
`patients taking DPP-4 inhibitors. Consider as a possible cause for
`
`severe joint pain and discontinue drug if appropriate. (5.5)
`
`
`
`
`• Macrovascular outcomes: There have been no clinical studies
`
`establishing conclusive evidence of macrovascular risk reduction
`
`
`
`
`
`with NESINA or any other antidiabetic drug. (5.6)
`
`
`----------------------------ADVERSE REACTIONS---------------------------­
`
`
`Common adverse reactions (reported in ≥4% of patients treated with
`
`
`
`NESINA 25 mg and more frequently than in patients who received
`
`
`
`
`
`placebo) are: nasopharyngitis, headache and upper respiratory tract
`
`
`infection. (6.1)
`
`
`•
`
`
`•
`
`
`----------------------DOSAGE FORMS AND STRENGTHS--------------------­
`
`
`
`Tablets: 25 mg, 12.5 mg and 6.25 mg (3)
`
`
`
`
`-----------------------------CONTRAINDICATIONS--------------------------­
`
`History of a serious hypersensitivity reaction to alogliptin-containing
`
`
`
`
`
`products, such as anaphylaxis, angioedema or severe cutaneous
`
`
`adverse reactions. (4)
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Takeda
`
`
`
`
`Pharmaceuticals at 1-877-TAKEDA-7 (1-877-825-3327) or FDA at
`
`
`1-800-FDA-1088 or www.fda.gov/medwatch.
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`
`
`Revised: 8/2015
`
`
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`
`1
`
`
`
`INDICATIONS AND USAGE
`
`
`1.1 Monotherapy and Combination Therapy
`
`
`1.2
`Limitation of Use
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`
`2.1 Recommended Dosing
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`4 CONTRAINDICATIONS
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Pancreatitis
`
`
`5.2 Hypersensitivity Reactions
`
`
`
`5.3 Hepatic Effects
`
`
`
`5.4 Use with Medications Known to Cause Hypoglycemia
`
`
`
`5.5 Severe and Disabling Arthralgia
`
`
`5.6 Macrovascular Outcomes
`
`
`6 ADVERSE REACTIONS
`
`
`
`
`6.1 Clinical Studies Experience
`
`
`6.2 Postmarketing Experience
`
`
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`
`
`
`Reference ID: 3816801
`
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`
`8.5 Geriatric Use
`
`
`8.6 Hepatic Impairment
`
`10 OVERDOSAGE
`
`
`
`11 DESCRIPTION
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`
`12.1 Mechanism of Action
`
`
`12.2 Pharmacodynamics
`
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`
`
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 Patients with Inadequate Glycemic Control on Diet and
`
`Exercise
`
`
`14.2 Combination Therapy
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
`17 PATIENT COUNSELING INFORMATION
`
`
`Instructions
`17.1
`
`
`
`
`
`*Sections or subsections omitted from the full prescribing information
`
`are not listed
`
`AstraZeneca Exhibit 2079
`Mylan v. AstraZeneca
`IPR2015-01340
`
`Page 1 of 33
`
`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` Page 2 of 33
`
`
`
` 1
`
`
`
` INDICATIONS AND USAGE
`
`
`
` 1.1 Monotherapy and Combination Therapy
`
`
`
`
` NESINA is indicated as an adjunct to diet and exercise to improve glycemic control in
`
`
` adults with type 2 diabetes mellitus in multiple clinical settings [see Clinical Studies
`
`
`
`
`(14)].
`1.2 Limitation of Use
`
`
`NESINA should not be used in patients with type 1 diabetes mellitus or for the treatment
`
`
`
`
`of diabetic ketoacidosis, as it would not be effective in these settings.
`
`
`
`
`2 DOSAGE AND ADMINISTRATION
`
`
`2.1 Recommended Dosing
`
`
`The recommended dose of NESINA is 25 mg once daily.
`
`
`
`
`NESINA may be taken with or without food.
`
`
`
`2.2 Patients with Renal Impairment
`
`
`
`
`No dose adjustment of NESINA is necessary for patients with mild renal impairment
`
`
`
`(creatinine clearance [CrCl] ≥60 mL/min).
`
`The dose of NESINA is 12.5 mg once daily for patients with moderate renal impairment
`
`
`
`(CrCl ≥30 to <60 mL/min).
`
`The dose of NESINA is 6.25 mg once daily for patients with severe renal impairment
`
`
`
`(CrCl ≥15 to <30 mL/min) or with end-stage renal disease (ESRD) (CrCl <15 mL/min or
`
`
`
`requiring hemodialysis). NESINA may be administered without regard to the timing of
`
`
`
`
`dialysis. NESINA has not been studied in patients undergoing peritoneal dialysis [see
`
`
`
`
`
`Clinical Pharmacology (12.3)].
`
`Because there is a need for dose adjustment based upon renal function, assessment of
`
`
`
`
`renal function is recommended prior to initiation of NESINA therapy and periodically
`
`
`thereafter.
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`
`
`25 mg tablets are light red, oval, biconvex, film-coated, with “TAK ALG-25” printed
`
`
`
`•
`on one side.
`
`12.5 mg tablets are yellow, oval, biconvex, film-coated, with “TAK ALG-12.5”
`
`
`
`printed on one side.
`
`6.25 mg tablets are light pink, oval, biconvex, film-coated, with “TAK ALG-6.25”
`
`
`printed on one side.
`
`
`
`•
`
`
`•
`
`4 CONTRAINDICATIONS
`
`
`History of a serious hypersensitivity reaction to alogliptin-containing products, such as
`
`
`anaphylaxis, angioedema or severe cutaneous adverse reactions.
`
`
`
`
`Reference ID: 3816801
`
`Page 2 of 33
`
`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 3 of 33
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
` 5.1 Pancreatitis
`
`
` There have been postmarketing reports of acute pancreatitis in patients taking NESINA.
`
`
` After initiation of NESINA, patients should be observed carefully for signs and
` symptoms of pancreatitis. If pancreatitis is suspected, NESINA should promptly be
`
`
` discontinued and appropriate management should be initiated. It is unknown whether
` patients with a history of pancreatitis are at increased risk for the development of
`
`
`
` pancreatitis while using NESINA.
` 5.2 Hypersensitivity Reactions
`
`
`
` There have been postmarketing reports of serious hypersensitivity reactions in patients
`
`
` treated with NESINA. These reactions include anaphylaxis, angioedema and severe
` cutaneous adverse reactions, including Stevens-Johnson syndrome. If a serious
`
`
`
`
`
`
` hypersensitivity reaction is suspected, discontinue NESINA, 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 with another
`
`DPP-4 inhibitor because it is unknown whether such patients will be predisposed to
`
`angioedema with NESINA.
`
`
`5.3 Hepatic Effects
`
`
`
`There have been postmarketing reports of fatal and nonfatal hepatic failure in patients
`
`
`
`taking NESINA, although some of the reports contain insufficient information necessary
`to establish the probable cause [see Adverse Reactions (6.2)]. In randomized controlled
`
`
`studies, serum alanine aminotransferase (ALT) elevations greater than three times the
`
`
`
`
`upper limit of normal (ULN) were observed: 1.3% in alogliptin-treated patients and 1.5%
`
`in all comparator-treated patients.
`
`
`
`Patients with type 2 diabetes may have fatty liver disease, which may cause liver test
`
`
`
`abnormalities, and they may also have other forms of liver disease, many of which can
`
`
`
`
`
`be treated or managed. Therefore, obtaining a liver test panel and assessing the patient
`
`before initiating NESINA therapy is recommended. In patients with abnormal liver tests,
`
`NESINA should be initiated with caution.
`
`
`
`Measure liver tests promptly in patients who report symptoms that may indicate liver
`
`
`
`injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or
`
`
`
`jaundice. In this clinical context, if the patient is found to have clinically significant liver
`
`
`enzyme elevations and if abnormal liver tests persist or worsen, NESINA should be
`
`
`
`interrupted and investigation done to establish the probable cause. NESINA should not
`
`be restarted in these patients without another explanation for the liver test abnormalities.
`
`
`
`5.4 Use with Medications Known to Cause Hypoglycemia
`
`
`
`Insulin and insulin secretagogues, such as sulfonylureas, are known to cause
`
`
`
`hypoglycemia. Therefore, a lower dose of insulin or insulin secretagogue may be
`
`
`required to minimize the risk of hypoglycemia when used in combination with NESINA.
`
`
`
`Reference ID: 3816801
`
`Page 3 of 33
`
`

`
`
`
`
`
`
`
` Page 4 of 33
`
` 5.5 Severe and Disabling Arthralgia
`
`
`
`There have been postmarketing reports of severe and disabling arthralgia in patients
`
`taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug
`
`
`
`therapy varied from one day to years. Patients experienced relief of symptoms upon
`
`
`discontinuation of the medication. A subset of patients experienced a recurrence of
`
`
`
`symptoms when restarting the same drug or a different DPP-4 inhibitor. Consider DPP­
`
`
`
`4 inhibitors as a possible cause for severe joint pain and discontinue drug if appropriate.
`
`5.6 Macrovascular Outcomes
`
`
`
`There have been no clinical studies establishing conclusive evidence of macrovascular
`
`
`risk reduction with NESINA or any other antidiabetic drug.
`
`
`
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Studies 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 clinical practice.
`
`Approximately 8500 patients with type 2 diabetes have been treated with NESINA in
`
`
`14 randomized, double-blind, controlled clinical trials with approximately 2900 subjects
`
`
`
`
`
`
`
`randomized to placebo and approximately 2200 to an active comparator. The mean
`
`
`
`
`
`
`exposure to NESINA was 40 weeks with more than 2400 subjects treated for more than
`one year. Among these patients, 63% had a history of hypertension, 51% had a history
`
`
`
`
`
`
`of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable
`
`
`
`
`
`
`angina and 7% had a history of congestive heart failure. The mean duration of diabetes
`
`
`
`was seven years, the mean body mass index (BMI) was 31 kg/m2 (51% of patients had
`
`
`
`
`
`
`
`a BMI ≥30 kg/m2), and the mean age was 57 years (24% of patients ≥65 years of age).
`
`
`
`
`
`
`
`
`Two placebo-controlled monotherapy trials of 12 and 26 weeks of duration were
`
`
`
`
`conducted in patients treated with NESINA 12.5 mg daily, NESINA 25 mg daily and
`
`
`
`
`placebo. Four placebo-controlled add-on combination therapy trials of 26 weeks
`duration were also conducted: with metformin, with a sulfonylurea, with a
`
`thiazolidinedione and with insulin.
`
`
`Four placebo-controlled and one active-controlled trials of 16 weeks up through two
`years in duration were conducted in combination with metformin, in combination with
`
`
`
`
`
`pioglitazone and with pioglitazone added to a background of metformin therapy.
`
`Three active-controlled trials of 52 weeks in duration were conducted in patients treated
`
`
`with pioglitazone and metformin, in combination with metformin and as monotherapy
`
`compared to glipizide.
`
`
`
`
`In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse
`
`
`
`events was 66% in patients treated with NESINA 25 mg compared to 62% with placebo
`
`
`
`
`and 70% with active comparator. Overall discontinuation of therapy due to adverse
`
`
`
`
`
`
`
`events was 4.7% with NESINA 25 mg compared to 4.5% with placebo or 6.2% with
`
`active comparator.
`
`
`
`
`
`
`Adverse reactions reported in ≥4% of patients treated with NESINA 25 mg and more
`
`
`
`frequently than in patients who received placebo are summarized in Table 1.
`
`
`
`
`Reference ID: 3816801
`
`Page 4 of 33
`
`

`
`
`
`
`
` Page 5 of 33
`
`Table 1. Adverse Reactions Reported in ≥4% Patients Treated with NESINA 25 mg
`
`
`
`and More Frequently Than in Patients Given Placebo in Pooled Studies
`
`Number of Patients (%)
`
`
` Placebo
`
` Active
`
`
` Comparator
`
` N=2257
`
`113 (5.0)
`
`121 (5.4)
`
`113 (5.0)
`
`
` N=2926
`
`89 (3.0)
`
`72 (2.5)
`
`61 (2.1)
`
`NESINA
`25 mg
`
` N=5902
`
`257 (4.4)
`
`247 (4.2)
`
`247 (4.2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Nasopharyngitis
`
`Headache
`
`
`
`
`Upper Respiratory Tract Infection
`
` Pancreatitis
`
`
`
`
`
`
` In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients
`
` receiving NESINA 25 mg daily compared to five of 5183 (˂0.1%) patients receiving
`
`
`
`
`
`
`
`
` all comparators.
`
` Hypersensitivity Reactions
`
` In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6%
`
`
`
` with NESINA 25 mg compared to 0.8% with all comparators. A single event of serum
` sickness was reported in a patient treated with NESINA 25 mg.
`
`
`
`
` Hypoglycemia
` Hypoglycemic events were documented based upon a blood glucose value and/or
`
`
`
` clinical signs and symptoms of hypoglycemia.
` In the monotherapy study, the incidence of hypoglycemia was 1.5% in patients
`
`
`
`
`
`
`
` treated with NESINA compared to 1.6% with placebo. The use of NESINA as add-on
` therapy to glyburide or insulin did not increase the incidence of hypoglycemia
`
`
`
`
` compared to placebo. In a monotherapy study comparing NESINA to a sulfonylurea
`
`
`
` in elderly patients, the incidence of hypoglycemia was 5.4% with NESINA compared
`
`
`
`
`
`
` to 26% with glipizide (Table 2).
`
`
`
`
`
`
`
`Reference ID: 3816801
`
`Page 5 of 33
`
`

`
`
`
`
`
` Page 6 of 33
`
`
`
` Table 2. Incidence and Rate of Hypoglycemia* in Placebo and Active-Controlled
`
` Studies when NESINA Was Used as Add-On Therapy to Glyburide, Insulin,
`
`
`
`
`
` Metformin, Pioglitazone or Compared to Glipizide
`
`
`
`
`Add-On to Glyburide
`
`(26 Weeks)
`
`
`Overall (%)
`
`†
`
`Severe (%)
`
`Add-On to Insulin (± Metformin)
`
`
`(26 Weeks)
`
`
`
`
`Overall (%)
`
`†
`
`Severe (%)
`
`Add-On to Metformin
`
`(26 Weeks)
`
`
`Overall (%)
`
`†
`Severe (%)
`
`
`
`NESINA 25 mg
`
`
`+ Glyburide
`
`N=198
`19 (9.6)
`
`
` 0
`
`NESINA 25 mg
`
`+ Insulin
`
`
`(± Metformin)
`
`
`
`N=129
`35 (27)
`
`
` 1 (0.8)
`
`NESINA 25 mg
`
`+ Metformin
`
`
`
`N=207
`
`0
`
`
` 0
`
`
`Placebo
`
`
`+ Glyburide
`
`N=99
`11 (11.1)
`
`
` 1 (1)
`
`Placebo
`
`+ Insulin
`
`
`(± Metformin)
`
`
`
`N=129
`31 (24)
`
`
` 2 (1.6)
`
`
`Placebo
`
`+ Metformin
`
`
`
`N=104
`
`3 (2.9)
`
`
`
` 0
`
`Add-On to Pioglitazone
`
`(± Metformin or Sulfonylurea)
`
`
`(26 Weeks)
`
`
`NESINA 25 mg
`
`+ Pioglitazone
`
`
`
`Placebo
`
`+ Pioglitazone
`
`
`
`
`
`Overall (%)
`
`†
`Severe (%)
`
`
`
`Compared to Glipizide
`
`(52 Weeks)
`
`
`
`Overall (%)
`
`†
`
`Severe (%)
`
`
`
`Add-On to Metformin
`
`
`(26 Weeks)
`
`
`N=199
`
`14 (7.0)
`
`
`
` 0
`
`
`NESINA 25 mg
`
`
`N=222
`12 (5.4)
`
`
` 0
`
`NESINA 25 mg
`
`
`
`N=112
`
`N=97
`
`5 (5.2)
`
`
` 1 (1)
`
`
`
`Glipizide
`
`
`N=219
`57 (26)
`
`
` 3 (1.4)
`
`
`Metformin 500 mg
`twice daily
`
`
`N=109
`
`
`
`
`
`Reference ID: 3816801
`
`Page 6 of 33
`
`

`
`
`
` Overall (%)
`
`†
`
`Severe (%)
` Add-On to Metformin
`
`
` Compared to Glipizide
`
`
` (52 Weeks)
`
`
`
`
`
`
`
` Page 7 of 33
`
`
`2 (1.8)
`
`
`0
`
`NESINA 25 mg
`
`+ Metformin
`
`
`N=877
`
`
`
`2 (1.8)
`
`
`0
`
`Glipizide
`
`+ Metformin
`
`
`N=869
`
`
`Overall (%)
`
`†
`Severe (%)
`
`*Adverse reactions of hypoglycemia were based on all reports of symptomatic and
`
` asymptomatic hypoglycemia; a concurrent glucose measurement was not required; intent-to­
`
`
` treat population.
`
` †Severe events of hypoglycemia were defined as those events requiring medical assistance or
`
`
`
` exhibiting depressed level or loss of consciousness or seizure.
`
`
`
`12 (1.4)
`
`
`
`
` 0
`
`207 (23.8)
`
`
`
`
`
` 4 (0.5)
`
`
`
`
`
`
`
`
`
`
`
`
`
` Vital Signs
`
` No clinically meaningful changes in vital signs or in electrocardiograms were observed
`
`
` in patients treated with NESINA.
` Laboratory Tests
`
` No clinically meaningful changes in hematology, serum chemistry or urinalysis were
` observed in patients treated with NESINA.
`
`
`
` 6.2 Postmarketing Experience
` The following adverse reactions have been identified during the postmarketing use of
`
`
`
`
`
`
` NESINA. Because these reactions are reported voluntarily from a population of
`
` uncertain size, it is not always possible to reliably estimate their frequency or establish a
`
` causal relationship to drug exposure.
`
`
`
`
` Hypersensitivity reactions including anaphylaxis, angioedema, rash, urticaria and
`
`
` severe cutaneous adverse reactions, including Stevens-Johnson syndrome, hepatic
`
`
` enzyme elevations, fulminant hepatic failure, severe and disabling arthralgia and acute
`
`
`
`
` pancreatitis [see Warnings and Precautions (5.1, 5.2, 5.3, 5.5)].
`
`
`
`
`
`
`
`
` 7 DRUG INTERACTIONS
`
`
` NESINA is primarily renally excreted. Cytochrome (CYP) P450-related metabolism is
`
`
`
`
`
`
` negligible. No significant drug-drug interactions were observed with the CYP-substrates
` or inhibitors tested or with renally excreted drugs [see Clinical Pharmacology (12.3)].
`
`
`
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
` 8.1 Pregnancy
`
`
` Pregnancy Category B
`
`
`No adequate or well-controlled studies in pregnant women have been conducted with
`
`
`
` NESINA. Based on animal data, NESINA is not predicted to increase the risk of
` developmental abnormalities. Because animal reproduction studies are not always
`
`
`
`
`
`
`
`Reference ID: 3816801
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`Page 7 of 33
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`

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` Page 8 of 33
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`
` predictive of human risk and exposure, NESINA, like other antidiabetic medications,
` should be used during pregnancy only if clearly needed.
`
`
`
`
` Alogliptin administered to pregnant rabbits and rats during the period of organogenesis
`
` was not teratogenic at doses of up to 200 mg/kg and 500 mg/kg, or 149 times and 180
`
`
`
`
`
`
` times, respectively, the clinical dose based on plasma drug exposure (AUC).
`
`
` Doses of alogliptin up to 250 mg/kg (approximately 95 times clinical exposure based on
`
`
`
` AUC) given to pregnant rats from gestation Day 6 to lactation Day 20 did not harm the
`
`
`
` developing embryo or adversely affect growth and development of offspring.
`
`
`
`
` Placental transfer of alogliptin into the fetus was observed following oral dosing to
`
`
`
`
` pregnant rats.
` 8.3 Nursing Mothers
`
`
` Alogliptin is secreted in the milk of lactating rats in a 2:1 ratio to plasma . It is not known
`
`
`
`
`
`
` whether alogliptin is excreted in human milk. Because many drugs are excreted in
` human milk, caution should be exercised when NESINA is administered to a nursing
`
`
` woman.
` 8.4 Pediatric Use
`
`
` Safety and effectiveness of NESINA in pediatric patients have not been established.
`
` 8.5 Geriatric Use
`
`
`
`
` Of the total number of patients (N=8507) in clinical safety and efficacy studies treated
` with NESINA, 2064 (24.3%) patients were 65 years and older and 341 (4%) patients
`
`
`
`
`
`
`
`
` were 75 years and older. No overall differences in safety or effectiveness were
` observed between patients 65 years and over and 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.
` 8.6 Hepatic Impairment
`
`
`
`
`
`
`
`
` No dose adjustments are required in patients with mild to moderate hepatic impairment
`
` (Child-Pugh Grade A and B) based on insignificant change in systemic exposures (e.g.,
`
` AUC) compared to subjects with normal hepatic function in a pharmacokinetic study.
`
`
` NESINA has not been studied in patients with severe hepatic impairment (Child-Pugh
`
`
`
`
`Grade C). Use caution when administering NESINA to patients with liver disease [see
`
` Warnings and Precautions (5.3)].
`
`
`
`
`
`
`
`
`10 OVERDOSAGE
`
`The highest doses of NESINA administered in clinical trials were single doses of
`
`
`
`
`
`
`
`800 mg to healthy subjects and doses of 400 mg once daily for 14 days to patients with
`
`
`
`type 2 diabetes (equivalent to 32 times and 16 times the maximum recommended
`
`
`
`
`
`
`clinical dose of 25 mg, respectively). No serious adverse events were observed at these
`
`doses.
`
`
`
`In the event of an overdose, it is reasonable to institute the necessary clinical monitoring
`
`and supportive therapy as dictated by the patient's clinical status. Per clinical judgment,
`
`
`it may be reasonable to initiate removal of unabsorbed material from the gastrointestinal
`
`tract.
`
`
`
`
`
`Reference ID: 3816801
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`Page 8 of 33
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` Page 9 of 33
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`
` Alogliptin is minimally dialyzable; over a three-hour hemodialysis session, approximately
` 7% of the drug was removed. Therefore, hemodialysis is unlikely to be beneficial in an
`
`
`
` overdose situation. It is not known if NESINA is dialyzable by peritoneal dialysis.
`
`
`
`
`
`
` 11 DESCRIPTION
`
`
`
`
` NESINA tablets contain the active ingredient alogliptin, which is a selective, orally
`
` bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4).
`
`
` Chemically, alogliptin is prepared as a benzoate salt, which is identified as 2-({6-[(3R)-3­
`
`
`aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)­
`yl}methyl)benzonitrile monobenzoate. It has a molecular formula of
`
`
`
`
`C18H21N5O2•C7H6O2 and a molecular weight of 461.51 daltons. The structural formula
`
`
`
`
`
`
`
` is:
`
`
`
`O
`
`CN
`
`H3C
`
`N
`
`N
`
`•
`
`HO2C
`
`O
`
`( Z)
`
`N
`
`(R)
`
`NH2
`
` Alogliptin benzoate is a white to off-white crystalline powder containing one asymmetric
`
`
`
` carbon in the aminopiperidine moiety. It is soluble in dimethylsulfoxide, sparingly soluble
`
` in water and methanol, slightly soluble in ethanol and very slightly soluble in octanol and
`
`
`
`
` isopropyl acetate.
`
`
`
`
`
`
`
`
` Each NESINA tablet contains 34 mg, 17 mg or 8.5 mg alogliptin benzoate, which is
`
`
`
` equivalent to 25 mg, 12.5 mg or 6.25 mg, respectively, of alogliptin and the following
`
`
` inactive ingredients: mannitol, microcrystalline cellulose, hydroxypropyl cellulose,
`
`
` croscarmellose sodium and magnesium stearate. In addition, the film coating contains
`
`
`
`
` the following inactive ingredients: hypromellose, titanium dioxide, ferric oxide (red or
`
`
`
` yellow) and polyethylene glycol, and is marked with printing ink (Gray F1).
`
`
`
`
`
`
`
`
`
`
`
`
` 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 DPP-4 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. Alogliptin is a DPP-4 inhibitor that slows the inactivation of the incretin
`
`
` hormones, thereby increasing their bloodstream concentrations and reducing fasting
`
`
`
`
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`Reference ID: 3816801
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`Page 9 of 33
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` Page 10 of 33
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` and postprandial glucose concentrations in a glucose-dependent manner in patients
`
` with type 2 diabetes mellitus . Alogliptin selectively binds to and inhibits DPP-4 but not
`
`
`
`
` DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.
`
`12.2 Pharmacodynamics
`
`
`Single-dose administration of NESINA to healthy subjects resulted in a peak inhibition of
`
`
`
`
`
`
`DPP-4 within two to three hours after dosing. The peak inhibition of DPP-4 exceeded
`
`
`
`
`
`
`93% across doses of 12.5 mg to 800 mg. Inhibition of DPP-4 remained above 80% at
`
`
`
`
`
`
`24 hours for doses greater than or equal to 25 mg. Peak and total exposure over 24
`
`
`
`
`
`
`hours to active GLP-1 were three- to four-fold greater with NESINA (at doses of 25 to
`
`
`
`
`
`
`
`
`
`200 mg) than placebo. In a 16-week, double-blind, placebo-controlled study, NESINA
`
`
`25 mg demonstrated decreases in postprandial glucagon while increasing postprandial
`
`
`
`active GLP-1 levels compared to placebo over an eight-hour period following a
`
`
`standardized meal. It is unclear how these findings relate to changes in overall glycemic
`
`
`control in patients with type 2 diabetes mellitus. In this study, NESINA 25 mg
`
`
`
`demonstrated decreases in two-hour postprandial glucose compared to placebo (-30
`
`mg/dL versus 17 mg/dL, respectively).
`
`
`
`Multiple-dose administration of alogliptin to patients with type 2 diabetes also resulted in
`
`
`
`
`
`a peak inhibition of DPP-4 within one to two hours and exceeded 93% across all doses
`
`
`
`
`
`
`
`(25 mg, 100 mg and 400 mg) after a single dose and after 14 days of once-daily dosing.
`
`
`
`
`
`
`
`
`
`At these doses of NESINA, inhibition of DPP-4 remained above 81% at 24 hours after
`
`
`
`
`
`14 days of dosing.
`
`Cardiac Electrophysiology
`
`In a randomized, placebo-controlled, four-arm, parallel-group study, 257 subjects were
`
`
`
`administered either alogliptin 50 mg, alogliptin 400 mg, moxifloxacin 400 mg or placebo
`
`once daily for a total of seven days. No increase in QTc was observed with either dose
`
`
`
`
`
`of alogliptin. At the 400 mg dose, peak alogliptin plasma concentrations were 19-fold
`
`higher than the peak concentrations following the maximum recommended clinical dose
`
`
`
`
`
`of 25 mg.
`
`
`12.3 Pharmacokinetics
`
`
`The pharmacokinetics of NESINA has been studied in healthy subjects and in patients
`
`
`
`
`
`with type 2 diabetes. After administration of single, oral doses up to 800 mg in healthy
`
`
`
`
`
`
`subjects, the peak plasma alogliptin concentration (median Tmax) occurred one to two
`
`
`
`
`
`
`
`
`
`hours after dosing. At the maximum recommended clinical dose of 25 mg, NESINA was
`
`
`eliminated with a mean terminal half-life (T 1/2 ) of approximately 21 hours.
`
`After multiple-dose administration up to 400 mg for 14 days in patients with type 2
`
`
`
`
`
`diabetes, accumulation of alogliptin was minimal with an increase in total (i.e., AUC) and
`
`
`
`
`
`
`
`
`peak (i.e., C max) alogliptin exposures of 34% and 9%, respectively. Total and peak
`
`
`
`exposure to alogliptin increased proportionally across single doses and multiple doses
`
`
`
`
`
`
`
`
`of alogliptin ranging from 25 mg to 400 mg. The intersubject coefficient of variation for
`
`
`
`
`
`
`alogliptin AUC was 17%. The pharmacokinetics of NESINA was also shown to be
`
`
`
`
`similar in healthy subjects and in patients with type 2 diabetes.
`
`
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`Reference ID: 3816801
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`Page 10 of 33
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` Page 11 of 33
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` Absorption
`
`
`
`
` The absolute bioavailability of NESINA is approximately 100%. Administration of
` NESINA with a high-fat meal results in no significant change in total and peak exposure
`
`
`
`
` to alogliptin. NESINA may therefore be administered with or without food.
`
`
`
`
` Distribution
` Following a single, 12.5 mg intravenous infusion of alogliptin to healthy subjects, the
`
`
`
`
`
`
`
`
` volume of distribution during the terminal phase was 417 L, indicating that the drug is
` well distributed into tissues.
`
`
`
` Alogliptin is 20% bound to plasma proteins.
` Metabolism
`
` Alogliptin does not undergo extensive metabolism and 60% to 71% of the dose is
`
`
` excreted as unchanged drug in the urine.
`
` Two minor metabolites were detected following administration of an oral dose of
`
`
`[14C] alogliptin, N-demethylated, M-I (<1% of the parent compound), and N-acetylated
`
`
`
`
`
`
`
`
`
`
`
`
`
`alogliptin, M-II (<6% of the parent compound). M-I is an active metabolite and is an
`
`
`
`inhibitor of DPP-4 similar to the parent molecule; M-II does not display any inhibitory
`
`
`
`
`activity toward DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6
`
`
`
`
`
`and CYP3A4 contribute to the limited metabolism of alogliptin.
`
`Alogliptin exists predominantly as the (R)-enantiomer (>99%) and undergoes little or no
`
`
`
`
`chiral conversion in vivo to the (S)-enantiomer. The (S)-enantiomer is not detectable
`
`
`at the 25 mg dose .
`
`Excretion
`The primary route of elimination of [14C] alogliptin-derived radioactivity occurs via renal
`
`
`
`
`
`
`
`
`
`
`
`
`excretion (76%) with 13% recovered in the feces, achieving a total recovery of 89% of
`
`
`
`
`the administered radioactive dose. The renal clearance of alogliptin (9.6 L/hr) indicates
`
`
`
`some active renal tubular secretion and systemic clearance was 14.0 L/hr.
`
`
`Specific Populations
`
`
`Renal Impairment
`
`
`
`
`A single-dose, open-label study was conducted to evaluate the pharmacokinetics of
`
`
`
`
`
`
`
`
`
`alogliptin 50 mg in patients with chronic renal impairment compared with healthy
`
`subjects.
`
`
`
`In patients with mild renal impairment (creatinine clearance [CrCl] ≥60 to <90 mL/min),
`an approximate 1.2-fold increase in plasma AUC of alogliptin was observed. Because
`
`
`
`increases of this magnitude are not considered clinically relevant, dose adjustment for
`
`
`
`
`
`patients with mild renal impairment is not recommended.
`
`
`In patients with moderate renal impairment (CrCl ≥30 to <60 mL/min), an approximate
`
`
`
`two-fold increase in plasma AUC of alogliptin was observed. To maintain similar
`
`
`systemic exposures of NESINA to those with normal renal function, the recommended
`
`
`
`dose is 12.5 mg once daily in patients with moderate renal impairment.
`
`
`
`
`In patients with severe renal impairment (CrCl ≥15 to <30 mL/min) and ESRD (CrCl <15
`
`
`
`
`mL/min or requiring dialysis), an approximate three- and four-fold increase in plasma
`
`AUC of alogliptin were observed, respectively. Dialysis removed approximately 7% of
`
`
`
`Reference ID: 3816801
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`Page 11 of 33
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`

`
` the drug during a three-hour dialysis session. NESINA may be administered without
`
`
`
`
`
`
` regard to the timing of the dialysis. To maintain similar systemic exposures of NESINA
` to those with normal renal function, the