(A) TO PREPARE AN APPLICATION FOR IND SUBMISSION FOR AZILSARTAN TABLET IN USA. (B) TO PREPARE CHECKLIST FOR AZILSARTAN TABLET AS PER USA.

Drug Regulation & Regulatory Authorities
Dept. Of Quality Assurance & Regulatory Affairs
L. J. Institute of Pharmacy, Ahmedabad.
EXPERIMENT NO: DATE:
AIM: (A) TO PREPARE AN APPLICATION FOR IND SUBMISSION FOR
AZILSARTAN TABLET IN USA.
(B) TO PREPARE CHECKLIST FOR AZILSARTAN TABLET AS PER USA.
REFERENCES:
1. http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/
sbd_smd_2012_edarbi_145305-eng.php
2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000chemR.pdf
3. http://www.biomedcentral.com/1471-2261/13/46
4. http://en.wikipedia.org/wiki/azilsartan
5. www.edarbi.com/docx./Edarbi_pi.html
6. www.medicines.org.uk/cmc/medicine/26412/spc
Investigational New Drug Application
1. FDA Forms.
2. Table of contents
3. Introductory statements & General investigational plan
3.1 Product Information
3.1.1 Product Name
3.1.2 Brand Name
3.1.3 Active & Inactive Ingredient
3.1.4 Pharmacological Information
3.1.4.1 Mechanism Of Action
3.1.5 Structural Formula
3.1.6 Route of Administration
3.1.7 Indication
3.2 Brief summary of previous human experiments
3.3 General investigational plan
3.3.1 Rationale for Azilsartan
3.3.2 Indication
3.3.3 Clinical study & no. of patient to be given Azilsartan drug for study
3.3.4 Toxicological Data
4. Investigator’s Brochure
4.1 Brief description of Azilsartan
4.2 A summary of Pharmacological and toxicological effects of Azilsartan
4.3 A summary of pharmacokinetics and biological disposition of Azilsartan in animal
4.4 Description of possible risk and side effects to be anticipated on the basis of prior
experiment with Azilsartan under investigation.
5. Protocol
5.1 Study protocol
5.2 Clinical trial investigator information
5.3 Overall clinical trial official and content
6. Chemistry Manufacturing and Control data
6.1 Product data
7. Pharmacological and Toxicological data
8. Previous human experience
9. Additional information

Content
3. Introductory statement and general investigational plan
3.1Product Information:
3.1.1. Generic Name: Azilsartan (AY-zil-SAR-tan)
3.1.2. Brand Name: Edarbi
3.1.3. Active ingredients: tablet contains 42.68 or 85.36 mg of Azilsartan
kamedoxomil, which is equivalent to containing 40 mg or 80 mg respectively, of azilsartan
medoxomil.
Inactive ingredients:
Mannitol (E 421)
Fumaric acid (E 297)
Sodium hydroxide
Hydroxypropylcellulose (E 463)
Croscarmellose sodium
Cellulose, microcrystalline (E 460)
Magnesium stearate (E 572)
3.1.4. Pharmacological information:
3.1.4.1 Mechanism of Action :
Refer CMC section 6.
3.1.5. Structural Formula:
Refer CMC section 6.
3.1.6. Route of administration: Oral route.
Dose :- Tablets, oral 40 mg
- Tablets, oral 80 mg
3.1.7. Broad objectives: Indications:
Indications and Usage: Treatment of hypertension alone or in combination with other
antihypertensives.
Contraindications: Do not co-administer aliskiren with Edarbi in patients with diabetes
Precautions :
 Fetal/Neonatal Morbidity and Mortality (Black Box Warning): Drugs that interfere
with therein‐angiotensin system can cause morbidity and death of the fetus when
given to a pregnant woman during the second or third trimester.
Drug Trade
Name
Biological
half-life
[h]
Protein
binding
[%]
Bioavailability
[%]
Renal/hepatic
clearance
[%]
Food
effect
Daily
dosage
[mg]
Azilsartan Edarbi 11 h >99% 60% 55%/42% No 40–80 mg

 Azilsartan is a category C drug during the first trimester and category D in the
second and third trimesters.
 Azilsartan should be discontinued as soon as possible when pregnancy is detected.
Using azilsartan during breastfeeding is not recommended as it is unknown if
azilsartan is excreted in breast milk.
 Hypotension in Volume – or Salt‐Depleted Patients: After starting azilsartan,
symptomatic hypotension may occur in these patients. Before initiating azilsartan,
correct volume or salt depletion or start azilsartan at 40mg. If hypotension does
occur, place the patient in supine position and given an infusion of normal saline, if
necessary. Once the blood pressure has stabilized, treatment with azilsartan can be
continued.
 Impaired Renal Function: In patients whose renal function may depend on the
activity of the renin angiotensin system, treatment with angiotensin receptor
blockers and angiotensinconverting enzyme inhibitors has been associated with
oliguria or progressive azotemia and rarely with acute renal failure and death.
 Anaphylactic Reactions and Angioedema: Use caution when prescribing azilsartan
for patients with a history of angioedema related to ACE inhibitor therapy.
Although angiotensin II receptor blockers do cause an accumulation of kinins,
angioedema has been reported rarely in patients taking an angiotensin II receptor
blocker.
Pediatric Use: Safe use has not been evaluated in children under the age of 18.
Geriatric Use: No dosage adjustment is needed. Significant increases in serum creatinine
were seen more often in adults greater than 75 years of age.
Adverse Effects :
Occurring in > 1% and < 10% of patients
Gastrointestinal: Diarrhea (2%)
Other Fatigue (1.1‐2.5%) Occurring in < 1%
Cardiovascular: Hypotension/Orthostatic hypotension (0.4%)
Gastrointestinal: Nausea (0.3%)
Hematologic: Low hemoglobin (0.2%)
Low hematocrit (0.4%)
Low red blood cell count (0.3%)
Neurologic: Asthenia (0.3%)
Dizziness (0.3%)
Postural dizziness (0.3%)
Renal : Oliguria
Progressive azotemia
Respiratory: Cough (0.3%)
Drug Interactions:
 Non‐steroidal anti‐inflammatory agents including selective cyclooxygenase‐2
inhibitors
 Co‐administration of NSAIDs with azilsartan in patients who are elderly, volume-
depleted, or who have compromised renal function may result in deterioration of
renal function.
 The antihypertensive effects of azilsartan may be lessened by NSAIDs.

 Co‐administration with drugs that cause hyperkalemia, Eplerenone, potassium
salts, postassium‐sparing diuretics, tolvaptan, trimethoprim
 Co‐administration with drugs that cause hypotension
 Other antihypertensives, amifostine, diazoxide, ethanol, MAO inhibitors,
pentoxyifylline, Phosphor diesterase 5 inhibitors, prostacyclin analogues
 Co‐administration with drugs that diminish the antihypertensive effect of
antihypertensives , Methylphenidate, yohimbine ,Lithium
 Azilsartan may increase the serum concentration of lithium.
 Rifamycin derivatives: Rifamycin derivatives may increase the metabolism of
azilsartan.
Pharmacokinetics:
Absorption:
Tmax : 1.5‐3 hours
Vd : 16 L
t1/2 : 11 hours
Clearance : 2.3 mL/min
Protein binding: >99%
Bioavailability: 60%
Metabolism: Azilsartan is metabolized via O‐dealkylation and decarboxylation into two
primary metabolites. CYP2C9 is the major enzyme responsible for azilsartan metabolism.
Elimination: Azilsartan is eliminated through the feces (55%) and the urine (42%). Only
15% is eliminated as the unchanged drug.
3.2. Brief summary of previous human experience:
NOT APPLICABLE
3.3 GENERAL INVESTIGATIONAL PLAN
3.3.1 The Rational for Azilsartan
Objectives: EARLY have two co-primary objectives:
1) Description of the safety profile of AZM (Azilsartan Medoxomil)
2) Achievement of Blood Pressure targets based on recent national and
international guidelines for patients treated with AZM in comparison to those
treated with ACE-inhibitors..
Secondary objectives are as follows:
1) Absolute and relative BP reduction with antihypertensive treatment over the
duration of one year.
2) Documentation of the adherence to guidelines for the diagnosis and treatment of
hypertension in ambulatory care.
3) Persistence understood as the mean duration of monotherapy and / or AZM
based combination therapy during follow-up.
4) Documentation of adverse events.
5) Prospective documentation of cardiovascular and renal events.

6) A pharmaco-economic evaluation of AZM use.
Additional objectives in a subgroup of patients with ABPM (Ambulatory Blood
Pressure Monitoring) are to document BP lowering and pulse pressure reduction over the 1
year follow-up considering prior and concomitant antihypertensive pharmacotherapy as
well as BP at baseline, and BP control with AZM in comparison to ACE-inhibitors
(specific ACE inhibitors will be considered given their sample size is sufficient). Second,
BP values obtained from ABPM will be compared to corresponding office Blood Pressure
values. Finally, central systolic and diastolic blood pressure, cardiac output (per minute),
peripheral resistance, augmentation index, and pulse wave velocity will be determined and
compared between patients receiving AZM or ACE-inhibitor treatment.
Adult patients (≥ 18 years) with essential arterial hypertension are included on a
consecutive basis, given they have provide written informed consent and fulfill the
following two criteria: 1) Participants have either no anti-hypertensive treatment prior to
inclusion or a prior non-RAS (Rennin Angiotensin System) based antihypertensive
monotherapy. 2) A monotherapy using AZM or any ACE-inhibitor is initiated at baseline.
Patients are excluded from participation if they 1) receive antihypertensive drugs
for an indication other than hypertension (e.g. beta blockers or diuretics for heart failure),
2) have a history of alcohol, drug abuse or illegal drug addiction, 3) have a life expectancy
of less than one year, 4) are pregnant or breast feeding, or 5) are participating in other
trials or registries. Further to this, patients with contraindications as to the summary of
product characteristics of AZM or the ACE inhibitors will not be permitted. Patient
recruitment started in January 2012 and will end on February 28th
2013 at the latest or as
soon as the recruitment target of 5000 patients is met.
3.3.2 Indications
As per section 3.1.7
3.3.3 Clinical Studies & No. of patients to be given AZILSARTAN drug for studies:
The antihypertensive effects of Edarbi have been demonstrated in a total of seven
double-blind, randomized studies, which included five placebo-controlled and four active
comparator-controlled studies (not mutually exclusive). The studies ranged from six weeks
to six months in duration, at doses ranging from 20 mg to 80 mg once daily. A total of
5941 patients (3672 given Edarbi, 801 given placebo, and 1468 given active comparator)
with mild, moderate or severe hypertension were studied. Overall, 51% of patients were
male and 26% were 65 years or older; 67% were white and 19% were black.
Two 6-week, randomized, double-blind studies compared the effect on blood
pressure of Edarbi at doses of 40 mg and 80 mg, with placebo and with active
comparators. Blood pressure reductions compared to placebo based on clinic blood
pressure measurements at trough and 24-hour mean blood pressure by ambulatory blood
pressure monitoring (ABPM) are shown in Table 1 for both studies. Edarbi, 80 mg, was
statistically superior to placebo and active comparators for both clinic and 24-hour mean
blood pressure measurements.

Table 1. Placebo Corrected Mean Change from Baseline in Systolic/Diastolic Blood
Pressure at 6 Weeks (mm Hg)
Study 1
N=1285
Study 2
N=989
Clinic Blood
Pressure
(Mean Baseline
157.4/92.5)
24 Hour Mean by
ABPM
(Mean Baseline
144.9/88.7)
Clinic Blood
Pressure
(Mean Baseline
159.0/91.8)
24 Hour Mean by
ABPM
(Mean Baseline
146.2/87.6)
Edarbi 40 mg -14.6/-6.2 -13.2/-8.6 -12.4/-7.1 -12.1/-7.7
Edarbi 80 mg -14.9/-7.5 -14.3/-9.4 -15.5/-8.6 -13.2/-7.9
Olmesartan 40
mg
-11.4/-5.3 -11.7/-7.7 -12.8/-7.1 -11.2/-7.0
Valsartan 320
mg
-9.5/-4.4 -10.0/-7.0
3.3.4 Toxicological Data
General nonclinical pharmacology/toxicology considerations
Azilsartan medoxomil is a competitive reversible ARB (IC50 = 0.62-2.6 nmol/L). The
drug produces a dose-dependent decrease in arterial blood pressure in a variety of
hypertensive animal models such as spontaneously hypertensive rats and renal
hypertensive dogs; it blocks the pressor effect of angiotensin II in rats.
3.3.4.1 Toxicology:
The toxicology program included assessment of the pro-drug (TAK-491) and
active moiety (TAK-536) in single and repeat-dose toxicity studies in rats (up to 26
weeks, ≤ 2000 mg/kg) and dogs (up to 26 weeks with TAK-491 (≤ 60 mg/kg) and up to
52 weeks with TAK-536 (≤300 mg/kg), rodent carcinogenicity studies, genotoxicity
studies, and reproduction and developmental toxicity studies. The major human
metabolite, TAK-536 M-II, was examined in rat and dog repeat-dose toxicity studies
(up to 13 weeks in duration), in 6-month transgenic mouse and 2-year rat
carcinogenicity assays, and in genotoxicity and reproduction/developmental studies.
The following toxicologic findings were observed with azilsartan medoxomil:
1. Dark red foci and stomach erosion (rats, 20-fold higher AUC than humans) and
GI ulceration (dogs, 5-fold higher AUC than humans); olmesartan medoxomil
produced similar findings.
2. Juxtaglomerular cell hypertrophy, consistent with chronic pharmacologic
effects of angiotensin-receptor blockers and ACE inhibitors;
3. Minimal or mild atrophy of the adrenal zona glomerulosa. These effects
appear in toxicology studies of other ARB and ACE inhibitors.

Toxicologic studies of the major metabolite TAK-536 M-II showed that this
compound is relatively devoid of pharmacologic activity; in 13-week repeat-dose rat
toxicity studies, renal/adrenal/stomach toxicities were not observed with reported
NOAELs in the 300 mg/kg/day (male) and 3000 mg/kg/day range.
3.3.4.2 Genetic toxicology:
Structural chromosomal aberrations were observed in the Chinese Hamster Lung
Cytogenetic Assay with the prodrug, azilsartan medoxomil (TAK-491) and the metabolite,
TAK-536 MII without metabolic activation. The active moiety, azilsartan (TAK-536) was
also positive in this assay both with and without metabolic activation. Other genetic
toxicity assays were negative. The reviewers recommended that these findings be added
to labeling.
4. Investigator’s brochure:
4.1. Brief description of azilsartan:
As per 3.1
4.2. A summary of pharmacological and toxicological effects of azilsartan :
As per 3.1.4 and 3.3.4
4.3. A summary of pharmacokinetics and biological disposition of azilsartan in
animals:
Absorption: Azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active
metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is
not detected in plasma after oral administration. Dose proportionality in exposure
was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to
320 mg after single or multiple dosing.
The estimated absolute bioavailability of azilsartan following administration of
azilsartan medoxomil is approximately 60%. After oral administration of azilsartan
medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to
3 hours. Food does not affect the bioavailability of azilsartan.
Distribution Azilsartan medoxomil: The volume of distribution of azilsartan is
approximately 16L. Azilsartan is highly bound to human plasma proteins (>99%), mainly
serum albumin. Protein binding is constant at azilsartan plasma concentrations well above
the range achieved with recommended doses.
In rats, minimal azilsartan-associated radioactivity crossed the blood-brain barrier.
Azilsartan passed across the placental barrier in pregnant rats and was distributed to the
fetus. Chlorthalidone: In whole blood, chlorthalidone is predominantly bound to
erythrocyte carbonic anhydrase. In the plasma, approximately 75% of chlorthalidone is
bound to plasma proteins, 58% of the drug being bound to albumin.
Metabolism and Elimination Azilsartan medoxomil: Azilsartan is metabolized to two
primary metabolites. The major metabolite in plasma is formed by O-dealkylation,
referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation,
referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in

humans were approximately 50% and less than 1% of azilsartan, respectively. M-I and
MII do not contribute to the pharmacologic activity of azilsartan medoxomil. The major
enzyme responsible for azilsartan metabolism is CYP2C9.
Following an oral dose of
14
C-labeled azilsartan medoxomil, approximately 55% of
radioactivity was recovered in feces and approximately 42% in urine, with 15% of the
dose excreted in urine as azilsartan. The elimination half-life of azilsartan is
approximately 11 hours and renal clearance is approximately 2.3 mL/min. Steady-state
levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with
repeated once-daily dosing.
 Vd = 16 liters
 Half life = 11 hours
4.4. A description of possible risk and side effects and to be anticipated in the basis of
prior experiment with azilsartan under investigation:
General Disorders and Administration Site Conditions: asthenia, fatigue
Musculoskeletal and Connective Tissue Disorders: muscle spasm
Nervous System Disorders: dizziness, dizziness postural
Respiratory, Thoracic and Mediastinal Disorders: cough
Possible risk:
Fetal/Neonatal Morbidity and Mortality
Hypotension in Volume- or Salt-Depleted Patients
Impaired Renal Function
5. Protocols:
5.1. Study protocol:
Study Type Interventional
Study Phase Phase 3
Condition Hypertension
Intervention Drug: Azilsartan Medoxomil
Study Design Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Asses
sor)
Primary Purpose Treatment
Eligibility:
Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Primary Endpoint:

 Change in 24 hour mean systolic blood pressure (SBP) per ambulatory blood
pressure monitoring (ABPM) at 6 weeks 8.9 and 24 weeks 10.
Secondary and Other Endpoints:
 Change in trough sitting SBP at 6 weeks8,9 and 24 weeks10
 Change from baseline in 24 hour mean diastolic blood pressure (DBP) per
ABPM8-10
 Change in trough sitting DBP8-10
 Change in daytime mean, nighttime mean, mean at 0 to 12 hours, mean at trough
SBP and DBP per ABPM8
 % responders (SBP < 140 mm Hg and/or decreased by > 20 mm Hg)8-10
This study has been completed.
5.2. Clinical trial investigator information:
Confidential
5.3. Overall clinical trial officials and contacts:
Confidential
6. Chemistry manufacturing and control data:
6.1. Product information:
The drug is medoxomil ester and potassium salt of azilsartan.
Chemical Name: (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(5-oxo-4,5-
dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate
monopotassium salt
Molecular Formula: C30H23KN4O8
Molecular Weight: 606.62
The drug substance is a hygroscopic white powder.
It is poorly soluble in aqueous solution but becomes slightly soluble at ph 9 and above.
It is fully characterized by a combination of quantitative elimental analysis uv
spectroscopy ir spectroscopy and mass spectroscopy .
Drug product name / code / type:

a) Proprietary name NA
b) Non proprietary name (USAN)
c) Code name
d) Chem. Type
Pharmacological category : Anti-hypertensive
Dosage form: tablet
Strength or potency: 40mg , 80 mg
Route of administration : oral
. Mechanism of Action:
 Azilsartan (INN, codenamed TAK-536) is an angiotensin-II receptor antagonist
used in the treatment of hypertension that was developed by Takeda.
 Azilsartan medoxomil lowers blood pressure by blocking the action of angiotensin
II, a vasopressor hormone.
 Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-
converting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent
of the renin-angiotensin system, with effects that include vasoconstriction,
stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal
reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-
secreting effects of angiotensin II by selectively blocking the binding of
angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle
and the adrenal gland. Its action is, therefore, independent of the pathway for
angiotensin II synthesis.
 Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of
angiotensin II on renin secretion, but the resulting increased plasma renin activity
and angiotensin II circulating levels do not overcome the effect of azilsartan on
blood pressure.
7. Pharmacology and toxicology data:
As per 3.1.4 and 3.3.4
8. Previous human experience : NA
9. Additional information : NA

(A) TO PREPARE AN APPLICATION FOR IND SUBMISSION FOR AZILSARTAN TABLET IN USA. (B) TO PREPARE CHECKLIST FOR AZILSARTAN TABLET AS PER USA.

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