(a) to prepare an application for ind submission for azilsartan tablet in usa. (b) to prepare...

Drug Regulation & Regulatory Authorities

Dept. Of Quality Assurance & Regulatory AffairsL. 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.php2. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000chemR.pdf3. http://www.biomedcentral.com/1471-2261/13/464. http://en.wikipedia.org/wiki/azilsartan5. www.edarbi.com/docx./Edarbi_pi.html6. www.medicines.org.uk/cmc/medicine/26412/spc

Investigational New Drug Application

1. FDA Forms.2. Table of contents3. 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 content6. Chemistry Manufacturing and Control data 6.1 Product data 7. Pharmacological and Toxicological data8. Previous human experience9. Additional information



Content3. Introductory statement and general investigational plan3.1Product 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 hydroxideHydroxypropylcellulose (E 463)Croscarmellose sodiumCellulose, 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 patientsGastrointestinal: 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 azotemiaRespiratory: 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 hoursVd : 16 Lt1/2 : 11 hoursClearance : 2.3 mL/minProtein 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


Clinic Blood Pressure


24 Hour Mean by ABPM


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 considerationsAzilsartan 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 humanmetabolite, 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 medoxomilproduced 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 rattoxicity 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, fatigueMusculoskeletal and Connective Tissue Disorders: muscle spasmNervous System Disorders: dizziness, dizziness posturalRespiratory, Thoracic and Mediastinal Disorders: cough

Possible risk:Fetal/Neonatal Morbidity and MortalityHypotension in Volume- or Salt-Depleted Patients Impaired Renal Function

5. Protocols: 5.1. Study protocol:

Study Type InterventionalStudy Phase Phase 3Condition HypertensionIntervention Drug: Azilsartan Medoxomil Study Design Allocation: Randomized

Endpoint Classification: Safety/Efficacy StudyIntervention Model: Parallel AssignmentMasking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)

Primary Purpose Treatment

Eligibility:

Ages Eligible for Study: 18 Years and olderGenders Eligible for Study: BothAccepts 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 saltMolecular Formula: C30H23KN4O8

Molecular Weight: 606.62The 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 NAb) Non proprietary name (USAN)c) Code name d) Chem. Type Pharmacological category : Anti-hypertensiveDosage form: tabletStrength or potency: 40mg , 80 mgRoute 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...

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