IRBESARTAN - irbesartan tablet

United States - English - NLM (National Library of Medicine)

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Active ingredient:
IRBESARTAN (UNII: J0E2756Z7N) (IRBESARTAN - UNII:J0E2756Z7N)
Available from:
Bryant Ranch Prepack
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Irbesartan tablets  are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with differ
Product summary:
Product: 71335-1263 NDC: 71335-1263-1 30 TABLET in a BOTTLE NDC: 71335-1263-2 60 TABLET in a BOTTLE NDC: 71335-1263-3 90 TABLET in a BOTTLE
Authorization status:
Abbreviated New Drug Application
Authorization number:
71335-1263-1, 71335-1263-2, 71335-1263-3

IRBESARTAN - irbesartan tablet

Bryant Ranch Prepack

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use IRBESARTAN TABLETS safely and

effectively. See full prescribing information for IRBESARTAN TABLETS.

IRBESARTAN tablets, USP for oral use

Initial U.S. Approval: 1997

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

When pregnancy is detected, discontinue irbesartan tablets as soon as possible. (5.1)

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing

fetus. (5.1)

INDICATIONS AND USAGE

Irbesartan is an angiotensin II receptor blocker (ARB) indicated for:

Treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal

cardiovascular events, primarily strokes and myocardial infarctions. (1.1)

Treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine, and

proteinuria. (1.2)

DOSAGE AND ADMINISTRATION

Indication

Dose

Hypertension (2.2)

150 mg to 300 mg once daily

Diabetic Nephropathy (2.3)

300 mg once daily

DOSAGE FORMS AND STRENGTHS

Tablets: 75 mg, 150 mg, 300 mg (3)

CONTRAINDICATIONS

Hypersensitivity to any component of this product. (4)

Coadministration with aliskiren in patients with diabetes. (4)

WARNINGS AND PRECAUTIONS

Hypotension: Correct volume or salt depletion prior to administration. (5.2)

Monitor renal function and serum potassium. (5.3)

ADVERSE REACTIONS

Nephropathy in type 2 diabetic patients: The most common adverse reactions which were more frequent than placebo

were hyperkalemia dizziness, orthostatic dizziness, and orthostatic hypotension. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or FDA

at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Lithium: Risk of lithium toxicity (7)

Non-Steroidal Anti-inflammatory Drugs (NSAIDs) and COX-2 inhibitors: Increased risk of renal impairment. Reduced

antihypertensive effects. (7)

Dual blockade of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia. (7)

USE IN SPECIFIC POPULATIONS

Nursing Mothers: Potential for adverse effects in infant. (8.3)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: FETAL TOXICITY

1 INDICATIONS & USAGE

1.1 Hypertension

1.2 Nephropathy in Type 2 Diabetic Patients

2 DOSAGE & ADMINISTRATION

2.1 General Considerations

2.2 Hypertension

2.3 Nephropathy in Type 2 Diabetic Patients

2.4 Dose Adjustment in Volume and Salt-Depleted Patients

3 DOSAGE FORMS & STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

5.2 Hypotension in Volume or Salt-Depleted Patients

5.3 Impaired Renal Function

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

7.2 Lithium

7.3 Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2

Inhibitors (COX-2 Inhibitors)

7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

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

13.2 Animal Toxicology & OR Pharmacology

14 CLINICAL STUDIES

14.1 Hypertension

14.2 Nephropathy in Type 2 Diabetic Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue irbesartan tablets as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the

developing fetus [see Warnings and Precautions (5.1)].

1 INDICATIONS & USAGE

1.1 Hypertension

Irbesartan tablets are indicated for the treatment of hypertension, to lower blood pressure. Lowering

blood pressure lowers the risk of fatal and non-fatal cardiovascular (CV) events, primarily strokes and

myocardial infarction. These benefits have been seen in controlled trials of antihypertensive drugs from

a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management,

including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation,

exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood

pressure goals. For specific advice on goals and management, see published guidelines, such as those

of the National High Blood Pressure Education Program’s Joint National Committee on Prevention,

Sections or subsections omitted from the full prescribing information are not listed.

Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different

mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular

morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other

pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and

most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions

in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk

increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe

hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is

similar across populations with varying absolute risk, so the absolute benefit is greater in patients who

are at higher risk independent of their hypertension (for example, patients with diabetes or

hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a

lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and

many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart

failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Irbesartan tablets may be used alone or in combination with other antihypertensive agents.

1.2 Nephropathy in Type 2 Diabetic Patients

Irbesartan tablets are indicated for the treatment of diabetic nephropathy in patients with type 2 diabetes

and hypertension, an elevated serum creatinine, and proteinuria (>300 mg/day). In this population,

irbesartan tablets reduces the rate of progression of nephropathy as measured by the occurrence of

doubling of serum creatinine or end-stage renal disease (need for dialysis or renal transplantation) [see

Clinical Studies (14.2)].

2 DOSAGE & ADMINISTRATION

2.1 General Considerations

Irbesartan tablets may be administered with other antihypertensive agents and with or without food.

2.2 Hypertension

The recommended initial dose of irbesartan tablets are 150 mg once daily. The dosage can be increased

to a maximum dose of 300 mg once daily as needed to control blood pressure [see Clinical Studies

(14.1)].

2.3 Nephropathy in Type 2 Diabetic Patients

The recommended dose is 300 mg once daily [see Clinical Studies (14.2)].

2.4 Dose Adjustment in Volume and Salt-Depleted Patients

The recommended initial dose is 75 mg once daily in patients with depletion of intravascular volume or

salt (e.g., patients treated vigorously with diuretics or on hemodialysis) [see Warnings and Precautions

(5.2)].

3 DOSAGE FORMS & STRENGTHS

Irbesartan tablets 75 mg are a white to off-white film coated, oval, debossed on one side with “ML 94”

and plain on the other side.

Irbesartan tablets 150 mg are a white to off-white film coated, oval, debossed on one side with “ML 95”

and plain on the other side.

Irbesartan tablets 300 mg are a white to off-white film coated, oval, debossed on one side with “ML

96” and plain on the other side.

4 CONTRAINDICATIONS

Irbesartan tablets are contraindicated in patients who are hypersensitive to any component of this

product.

Do not coadminister aliskiren with irbesartan tablets in patients with diabetes.

5 WARNINGS AND PRECAUTIONS

5.1 Fetal Toxicity

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of

pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting

oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential

neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When

pregnancy is detected, discontinue irbesartan tablets as soon as possible [see Use in Specific Populations

(8.1)].

5.2 Hypotension in Volume or Salt-Depleted Patients

In patients with an activated renin-angiotensin system, such as volume or salt-depleted patients (e.g.

those being treated with high doses of diuretics), symptomatic hypotension may occur after initialization

of treatment with irbesartan tablets. Correct volume or salt depletion prior to administration of irbesartan

tablets or use a lower starting dose [see Dosage and Administration (2.4)].

5.3 Impaired Renal Function

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-

angiotensin system. Patients whose renal function may depend in part on the activity of the renin-

angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe heart failure,

or volume depletion) may be at particular risk of developing acute renal failure or death on irbesartan

tablets. Monitor renal function periodically in these patients. Consider withholding or discontinuing

therapy in patients who develop a clinically significant decrease in renal function on irbesartan tablets

[see Drug Interactions (7.3)].

6 ADVERSE REACTIONS

The following important adverse reactions are described elsewhere in the labeling:

Hypotension in Volume or Salt-Depleted Patients [see Warnings and Precautions (5.2)]

Impaired Renal Function [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice. The adverse reaction information from clinical trials

does, however, provide a basis for identifying the adverse events that appear to be related to drug use

and for approximating rates.

Hypertens ion

Irbesartan tablets has been evaluated for safety in more than 4300 patients with hypertension and about

5000 subjects overall. This experience includes 1303 patients treated for over 6 months and 407

patients for 1 year or more.

In placebo-controlled clinical trials, the following adverse reactions were reported in at least 1% of

patients treated with irbesartan tablets (n=1965) and at a higher incidence versus placebo (n=641),

excluding those too general to be informative and those not reasonably associated with the use of drug

because they were associated with the condition being treated or are very common in the treated

population, include: diarrhea (3% vs 2%), dyspepsia/heartburn (2% vs 1%), and fatigue (4% vs 3%).

Irbesartan use was not associated with an increased incidence of dry cough, as is typically associated

with ACE inhibitor use. In placebo-controlled studies, the incidence of cough in irbesartan-treated

patients was 2.8% versus 2.7% in patients receiving placebo.

Nephropathy in Type 2 Diabetic Patients

Hyperkalemia: In the Irbesartan Diabetic Nephropathy Trial (IDNT) (proteinuria ≥900 mg/day, and

serum creatinine ranging from 1.0-3.0 mg/dL), the percent of patients with potassium >6 mEq/L was

18.6% in the irbesartan tablets group versus 6.0% in the placebo group. Discontinuations due to

hyperkalemia in the irbesartan tablets group were 2.1% versus 0.4% in the placebo group.

In IDNT, the adverse reactions were similar to those seen in patients with hypertension with the

exception of an increased incidence of orthostatic symptoms which occurred more frequently in the

irbesartan tablets versus placebo group: dizziness (10.2% vs 6.0%), orthostatic dizziness (5.4% vs

2.7%) and orthostatic hypotension (5.4% vs 3.2%).

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of irbesartan tablets.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always

possible to estimate reliably their frequency or to establish a causal relationship to drug exposure.

Urticaria; angioedema (involving swelling of the face, lips, pharynx, and/or tongue); anaphylactic

reaction including anaphylactic shock; increased liver function tests; jaundice; hepatitis; hyperkalemia;

thrombocytopenia; increased CPK; tinnitus.

7 DRUG INTERACTIONS

7.1 Agents Increasing Serum Potassium

Coadministration of irbesartan tablets with other drugs that raise serum potassium levels may result in

hyperkalemia, sometimes severe. Monitor serum potassium in such patients.

7.2 Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use

of irbesartan and lithium. Monitor lithium levels in patients receiving irbesartan and lithium.

7.3 Non-Steroidal Anti-inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2

Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume depleted (including those on diuretic therapy), or with compromised

renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II

receptor antagonists (including irbesartan) may result in deterioration of renal function, including

possible acute renal failure. These effects are usually reversible. Monitor renal function periodically

in patients receiving irbesartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be

attenuated by NSAIDs including selective COX-2 inhibitors.

7.4 Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is

associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including

acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS

inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use

of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on

irbesartan tablets and other agents that affect the RAS.

Do not coadminister aliskiren with irbesartan tablets in patients with diabetes. Avoid use of aliskiren

with irbesartan tablets in patients with renal impairment (GFR <60 mL/min).

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of

pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting

oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential

neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When

pregnancy is detected, discontinue irbesartan tablets as soon as possible. These adverse outcomes are

usually associated with use of these drugs in the second and third trimesters of pregnancy. Most

epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first

trimester have not distinguished drugs affecting the renin-angiotensin system from other

antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is

important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-

angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform

serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed,

discontinue irbesartan tablets, unless it is considered lifesaving for the mother. Fetal testing may be

appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that

oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe

infants with histories of in utero exposure to irbesartan tablets for hypotension, oliguria, and

hyperkalemia [see Use in Specific Populations (8.4)].

Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than

the maximum recommended human dose (MRHD), fetuses showed increased incidences of renal pelvic

cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also occurred in fetuses at

doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant

rats received irbesartan through Day 20 of gestation but not when drug was stopped on gestation Day

15. The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given

oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality

and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease

in live fetuses [see Nonclinical Toxicology (13.2)].

Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral

doses of radiolabeled irbesartan.

8.3 Nursing Mothers

It is not known whether irbesartan is excreted in human milk, but irbesartan or some metabolite of

irbesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for

adverse effects on the nursing infant, discontinue nursing or discontinue irbesartan tablets.

8.4 Pediatric Use

In infants with histories of in utero exposure to an angiotensin II receptor antagonist, observe for

hypotension, oliguria, and hyperkalemia. If oliguria occurs support blood pressure and renal perfusion.

Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting

for disordered renal function.

Irbesartan, in a study at a dose of up to 4.5 mg/kg/day, once daily, did not appear to lower blood

pressure effectively in pediatric patients ages 6 to 16 years.

Irbesartan tablets has not been studied in pediatric patients less than 6 years old.

8.5 Geriatric Use

Of 4925 subjects receiving irbesartan tablets in controlled clinical studies of hypertension, 911 (18.5%)

were 65 years and over, while 150 (3.0%) were 75 years and over. No overall differences in

effectiveness or safety were observed between these subjects and younger subjects, but greater

sensitivity of some older individuals cannot be ruled out. [See Clinical Pharmacology (12.3) and Clinical

Studies (14.1).]

10 OVERDOSAGE

No data are available in regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks

were well-tolerated. The most likely manifestations of overdosage are expected to be hypotension and

tachycardia; bradycardia might also occur from overdose. Irbesartan is not removed by hemodialysis.

Acute oral toxicity studies with irbesartan in mice and rats indicated acute lethal doses were in excess

of 2000 mg/kg, about 25-fold and 50-fold the MRHD (300 mg) on a mg/m basis, respectively.

11 DESCRIPTION

Irbesartan USP is an angiotensin II receptor (AT subtype) antagonist.

Irbesartan USP is a non-peptide compound, chemically described as a 2-butyl-3-[p-(o-1H-tetrazol-5-

ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

Its molecular formula is C

H N O, and the structural formula:

Irbesartan USP is a white to off-white crystalline powder with a molecular weight of 428.5. It is a

nonpolar compound with a partition coefficient (octanol/water) of 10.1 at pH of 7.4. Irbesartan USP is

slightly soluble in alcohol and methylene chloride and practically insoluble in water.

Irbesartan is available for oral administration in unscored tablets containing 75 mg, 150 mg, or 300 mg

of irbesartan USP. Inactive ingredients include: carboxymethylcellulose calcium, povidone, colloidal

silicon dioxide, sodium starch glycolate, talc and magnesium stearate. The film coating comprises of

hypromellose, lactose monohydrate, titanium dioxide and polyethylene glycol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalyzed by

angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the primary vasoactive hormone of

the renin-angiotensin system, and an important component in the pathophysiology of hypertension. It also

stimulates aldosterone secretion by the adrenal cortex. Irbesartan blocks the vasoconstrictor and

aldosterone-secreting effects of angiotensin II by selectively binding to the AT angiotensin II receptor

found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT receptor in

many tissues, but it is not involved in cardiovascular homeostasis.

Irbesartan is a specific competitive antagonist of AT receptors with a much greater affinity (more than

8500-fold) for the AT receptor than for the AT receptor and no agonist activity.

Blockade of the AT receptor removes the negative feedback of angiotensin II on renin secretion, but

the resulting increased plasma renin activity and circulating angiotensin II do not overcome the effects

of irbesartan on blood pressure.

Irbesartan does not inhibit ACE or renin or affect other hormone receptors or ion channels known to be

involved in the cardiovascular regulation of blood pressure and sodium homeostasis.

12.2 Pharmacodynamics

In healthy subjects, single oral irbesartan doses of up to 300 mg produced dose-dependent inhibition of

the pressor effect of angiotensin II infusions. Inhibition was complete (100%) 4 hours following oral

doses of 150 mg or 300 mg and partial inhibition was sustained for 24 hours (60% and 40% at 300 mg

and 150 mg, respectively).

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan

causes a 1.5-fold to 2-fold rise in angiotensin II plasma concentration and a 2-fold to 3-fold increase in

plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan

administration, but serum potassium levels are not significantly affected at recommended doses.

In hypertensive patients, chronic oral doses of irbesartan (up to 300 mg) had no effect on glomerular

filtration rate, renal plasma flow, or filtration fraction. In multiple dose studies in hypertensive patients,

there were no clinically important effects on fasting triglycerides, total cholesterol, HDL-cholesterol,

or fasting glucose concentrations. There was no effect on serum uric acid during chronic oral

administration, and no uricosuric effect.

12.3 Pharmacokinetics

Absorption

The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60%

to 80%. Following oral administration of irbesartan tablets, peak plasma concentrations of irbesartan are

attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of irbesartan.

Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.

Distribution

Irbesartan is 90% bound to serum proteins (primarily albumin and α1-acid glycoprotein) with negligible

binding to cellular components of blood. The average volume of distribution is 53 to 93 liters.

Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and

placenta. Irbesartan is excreted in the milk of lactating rats.

Elimination

Total plasma and renal clearances are in the range of 157 to 176 mL/min and 3.0 to 3.5 mL/min,

respectively. The terminal elimination half-life of irbesartan averages 11 to 15 hours. Steady-state

concentrations are achieved within 3 days. Limited accumulation of irbesartan (<20%) is observed in

plasma upon repeated once-daily dosing and is not clinically relevant.

Metabolism

Irbesartan is an orally active agent that does not require biotransformation into an active form. Irbesartan

is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration

C-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to

unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide

conjugate (approximately 6%). The remaining oxidative metabolites do not add appreciably to

irbesartan’s pharmacologic activity.

In vitro studies indicate irbesartan is oxidized primarily by CYP2C9; metabolism by CYP3A4 is

negligible.

Excretion

Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or

intravenous administration of

C-labeled irbesartan, about 20% of radioactivity is recovered in the

urine and the remainder in the feces, as irbesartan or irbesartan glucuronide.

Specific Populations

Sex

No sex-related differences in pharmacokinetics are observed in healthy elderly (age 65-80 years) or in

healthy young (age 18-40 years) subjects. In studies of hypertensive patients, there is no sex difference

in half-life or accumulation, but somewhat higher plasma concentrations of irbesartan are observed in

females (11%-44%). No sex-related dosage adjustment is necessary.

Geriatrics

In elderly subjects (age 65-80 years), irbesartan elimination half-life is not significantly altered, but

AUC and C

values are about 20% to 50% greater than those of young subjects (age 18-40 years).

No dosage adjustment is necessary in the elderly.

Race/Ethnicity

In healthy black subjects, irbesartan AUC values are approximately 25% greater than whites; there is no

difference in C

values.

Renal Impairment

The pharmacokinetics of irbesartan is not altered in patients with renal impairment or in patients on

hemodialysis. Irbesartan is not removed by hemodialysis. No dosage adjustment is necessary in patients

with mild to severe renal impairment unless a patient with renal impairment is also volume depleted [see

Warnings and Precautions (5.2) and Dosage and Administration (2.4)].

Hepatic Insufficiency

The pharmacokinetics of irbesartan following repeated oral administration are not significantly affected

in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients

with hepatic insufficiency.

Drug-Drug Interactions

In vitro studies show significant inhibition of the formation of oxidized irbesartan metabolites with the

known cytochrome CYP 2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine. However,

in clinical studies the consequences of concomitant irbesartan on the pharmacodynamics of warfarin

were negligible. Based on in vitro data, no interaction would be expected with drugs whose metabolism

is dependent upon cytochrome P450 isoenzymes 1A1, 1A2, 2A6, 2B6, 2D6, 2E1, or 3A4.

In separate studies of patients receiving maintenance doses of warfarin, hydrochlorothiazide, or

digoxin, irbesartan administration for 7 days has no effect on the pharmacodynamics of warfarin

(prothrombin time) or pharmacokinetics of digoxin. The pharmacokinetics of irbesartan are not affected

by coadministration of nifedipine or hydrochlorothiazide.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis & Mutagenesis & Impairment Of Fertility

No evidence of carcinogenicity was observed when irbesartan was administered at dosages of up to

500/1000 mg/kg/day (males/females, respectively) in rats and 1000 mg/kg/day in mice for up to 2 years.

For male and female rats, 500 mg/kg/day provided an average systemic exposure to irbesartan (AUC

hour, bound plus unbound) about 3 and 11 times, respectively, the average systemic exposure in humans

receiving the maximum recommended dose (MRD) of 300 mg irbesartan/day, whereas 1000 mg/kg/day

(administered to females only) provided an average systemic exposure about 21 times that reported for

humans at the MRD. For male and female mice, 1000 mg/kg/day provided an exposure to irbesartan

about 3 and 5 times, respectively, the human exposure at 300 mg/day.

Irbesartan was not mutagenic in a battery of in vitro tests (Ames microbial test, rat hepatocyte DNA

repair test, V79 mammalian-cell forward gene-mutation assay). Irbesartan was negative in several tests

for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse

micronucleus study).

Irbesartan had no adverse effects on fertility or mating of male or female rats at oral dosages ≤650

mg/kg/day, the highest dose providing a systemic exposure to irbesartan (AUC

hour, bound plus

unbound) about 5 times that found in humans receiving the MRD of 300 mg/day.

13.2 Animal Toxicology & OR Pharmacology

When pregnant rats were treated with irbesartan from Day 0 to Day 20 of gestation (oral doses of 50

mg/kg/day, 180 mg/kg/day, and 650 mg/kg/day), increased incidences of renal pelvic cavitation,

hydroureter and/or absence of renal papilla were observed in fetuses at dosages ≥50 mg/kg/day

(approximately equivalent to the maximum recommended human dose [MRHD], 300 mg/day, on a body

surface area basis). Subcutaneous edema was observed in fetuses at dosages ≥180 mg/kg/day (about 4

times the MRHD on a body surface area basis). As these anomalies were not observed in rats in which

irbesartan exposure (oral doses of 50, 150, and 450 mg/kg/day) was limited to gestation days 6 to 15,

they appear to reflect late gestational effects of the drug. In pregnant rabbits, oral doses of 30 mg

irbesartan/kg/day were associated with maternal mortality and abortion. Surviving females receiving this

dose (about 1.5 times the MRHD on a body surface area basis) had a slight increase in early resorptions

and a corresponding decrease in live fetuses. Irbesartan was found to cross the placental barrier in rats

and rabbits.

14 CLINICAL STUDIES

14.1 Hypertension

The antihypertensive effects of irbesartan tablets were examined in 7 placebo-controlled 8-to 12-week

trials in patients with baseline diastolic blood pressures of 95 to 110 mmHg. Doses of 1 mg to 900 mg

were included in these trials in order to fully explore the dose-range of irbesartan. These studies

allowed comparison of once-or twice-daily regimens at 150 mg/day, comparisons of peak and trough

effects, and comparisons of response by sex, age, and race. Two of the seven placebo-controlled trials

identified above examined the antihypertensive effects of irbesartan and hydrochlorothiazide in

combination.

The 7 studies of irbesartan monotherapy included a total of 1915 patients randomized to irbesartan (1mg

to 900 mg) and 611 patients randomized to placebo. Once-daily doses of 150 mg and 300 mg provided

statistically and clinically significant decreases in systolic and diastolic blood pressure with trough (24

hours post dose) effects after 6 to 12 weeks of treatment compared to placebo, of about 8-10/5-6 mmHg

and 8-12/5-8 mmHg, respectively. No further increase in effect was seen at dosages greater than 300

mg. The dose-response relationships for effects on systolic and diastolic pressure are shown in

Figures 1 and 2.

0-24

0-24

Once-daily administration of therapeutic doses of irbesartan gave peak effects at around 3 to 6 hours

and, in one ambulatory blood pressure monitoring study, again around 14 hours. This was seen with both

once-daily and twice-daily dosing. Trough-to-peak ratios for systolic and diastolic response were

generally between 60% and 70%. In a continuous ambulatory blood pressure monitoring study, once-

daily dosing with 150 mg gave trough and mean 24-hour responses similar to those observed in patients

receiving twice-daily dosing at the same total daily dose.

In controlled trials, the addition of irbesartan to hydrochlorothiazide doses of 6.25 mg, 12.5 mg, or 25

mg produced further dose-related reductions in blood pressure similar to those achieved with the same

monotherapy dose of irbesartan. HCTZ also had an approximately additive effect.

Analysis of age, sex, and race subgroups of patients showed that men and women, and patients over and

under 65 years of age, had generally similar responses. Irbesartan was effective in reducing blood

pressure regardless of race, although the effect was somewhat less in blacks (usually a low-renin

population).

The effect of irbesartan is apparent after the first dose, and it is close to its full observed effect at 2

weeks. At the end of an 8-week exposure, about 2/3 of the antihypertensive effect was still present one

week after the last dose. Rebound hypertension was not observed. There was essentially no change in

average heart rate in irbesartan-treated patients in controlled trials.

14.2 Nephropathy in Type 2 Diabetic Patients

The Irbesartan Diabetic Nephropathy Trial (IDNT) was a randomized, placebo-and active-controlled,

double-blind, multicenter study conducted worldwide in 1715 patients with type 2 diabetes, hypertension

(SeSBP >135 mmHg or SeDBP >85 mmHg), and nephropathy (serum creatinine 1.0 to 3.0 mg/dL in

females or 1.2 to 3.0 mg/dL in males and proteinuria ≥900 mg/day). Patients were randomized to receive

irbesartan 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were titrated to a

maintenance dose of irbesartan 300 mg, or amlodipine 10 mg, as tolerated. Additional antihypertensive

agents (excluding ACE inhibitors, angiotensin II receptor antagonists and calcium channel blockers)

were added as needed to achieve blood pressure goal (≤135/85 or 10 mmHg reduction in systolic blood

pressure if higher than 160 mmHg) for patients in all groups.

The study population was 66.5% male, 72.9% below 65 years of age, and 72% White (Asian/Pacific

Islander 5.0%, Black 13.3%, Hispanic 4.8%). The mean baseline seated systolic and diastolic blood

pressures were 159 mmHg and 87 mmHg, respectively. The patients entered the trial with a mean serum

creatinine of 1.7 mg/dL and mean proteinuria of 4144 mg/day.

The mean blood pressure achieved was 142/77 mmHg for irbesartan, 142/76 mmHg for amlodipine, and

145/79 mmHg for placebo. Overall, 83.0% of patients received the target dose of irbesartan more than

50% of the time. Patients were followed for a mean duration of 2.6 years.

The primary composite endpoint was the time to occurrence of any one of the following events:

doubling of baseline serum creatinine, end-stage renal disease (ESRD; defined by serum creatinine ≥6

mg/dL, dialysis, or renal transplantation), or death. Treatment with irbesartan tablets resulted in a 20%

risk reduction versus placebo (p=0.0234) (see Figure 3 and Table 1). Treatment with irbesartan tablets

also reduced the occurrence of sustained doubling of serum creatinine as a separate endpoint (33%), but

had no significant effect on ESRD alone and no effect on overall mortality (see Table 1).

The percentages of patients experiencing an event during the course of the study can be seen in Table 1

below:

Table 1: IDNT: Components of Primary Composite Endpoint

IRBESARTAN

TABLETS

N=579 (%)

Comparison With Placebo

Comparison With Amlodipine

Placebo

N=569 (%)

Hazard

Ratio

95% CI

Amlodipine

N=567 (%)

Hazard

Ratio

95% CI

Primary Composite

Endpoint

32.6

39.0

0.80

0.66-0.97

(p=0.0234)

41.1

0.77

0.63-0.93

Breakdown of first occurring event contributing to primary endpoint

2x creatinine

14.2

19.5

22.8

ESRD

Death

11.1

11.2

Incidence of total events over entire period of follow-up

2x creatinine

16.9

23.7

0.67

0.52-0.87

25.4

0.63

0.49-0.81

ESRD

14.2

17.8

0.77

0.57-1.03

18.3

0.77

0.57-1.03

Death

15.0

16.3

0.92

0.69-1.23

14.6

1.04

0.77-1.40

The secondary endpoint of the study was a composite of cardiovascular mortality and morbidity

(myocardial infarction, hospitalization for heart failure, stroke with permanent neurological deficit,

amputation). There were no statistically significant differences among treatment groups in these

endpoints. Compared with placebo, irbesartan tablets significantly reduced proteinuria by about 27%, an

effect that was evident within 3 months of starting therapy. Irbesartan tablets significantly reduced the

rate of loss of renal function (glomerular filtration rate), as measured by the reciprocal of the serum

creatinine concentration, by 18.2%.

Table 2 presents results for demographic subgroups. Subgroup analyses are difficult to interpret, and it

is not known whether these observations represent true differences or chance effects. For the primary

endpoint, irbesartan tablets favorable effects were seen in patients also taking other antihypertensive

medications (angiotensin II receptor antagonists, angiotensin-converting-enzyme inhibitors, and calcium

channel blockers were not allowed), oral hypoglycemic agents, and lipid-lowering agents.

Table 2: IDNT: Primary Efficacy Outcome Within Subgroups

Baseline Factors

Irbesartan tablets

N=579 (%)

Comparison With Placebo

Placebo N=569 (%)

Hazard Ratio

95% Cl

Male

27.5

36.7

0.68

0.53-0.88

Female

42.3

44.6

0.98

0.72-1.34

Race

White

29.5

37.3

0.75

0.60-0.95

Non-White

42.6

43.5

0.95

0.67-1.34

Age (years)

<65

31.8

39.9

0.77

0.62-0.97

≥65

35.1

36.8

0.88

0.61-1.29

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 71335-1263

NDC: 71335-1263-1 30 TABLET in a BOTTLE

NDC: 71335-1263-2 60 TABLET in a BOTTLE

NDC: 71335-1263-3 90 TABLET in a BOTTLE

17 PATIENT COUNSELING INFORMATION

Pregnancy

Advise female patients of childbearing age about the consequences of exposure to irbesartan tablets

during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should

be asked to report pregnancies to their physicians as soon as possible.

Potassium Supplements

Advise patients receiving irbesartan tablets not to use potassium supplements or salt substitutes

containing potassium without consulting their healthcare provider [see Drug Interactions (7.1)].

Manufactured for :

Macleods Pharma USA, Inc.

Plainsboro, NJ 08536

Manufactured by :

Macleods Pharmaceuticals Ltd.

Daman (U.T.), INDIA

Packaged by:

Legacy Pharmaceutical Packaging LLC,

Earth City, MO 63045

OR

Macleods Pharmaceuticals Ltd.

Daman (U.T.), INDIA

Irbesartan 150mg Tablet

IRBESARTAN

Bryant Ranch Prepack

irbesartan tablet

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:71335-126 3(NDC:33342-0 48 )

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

IRBESARTAN (UNII: J0 E2756 Z7N) (IRBESARTAN - UNII:J0 E2756 Z7N)

IRBESARTAN

150 mg

Inactive Ingredients

Ingredient Name

Stre ng th

CARBO XYMETHYLCELLULO SE CALCIUM (UNII: UTY7PDF9 3L)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

SO DIUM STARCH GLYCO LATE TYPE A PO TATO (UNII: 58 56 J3G2A2)

PO VIDO NE K2 9 /3 2 (UNII: 39 0 RMW2PEQ)

TALC (UNII: 7SEV7J4R1U)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

HYPRO MELLO SE 2 9 10 ( 5 MPA.S) (UNII: R75537T0 T4)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

PO LYETHYLENE GLYCO L 3 0 0 0 (UNII: SA1B76 4746 )

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

14mm

Flavor

Imprint Code

ML9 5

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:71335-126 3-1

30 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/18 /20 15

2

NDC:71335-126 3-2

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/18 /20 15

3

NDC:71335-126 3-3

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 5/18 /20 15

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 2254

0 9 /27/20 12

Labeler -

Bryant Ranch Prepack (171714327)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Bryant Ranch Prepack

171714327

REPACK(71335-126 3) , RELABEL(71335-126 3)

Revised: 8/2019

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