Irbesartan

428.53

428.53

1592732-453-0

J0E2756Z7N

758696

DTXSID0023169

C29130

Crystals from 96% ethanol

C09CA04|C09DA04|C - Cardiovascular system

29332900

87.1

4.1

white to off-white

1.3±0.1 g/cm3

180-181 °C

648.6±65.0 °C(Predicted)

346.0±34.3 °C

1.690

DMSO: >25mg/mL

-20°C Freezer

1.23X10-15 mm Hg at 25 deg C (est)

Henry's Law constant = 7.04X10-15 atm-cu m/mol at 25 °C (est)

200.8 Ų [M+H]+ [CCS Type: TW, Method: Major Mix IMS/Tof Calibration Kit (Waters)]|201.2 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]|214.21 Ų [M-H]-

Hydroxyl radical reaction rate constant = 3.72X10-11 cu cm/molec-sec at 25 °C (est)

III

6.1

3276

3

22

26-24/25

HM2950270

Xn

Stable under recommended storage conditions.

P201, P202, P260, P261, P263, P264, P270, P271, P273, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P332+P313, P337+P313, P362, P403+P233, P405, P501

H315

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.|Waste treatment methods. Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Incompatible materials: Strong oxidizing agents.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including irbesartan, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Danger|H315 (57.84%): Causes skin irritation [Warning Skin corrosion/irritation]|P201, P202, P260, P261, P263, P264, P270, P271, P273, P280, P281, P302+P352, P304+P340, P305+P351+P338, P308+P313, P312, P314, P321, P332+P313, P337+P313, P362, P403+P233, P405, and P501|Aggregated GHS information provided by 103 companies from 15 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).|Skin protection: Handle with gloves.|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.|Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Avoid breathing dust. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Precautions for safe handling: Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed.|Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

The oral TDLO in humans is 30mg/kg/6W. Symptoms of overdose include hypotension and tachycardia or bradycardia. Terlipressin may be given to treat hypotension and tachycardia if conventional vasopressors fail to control blood pressure.|IDENTIFICATION AND USE: Irbesartan crystals are formulated into oral tablets. Irbesartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive drugs in the management of hypertension. It is also used for the treatment of diabetic nephropathy in patients with type 2 diabetes and hypertension. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of irbesartan overdose include hypotension and tachycardia; bradycardia might also occur from overdose. The use of irbesartan in pregnancy is contraindicated. While use during the first trimester does not suggest a risk of major anomalies, use during the second and third trimester may cause teratogenicity and severe fetal and neonatal toxicity. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion may occur in the newborn following in utero exposure to irbesartan. ANIMAL STUDIES: No evidence of carcinogenicity was observed when irbesartan was administered in rats or mice for up to 2 years. Also, the fertility or mating of male and female rats was unaffected by administration of irbesartan. When pregnant rats were treated with the drug from day 0 to day 20 of gestation, increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla were observed in fetuses at doses as low as 50 mg/kg/day. Subcutaneous edema was observed in fetuses at doses as low as 180 mg/kg/day. As these anomalies were not observed in rats in which drug exposure 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 had a slight increase in early resorptions and a corresponding decrease in live fetuses. 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 also negative in several tests for induction of chromosomal aberrations (in vitro-human lymphocyte assay; in vivo-mouse micronucleus study).

Irbesartan has been associated with a low rate of serum aminotransferase elevations (

Do not coadminister aliskiren with Avapro in patients with diabetes. Avoid use of aliskiren with AVAPRO in patients with renal impairment (GFR <60 mL/min).|Dual blockade of the renin-angiotensin system (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. Closely monitor blood pressure, renal function, and electrolytes in patients on Avapro and other agents that affect the RAS.|Concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.|Possible decreased irbesartan metabolism when irbesartan is used concomitantly with tolbutamide.|For more Interactions (Complete) data for Irbesartan (6 total), please visit the HSDB record page.

When pregnancy is detected, discontinue Avapro as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|Renal Impairment: Use with caution. Deterioration of renal function may occur in patients receiving irbesartan.|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.

Irbesartan is 90% protein bound in plasma, mainly to albumin and α₁-acid glycoprotein.

Irbesartan's production and administration as an antihypertensive(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that irbesartan is expected to be immobile in soil(SRC). The estimated pKa values of irbesartan are 4.08 and 4.29(3), indicating that this compound will exist partially in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization of ibesartan from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 7.0X10-15 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Irbesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2014).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1.3X10+6(SRC), determined from a structure estimation method(2), indicates that irbesartan is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 5.0X10-15 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 1500(SRC), from its estimated log Kow(2)and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is very high, provided the compound is not metabolized by the organism(SRC). Biodegradation data in water were not available(SRC, 2014).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), irbesartan, which has an estimated vapor pressure of 1.2X10-15 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase irbesartan may be removed from the air by wet and dry deposition(SRC). Irbesartan contains chromophores that absorb at wavelengths >290 nm(3) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Irbesartan is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Irbesartan contains chromophores that absorb at wavelengths >290 nm(1) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 1500 was calculated in fish for irbesartan(SRC), using an estimated log Kow of 5.31(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is very high(SRC), provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of irbesartan can be estimated to be 1.3X10+6(SRC). According to a classification scheme(2), this estimated Koc value suggests that irbesartan is expected to be immobile in soil. The estimated pKa values of 4.08 and 4.29(3) indicate that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Irbesartan adsorption isotherms (Kd) of 7.0X10+2 L/kg and 9.4X10+2 L/kg were measured in primary sludge and long-age secondary sludge, respectively. Sludge was obtained from 2 wastewater treatment plants that were representative of plants utilized in industrialized countries(5).

The Henry's Law constant for irbesartan is estimated as 7.0X10-15 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that irbesartan is expected to be essentially nonvolatile from water and moist soil surfaces(2). Irbesartan is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-15 mm Hg(SRC), determined from a fragment constant method(3).

DRINKING WATER: Irbesartan was detected at a mean concentrations of 81, 7, 53 and 15 ng/L in water samples collected during the clarification and sand infiltration, groundwater dilution, ozonation and GAC filtration processes, respectively. Drinking water tested was produced in Spain from October 2008 to January 2009. The compound was not present in the finished product (limit of quantication = 40 ng/L). The treatment plant processes about 400 million liters per day, serving a population of over one million people(1).|SURFACE WATER: Irbesartan was detected at a mean concentration of 330 ng/L (max of 830 ng/L) in raw water from the Llobregat River, north-east Spain used for drinking water production(1).

EXPERIMENTAL: 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.

Occupational exposure to irbesartan may occur through inhalation and dermal contact with this compound at workplaces where irbesartan is produced or used. Exposure to irbesartan among the general population may be limited to those administered the drug Avapro, an hypertensive. (SRC)

Irbesartan is indicated to treat hypertension and diabetic nephropathy in hypertensive patients with type 2 diabetes, elevated serum creatinine, and proteinuria. A combination product with hydrochlorothiazide is indicated for hypertension in patients with uncontrolled hypertension with monotherapy or first line in patients not expected to be well controlled with monotherapy.|FDA Label|Treatment of essential hypertension.Treatment of renal disease in patients with hypertension and type-2 diabetes mellitus as part of an antihypertensive medicinal product regimen.|Treatment of essential hypertension.This fixed-dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone.|Treatment of essential hypertension. This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone.|Treatment of essential hypertension.Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen.|Treatment of essential hypertension., , Treatment of renal disease in patients with hypertension and type-2 diabetes mellitus as part of an antihypertensive medicinal-product regimen.,|Treatment of essential hypertension. This fixed-dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone.|Treatment of essential hypertension.Treatment of renal disease in patients with hypertension and type-2 diabetes mellitus as part of an antihypertensive medicinal-product regimen.|Sabervel is indicated in adults for the treatment of essential hypertension.It is also indicated for the treatment of renal disease in adult patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen.|Treatment of essential hypertension.Treatment of renal disease in patients with hypertension and type 2 diabetes mellitus as part of an antihypertensive medicinal product regimen (see section 5.1).|Treatment of essential hypertension.This fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on irbesartan or hydrochlorothiazide alone (see section 5.1).|Treatment of hypertension

Irbesartan is an angiotensin II receptor blocker used alone or in combination with other agents in the therapy of hypertension and diabetic nephropathy. Irbesartan is associated with a low rate of transient serum aminotransferase elevations and has been linked to rare instances of acute liver injury.

Angiotensin II Receptor Antagonists

Irbesartan has known transformation products that include Valsartan acid.

Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents|Avapro (irbesartan) is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. /Included in US product label/|Avapro is indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, Avapro 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). /Included in US product label/|Angiotensin II receptor antagonists /including irbesartan/ have been used in the management of congestive heart failure. /NOT included in US product label/

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Avapro as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|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 Avapro 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 Avapro, 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.|Neonates with a history of in utero exposure to Avapro: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.|FDA Pregnancy Risk Category: D /POSITIVE EVIDENCE OF RISK. Studies in humans, or investigational or post-marketing data, have demonstrated fetal risk. Nevertheless, potential benefits from the use of the drug may outweigh the potential risk. For example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective./|For more Drug Warnings (Complete) data for Irbesartan (16 total), please visit the HSDB record page.

Irbesartan is an angiotensin receptor blocker used to treat hypertension and diabetic nephropathy. It has a long duration of action as it is usually taken once daily and a wide therapeutic index as doses may be as low as 150mg daily but doses of 900mg/day were well tolerated in healthy human subjects.

Agents that antagonize ANGIOTENSIN II TYPE 1 RECEPTOR. Included are ANGIOTENSIN II analogs such as SARALASIN and biphenylimidazoles such as LOSARTAN. Some are used as ANTIHYPERTENSIVE AGENTS. (See all compounds classified as Angiotensin II Type 1 Receptor Blockers.)|Drugs used in the treatment of acute or chronic vascular HYPERTENSION regardless of pharmacological mechanism. Among the antihypertensive agents are DIURETICS; (especially DIURETICS, THIAZIDE); ADRENERGIC BETA-ANTAGONISTS; ADRENERGIC ALPHA-ANTAGONISTS; ANGIOTENSIN-CONVERTING ENZYME INHIBITORS; CALCIUM CHANNEL BLOCKERS; GANGLIONIC BLOCKERS; and VASODILATOR AGENTS. (See all compounds classified as Antihypertensive Agents.)

Irbesartan is 60-80% bioavailable with a T_max of 1.5-2hours. Taking irbesartan with food does not affect the bioavailability. In one study, healthy subjects were given single or multiple oral doses of 150mg, 300mg, 600mg, and 900mg of irbesartan. A single 150mg dose resulted in an AUC of 9.7±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 16±7 hours, and a C_max of 1.9±0.4µg/mL. A single 300mg dose resulted in an AUC of 20.0±5.2µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±7 hours, and a C_max of 2.9±0.9µg/mL. A single 600mg dose resulted in an AUC of 32.6±11.9µg\•hr/mL, a T_max of 1.5 hours, a half life of 14±8 hours, and a C_max of 4.9±1.2µg/mL. A single 900mg dose resulted in an AUC of 44.8±20.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 17±7 hours, and a C_max of 5.3±1.9µg/mL. Multiple 150mg doses resulted in an AUC of 9.3±3.0µg\•hr/mL, a T_max of 1.5 hours, a half life of 11±4 hours, and a C_max of 2.04±0.4µg/mL. Multiple 300mg doses resulted in an AUC of 19.8±5.8µg\•hr/mL, a T_max of 2.0 hours, a half life of 11±5 hours, and a C_max of 3.3±0.8µg/mL. Multiple 600mg doses resulted in an AUC of 31.9±9.7µg\•hr/mL, a T_max of 1.5 hours, a half life of 15±7 hours, and a C_max of 4.4±0.7µg/mL. Multiple 900mg doses resulted in an AUC of 34.2±9.3µg\•hr/mL, a T_max of 1.8 hours, a half life of 14±6 hours, and a C_max of 5.6±2.1µg/mL.|20% of a radiolabelled oral dose of irbesartan is recovered in urine, and the rest is recovered in the feces. <2% of the dose is recovered in urine as the unchanged drug.|The volume of distribution of irbesartan is 53-93L.|Total plasma clearance of irbesartan is 157-176mL/min while renal clearance is 3.0-3.5mL/min.|Irbesartan is an orally active agent that does not require biotransformation into an active form. The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60% to 80%. Following oral administration of Avapro, peak plasma concentrations of irbesartan are attained at 1.5 to 2 hours after dosing. Food does not affect the bioavailability of Avapro. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range. The terminal elimination half-life of irbesartan averaged 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.|Studies in animals indicate that radiolabeled irbesartan weakly crosses the blood-brain barrier and placenta.|Irbesartan is 90% bound to serum proteins (primarily albumin and a1-acid glycoprotein) with negligible binding to cellular components of blood. The average volume of distribution is 53 liters to 93 liters. Total plasma and renal clearances are in the range of 157 mL/min to 176 mL/min and 3.0 mL/min to 3.5 mL/min, respectively. With repetitive dosing, irbesartan accumulates to no clinically relevant extent.|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.

Irbesaran is largely metabolized by glucuronidation and oxidation in the liver. The majority of metabolism occurs through the action of CYP2C9 with a negligible contribution from CYP3A4. Some hydroxylation also occurs in irbesartan metabolism. Irbesartan can be glucuronidated by UGT1A3 to the M8 metabolite, oxidized to the M3 metabolite, or hydroxylated by CYP2C9 to one of the M4, M5, or M7 metabolites. The M4, M5, and M7 metabolites are all hydroxylated to become the M1 metabolite, which is then oxidized to the M2 metabolite. The M4 metabolite can also be oxidized to the M6 metabolite before hydroxylation to the M2 metabolite. Finally, the minor metabolite SR 49498 is generated from irbesartan by an unknown mechanism.|Irbesartan is metabolized via glucuronide conjugation and oxidation. Following oral or intravenous administration of (14)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. Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or intravenous administration of (14)C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes indicated irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.|Irbesartan has known human metabolites that include (1S,4S,5S,6R)-3-[5-[2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]phenyl]phenyl]-5H-tetrazol-2-ium-2-yl]-2,4,5,6-tetrahydroxycyclohexane-1-carboxylic acid, 2-(3-hydroxybutyl)-3-({4-[2-(2H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-1,3-diazaspiro[4.4]non-1-en-4-one, M3, and M7.

The terminal elimination half life of irbesartan is 11-15 hours.|The terminal elimination half-life of irbesartan averaged 11 to 15 hours.

Irbesartan prevents angiotensin II binding to the AT₁ receptor in tissues like vascular smooth muscle and the adrenal gland. Irbesartan and its active metabolite bind the AT₁ receptor with 8500 times more affinity than they bind to the AT₂ receptor. Irbesartan's prevention of angiotensin II binding causes vascular smooth muscle relaxation and prevents the secretion of aldosterone, lowering blood pressure. Angiotensin II would otherwise bind to the AT₁ receptor, inducing vasoconstriction and aldosterone secretion, raising blood pressure.|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 principal pressor agent of the renin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of the sympathetic nervous system, and smooth muscle cell growth. Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively binding to the AT1 angiotensin II receptor. There is also an AT2 receptor in many tissues, but it is not involved in cardiovascular homeostasis. Irbesartan is a specific competitive antagonist of AT1 receptors with a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor and no agonist activity. Blockade of the AT1 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. Because irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/|Treatment and supportive measures. Monitor blood pressure and heart rate for 6 hours after ingestion. If symptomatic or significant hypotension develops, observe for at least 24 hours. 1. If hypotension occurs, treat it with supine positioning and IV fluids. Vasopressors are rarely necessary. 2. Treat angioedema with usual measures (eg, diphenhydramine, corticosteroids) and discontinue the ACE inhibitors. Switching to an AR blocker may not be appropriate as angioedema has also been reported with these agents. 3. Treat hyperkalemia if it occurs. /Angiotensin blockers and ACE inhibitors/|For more Antidote and Emergency Treatment (Complete) data for Irbesartan (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ 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.|/GENOTOXICITY/ IIrbesartan was negative in ... /the/ in vitro-human lymphocyte assay ... .|/OTHER TOXICITY INFORMATION/ Drugs that act directly on the renin-angiotensin system (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists) can cause fetal and neonatal morbidity and mortality when used in pregnancy during the second and third trimesters. ACE inhibitors also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Irbesartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.|/OTHER TOXICITY INFORMATION/ The human pregnancy experience with irbesartan is limited. However, the antihypertensive mechanisms of action of irbesartan and angiotensin-converting enzyme (ACE) inhibitors are very close. That is, the former selectively blocks the binding of angiotensin II to AT1 receptors, whereas the latter prevents the formation of angiotensin II itself. Therefore, use of this drug during the 2nd and 3rd trimesters may cause teratogenicity and severe fetal and neonatal toxicity identical to that seen with ACE inhibitors. Fetal toxic effects may include anuria, oligohydramnios, fetal hypocalvaria, intrauterine growth restriction, premature birth, and patent ductus arteriosus. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension that are resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to irbesartan. Newborn function and blood pressure should be closely monitored.|/OTHER TOXICITY INFORMATION/ In July 2010, the US Food and Drug Administration (FDA) initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis suggested a possible association between the use of these agents and an increased risk of cancer. The meta-analysis, which combined cancer-related findings from 5 randomized, controlled trials in over 60,000 patients, found a modest but significant increase in the risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist (mostly telmisartan) compared with those in control groups (7.2 versus 6%, respectively; risk ratio 1.08). However, because of several limitations of the study (e.g., trials included in the meta-analysis were not specifically designed to evaluate cancer outcomes, lack of individual patient data), the validity of these findings has been questioned. Subsequent studies, including a larger, more comprehensive meta-analysis conducted by FDA, have not shown an increased risk of cancer in patients receiving angiotensin II receptor antagonists. FDA's meta-analysis, which included trial-level data from 31 randomized studies (total of approximately 156,000 patients), found no evidence of an increased risk of cancer in patients who received an angiotensin II receptor antagonist compared with those who received other treatments (placebo or active control). The overall rate of new cancer occurrence was essentially the same in both groups of patients (1.82 and 1.84 cases per 100 patient-years, respectively). In addition, there was no difference in the risk of cancer-related death, breast cancer, lung cancer, or prostate cancer between the groups. Based on these results and a review of all currently available data related to this potential safety concern, FDA has concluded that use of angiotensin II receptor antagonists is not associated with an increased risk of cancer.

2-n-butyl-3-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1,3-diazaspiro(4,4)non-1-en-4-one

Table: Irbesartan Preparations [Table#8212]|Table: Irbesartan Combination Preparations [Table#8213]

HPLC determination in plasma and urine.

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