Azilsartan

456.45

456.45

1308068-626-2

F9NUX55P23

DTXSID70163712

Colorless prisms from ethanol

115

4.4

white to beige

1.42

212-214 deg C

1.695

DMSO: soluble15mg/mL (clear solution)

2-8°C

1.45X10-20 mm Hg at 25 deg C (est)

Henry's Law constant = 5.45X10-20 atm-cu m/mol at 25 °C (est)

pKa at 0.1 N NaOH (26 eg C): 6.1

Hydroxyl radical reaction rate constant = 5.38X10-10 cu cm/molec-sec at 25 °C (est)|Crystals from ethanol /Azilsartan medoxomil/|Crystals; mp 196 °C (decomposes). Freely soluble in methanol. Practically insolluble in water /Azilsartan kamedoxomil/

NONH for all modes of transport

3

Stable under recommended storage conditions.

P201, P202, P260, P263, P264, P270, P281, P308+P313, P314, P405, P501

H360

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.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contaminated packaging: Dispose of as unused product.

Strong oxidizing agents.

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

|Danger|H360 (25%): May damage fertility or the unborn child [Danger Reproductive toxicity]|P201, P202, P260, P263, P264, P270, P281, P308+P313, P314, P405, and P501|Aggregated GHS information provided by 4 companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

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).|Skin and 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.|Hand protection: Handle with gloves.|Eye protection; Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

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

Personal precautions: Avoid dust formation. Avoid breathing vapors, mist or gas. Environmental precautions: Do not let product enter drains. Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal.

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.|Provide appropriate exhaust ventilation at places where dust is formed.|Hygiene measures: General industrial hygiene practice.

IDENTIFICATION AND USE: Azilsartan is a white crystalline powder formulated into oral tablets. Azilsartan is an angiotensin II type 1 (AT1) receptor antagonist. It is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Azilsartan medoxomil, a prodrug, which is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. HUMAN EXPOSURE AND TOXICITY: Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once-daily doses up to 320 mg of azilsartan were administered for seven days and were well tolerated. The use of azilsartan during pregnancy is contraindicated. Drugs that act directly on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase 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. Azilsartan should be discontinued as soon as possible when pregnancy is detected, unless continued use is considered life-saving. ANIMAL STUDIES: There was no evidence of carcinogenicity when azilsartan was administered in the diet to mice and rats for up to two years. Also, azilsartan had no adverse effects on fertility of male or female rats at oral doses of up to 1,000 mg/kg/day. Azilsartan was not teratogenic when administered at oral doses up to 1,000 mg/kg/day to pregnant rats or up to 50 mg/kg/day to pregnant rabbits. However, embryo-fetal toxicity occurred at azilsartan doses of 1,000 mg/kg/day in rats (dilated renal pelvis and short supernumerary ribs) and 50 mg/kg/day in rabbits (increased post-implantation loss, embryo-fetal deaths, and decreased number of live fetuses). Embryo-fetal toxicity was also reported in rats with azilsartan doses as low as 30 mg/kg/day (delayed ossification in the caudal vertebrae) and 100 mg/kg/day (lower male fetal body weight) and at 500 mg/kg/day in rabbits (increased post-implantation loss). Azilsartan medoxomil, azilsartan, and the M-II metabolite were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was positive in this assay during a 24-hour assay without metabolic activation. Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.

Azilsartan has been associated with a low rate of serum aminotransferase elevations that, in controlled trials, was no higher than with placebo therapy. These elevations were transient and rarely required dose modification. No specific instances of clinically apparent acute liver injury have been reported in association with azilsartan therapy, but it has been available for a limited time. Other ARBs have been linked to rare instances of symptomatic hepatotoxicity. The onset of liver injury is usually within 1 to 8 weeks of starting therapy and the serum enzyme pattern is typically hepatocellular with an acute hepatitis-like clinical syndrome. In some instances, cholestasis has developed which can be prolonged and relapsing, but ARB therapy has not been associated with vanishing bile duct syndrome or chronic liver injury. Immunoallergic manifestations (rash, fever, eosinophilia) are not common, nor is autoantibody formation.

Since the use of potassium supplements and potassium-containing salt substitutes with an angiotensin II receptor antagonist (e.g., azilsartan medoxomil) can increase the potential for hyperkalemia, some clinicians have suggested that concomitant administration of these agents with azilsartan medoxomil should be avoided.|Since the use of potassium-sparing diuretics (i.e., amiloride, spironolactone, triamterene) with an angiotensin II receptor antagonist (i.e., azilsartan medoxomil) can increase the potential for hyperkalemia, some clinicians have suggested that concomitant administration of these drugs with azilsartan medoxomil should be avoided.|Concomitant treatment with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors, and angiotensin II receptor antagonists may result in deterioration of renal function, including possible acute renal failure, in patients who are geriatric, volume-depleted (including those on diuretic therapy), or have compromised renal function. These effects usually are reversible. Renal function should be periodically monitored in patients receiving azilsartan and NSAIA therapy. The antihypertensive effect of azilsartan may be attenuated in patients receiving NSAIAs, including selective COX-2 inhibitors.|Reversible increases in serum creatinine, which may occur in patients receiving azilsartan medoxomil, may be larger in patients also receiving hydrochlorothiazide.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.|Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide. In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.

EXPERIMENTAL: Azilsartan is distributed into milk in rats; it is not known whether azilsartan is distributed into human milk.

Azilsartan is an angiotensin II receptor blocker (ARB) used in the therapy of hypertension. It is associated with a low rate of transient serum aminotransferase elevations, but has yet to be linked to instances of acute liver injury.

Angiotensin II Receptor Antagonists

Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. /Included in US product label/|Edarbi may be used alone or in combination with other antihypertensive agents.|Both angiotensin II receptor antagonists /eg, azilsartan/ and ACE inhibitors have been shown to slow the rate of progression of renal disease in hypertensive patients with diabetes mellitus and microalbuminuria or overt nephropathy, and use of a drug from either class is recommended in such patients. /NOT included in US product label/

/BOXED WARNING/ WARNING: FETAL TOXICITY. When pregnancy is detected, discontinue Edarbi as soon as possibl. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus|Drugs that act directly on the renin-angiotensin system (e.g., ACE inhibitors, angiotensin II receptor antagonists) reduce fetal renal function and increase 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. Azilsartan 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.|Use of drugs that affect 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 Edarbi as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester 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.|Because symptomatic hypotension may occur in patients with an activated renin-angiotensin system (e.g., patients with volume or salt depletion secondary to high doses of diuretics), azilsartan should be initiated in such patients after volume or salt depletion is corrected, or a lower initial dose of the drug should be used. If hypotension occurs in patients receiving azilsartan medoxomil, the patient should be placed in the supine position and, if necessary, an IV infusion of 0.9% sodium chloride injection should be administered. Transient hypotension is not a contraindication to additional doses of azilsartan, and therapy with the drug can be cautiously reinstated after blood pressure has been stabilized (e.g., with volume expansion).|For more Drug Warnings (Complete) data for Azilsartan (14 total), please visit the HSDB record page.

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.|The volume of distribution of azilsartan is approximately 16 L. 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.|Following an oral dose of 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 five days, and no accumulation in plasma occurs with repeated once-daily dosing.|Azilsartan medoxomil is 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.|For more Absorption, Distribution and Excretion (Complete) data for Azilsartan (8 total), please visit the HSDB record page.

Azilsartan medoxomil is rapidly hydrolysed to the active moiety azilsartan by esterases in the gastrointestinal tract and/or during drug absorption. Based on vitro studies, the enzymes involved in the hydrolysis of azilsartan medoxomil to azilsartan in human plasma, and in human liver and small intestinal cytosol seem to be similar to those involved in the hydrolysis of olmesartan medoxomil. Currently, no drug interactions are listed for the hydrolysis of azilsartan medoxomil. The enzyme carboxymethylenebutenolidase is a recently discovered hydrolysis mechanism for azilsartan medoxomi in the intestine and liver, but no interactions with other drugs have been reported for this enzyme in the Metabolism and Transport Drug Interaction Database (DIDB). Also no interactions have been reported for human serum albumin or arylesterases. Since there are multiple esterase pathways involved in the conversion of azilsartan medoxomil to azilsartan, the potential for interactions via this pathway is considered to be minimal. The metabolites M-I and M-II were formed by decarboxylation and dealkylation of azilsartan, respectively, and are pharmacologically inactive. CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 are all capable of metabolising azilsartan. However, CYP2C9 showed the highest activity in metabolising azilsartan to M-II and CYP2C8 in metabolising azilsartan to M-I.|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 M-II do not contribute to the pharmacologic activity of Edarbi. The major enzyme responsible for azilsartan metabolism is CYP2C9.

The half-life of azilsartan in plasma was between 4 and 6 hr in rats and dogs and approximately 12 hr in humans.|The elimination half-life of azilsartan is approximately 11 hours ... .

Azilsartan medoxomil is a newly approved angiotensin receptor blocker (ARB) reported to lower 24 hr blood pressure more effectively than maximally recommended doses of older ARBs. Although azilsartan is considered to be an unusually potent angiotensin II type 1 (AT1) receptor antagonist, little is known about the potential pleiotropic effects of this molecule. /The purpose of this study was to investigate/ pleiotropic features of azilsartan in cell-based assay systems independent of its effects on blood pressure. In cultured 3T3-L1 preadipocytes, azilsartan enhanced adipogenesis and exerted greater effects than valsartan on expression of genes encoding peroxisome proliferator-activated receptor-a (PPARa), PPARd, leptin, adipsin, and adiponectin. The effects of azilsartan on adipocyte differentiation and gene expression were observed at concentrations of azilsartan that did not classically stimulate PPAR activity in cell-based transactivation assays. Azilsartan also potently inhibited vascular cell proliferation in the absence of exogenously supplemented angiotensin II. In aortic endothelial cells, azilsartan inhibited cell proliferation at concentrations as low as 1 umol/L, whereas valsartan showed little or no antiproliferative effects at concentrations below 10 umol/L. Antiproliferative effects of azilsartan were also observed in cells lacking AT1 receptors. In addition, azilsartan, but not valsartan, blocked angiotensin II-induced activation of mitogen-activated protein kinase in vascular smooth muscle cells 4-8 hr after washout of drug from the incubation media. These findings suggest that azilsartan can function as a pleiotropic ARB with potentially beneficial effects on cellular mechanisms of cardiometabolic disease through actions that could involve more than just blockade of AT1 receptors and/or reduction in blood pressure.|Angiotensin receptor (type 1) blockers (ARBs) can reduce both hypertension and insulin resistance induced by local and systemic activation of the renin-angiotensin-aldosterone system. The effectiveness of azilsartan medoxomil (AZIL-M), a novel imidazole-based ARB, to facilitate metabolic improvements in conditions of angiotensin II (Ang II)-associated insulin resistance is currently unknown. The aim of this study was to determine the impact of chronic AZIL-M treatment on glucose transport activity and key insulin signaling elements in red skeletal muscle of Ang II-treated rats. Male Sprague-Dawley rats were treated for 8 weeks with or without Ang II (200 ng/kg/min) combined with either vehicle or AZIL-M (1 mg/kg/day). Ang II induced significant (p < 0.05) increases in blood pressure, which were completely prevented by AZIL-M. Furthermore, Ang II reduced insulin-mediated glucose transport activity in incubated soleus muscle, and AZIL-M co-treatment increased this parameter. Moreover, AZIL-M treatment of Ang II-infused animals increased the absolute phosphorylation of insulin signaling molecules, including Akt [both Ser473 (81%) and Thr308 (23%)] and AS160 Thr642 (42%), in red gastrocnemius muscle frozen in situ. Absolute AMPKalpha (Thr172) phosphorylation increased (98%) by AZIL-M treatment, and relative Thr389 phosphorylation of p70 S6K1, a negative regulator of insulin signaling, decreased (51%) with AZIL-M treatment. These results indicate that ARB AZIL-M improves the in vitro insulin action on glucose transport in red soleus muscle and the functionality of the Akt/AS160 axis in red gastrocnemius muscle in situ in Ang II-induced insulin-resistant rats, with the latter modification possibly associated with enhanced AMPKalpha and suppressed p70 S6K1 activation.

/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 Azilsartan (6 total), please visit the HSDB record page.

/SIGNS AND SYMPTOMS/ Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once-daily doses up to 320 mg of Edarbi were administered for seven days and were well tolerated.

2-ethoxy-1-((2'-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylic acid

Oral: Tablet (fixed combination) 40 mg (with 12.5 or 25 mg chlorthalidone), Edarbyclor (Takeda). /Azilsartan kamedoxomil/|Table: Azilsartan Kamedoxomil Preparations [Table#8206]

The recently approved angiotensin II receptor blocker, azilsartan medoxomil (AZL), was determined spectrophotometrically and spectrofluorimetrically in its combination with chlorthalidone (CLT) in their combined dosage form. The UV-spectrophotometric technique depends on simultaneous measurement of the first derivative spectra for AZL and CLT at 286 and 257 nm, respectively, in methanol. The spectrofluorimetric technique depends on measurement of the fourth derivative of the synchronous spectra intensities of AZL in presence of CLT at 298 nm in methanol. The effects of different solvents on spectrophotometric and spectrofluorimetric responses were studied. For, the spectrofluorimetric study, the effect of pH and micelle-assisted fluorescence enhancement were also studied. Linearity, accuracy, and precision were found to be satisfactory over the concentration ranges of 8-50 ug mL(-1) and 2-20 ug mL(-1) for AZL and CLT, respectively, in the spectrophotometric method as well as 0.01-0.08 ug mL(-1) for AZL in the spectrofluorimetric method. The methods were successfully applied for the determination of the studied drugs in their co-formulated tablets. The developed methods are inexpensive and simple for the quality control and routine analysis of the cited drugs in bulk and in pharmaceuticals.