Azilsartan

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.

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.

Overall, azilsartan is well-tolerated in most patients, with few adverse effects. In a controlled, double-blind, randomized clinical trial comparing the efficacy of azilsartan medoxomil with ramipril in 784 patients, the overall rate of adverse events was significantly lower with azilsartan. Patients were started on 20 mg of azilsartan and 2.5 mg of ramipril once daily for 2 weeks, followed by titration to 40 or 80 mg of azilsartan and 10 mg of ramipril for 22 weeks.

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.

/LABORATORY ANIMALS: Acute Exposure/ Azilsartan medoxomil has low oral acute toxicity in rats and dogs. Doses up to 2,000 mg/kg were administered to rats and 30 mg/kg to dogs with no severe clinical signs or mortality. Transient diarrhea and vomiting occurred in dogs at > or = 30 mg/kg. Severe clinical signs (including convulsions) occurred after intravenous bolus dosing of azilsartan medoxomil (> or = 40 mg/kg) in rats, with lethality at 40 mg/kg in males and 200 mg/kg in females.

/LABORATORY ANIMALS: Acute Exposure/ Severe clinical signs (including convulsions) occurred after intravenous bolus dosing of azilsartan medoxomil (> or = 40 mg/kg) in rats, with lethality at 40 mg/kg in males and 200 mg/kg in females.

/LABORATORY ANIMALS: Acute Exposure/ Azilsartan medoxomil has low oral acute toxicity in rats and dogs. Doses up to 2,000 mg/kg were administered to rats and 30 mg/kg to dogs with no severe clinical signs or mortality. Transient diarrhea and vomiting occurred in dogs at 30 mg/kg.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Oral repeat-dose toxicity studies demonstrated that the NOAELs for azilsartan medoxomil occurred at 20 mg/kg/day in mice (13 weeks), 20 (males) and 200 (females) mg/kg/day in rats (6 months), and 60 (males) and 12 (females) mg/kg/day in dogs (6 months). Severe toxicity, including mortality, occurred in dogs administered azilsartan medoximil at 300 mg/kg/day (males) and > or = 100 mg/kg/day (females). Following administration of 300 mg/kg/day (males) and 100 mg/kg/day (females) of azilsartan in the chronic dog study, systemic exposure to azilsartan at 6 months was about 7- fold (both males and females,) compared with exposure at the maximum recommended human dose (MRHD). Clinical and clinical pathology findings and pathologic lesions in several organs (including kidney, gastrointestinal tract and heart) reflected effects secondary to uremia and altered body fluid balance/poor general condition. Deaths were reported in mice at doses > or = 200 mg/kg/day. No deaths occurred in rats administered < or = 2,000 mg/kg/day for 6 months. Hematological effects in animals included decreases in erythroid parameters, such as erythrocyte count, hemoglobin concentration, and hematocrit value. Clinical chemistry changes included increases in blood urea nitrogen, creatinine, and total cholesterol, as well as decreased levels of triglycerides, sodium, chloride and calcium. Increased plasma/serum aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase occurred following administration of relatively high dose levels. Urinary excretion of sodium and chloride were decreased. Histopathological findings in the stomach and kidneys of rodents and dogs, and in adrenals of rats were observed, including changes in the glandular stomach that were seen in mice, rats and dogs. In kidney, hypertrophy or hyperplasia of the juxtaglomerular apparatus is considered to be due to the pharmacological effects of azilsartan on the RAAS. Renal tubular dilatation, basophilia, vacuolization and regeneration were observed in mice, rats, and dogs. These histopathological findings in kidneys (and in stomach in one rat study) occurred, in repeat-dose toxicity studies, at systemic exposure levels similar to the MRHD of 80 mg/day in humans. Atrophy of the adrenal cortex zona glomerulosa, considered to represent a pharmacologic effect, occurred in rats at systemic exposure values of azilsartan that were lower than at the MRHD of 80 mg/day. Reversibility of the adrenal zona glomerulosa atrophy was not evaluated in non-clinical studies. Decreased heart weights were also observed in rats and mice treated with repeated dose of azilsartan medoxomil. Decreased red blood cell parameters and heart weight, and pathologic changes in kidneys and stomach are anticipated effects in animals secondary to antagonism at angiotensin II type 1 (AT1) receptors.

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.

/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.

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/

Oral: Tablet (fixed combination) 40 mg (with 12.5 or 25 mg chlorthalidone), Edarbyclor (Takeda). /Azilsartan kamedoxomil/

Table: Azilsartan Kamedoxomil Preparations [Table#8194]