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Pharmaceuticals -> Antihypertensives

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Pharmaceuticals -> Metabolite of Candesartan cilexetil

Breast Feeding; Lactation; Milk, Human; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Blockers

Pharmaceuticals

Colorless crystals from ethanol + water, mp 163 °C (decomposes). Also reported as white to off-white powder, sparingly soluble in methanol. Practically insoluble in water. /Candesartan 1-[[(Cyclohexyloxy)carbonyl]oxy]ethyl ester/

White to off-white powder, mw - 610.67. Practically insoluble in water and sparingly soluble in methanol. ... a racemic mixture containing one chiral center at the cyclohexyloxycarbonyloxy ethyl ester group. Following oral administration ... undergoes hydrolysis at the ester link to form the active drug, candesartan, which is achiral. /Cilexetil/

White, or practically white, crystalline powder, mw - 297.72 .. Slightly soluble in water, but freely soluble in hydroxide solution /Cilexetil hydrochlorothiazide/

Warning

H302 (16.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P261, P264, P264+P265, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P317, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 6 reports by companies from 6 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H361: Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

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

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.

Store at 25 °C (77 °F); excursions permitted to 15-30 °C (59-86 °F). Keep container tightly closed.

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature: 2 - 8 °C.

Accidental Release Measures. Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. 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.

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. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

Precautions for safe handling: Avoid contact with skin and eyes. 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.

Eye/face protection: Safety glasses with side-shields conforming to EN166 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: Impervious clothing, The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Do not co-administer aliskiren with Atacand in patients with diabetes. Avoid use of aliskiren with Atacand in patients with renal impairment (GFR <60 mL/min).

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors, and with some angiotensin II receptor antagonists. An increase in serum lithium concentration has been reported during concomitant administration of lithium with Atacand. Monitor serum lithium levels.

Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Atacand. The possibility of symptomatic hypotension with the use of Atacand can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of Atacand. /From table/

Atacand decreases the production of aldosterone. Potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitute should also be used with caution. /From table/

For more Interactions (Complete) data for CANDESARTAN (8 total), please visit the HSDB record page.

The most common adverse effects reported for candesartan include symptomatic hypotension, abnormal renal function, and hyperkalemia. In the CHARM trial, symptomatic hypotension, impaired renal function (elevated serum creatinine), and hyperkalemia occurred with an incidence of 18.8%, 12.5%, and 6.3%, respectively. Hypotension is more common in patients who are volume- or salt-depleted due to dietary restriction, dialysis, diarrhea, emesis, or diuretic use. Other reported adverse effects include headache, back pain, angioedema, and upper respiratory tract infections. A case of candesartan-induced lichenoid drug eruption has been reported.

IDENTIFICATION AND USE: Candesartan is a white to off white powder that is formulated into oral tablets. Candesartan 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 in adults and children from 1 to less than 17 years of age. It is also used for the treatment of heart failure in adults with left ventricular systolic dysfunction to reduce cardiovascular death and heart failure hospitalizations. HUMAN EXPOSURE AND TOXICITY: The most likely manifestations of candesartan overdose include hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. While candesartan can be used in hypertensive children, it is not approved for use in children less one 1 year of age as drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys. The use of candesartan is also contraindicated during pregnancy. 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. Stillbirth or neonatal death may occur. Anuria-associated oligohydramnios may produce fetal limb contractures, craniofacial deformation, and pulmonary hypoplasia. Severe anuria and hypotension, resistant to both pressor agents and volume expansion, may occur in the newborn following in utero exposure to candesartan. ANIMAL STUDIES: There was no evidence of carcinogenicity when candesartan was orally administered to mice. Also, the fertility of male and female rats was unaffected by administration of candesartan. No maternal toxicity or adverse effects on fetal development were observed when candesartan was administered to pregnant mice at oral doses up to 1000 mg/kg. However, doses as low as 10 mg/kg/day administered to rats were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. Candesartan given to pregnant rabbits at an oral dose of 3 mg/kg/day caused maternal toxicity (decreased body weight and death) but had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. Candesartan and its O-deethyl metabolite tested positive for genotoxicity in the in vitro Chinese hamster lung (CHL) chromosomal aberration assay. Neither compound tested positive in the Ames microbial mutagenesis assay or the in vitro mouse lymphoma cell assay. Candesartan (but not its O-deethyl metabolite) was also evaluated in vivo in the mouse micronucleus test and in vitro in the Chinese hamster ovary (CHO) gene mutation assay, in both cases with negative results. Candesartan cilexetil was evaluated in the Ames test, the in vitro mouse lymphoma cell and rat hepatocyte unscheduled DNA synthesis assays and the in vivo mouse micronucleus test, in each case with negative results.

Signs and Symptoms of Overdose

/SIGNS AND SYMPTOMS/ The most likely manifestation of overdosage with Atacand would be hypotension, dizziness, and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted.

/CASE REPORTS/ ... A patient with generalized pustular psoriasis induced by candesartan cilexetil (AT1 receptor antagonist), who was previously diagnosed as flexural psoriasis /is described/.

/CASE REPORTS/ Despite data suggesting that angiotensin-receptor blockers (ARBs) are associated with increased risk to the fetus, there has been an increasing exposure of ARBs in pregnancy. We report a case report regarding a woman, who accidentally was treated with Candesartan during the first 22 weeks of pregnancy. At 22 weeks of gestation the fetal kidneys were oedematous with very little amniotic fluid. The prognosis for the fetus was considered poor. Five weeks after discontinuation of Candesartan normal quantities of amnionic fluid and a visible fetal bladder was registered. After delivery at week 31, creatinine clearance, diuresis and urine examination of the neonate were within normal limits. Ultrasound examinations of the kidneys showed bilaterally marked calices, small cysts and parenchymal increased echogenety at 1 week with complete sonographic normalization at 6 weeks. However, experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood.

/CASE REPORTS/ A 41 year old woman was treated with candesartan throughout a 32 week gestation. Because of anhydramnios, she was delivered of a 1120 gram (0.4th percentile) male infant in poor condition. The infant had defective ossification of the roof of the calvarium, joint contractures, mild hypospadias, rocker bottom feet, a large abdominal left kidney and absent right kidney. He developed intractable hypotension, unresponsive to hydration, and remained anuric until he died.

For more Human Toxicity Excerpts (Complete) data for CANDESARTAN (14 total), please visit the HSDB record page.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

candesartan

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There was no evidence of carcinogenicity when candesartan cilexetil was orally administered to mice and rats for up to 104 weeks at doses up to 100 and 1000 mg/kg/day, respectively. Rats received the drug by gavage, whereas mice received the drug by dietary administration. These (maximally-tolerated) doses of candesartan cilexetil provided systemic exposures to candesartan (AUCs) that were, in mice, approximately 7 times and, in rats, more than 70 times the exposure in man at the maximum recommended daily human dose (32 mg).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Oral doses > or = 10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10 mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/sq m basis (comparison assumes human body weight of 50 kg).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/sq m basis) were administered to pregnant mice.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/sq m basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development.

For more Non-Human Toxicity Excerpts (Complete) data for CANDESARTAN (8 total), please visit the HSDB record page.

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.

Sensitivity reactions, including various anaphylactoid reactions and/or angioedema, have been reported with use of angiotensin II receptor antagonists, including candesartan. Candesartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE or angiotensin II receptor antagonist therapy.

Children < 1 year of age must not receive Atacand for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.

Despite data suggesting that angiotensin-receptor blockers (ARBs) are associated with increased risk to the fetus, there has been an increasing exposure of ARBs in pregnancy. We report a case report regarding a woman, who accidentally was treated with Candesartan during the first 22 weeks of pregnancy. At 22 weeks of gestation the fetal kidneys were oedematous with very little amniotic fluid. The prognosis for the fetus was considered poor. Five weeks after discontinuation of Candesartan normal quantities of amnionic fluid and a visible fetal bladder was registered. After delivery at week 31, creatinine clearance, diuresis and urine examination of the neonate were within normal limits. Ultrasound examinations of the kidneys showed bilaterally marked calices, small cysts and parenchymal increased echogenety at 1 week with complete sonographic normalization at 6 weeks. However, experimental studies raise the question of potential long-term adverse effects, including renal dysfunction and arterial hypertension in adulthood.

For more Populations at Special Risk (Complete) data for CANDESARTAN (7 total), please visit the HSDB record page.

While data specific to candesartan were not located(SRC, 2007), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

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

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

C - Cardiovascular system

QC - Cardiovascular system

Although these agents /angiotensin II receptor antagonists/ are similar to ACE inhibitors in that they decrease the effects of angiotensin II, rather than decreasing the formation of angiotensin II, drugs antagonize angiotensin II at the type I angiotensin receptor. This allows the drugs to inhibit the vasoconstrictive and aldosterone promoting effects of angiotensin II without interfering with bradykinin degradation, significantly reducing the adverse effects of cough and angioedema seen with ACE inhibitor therapy. ... /Angiotensin II receptor antagonists/

Angiotensin II is 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, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Candesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathways for angiotensin II synthesis. There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Candesartan has much greater affinity (>10,000-fold) for the ATI receptor than for the AT2 receptor. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because candesartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Candesartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of candesartan on blood pressure.

Candesartan cilexetil is rapidly and completely bioactivated by ester hydrolysis during absorption from the gastrointestinal tract to candesartan, a selective AT1 subtype angiotensin II receptor antagonist. Candesartan is mainly excreted unchanged in urine and feces (via bile). It undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite.

Candesartan has known human metabolites that include (2S,3S,4S,5R)-6-[2-Ethoxy-3-[[4-[2-(2H-tetrazol-5-yl)phenyl]phenyl]methyl]benzimidazole-4-carbonyl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid and 3-[[4-[2-[2-[(3R,4S,5S,6S)-6-carboxy-3,4,5-trihydroxyoxan-2-yl]tetrazol-5-yl]phenyl]phenyl]methyl]-2-ethoxy-1H-benzimidazol-3-ium-4-carboxylic acid.

S8Q36MD2XX

CANDESARTAN

Mechanisms of Action [MoA] - Angiotensin 2 Receptor Antagonists

Established Pharmacologic Class [EPC] - Angiotensin 2 Receptor Blocker

Candesartan is an Angiotensin 2 Receptor Blocker. The mechanism of action of candesartan is as an Angiotensin 2 Receptor Antagonist.

CANDESARTAN

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.

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.

The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. The protein binding is constant at candesartan plasma concentrations well above the range achieved with recommended doses. In rats, it has been demonstrated that candesartan crosses the blood-brain barrier poorly, if at all. It has also been demonstrated in rats that candesartan passes across the placental barrier and is distributed in the fetus.

Following administration of candesartan cilexetil, the absolute bioavailability of candesartan was estimated to be 15%. After tablet ingestion, the peak serum concentration (Cmax) is reached after 3 to 4 hours. Food with a high fat content does not affect the bioavailability of candesartan after candesartan cilexetil administration.

Total plasma clearance of candesartan is 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of (14)C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Following an intravenous dose of (14)C-labeled candesartan, approximately 59% of radioactivity is recovered in urine and approximately 36% in feces. Biliary excretion contributes to the elimination of candesartan.

It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk.

Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents

THERAP CAT: Antihypertensive. In treatment of congestive heart failure

MEDICATION

Trade Name: Amias, Kenzen /From table/

Table: Candesartan Cilexetil Preparations [Table#7216]

Table: Candesartan Cilexetil Combination Preparations [Table#7217]

Pharmaceuticals

Pharmaceuticals -> Sartans