Eprosartan

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor agonists. Monitor serum lithium levels during concomitant use.

Do not co-administer aliskiren with Teveten in patients with diabetes. Avoid use of aliskiren with Teveten 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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on Teveten and other agents that affect the RAS.

Potential pharmacologic interaction (attenuated hypotensive effects) when angiotensin II receptor antagonists are used concomitantly with nonsteroidal anti-inflammatory agents (NSAIAs), including selective cyclooxygenase-2 (COX-2) inhibitors. Possible deterioration of renal function in geriatric, volume-depleted (including those receiving concomitant diuretic therapy), or renally impaired patients; renal function should be monitored periodically in patients receiving concomitant therapy with eprosartan and an NSAIA, including selective COX-2 inhibitors.

For more Interactions (Complete) data for EPROSARTAN (7 total), please visit the HSDB record page.

IDENTIFICATION AND USE: Eprosartan is a white to off-white crystalline powder that is formulated into oral tablets. Eprosartan 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. HUMAN EXPOSURE AND TOXICITY: The use of eprosartan during 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 eprosartan. In human peripheral lymphocytes in vitro, eprosartan was equivocal for clastogenicity with metabolic activation, and was negative without metabolic activation. In the same assay, eprosartan was positive for polyploidy with metabolic activation and equivocal for polyploidy without metabolic activation. ANIMAL STUDIES: Eprosartan was not carcinogenic in dietary restricted rats or ad libitum fed mice dosed at 600 mg and 2000 mg/kg/day, respectively, for up to 2 years. Also, the reproductive performance of male and female rats was unaffected by administration of eprosartan. No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan was administered to pregnant rats at oral doses up to 1000 mg /kg/day. Eprosartan has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses. Eprosartan was not mutagenic in vitro in bacteria or mammalian cells (mouse lymphoma assay). Eprosartan also did not cause structural chromosomal damage in vivo (mouse micronucleus assay).

/SIGNS AND SYMPTOMS/ The most likely manifestations of overdosage are hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Hyperkalemia may also occur in patients with renal disease or in patients taking potassium-sparing medications. /Angiotensin receptor blockers/

/GENOTOXICITY/ In human peripheral lymphocytes in vitro , eprosartan mesylate was equivocal for clastogenicity with metabolic activation, and was negative without metabolic activation. In the same assay, eprosartan mesylate was positive for polyploidy with metabolic activation and equivocal for polyploidy without metabolic activation.

/OTHER TOXICITY INFORMATION/ ... Nine healthy subjects were studied in high sodium balance (ie, sodium intake 200 mmol/d). On the first day, the subjects received 600 mg eprosartan orally, and renal plasma flow and glomerular filtration rate were measured. Glucose was infused intravenously on the second and third study days to increase plasma glucose to a level below the threshold for glycosuria (approximately 8.8 mmol/L). Eprosartan at a dose of 600 mg or placebo was administered randomly on the second or third study day 1 hour after initiation of glucose infusion. Renal plasma flow increased (by 76+/-7 mL. min(-1). 1.73 m(-2), P<0.01) in response to sustained moderate hyperglycemia and then increased further (by 147+/-15 mL. min(-1). 1.73 m(-2), P<0.01) when eprosartan was administered during hyperglycemia. Eprosartan, conversely, did not affect renal plasma flow and glomerular filtration rate in normoglycemic subjects. Glomerular filtration rate was not affected by either hyperglycemia or eprosartan. Neither plasma renin activity nor plasma Ang II concentration changed during hyperglycemia, suggesting that the hormonal responses responsible for the enhanced renal vasodilator response to eprosartan occurred within the kidney. The enhancement of the renal vasodilator effect of eprosartan during hyperglycemia is consistent with activation of the intrarenal renin-angiotensin system.

/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.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

eprosartan

DILI Negative

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Eprosartan mesylate was not carcinogenic in dietary restricted rats or ad libitum fed mice dosed at 600 mg and 2000 mg eprosartan/kg/day, respectively, for up to 2 years.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No adverse effects on in utero or postnatal development and maturation of offspring were observed when eprosartan mesylate was administered to pregnant rats at oral doses up to 1000 mg eprosartan/kg/day (the 1000 mg eprosartan/kg/day dose in non-pregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Eprosartan mesylate has been shown to produce maternal and fetal toxicities (maternal and fetal mortality, low maternal body weight and food consumption, resorptions, abortions and litter loss) in pregnant rabbits given oral doses as low as 10 mg eprosartan/kg/day. No maternal or fetal adverse effects were observed at 3 mg/kg/day; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan 0.8 times that achieved in humans given 400 mg b.i.d.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Eprosartan mesylate had no adverse effects on the reproductive performance of male or female rats at oral doses up to 1000 mg eprosartan/kg/day. This dose provided systemic exposure (AUC) to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg b.i.d.

/GENOTOXICITY/ Eprosartan mesylate was not mutagenic in vitro in bacteria or mammalian cells (mouse lymphoma assay). Eprosartan mesylate also did not cause structural chromosomal damage in vivo (mouse micronucleus assay).

Facial edema occurred in patients receiving eprosartan. Sensitivity reactions including various anaphylactoid reactions and/or angioedema have been reported in patients receiving other angiotensin II receptor antagonists. Eprosartan is not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.

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

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.

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

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

MEDICATION

Angiotensin II Type 2 Receptor Blockers; Antihypertensive Agents

Use (kg) in Switzerland (2009): >1000

Preparation: J. A. Finkelstein et al., European Patent Office patent 403159 (1990 to SmithKline Beckman); eidem, United States of America patent 5185351 (1993 to SmithKline Beecham).

Methyl 4-(bromomethyl)benzoate and 5-chloro-2-propylimidazole are condensed using potassium carbonate in DMF to give the 1-(4-methoxycarbonyl)benzyl derivative of the imidazole (I). I, with the monomethyl ester of 2-thenylmalonate, in a solution of piperidine and pyridine in toluene forms the dimethyl ester of eprosartan, which is saponified to the diacid. The mesylate salt is obtained with methanesulfonic acid. /Eprosartan mesylate/

Table: Eprosartan Mesylate Preparations [Table#7218]

Table: Eprosartan Mesylate Combination Preparations [Table#7219]