Eprosartan

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Eprosartan
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

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Black Box Warning

WARNING: FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
* When pregnancy is detected, discontinue eprosartan as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Overview

Eprosartan is an angiotensin II receptor blocker that is FDA approved for the {{{indicationType}}} of hypertension. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, myalgia, dizziness, upper respiratory infection and fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension
  • Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.
  • Initial dosage:
  • 600 mg/day, in patients who are not volume depleted.
  • May be administered once or twice daily with total daily doses ranging from 400 - 800 mg.
  • There is limited experience with doses beyond 800 mg/day.
  • If the antihypertensive effect measured at trough using once-daily dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response.
  • Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks.
  • Elderly, Hepatically Impaired or Renally Impaired Patients
  • No initial dosing adjustment is generally necessary in patients with moderate and severe renal impairment, with maximum dose not exceeding 600 mg daily.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in adult patients.

Non–Guideline-Supported Use

Condition 1
  • Dosing Information
  • (Dosage)
Condition 2
  • Dosing Information
  • (Dosage)
Condition 3
  • Dosing Information
  • (Dosage)

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Label Guideline-Supported Use of eprosartan in children.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of eprosartan in children.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Nonguideline-Supported Use of eprosartan in children.

Contraindications

Warnings

WARNING: FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
* When pregnancy is detected, discontinue eprosartan as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
Fetal Toxicity
  • Pregnancy Category D
  • 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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. Closely observe infants with histories of in utero exposure to eprosartan for hypotension, oliguria, and hyperkalemia.
  • 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. 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.).
Hypotension in Volume- and/or Salt-Depleted Patients
  • In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of eprosartan mesylate, or the treatment should start under close medical supervision. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Adverse Reactions

Clinical Trials Experience

  • Eprosartan has been evaluated for safety in more than 3,300 healthy volunteers and patients worldwide, including more than 1,460 patients treated for more than 6 months, and more than 980 patients treated for 1 year or longer. Eprosartan was well tolerated at doses up to 1200 mg daily. Most adverse events were of mild or moderate severity and did not require discontinuation of therapy. The overall incidence of adverse experiences and the incidences of specific adverse events reported with eprosartan were similar to placebo.
  • Adverse experiences were similar in patients regardless of age, gender, or race.
  • Adverse experiences were not dose-related.
  • In placebo-controlled clinical trials, about 4% of 1,202 patients treated with eprosartan discontinued therapy due to clinical adverse experiences, compared to 6.5% of 352 patients given placebo.
  • Adverse events occurring at an Incidence of 1% or more among eprosartan-treated patients.
  • The following table lists adverse events that occurred at an incidence of 1% or more among eprosartan-treated patients who participated in placebo-controlled trials of 8 to 13 weeks' duration, using doses of 25 mg to 400 mg twice daily, and 400 mg to 1200 mg once daily.
This image is provided by the National Library of Medicine.
  • The following adverse events were also reported at a rate of 1% or greater in patients treated with eprosartan, but were as, or more, frequent in the placebo group:
  • Facial edema was reported in 5 patients receiving eprosartan.
  • In addition to the adverse events above, potentially important events that occurred in at least two patients/subjects exposed to eprosartan or other adverse events that occurred in <1% of patients in clinical studies are listed below. It cannot be determined whether events were causally related to eprosartan:
Body as a Whole
Cardiovascular
Gastrointestinal
Hematologic
Liver and Biliary
Metabolic and Nutritional
Musculoskeletal
Nervous System/Psychiatric
Resistance Mechanism
Respiratory
Skin and Appendages
Special Senses
Urinary
Vascular
Laboratory Test Findings
  • Minor elevations in creatinine and in BUN occurred in 0.6% and 1.3%, respectively, of patients taking eprosartan and 0.9% and 0.3%, respectively, of patients given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for elevations in serum creatinine and BUN, and three additional patients were withdrawn for increases in serum creatinine.
  • Liver Function Tests
  • Leukopenia
  • A WBC count of ≤3.0 x 103/mm3 occurred in 0.3% of patients taking eprosartan and in 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for leukopenia.
  • Neutropenia

Postmarketing Experience

There is limited data regarding adverse reactions reported from post marketing experience.

Drug Interactions

  • Dual Blockade of the Renin-Angiotensin System (RAS):
  • Eprosartan doses of up to 300 mg b.i.d. have been safely used concomitantly with sustained-release calcium channel blockers (sustained-release nifedipine) with no clinically significant adverse interactions.
  • These effects are usually reversible.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): D

  • Female patients of childbearing age should be told about the consequences of exposure to eprosartan during pregnancy.
  • Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
  • 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 examination to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue eprosartan, 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. Closely observe infants with histories of in utero exposure to eprosartan for hypotension, oliguria, and hyperkalemia.
  • 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. 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.).


Pregnancy Category (AUS): D There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of eprosartan in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Eprosartan during labor and delivery.

Nursing Mothers

  • Eprosartan is excreted in animal milk; it is not known whether eprosartan is excreted in human milk.
  • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from eprosartan, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

  • Eprosartan pharmacokinetics have not been investigated in patients younger than 18 years of age.
  • Neonates with a history of in utero exposure to eprosartan:

Geriatic Use

  • Following single oral dose administration of eprosartan to healthy elderly men (aged 68 to 78 years), AUC, Cmax, and Tmax eprosartan values increased, on average by approximately twofold, compared to healthy young men (aged 20 to 39 years) who received the same dose.
  • The extent of plasma protein binding was not influenced by age.
  • Of the total number of patients receiving eprosartan in clinical studies, 29% (681 of 2,334) were 65 years and over, while 5% (124 of 2,334) were 75 years and over.
  • Based on the pooled data from randomized trials, the decrease in diastolic blood pressure and systolic blood pressure with eprosartan was slightly less in patients ≥65 years of age compared to younger patients.
  • In a study of only patients over the age of 65, eprosartan at 200 mg twice daily (and increased optionally up to 300 mg twice daily) decreased diastolic blood pressure on average by 3 mmHg (placebo corrected).
  • Adverse experiences were similar in younger and older patients.

Gender

Race

  • A pooled population pharmacokinetic analysis of 442 Caucasian and 29 non-Caucasian hypertensive patients showed that oral clearance and steady-state volume of distribution were not influenced by race.

Renal Impairment

Hepatic Impairment

Females of Reproductive Potential and Males

  • 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. In male and female rats, the systemic exposure (AUC) to unbound eprosartan at the dose evaluated was only approximately 20% of the exposure achieved in humans given 400 mg b.i.d. In mice, the systemic exposure (AUC) to unbound eprosartan was approximately 25 times the exposure achieved in humans given 400 mg b.i.d.
  • 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.

Immunocompromised Patients

There is no FDA guidance one the use of Eprosartan in patients who are immunocompromised.

Administration and Monitoring

Administration

Oral

Monitoring

Hypertension
  • Dual Blockade of the Renin-Angiotensin System:

IV Compatibility

There is limited information regarding the compatibility of eprosartan and IV administrations.

Overdosage

  • Limited data are available regarding overdosage.
  • Appropriate symptomatic and supportive therapy should be given if overdosage should occur.
  • There was no mortality in rats and mice receiving oral doses of up to 3000 mg eprosartan/kg and in dogs receiving oral doses of up to 1000 mg eprosartan/kg.

Pharmacology

Eprosartan wiki.png
Eprosartan
Systematic (IUPAC) name
4-({2-Butyl-5-[2-carboxy-2-(thiophen-2-ylmethyl)eth-1-en-1-yl]-1H-imidazol-1-yl}methyl)benzoic acid
Identifiers
CAS number 133040-01-4
ATC code C09CA02
PubChem 5281037
DrugBank DB00876
Chemical data
Formula C23H24N2O4S 
Mol. mass Eprosartan mesylate: 520.625 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 15% (Eprosartan mesylate)
Metabolism not metabolized
Half life 5 to 9 hours
Excretion Renal 10%, biliary 90%
Therapeutic considerations
Pregnancy cat.

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Legal status
Routes Oral

Mechanism of Action

Structure

  • Eprosartan mesylate is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, eprosartan mesylate is chemically described as the monomethanesulfonate of (E )-2-butyl-1-(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5-acrylic acid.
  • Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is:
This image is provided by the National Library of Medicine.
  • Eprosartan mesylate is a white to off-white free-flowing crystalline powder that is insoluble in water, freely soluble in ethanol, and melts between 248°C and 250°C.
  • Eprosartan mesylate is available as aqueous film-coated tablets containing eprosartan mesylate equivalent to 400 mg or 600 mg eprosartan zwitterion (pink, oval, non-scored tablets or white, non-scored, capsule-shaped tablets, respectively).
  • Inactive Ingredients:
  • The 400 mg tablet contains the following: croscarmellose sodium, hypromellose, iron oxide red, iron oxide yellow, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide. The 600 mg tablet contains crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, and titanium dioxide.

Pharmacodynamics

  • Achievement of maximal blood pressure response to a given dose in most patients may take 2 to 3 weeks of treatment. Onset of blood pressure reduction is seen within 1 to 2 hours of dosing with few instances of orthostatic hypotension. Blood pressure control is maintained with once- or twice-daily dosing over a 24-hour period. Discontinuing treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.
  • Eprosartan increases mean effective renal plasma flow (ERPF) in salt-replete and salt-restricted normal subjects. A dose-related increase in ERPF of 25% to 30% occurred in salt-restricted normal subjects, with the effect plateauing between the 200 mg and 400 mg doses. There was no change in ERPF in hypertensive patients and patients with renal insufficiency on normal salt diets. Eprosartan did not reduce glomerular filtration rate in patients with renal insufficiency or in patients hypertension, after 7 days and 28 days of dosing, respectively. In hypertensive patients and patients with chronic renal insufficiency, eprosartan did not change fractional excretion of sodium and potassium.

Pharmacokinetics

  • General:
  • Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%.
  • Eprosartan plasma concentrations peak at 1 to 2 hours after an oral dose in the fasted state.
  • Administering eprosartan with food delays absorption, and causes variable changes (<25%) in Cmax and AUC values which do not appear clinically important. Plasma concentrations of eprosartan increase in a slightly less than dose-proportional manner over the 100 mg to 800 mg dose range. The mean terminal elimination half-life of eprosartan following multiple oral doses of 600 mg was approximately 20 hours.
  • Eprosartan does not significantly accumulate with chronic use.
  • Eprosartan is eliminated by biliary and renal excretion, primarily as unchanged compound.
  • Less than 2% of an oral dose is excreted in the urine as a glucuronide.
  • There are no active metabolites following oral and intravenous dosing with [14C] eprosartan in human subjects.
  • Eprosartan was the only drug-related compound found in the plasma and feces. Following intravenous [14C] eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of [14C] eprosartan, about 90% is recovered in the feces and about 7% in the urine. Approximately 20% of the radioactivity excreted in the urine was an acyl glucuronide of eprosartan with the remaining 80% being unchanged eprosartan.
  • Distribution:
  • Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses.
  • The pooled population pharmacokinetic analysis from two Phase 3 trials of 299 men and 172 women with mild to moderate hypertension (aged 20 to 93 years) showed that eprosartan exhibited a population mean oral clearance (CL/F) for an average 60-year-old patient of 48.5 L/hr. The population mean steady-state volume of distribution (Vss/F) was 308 L. Eprosartan pharmacokinetics were not influenced by weight, race, gender or severity of hypertension at baseline. Oral clearance was shown to be a linear function of age with CL/F decreasing 0.62 L/hr for every year increase.

Nonclinical Toxicology

There is limited information regarding the nonclinical toxicology of eprosartan.

Clinical Studies

  • The safety and efficacy of eprosartan mesylate have been evaluated in controlled clinical trials worldwide that enrolled predominantly hypertensive patients with sitting DBP ranging from 95 mmHg to ≤115 mmHg.
  • The antihypertensive effects of eprosartan mesylate were demonstrated principally in five placebo-controlled trials (4 to 13 weeks' duration) including dosages of 400 mg to 1200 mg given once daily (two studies), 25 mg to 400 mg twice daily (two studies), and one study comparing total daily doses of 400 mg to 800 mg given once daily or twice daily. The five studies included 1,111 patients randomized to eprosartan and 395 patients randomized to placebo. The studies showed dose-related antihypertensive responses.
  • At study endpoint, patients treated with eprosartan mesylate at doses of 600 mg to 1200 mg given once daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 5-10/3-6 mmHg. Limited experience is available with the dose of 1200 mg administered once daily. In a direct comparison of 200 mg to 400 mg b.i.d. with 400 mg to 800 mg q.d. of eprosartan mesylate, effects at trough were similar. Patients treated with eprosartan mesylate at doses of 200 mg to 400 mg given twice daily experienced significant decreases in sitting systolic and diastolic blood pressure at trough, with differences from placebo of approximately 7-10/4-6 mmHg.
  • Peak (1 to 3 hours) effects were uniformly, but moderately, larger than trough effects with b.i.d. dosing, with the trough-to-peak ratio for diastolic blood pressure 65% to 80%. In the once-daily dose-response study, trough-to-peak responses of ≤50% were observed at some doses (including 1200 mg), suggesting attenuation of effect at the end of the dosing interval.

The antihypertensive effect of eprosartan mesylate was similar in men and women, but was somewhat smaller in patients over 65. There were too few black subjects to determine whether their response was similar to Caucasians. In general, blacks (usually a low renin population) have had smaller responses to ACE inhibitors and angiotensin II inhibitors than caucasian populations.

How Supplied

  • TEVETEN® is available as aqueous film-coated tablets as follows:
  • 400 mg pink, non-scored, oval tablets, debossed with “5044” on one side.
  • NDC 0074–3025–11 (bottles of 100)
  • 600 mg white, non-scored, capsule-shaped tablets, debossed with “5046” on one side.
  • NDC 0074–3040–11 (bottles of 100)

Storage

Store at controlled room temperature 20 to 25°C (68 to 77°F) [see USP Controlled Room Temperature].

Images

Drug Images

Eprosartan pill.jpg

Drug Name: Eprosartan mesylate
Ingredient(s): crospovidone, lactose monohydrate, magnesium stearate, cellulose, microcrystalline, polysorbate 80, starch, corn, titanium dioxide and polyethylene glycols
Imprint: SOLVAY;5046
Dosage: 600 mg
Color(s): White
Shape: Oval
Size (mm): 20
Score: 1
NDC:00074-3040--11

Drug Label Author: Abbott Laboratories

This pill image is provided by the National Library of Medicine's PillBox.

Package and Label Display Panel

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Patient Counseling Information

Pregnancy
  • Female patients of childbearing age should be told about the consequences of exposure to eprosartan mesylate during pregnancy.
  • Discuss treatment options with women planning to become pregnant.
  • Patients should be asked to report pregnancies to their physicians as soon as possible.

Precautions with Alcohol

  • Some patients previously exposed to eprosartan showed signs of alcohol intolerance, however, it is not possible to confirm if eprosartan was directly involved in the adverse reaction.

Brand Names

Teveten®

Look-Alike Drug Names

N/A

Drug Shortage Status

Drug Shortage

Price

References

The contents of this FDA label are provided by the National Library of Medicine.


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