Eprosartan

Mechanism of Action

Angiotensin II blocker; displaces angiotensin II from AT1 receptor and may lower blood pressure by antagonizing AT1-induced vasoconstriction, aldosterone release, catecholamine release, arginine vasopressin release, water absorption, and hypertrophic responses

May induce more complete inhibition of renin-angiotensin system compared with ACE inhibitors; does not affect response to bradykinin

Inhibits the pressor effects of an angiotensin II infusion in a dose-related manner

Pharmacokinetics

Half-Life: 5-9 hr

Onset: 4 hr

Peak Plasma Time: 4 hr

Bioavailability: 13%, food & age increases absorption

Protein Bound: 98%

Vd: 3.8 L

Metabolism: Partially conjugated with glucuronic acid in liver

Metabolites: Acyl glucuronide metabolite (inactive)

Excretion: Feces (90%), urine (7%)

Clearance

• Total Body: 48.5 L/hr
• Renal: 39-45 mL/min

Eprosartan may be found in some form under the following brand names:

• Teveten

Serious side effects have been reported with eprosartan including:

• Angioedema (swelling under the skin). Tell your healthcare profession right away if you have signs or symptoms of angioedema, which include:
  • swelling of face, eyes, lips, tongue, larynx and extremities
  • difficulty in swallowing or breathing
  • hoarseness (having difficulty making sounds when trying to speak)
• Eprosartan can cause dizziness. Do not drive or operate heavy machinery until you know how eprosartan affects you.
• Hypotension. Excessive perspiration and dehydration may lead to an excessive fall in blood pressure (hypotension). Vomiting or diarrhea may also lead to a fall in blood pressure.
• Hyperkalemia. Eprosartan may lead to increased levels of potassium, which could lead to side effects such as heart arrhythmias (irregular heartbeat) and nausea. Check with your doctor before using potassium supplements or salt substitutes that contain potassium.
• Decline in kidney function. Your doctor may need to perform tests to determine how well your kidneys are working, especially if you already have kidney disease.

Do not take eprosartan if you:

• are pregnant. See "FDA Warning" section.
• are allergic to any ingredient found in this medication
• have diabetes and are taking aliskiren (Tekturna)

• Take eprosartan exactly as prescribed.
• This medication comes in tablet form and is usually taken once or twice daily.
• It can be taken with or without food.
• This medication should be taken at around the same time each day.
• If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of eprosartan at the same time.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

In addition to the use of eprosartan, treatment for your high blood pressure may include weight control and changes in the types of foods you eat, especially foods high in sodium (salt). Your doctor will tell you which of these is most important for you. You should check with your doctor before changing your diet.

Many patients who have high blood pressure will not notice any signs of the problem. In fact, many may feel normal. It is very important that you take your medicine exactly as directed and that you keep your appointments with your doctor even if you feel well.

Remember that eprosartan will not cure your high blood pressure but it does help control it. Therefore, you must continue to take it as directed if you expect to lower your blood pressure and keep it down. You may have to take high blood pressure medicine for the rest of your life. If high blood pressure is not treated, it can cause serious problems such as heart failure, blood vessel disease, stroke, or kidney disease.

You may take eprosartan with or without food.

Take all other medicines your doctor has prescribed to treat your condition.

Dosing

The dose of eprosartan will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of eprosartan. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For high blood pressure:
    • Adults— 400 to 800 milligrams (mg) per day, taken once a day or divided into two doses. Your doctor may increase your dose as needed.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of eprosartan, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

It is very important that your doctor check your progress at regular visits to make sure that eprosartan is working properly. Blood tests may be needed to check for unwanted effects.

Using eprosartan while you are pregnant can harm your unborn baby. Use an effective form of birth control to keep from getting pregnant. If you think you have become pregnant while using eprosartan, tell your doctor right away.

Dizziness, lightheadedness, or fainting may occur, especially when you get up from a lying or sitting position. Make sure you know how you react to eprosartan before you drive, use machines, or do anything else that could be dangerous if you are dizzy or not alert. If you feel dizzy, lie down so you do not faint. Then sit for a few moments before standing to prevent the dizziness from returning. If you faint, stop using eprosartan and call your doctor right away.

Check with your doctor right away if you become sick while taking eprosartan, especially with severe or continuing nausea and vomiting or diarrhea. These conditions may cause you to lose too much water and may lead to low blood pressure. You can also lose water by sweating, so drink plenty of water during exercise or in hot weather.

Do not take other medicines unless they have been discussed with your doctor. This especially includes nonprescription medicines for appetite control, asthma, colds, cough, hay fever, or sinus problems, since they may tend to increase your blood pressure.

• If you have an allergy to eprosartan or any other part of this medicine.
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you are taking a drug that has aliskiren in it and you also have high blood sugar (diabetes) or kidney problems. Check with your doctor or pharmacist if you are not sure if a drug you take has aliskiren in it.
• If you are breast-feeding or plan to breast-feed.

This is not a list of all drugs or health problems that interact with eprosartan.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

Fetal Toxicity

Pregnancy Category D

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. 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 Eprosartan mesylate 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.

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 mesylate, 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 mesylate for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS: Pediatric Use).

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, 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.

Eprosartan mesylate 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 one 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 mesylate 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. The overall incidence of adverse events reported with Eprosartan mesylate (54.4%) was similar to placebo (52.8%).

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: headache, myalgia, dizziness, sinusitis, diarrhea, bronchitis, dependent edema, dyspepsia, and chest pain.

Facial edema was reported in five patients receiving Eprosartan. Angioedema has been reported with other angiotensin II antagonists. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

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: alcohol intolerance, asthenia, substernal chest pain, peripheral edema, fatigue, fever, hot flushes, influenza-like symptoms, malaise, rigors, pain;

Cardiovascular: angina pectoris, bradycardia, abnormal ECG, specific abnormal ECG, extrasystoles, atrial fibrillation, hypotension (including orthostatic hypotension), tachycardia, palpitations;

Gastrointestinal: anorexia, constipation, dry mouth, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, nausea, periodontitis, toothache, vomiting;

Hematologic: anemia, purpura;

Liver and Biliary: increased SGOT, increased SGPT;

Metabolic and Nutritional: increased creatine phosphokinase, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia;

Musculoskeletal: arthritis, aggravated arthritis, arthrosis, skeletal pain, tendinitis, back pain;

Nervous System/Psychiatric: anxiety, ataxia, insomnia, migraine, neuritis, nervousness, paresthesia, somnolence, tremor, vertigo;

Resistance Mechanism: herpes simplex, otitis externa, otitis media, upper respiratory tract infection;

Respiratory: asthma, epistaxis;

Skin and Appendages: eczema, furunculosis, pruritus, rash, maculopapular rash, increased sweating;

Special Senses: conjunctivitis, abnormal vision, xerophthalmia, tinnitus;

Urinary: albuminuria, cystitis, hematuria, micturition frequency, polyuria, renal calculus, urinary incontinence;

Vascular: leg cramps, peripheral ischemia.

In placebo-controlled studies, clinically important changes in standard laboratory parameters were rarely associated with administration of Eprosartan mesylate. Patients were rarely withdrawn from Eprosartan mesylate because of laboratory test results.

Minor elevations in creatinine and in BUN occurred in 0.6% and 1.3%, respectively, of patients taking Eprosartan mesylate 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.

Minor elevations of ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of patients taking Eprosartan mesylate or placebo in controlled clinical trials. An elevated ALAT of > 3.5 x ULN occurred in 0.1% of patients taking Eprosartan mesylate (one patient) and in no patient given placebo in controlled clinical trials. Four patients were withdrawn from clinical trials for an elevation in liver function tests.

A greater than 20% decrease in hemoglobin was observed in 0.1% of patients taking Eprosartan mesylate (one patient) and in no patient given placebo in controlled clinical trials. Two patients were withdrawn from clinical trials for anemia.

A WBC count of ≤ 3 x 103/mm3 occurred in 0.3% of patients taking Eprosartan mesylate and in 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for leukopenia.

A neutrophil count of ≤ 1.5 x 103/mm3 occurred in 1.3% of patients taking Eprosartan mesylate and in 1.4% of patients given placebo in controlled clinical trials. No patient was withdrawn from any clinical trial for neutropenia.

A platelet count of ≤ 100 x 109/L occurred in 0.3% of patients taking Eprosartan mesylate (one patient) and in no patient given placebo in controlled clinical trials. Four patients receiving Eprosartan mesylate in clinical trials were withdrawn for thrombocytopenia. In one case, thrombocytopenia was present prior to dosing with Eprosartan mesylate.

A potassium value of ≥ 5.6 mmol/L occurred in 0.9% of patients taking Eprosartan mesylate and 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for hyperkalemia and three for hypokalemia.

Hypertension: Oral: Dosage must be individualized. Can administer once or twice daily with total daily doses of 400 to 800 mg. Usual starting dose is 600 mg once daily as monotherapy in patients who are euvolemic. Target dose (JNC 8 [James, 2013]): 600 to 800 mg daily in 1 or 2 divided doses. Limited clinical experience with doses >800 mg.

Serum potassium, serum creatinine, BUN, urinalysis, blood pressure

[US Boxed Warning]: Drugs that act on the renin-angiotensin system can cause injury and death to the developing fetus. Discontinue as soon as possible once pregnancy is detected. The use of drugs which act on the renin-angiotensin system are associated with oligohydramnios. Oligohydramnios, due to decreased fetal renal function, may lead to fetal lung hypoplasia and skeletal malformations. Use is also associated with anuria, hypotension, renal failure, skull hypoplasia, and death in the fetus/neonate. The exposed fetus should be monitored for fetal growth, amniotic fluid volume, and organ formation. Infants exposed in utero should be monitored for hyperkalemia, hypotension, and oliguria (exchange transfusions or dialysis may be needed). These adverse events are generally associated with maternal use in the second and third trimesters.

Untreated chronic maternal hypertension is also associated with adverse events in the fetus, infant, and mother. The use of angiotensin II receptor blockers is not recommended to treat chronic uncomplicated hypertension in pregnant women and should generally be avoided in women of reproductive potential (ACOG 2013).

US BOXED WARNING:
-FETAL TOXICITY: If pregnancy is detected, discontinue this drug as soon as possible. Drugs that act directly on the renin angiotensin system (RAS) can cause injury and death to the developing fetus.

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.