Teveten

Eprosartan has been shown not to inhibit human cytochrome P450 enzymes CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E, and 3A in vitro.

A lower starting dose of 400 mg once daily should be considered (see Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics and Warnings and Precautions, Special Populations, Geriatrics).

In patients receiving diuretics, TEVETEN therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued two to three days prior to the administration of TEVETEN to reduce the likelihood of hypotension (see Warnings and Precautions, Cardiovascular, Hypotension and Drug Interactions, Drug-Drug Interactions). If this is not possible because of the patient's condition, TEVETEN should be administered with caution and the blood pressure monitored closely. Thereafter, the dosage should be adjusted according to the individual response of the patient.

TEVETEN is formulated as an aqueous film-coated tablet. It may be taken with or without food, but it should be taken consistently with respect to food intake and at the same time every day.

If a dose is forgotten, the missed dose should be taken as soon as possible. The next dose should be taken at the normal time. Two doses should not be taken within six hours of each other.

The starting dose of 400 mg once daily should be considered for patients with impaired hepatic function.

The dosage of TEVETEN (eprosartan mesylate) must be individualized.

Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction, and other pertinent clinical factors (see Warnings and Precautions, Cardiovascular, Hypotension). The dosage of antihypertensive agents used with TEVETEN may need to be adjusted.

TEVETEN may be taken with or without food, but it should be taken consistently with respect to food intake and at the same time every day.

The safety and efficacy of TEVETEN have not been established in children.

The recommended initial dose of TEVETEN is 600 mg once daily.

Achievement of maximum blood pressure reduction in most patients may take 2-3 weeks after initiation of therapy.

In patients whose blood pressure is not adequately controlled, the dose may be increased to 800 mg once daily. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. If satisfactory control is not being maintained for 24 hours, twice daily administration with the same total daily dosage should be considered. If blood pressure is not adequately controlled with TEVETEN alone, a thiazide diuretic may be administered concomitantly.

A lower starting dose of 400 mg once daily should be considered in patients with severe renal impairment. Patients with moderate to severe renal impairment (creatinine clearance <60 mL/min) requiring 600 mg once daily to control their blood pressure should be monitored carefully and 600 mg once daily should be the maximum dose in these patients (see Action and Clinical Pharmacology, Special Populations and Conditions, Renal Insufficiency and Warnings and Precautions, Renal).

anorexia, constipation, dry mouth, esophagitis, flatulence, gastritis, gastroenteritis, gingivitis, nausea, periodontitis, toothache, vomiting.

The following adverse reactions have been identified during post-marketing use of TEVETEN:

• Headaches, dizziness, and asthenia have been rarely reported.

  
  

• Hypotension, including postural hypotension, has been very rarely reported.

  
  

• Skin reactions (rash, pruritus, urticaria) have been very rarely reported.

  
  

• Angioedema (involving swelling of the face, lips and/or tongue) has been very rarely reported.

  
  

Cases of muscle pain, muscle weakness, myositis and rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.

Since there is currently inadequate therapeutic experience in patients with severe cardiac insufficiency or renal artery stenosis, it cannot be ruled out that renal function may be impaired (including renal failure in patients at risk e.g. renal artery stenosis) with eprosartan due to inhibition of the renin-angiotensin-aldosterone system.

In placebo-controlled studies, clinically important changes in standard laboratory parameters were rarely associated with administration of TEVETEN.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

In placebo-controlled clinical trials, about 4% of 1202 patients treated with TEVETEN discontinued therapy due to clinical adverse experiences, compared to 6.5% of 352 patients given placebo.

albuminuria, cystitis, hematuria, micturition frequency, polyuria, renal calculus, urinary incontinence.

conjunctivitis, abnormal vision, xerophthalmia, tinnitus.

eczema, furunculosis, pruritus, rash, maculopapular rash, increased sweating.

alcohol intolerance, allergic reaction, allergy, substernal chest pain, leg edema, peripheral edema, fever, hot flushes, influenza-like symptoms, malaise, rigors.

asthma, epistaxis.

In addition, asthenia has been seen commonly in clinical trials.

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 regardless of drug relationship are listed below.

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

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

anxiety, ataxia, insomnia, migraine, neuritis, nervousness, paresthesia, somnolence, tremor, vertigo.

anemia, purpura.

arthritis, aggravated arthritis, arthrosis, leg cramps, skeletal pain, tendonitis.

TEVETEN (eprosartan mesylate) has been evaluated for safety in more than 3300 healthy volunteers and patients, including more than 1460 patients treated for more than 6 months, and more than 980 patients treated for 1 year or longer.

Adverse experiences were similar in patients regardless of age, gender, or race.

A WBC count of ≤3.0×10³/mm³ occurred in 0.3% of patients taking TEVETEN and in 0.3% of patients given placebo in controlled clinical trials. One patient was withdrawn from clinical trials for leukopenia.

increased creatine phosphokinase, diabetes mellitus, glycosuria, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hypokalemia, hyponatremia.

herpes simplex, otitis externa, otitis media, upper respiratory tract infection.

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

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

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

Minor elevations of ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of patients taking TEVETEN (eprosartan mesylate) or placebo in controlled clinical trials. An elevated ALAT of >3.5×ULN occurred in 0.1% of patients taking TEVETEN (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.

angina pectoris, bradycardia, nonspecific ST-T changes, T-wave inversion, extrasystoles, atrial fibrillation, hypotension, tachycardia, peripheral ischemia.

In elderly patients with essential hypertension eprosartan taken once daily for 12 weeks in doses of 600-800 mg is a well-tolerated and effective treatment. At study endpoint there were clinically significant and useful reductions in sitting SBP and DBP compared to baseline in both treatments. However, appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population (see Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics, and Dosage and Administration).

The safety and effectiveness in pediatric patients have not been established.

Each white, capsule-shaped, aqueous film-coated tablet, debossed with “SOLVAY” on one side and “5046” on the other side, contains: eprosartan mesylate equivalent to eprosartan 600 mg. Nonmedicinal ingredients: crospovidone, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch and titanium dioxide. May also contain: iron oxide red, iron oxide yellow and polysorbate 80. Blister packs of 28.

Each pink, oval, aqueous film-coated tablet, debossed with “SOLVAY” on one side and “5044” on the other side, contains: eprosartan mesylate equivalent to eprosartan 400 mg. Nonmedicinal ingredients: croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol, pregelatinized starch and titanium dioxide. May also contain: iron oxide red, iron oxide yellow and polysorbate 80. Blister packs of 28.

In elderly patients with essential hypertension eprosartan taken once daily for 12 weeks in doses of 600-800 mg is a well-tolerated and effective treatment. At study endpoint there were clinically significant and useful reductions in sitting SBP and DBP compared to baseline in both treatments. However, appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population (see Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics, and Dosage and Administration, Recommended Dose and Dosage Adjustment, Use in the Elderly).

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of eprosartan should include appropriate assessment of renal function (see Dosage and Administration).

Based on pharmacokinetic data which demonstrate increased plasma concentrations of eprosartan in hepatically impaired patients after administration of TEVETEN (eprosartan mesylate), a lower initial dose should be considered for patients with hepatic impairment or a history of hepatic impairment (see Dosage and Administration).

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medication.

Occasionally, symptomatic hypotension has occurred after administration of eprosartan, in some cases after the first dose. It is more likely to occur in patients who are volume-depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. In those patients, because of the potential fall in blood pressure, these conditions should be corrected prior to starting therapy and under close medical supervision. Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, TEVETEN should be discontinued as soon as possible (see Contraindications).

The use of ARBs is not recommended during pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting enzyme inhibitors (another class of therapeutic products interfering with the RAAS) during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Given the current evidence available on the risk with ARBs, similar risk may exist for this class of drugs. Patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

The use of ARBs during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).

Infants with a history of in utero exposure to ARBs should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.

Eprosartan is not removed from plasma by dialysis.

Animal Data: 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.).

The safety and effectiveness in pediatric patients have not been established.

It is not known whether eprosartan is excreted in human milk but significant levels have been found in the milk of lactating rats. Because many drugs are excreted in human milk and because of their potential for affecting the nursing infant adversely, if the initiation of treatment with eprosartan is regarded necessary, nursing should be discontinued first. Nursing women should not be treated with TEVETEN (see Contraindications).

There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Geometric mean eprosartan AUC values increased approximately 40% in a study of mild to moderate hepatically impaired men vs. healthy men who each received a single 100 mg oral dose of eprosartan. The extent of eprosartan plasma protein binding was not influenced by hepatic dysfunction (see Dosage and Administration). 

Following single oral dose administration of eprosartan to healthy elderly men (aged 68 to 78 years), both AUC and C_max eprosartan values increased, on average by approximately 2-fold, 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.

Plasma protein binding of eprosartan is high (approximately 98%) and constant over the concentration range achieved with therapeutic doses. After intravenous dosing, the eprosartan volume of distribution is about 13 L and total plasma clearance is about 8 L/h. The mean steady-state volume of distribution (Vss/F) was 308 liters in patients of all ages.

Eprosartan plasma concentrations peak at 1 to 2 hours after an oral dose in the fasted state. Absolute bioavailability following a single 300 mg oral dose of eprosartan is approximately 13%. Administering eprosartan with food delays absorption, and causes variable changes (25%) in C_max 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 to 800 mg dose-range. Eprosartan does not significantly accumulate with chronic use.

TEVETEN (eprosartan mesylate) antagonizes angiotensin II by blocking the angiotensin type 1 (AT₁) receptor. Angiotensin II is a potent vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component in the pathophysiology of hypertension. It also stimulates aldosterone secretion by the adrenal cortex. Eprosartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT₂ receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Eprosartan does not exhibit any partial agonist activity at the AT₁ receptor. Its affinity for the AT₁ receptor is 1000 times greater than for the AT₂ receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT₁ receptor.

TEVETEN does not inhibit angiotensin converting enzyme (ACE), also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

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.

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. Eprosartan was the only drug-related compound found in the plasma and feces. Following administration of intravenous eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of 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. The terminal elimination half-life of eprosartan following oral administration is 5 to 9 hours. Eprosartan exhibited a population mean oral clearance (CL/F) for an average 60-year-old patient of 48.5 L/h. Oral clearance was shown to be a linear function of age with CL/F decreasing 0.62 L/h for every year increase.

Following administration of eprosartan 200 mg b.i.d. for 7 days, patients with mild renal impairment (CLcr 60 to 80 mL/min) showed mean eprosartan C_max and AUC values similar to subjects with normal renal function. Following treatment once daily of 600 mg for seven days, the AUC (0-24 hours) values were two-fold increased in patients with moderate (Clcr 30 to 59 mL/min) or severe renal impairment (Clcr 5 to 29 mL/min) from that in the patients with normal renal function. The C_max values were also 30-50% higher in patients with moderate or severe renal impairment than in patients with normal renal function. The unbound eprosartan fraction was not influenced by mild to moderate renal impairment but increased approximately 2-fold in a few patients with severe renal impairment. Eprosartan was poorly removed by hemodialysis (CL_HD<1 L/h) (see Dosage and Administration).

There were no differences in the pharmacokinetics and plasma protein binding between men and women following administration of a single oral dose of eprosartan.

Eprosartan is not metabolized by the cytochrome P450 system. No active metabolites were detected following oral and intravenous dosing with eprosartan in human subjects.

Eprosartan pharmacokinetics was not influenced by weight, race, gender or severity of hypertension at baseline.

Eprosartan inhibits the pharmacologic effects of angiotensin II infusions in healthy adult men. Single oral doses of eprosartan from 10 mg to 400 mg have been shown to inhibit the vasopressor, renal vasoconstrictive and aldosterone secretory effects of infused angiotensin II with complete inhibition evident at doses of 350 mg and above. Eprosartan inhibits the pressor effects of angiotensin II infusions. A single oral dose of 350 mg of eprosartan inhibits pressor effects by approximately 100% at peak, with approximately 30% inhibition persisting for 24 hours. In hypertensive patients treated chronically with eprosartan, there was a twofold rise in angiotensin II plasma concentration and a twofold rise in plasma renin activity, while plasma aldosterone levels remained unchanged. Serum potassium levels also remained unchanged in these patients.

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 can be maintained with once- or twice-daily dosing over a 24-hour period. Attenuation of the effect towards the end of the 24 hour dosing period may occur in some patients with once daily dosing. Discontinuing treatment with eprosartan does not lead to a rebound increase in blood pressure.

There was no change in mean heart rate in patients treated with eprosartan in controlled clinical trials.

The antihypertensive effect of TEVETEN was similar in men and women, but was somewhat smaller in patients over 65.

Although data available to date indicate a similar pharmacodynamic effect of eprosartan in black and white hypertensive patients, this should be viewed with caution since antihypertensive drugs that affect the renin-angiotensin system, such as ACE inhibitors and angiotensin II AT₁ receptor blockers, have generally been found to be less effective in low-renin hypertensives (frequently blacks).

The safety and effectiveness in pediatric patients have not been established.