Teveten Plus 600mg/12.5mg

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 two-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.

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).

The components of TEVETEN PLUS have been shown to have an additive effect on blood pressure reduction, reducing blood pressure to a greater degree than either component alone.

The antihypertensive effect of TEVETEN PLUS is sustained over a 24 hour period. In clinical studies of one year's duration, the antihypertensive effect was maintained with continued therapy. Despite the significant decrease in blood pressure, administration of TEVETEN PLUS had no clinically significant effect on heart rate.

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

Onset of diuretic action following oral administration occurs in 2 hours and the peak action in about 4 hours. Diuretic activity lasts about 6 to 12 hours.

Following administration of eprosartan 200 mg b.i.d. for 7 days, patients with mild renal impairment (creatinine clearance 60 to 80 mL/min) showed mean eprosartan C_max and AUC values similar to subjects with normal renal function. Compared to patients with normal renal function, mean AUC and C_max values were approximately 30% higher in patients with moderate renal impairment (creatinine clearance 30 to 59 mL/min) and 50% higher in patients with severe renal impairment (creatinine clearance 5 to 29 mL/min). 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 (see Dosage, Eprosartan Monotherapy). Hemodialysis resulted in very limited effects on clearance (CL_HD<1L/h) and was essentially not dialyzed.

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 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 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 eprosartan was similar in men and women, but was somewhat smaller in patients over 65 years.

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).

Potentiation of orthostatic hypotension may occur with diuretic therapy.

By lowering serum potassium levels, hydrochlorothiazide can increase effects and side-effects of digoxin and antiarrhythmic drugs. Hypokalemia resulting from thiazide therapy may increase the risk of quinidine-induced ventricular arrhythmias.

The safety and efficacy in children have not been established. Treatment of children is not recommended.

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).

Thiazides should be used with caution in patients with renal disease. Because of the hydrochlorothiazide component, TEVETEN PLUS (eprosartan mesylate and hydrochlorothiazide) is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Dosage).

Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing and thiazide diuretics. Therefore, when TEVETEN PLUS and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired antihypertensive effect of the diuretic is obtained.

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance: hyokalemia, hyponatremia and hypochloremic alkalosis. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, arrhythmias, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia may develop, especially with brisk diuresis, when severe cirrhosis is present, or after prolonged therapy.

Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis. Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. Thiazides may decrease serum protein-bound iodine levels without signs of thyroid disturbance.

Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

Thiazides may decrease urinary calcium excretion. Thiazides may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

The antihypertensive effects of hydrochlorothiazide may be enhanced in postsympathectomy patients.

Intensified electrolyte depletion, particularly hypokalemia, may occur when given concomitantly with diuretics.

Since eprosartan decreases the production of aldosterone, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.

Concomitant thiazide diuretic use may attenuate any effect that eprosartan may have on serum potassium. Concomitant use of laxatives may increase the risk of hypokalemia.

Insulin requirements in diabetic patients treated with diuretics may be increased, decreased or unchanged.

Concomitant administration of eprosartan and warfarin had no effect on steady-state prothrombin time ratios (INR) in healthy volunteers.

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.

No overall differences in safety were observed between elderly patients and younger patients, but appropriate caution should nevertheless be used when prescribing to the elderly, as increased vulnerability to drug effect is possible in this patient population.

Lithium generally should not be given with diuretics. As with other drugs which eliminate sodium, lithium clearance may be reduced leading to lithium toxicity. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.

In diabetic patients, dosage adjustment of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus, latent diabetes mellitus may manifest during thiazide therapy.

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

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma (see Dosage).

Concomitant administration of ketoconazole or fluconazole (potent inhibitors of CYP 3A4 and 2C9, respectively) had no effect on steady state pharmacokinetics of eprosartan.

In the presence of diuretics, possible decreased response to pressor amines may be seen but not sufficient to preclude their use.

Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction in blood pressure after initiation of therapy with eprosartan. The possibility of symptomatic hypotension with the use of eprosartan can be minimized by discontinuing the diuretic prior to initiation of treatment (see Warnings, Hypotension, and Dosage). No pharmacokinetic drug interaction of clinical significance has been identified with eprosartan and thiazide diuretics.

Thiazide diuretics may increase the effects of non-depolarizing (tubocurarine-type) skeletal muscle relaxants.

Eprosartan pharmacokinetics were not affected by concomitant administration of ranitidine.

It is not known whether eprosartan is excreted in human milk but significant levels have been found in the milk of lactating rats. Thiazides appear in human milk. 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 and hydrochlorothiazide is regarded necessary, nursing should be discontinued first. Nursing women should not be treated with TEVETEN PLUS (see Contraindications).

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma.

Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.

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 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 twice daily. 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 nonpregnant rats yielded systemic exposure to unbound eprosartan approximately 0.6 times the exposure achieved in humans given 400 mg twice daily).

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 PLUS (eprosartan mesylate and hydrochlorothiazide) 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 risks 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.

Thiazides cross the placental barrier and appear in cord blood. The routine use of diuretics in otherwise healthy pregnant women is not recommended and exposes mother and fetus to unnecessary hazard including fetal or neonatal jaundice, thrombocytopenia and possibly other adverse experiences which have occurred in the adult. Diuretics do not prevent development of toxemia of pregnancy and there is no satisfactory evidence that they are useful in the treatment of toxemia.

Azotemia may be precipitated or increased by hydrochlorothiazide. Cumulative effects of the drug may develop in patients with impaired renal function. If increasing azotemia and oliguria occur during treatment of severe progressive renal disease the diuretic should be discontinued.

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, therapy should be started 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.

Eprosartan: Limited data are available in regard to overdosage with eprosartan. The most likely manifestations of overdosage would be hypotension and/or tachycardia. If symptomatic hypotension should occur, supportive treatment should be instituted. Eprosartan is not removed by hemodialysis.

Hydrochlorothiazide: The most common signs and symptoms observed are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis and may present as nausea and somnolence. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

See Symptoms.

Since dosage adjustment of eprosartan is required in patients with liver impairment, and thiazide diuretics may precipitate hepatic coma, a fixed combination product such as TEVETEN PLUS is not advisable (see Precautions, Patients with Liver Impairment).

In patients receiving diuretics, eprosartan 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, Hypotension, and Precautions, 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.

A lower initial starting dose of 400 mg eprosartan monotherapy once daily should be considered. The usual regimen of therapy with TEVETEN PLUS may generally be followed for patients with creatinine >30 mL/min. Because of the hydrochlorothiazide component, TEVETEN PLUS is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Precautions, Patients with Renal Impairment).

The recommended initial dose of eprosartan monotherapy 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 eprosartan alone, a thiazide diuretic may be administered concomitantly.