TEVETEN^® HCT
(eprosartan mesylate/hydrochlorothiazide)600/12.5mg 600/25mg

Rx Only

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, TEVETEN^® HCT Tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

TEVETEN^® HCT 600/12.5 and TEVETEN^® HCT 600/25 (eprosartan mesylate-hydrochlorothiazide) combine an angiotensin II receptor (AT₁ subtype) antagonist and a diuretic, hydrochlorothiazide. TEVETEN^® (eprosartan mesylate) is a non-biphenyl non-tetrazole angiotensin II receptor (AT₁) antagonist. A selective non-peptide molecule, TEVETEN^® is chemically described as the monomethanesulfonate of (E)-2-butyl-1-(p-carboxybenzyl)-α-2-thienylmethylimidazole-5-acrylic acid. Its empirical formula is C₂₃H₂₄N₂O₄S•CH₄O₃S and molecular weight is 520.625. Its structural formula is:

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. Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C₇H₈ClN₃O₄S₂ and its structural formula is:

Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.74, which is slightly soluble in water, but freely soluble in sodium hydroxide solution. TEVETEN^® HCT is available for oral administration in film-coated, non-scored, capsule-shaped tablet combinations of eprosartan mesylate and hydrochlorothiazide. TEVETEN^® HCT 600/12.5 contains 735.8 mg of eprosartan mesylate (equivalent to 600 mg eprosartan) and 12.5 mg hydrochlorothiazide in a butterscotch-colored tablet. TEVETEN^® HCT 600/25 contains 735.8 mg of eprosartan mesylate (equivalent to 600 mg eprosartan) and 25 mg hydrochlorothiazide in a brick-red tablet. Inactive ingredients of both tablets: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, crospovidone, magnesium stearate, and purified water. Ingredients of the OPADRY^® 85F27320 butterscotch film coating: polyethylene glycol 3350, talc, polyvinyl alcohol, titanium dioxide, iron oxide black, and iron oxide yellow. Ingredients of the OPADRY^® II 85F24297 pink film coating: polyethylene glycol 3350, titanium dioxide, talc, polyvinyl alcohol, iron oxide red, and iron oxide yellow.

TEVETEN^® HCT is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensives such as calcium channel blockers. This fixed dose combination is not indicated for initial therapy (see DOSAGE AND ADMINISTRATION).

TEVETEN^® HCT is contraindicated in patients who are hypersensitive to this product or any of its components. Because of the hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.

Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin-converting enzyme inhibitors. When pregnancy is detected, TEVETEN^® HCT should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should advise the patient to discontinue the use of eprosartan as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, TEVETEN^® HCT should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST) or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist 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 means of reversing hypotension and/or substituting for disordered renal function. Eprosartan mesylate, alone or in combination with hydrochlorothiazide, 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 and 3 mg hydrochlorothiazide/kg/day. No maternal or fetal adverse effects were observed in rabbits at 3 mg eprosartan/kg/day alone or in combination with 1 mg/kg/day of hydrochlorothiazide; this oral dose yielded a systemic exposure (AUC) to unbound eprosartan approximately equal to the human systemic exposure achieved with the dose of eprosartan mesylate contained in the maximum recommended human dose of TEVETEN^® HCT (600 mg eprosartan/day). 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 0.8 times the exposure achieved in humans given 600 mg/day). Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

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 TEVETEN^® HCT, 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.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy. 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. 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 become manifest during thiazide therapy. The antihypertensive effects of hydrochlorothiazide may be enhanced in postsympathectomy patients.

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: hyponatremia, hypochloremic alkalosis, and hypokalemia. 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, 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.

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been reported in susceptible individuals treated with angiotensin II antagonists; in some patients, these changes in renal function were reversible upon discontinuation of therapy. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. TEVETEN^® HCT would be expected to behave similarly. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or BUN have been reported. Similar effects have been reported with angiotensin II antagonists; in some patients, these effects were reversible upon discontinuation of therapy. Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function. If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

No carcinogenicity studies have been conducted with eprosartan mesylate in combination with hydrochlorothiazide. 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 25% of the exposure achieved in humans given TEVETEN^® HCT. In mice, the systemic exposure (AUC) to unbound eprosartan was approximately 35 times the exposure achieved in humans given TEVETEN^® HCT. Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses of up to approximately 600 mg/kg/day) or in male and female rats (at doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice. Eprosartan mesylate was not mutagenic in vitro in mammalian cells (mouse lymphoma assay). Eprosartan mesylate alone or in combination with hydrochlorothiazide was not mutagenic in vitro in bacteria (Ames test) and did not cause structural chromosomal damage in vivo (mouse micronucleus assay). In human peripheral lymphocytes in vitro, eprosartan mesylate in combination with hydrochlorothiazide was positive for clastogenicity with and without metabolic activation. In the same assay, eprosartan mesylate alone was associated with polyploidy but there was only equivocal evidence of structural chromosomal damage. Hydrochlorothiazide was not genotoxic in vitro in the Ames test and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in vivo in assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays and in the Aspergillus nidulans non-disjunction assay. No fertility studies have been conducted with eprosartan mesylate in combination with hydrochlorothiazide. 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. Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to conception and throughout gestation.

Pregnancy Category C (first trimester) and D (second and third trimesters): See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

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. Thiazides appear in human milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

In the controlled clinical trials where patients received eprosartan/hydrochlorothiazide combination therapy, 15% to 33% of the patients were 65 years of age or greater. There was no difference in the effect of TEVETEN^® HCT 600/12.5 treatment according to age. However, following single oral dose administration of eprosartan to healthy elderly men, (aged 68 to 78 years), AUC, C_max, and T_max eprosartan values increased, on average, by approximately twofold, compared to healthy young men (aged 20 to 38 years) who received the same dose. (See Pharmacokinetics, Special Populations).

TEVETEN^® HCT 600/12.5 has been evaluated for safety in 268 patients in double-blind, controlled clinical trials. Most of these patients were treated with TEVETEN^® HCT 600/12.5 for 29 to 60 days. Eprosartan/hydrochlorothiazide combination therapy has been evaluated for safety in 890 patients in open-label, long-term clinical trials. Approximately 50% of these patients were treated with eprosartan/hydrochlorothiazide for over 2 years. Eprosartan/hydrochlorothiazide combination therapy was well tolerated. Most adverse events were of mild or moderate severity and did not require discontinuation of therapy. Adverse experiences were similar in patients regardless of age, gender, or race. In the controlled clinical trials, about 3% of the 268 patients treated with TEVETEN^® HCT 600/12.5 discontinued therapy due to clinical adverse experiences.

The following table uls adverse events that occurred at an incidence of >3% among TEVETEN^® HCT 600/12.5- or monotherapy-treated patients who participated in the controlled clinical trials. Of the 268 patients who received TEVETEN^® HCT 600/12.5 during the double-blind treatment period in the controlled trials, 110 patients were reported to have adverse events.

The adverse events reported in over 600 patients that received TEVETEN^®/hydrochlorothiazide combination therapy for at least 1 year in the open-label, long-term clinical trials were comparable to those reported in the controlled trials.

In placebo-controlled studies, clinically important changes in standard laboratory parameters were rarely associated with administration of TEVETEN^®. Patients were rarely withdrawn from TEVETEN^® because of laboratory test results. Laboratory test findings that have been reported for TEVETEN^® are uled below: Creatinine, Blood Urea Nitrogen: 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. Liver Function Tests: Minor elevations of ALAT, ASAT, and alkaline phosphatase occurred for comparable percentages of patients taking TEVETEN^® or placebo in controlled clinical trials. An elevated ALAT of >3.5 x 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. Hemoglobin: 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. Leukopenia: A WBC count of ≤3.0 x 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. Neutropenia: A neutrophil count of ≤1.5 x 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. Thrombocytopenia: A platelet count of ≤100 x 10⁹/L 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^®. Serum Potassium: 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.

Among the adverse events reported for patients receiving either TEVETEN^® monotherapy or TEVETEN^®/hydrochlorothiazide combination therapy in the TEVETEN^® HCT clinical trials, some adverse events are not included in the current labeling for either TEVETEN^® or hydrochlorothiazide monotherapy. The adverse events which are not currently included in the labeling for TEVETEN^® or hydrochlorothiazide monotherapy include the following: angioedema, bilirubinemia, blood urea nitrogen increased, edema periorbital, eosinophilia, and NPN increased. The majority of these adverse events were reported in the open-label, long-term trials and were reported in small numbers of patients receiving TEVETEN^® alone or TEVETEN^® in combination with hydrochlorothiazide. All of these adverse events were either not reported in patients receiving TEVETEN^® monotherapy or combination therapy with hydrochlorothiazide during the double-blind period of the controlled trials, or were reported at an incidence of ≤1% or in only one patient per treatment group in the controlled trials. The overall safety profile of the TEVETEN^®/hydrochlorothiazide combination treatment is as expected based on the safety profile of each of the components and what is generally known about the patient population.

The usual recommended starting dose of eprosartan is 600 mg once daily when used as monotherapy in patients who are not volume-depleted (see WARNINGS, Hypotension in Volume- and/or Salt-Depleted Patients). Eprosartan can be administered once or twice daily and total daily doses ranging from 400 mg to 800 mg. There is limited experience with doses beyond 800 mg/day. If the antihypertensive effect measured at trough using once-daily monotherapy 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. Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. The side effects (see WARNINGS) of eprosartan are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent (primarily hypokalemia) and dose-independent (e.g., pancreatitis) phenomena, the former much more common than the latter. Therapy with any combination of eprosartan and hydrochlorothiazide will be associated with both sets of dose-independent side effects.

TEVETEN^® HCT may be substituted for the individual components. The usual recommended dose of TEVETEN^® HCT is 600 mg/12.5 mg once daily when used as combination therapy in patients who are not volume-depleted (see WARNINGS, Hypotension in Volume-and/or Salt-Depleted Patients). If the antihypertensive effect measured at trough using TEVETEN^® HCT 600/12.5 mg is inadequate, patients may be titrated to TEVETEN^® HCT 600/25 mg once daily. Higher doses have not been studied in combination. Achievement of maximum blood pressure reduction in most patients may take 2 to 3 weeks. If the patient under treatment with TEVETEN^® HCT requires additional blood pressure control at trough, or to maintain a twice a day dosing schedule of monotherapy, 300 mg TEVETEN^® may be added as evening dose. TEVETEN^® HCT may be used in combination with other antihypertensive agents such as calcium channel blockers if additional blood-pressure-lowering effect is required. Discontinuation of treatment with eprosartan does not lead to a rapid rebound increase in blood pressure.

TEVETEN^® HCT is available as film-coated, capsule-shaped tablets, debossed with “SOLVAY” on one side and “5147” or “5150” on the other, supplied as bottles of 100 tablets as follows:

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

Kos

Pioneering Medicines for a Better Life^®

Manufactured for:
Kos Pharmaceuticals, Inc.
Cranbury, NJ 08512

Tablets made in The Netherlands

400252/0306 ©2006 Kos Pharmaceuticals, Inc., Cranbury, NJ 08512, USA Printed in U.S.A.