Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3785
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Teveten HCT (Tablet)
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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-dailymonotherapy 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 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.<br/>Replacement Therapy: 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 . 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-loweringeffect is required. Discontinuation of treatment with eprosartan does
not lead to a rapid rebound increase in blood pressure. Elderly, Hepatically Impaired or Renally
Impaired Patients: No initial dosing adjustment is generally
necessary for elderly or hepatically impaired patients or those with
renal impairment. No initial dosing adjustment is generally necessary
in patients with moderate and severe renal impairment with maximum
dose not exceeding 600 mg daily. TEVETEN HCT may
be taken with or without food.
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dailymed-instance:descripti... |
TEVETEN HCT
600/12.5 mg and TEVETEN HCT 600/25 mg (eprosartan
mesylate-hydrochlorothiazide) combine an angiotensin II receptor (ATsubtype) antagonist and a diuretic, hydrochlorothiazide.
TEVETEN (eprosartan mesylate) is a non-biphenyl non-tetrazole
angiotensin II receptor (AT) antagonist. A selective non-peptide
molecule, TEVETEN is chemically described as the
monomethanesulfonate of (E)-2-butyl-1-(p-carboxybenzyl)-��-2-thienylmethylimidazole-5-acrylic
acid. Its empirical formula is CHNOS���CHOS 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 CHClNOSand 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 mg
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 mg 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.
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dailymed-instance:clinicalP... |
Mechanism of Action: Eprosartan: Angiotensin II (formed
from angiotensin I in a reaction catalyzed by angiotensin-converting
enzyme [kininase II]), a potent vasoconstrictor, is the principal
pressor agent of the renin-angiotensin system. Angiotensin II also
stimulates aldosterone synthesis and secretion by the adrenal cortex,
cardiac contraction, renal resorption of sodium, activity of the sympathetic
nervous system, and smooth muscle cell growth. Eprosartan blocks the
vasoconstrictor and aldosterone-secreting effects of angiotensin II
by selectively blocking the binding of angiotensin II to the ATreceptor found in many tissues (e.g., vascular smooth muscle,
adrenal gland). There is also an ATreceptor 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 ATreceptor. Its affinity for the ATreceptor is 1,000 times greater than for the ATreceptor. In vitro binding studies indicate that
eprosartan is a reversible, competitive inhibitor of the ATreceptor. Blockade of the ATreceptor removes the negative
feedback of angiotensin II on renin secretion, but the resulting increased
plasma renin activity and circulating angiotensin II do not overcome
the effect of eprosartan on blood pressure. TEVETEN HCT does not inhibit kininase II, the enzyme that converts angiotensin
I to angiotensin II and degrades bradykinin; whether this has clinical
relevance is not known. It does not bind to or block other hormone
receptors or ion channels known to be important in cardiovascular
regulation. Hydrochlorothiazide: Hydrochlorothiazide
is a thiazide diuretic. Thiazides affect the renal tubular mechanisms
of electrolyte reabsorption, directly increasing excretion of sodium
and chloride in approximately equivalent amounts. Indirectly, the
diuretic action of hydrochlorothiazide reduces plasma volume, withconsequent increases in plasma renin activity, increases in aldosterone
secretion, increases in urinary potassium loss, and decreases in serum
potassium. Therenin-aldosterone link is mediated by angiotensin II,
so coadministration of an angiotensin II receptor antagonist tends
to reverse the potassium loss associated with these diuretics. The
mechanism of the antihypertensive effect of thiazides is unknown.<br/>Pharmacokinetics:<br/>General:<br/>Metabolism and Excretion:: Eprosartan: 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 [C] eprosartan in human subjects. Eprosartan was
the only drug-related compound found in the plasma and feces. Following
intravenous [C] eprosartan, about 61% of the material
is recovered in the feces and about 37% in the urine. Following an
oral dose of [C] 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. Eprosartan is not metabolized
by cytochrome P450 enzymes. Hydrochlorothiazide: Hydrochlorothiazide
is not metabolized but is eliminated rapidly by the kidney. At least
61% of the oral dose is eliminated unchanged within 24 hours.<br/>Distribution: Eprosartan: 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. Hydrochlorothiazide: Hydrochlorothiazide
crosses the placental but not the blood-brain barrier and it is excreted
in breast milk.<br/>Special Populations: Pediatric: Eprosartan pharmacokinetics
have not been investigated in patients younger than 18 years of age. Geriatric: Following single oral
dose administration of eprosartan to healthy elderly men, (aged 68
to 78 years), AUC, C, and Teprosartan
values increased, on average, by approximately twofold, compared to
healthy young men (aged 20 to 38 years) who received the same dose.
The extent of plasma protein binding is not influenced by age. Gender: There was no difference
in the pharmacokinetics and plasma protein binding between men and
women following single oral dose administration of eprosartan. 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 Insufficiency: Following
administration of 600 mg once daily, there was a 70-90% increase in
AUC, and a 30-50% increase in Cin moderate or severe
renal impairment. The unbound eprosartan fractions increased by 35%
and 59% in patients with moderate and severe renal impairment, respectively.
No initial dosing adjustment is generally necessary in patients with
moderate or severe renal impairment, with maximum dose not exceeding
600 mg daily. Eprosartan was poorly removed by hemodialysis (CL<1L/hr) . Hepatic Insufficiency: Eprosartan
AUC (but not C) values increased, on average, by approximately
40% in men with decreased hepatic function compared to healthy men
after a single 100 mg oral dose of eprosartan. The extent of eprosartan
plasma protein binding was not influenced by hepatic dysfunction.
No dosage adjustment is necessary for patients with hepatic impairment.<br/>Drug Interactions: Eprosartan: Concomitant administration
of eprosartan with digoxin had no effect on a single oral-dose digoxin
pharmacokinetics. Concomitant administration of eprosartan and warfarin
had no effect on steady-state prothrombin time ratios (INR) in healthy
volunteers. Concomitant administration of eprosartan and glyburide
in diabetic patients did not affect 24-hour plasma glucose profiles.
Eprosartan pharmacokinetics were not affected by concomitant administration
of ranitidine. Eprosartan did not inhibit human cytochrome P450 enzymes
CYP1A, 2A6, 2C9/8, 2C19, 2D6, 2E, and 3A in vitro. Eprosartan steady-state plasma concentrations
were not affected by concomitant administration of ketoconazole or
fluconazole, potent inhibitors of CYP3A and 2C9, respectively. Eprosartan-Hydrochlorothiazide: There is no pharmacokinetic interaction between 600 mg eprosartan
and 12.5 mg hydrochlorothiazide.<br/>Pharmacodynamics and Clinical Effects: 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
of eprosartan inhibits pressor effects by approximately 100% at peak,
with approximately 30% inhibition persisting for 24 hours. The absence
of angiotensin II ATagonist activity has been demonstrated
in healthy adult men. 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 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. There was
no change in mean heart rate in patients treated with eprosartan in
controlled clinical trials. 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 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 with 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. Eprosartan (1200 mg once daily for 7 days or 300 mg
twice daily for 28 days) had no effect on the excretion of uric acid
in healthy men, patients with essential hypertension or those with
varying degrees of renal insufficiency. There were no effects on mean
levels of fasting triglycerides, total cholesterol, HDL cholesterol,
LDL cholesterol or fasting glucose.<br/>Clinical Trials: Eprosartan Mesylate: The safety
and efficacy of TEVETEN has been evaluated in controlled
clinical trials worldwide that enrolled predominantly hypertensive
patients with sitting DBP ranging from 95 mmHg to���115 mmHg.
There is also some experience with use of eprosartan together with
other antihypertensive drugs in more severe hypertension. The antihypertensive
effects of TEVETEN 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
TEVETEN 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 TEVETEN,
effects at trough were similar. Patients treated with TEVETEN 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 TEVETEN 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 toACE
inhibitors and angiotensin II inhibitors than Caucasian populations.
Angiotensin-converting enzyme (ACE) inhibitor-induced cough (a dry,
persistent cough) can lead to discontinuation of ACE inhibitor therapy.
In one study, patients who had previously coughed while taking an
ACE inhibitor were treated with eprosartan, an ACE inhibitor (enalapril)
or placebo for six weeks. The incidence of dry, persistent cough was
2.2% on eprosartan, 4.4% on placebo, and 20.5% on the ACE inhibitor;
p=0.008 for the comparison of eprosartan with enalapril. In a second
study comparing the incidence of cough in 259 patients treated with
eprosartan to 261 patients treated with the ACE inhibitor enalapril,
the incidence of dry, persistent cough in eprosartan-treated patients
(1.5%) was significantly lower (p=0.018) than that observed in patients
treated with the ACE inhibitor (5.4%). In addition, analysis of overall
data from six double-blind clinical trials involving 1,554 patients
showed an incidence of spontaneously reportedcough in patients treated
with eprosartan of 3.5%, similar to placebo (2.6%). Hydrochlorothiazide: After oral
administration of hydrochlorothiazide, diuresis begins within 2 hours,
peaks in about 4 hours, and lasts about 6 to 12 hours. Eprosartan Mesylate���Hydrochlorothiazide: Four adequate and well-controlled studies were conducted to assess
the antihypertensive effectiveness of TEVETEN/ hydrochlorothiazide
in 1457 patients with mild-to-moderate essential hypertension. In
a 2x2 factorial study with 112-119 hypertensive patients per arm,
the mean baseline- and placebo-subtracted reductions in blood pressure
at 8 weeks were 3.6/2.1 mmHg on eprosartan 600 mg, 5.6/1.9 mmHg on
hydrochlorothiazide 12.5 mg, and 10.0/5.0 mmHg on the combination.
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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.
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dailymed-instance:supply |
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:
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dailymed-instance:boxedWarn... |
USE IN PREGNANCY: 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.
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dailymed-ingredient:crospovidone,
dailymed-ingredient:iron_oxide_black,
dailymed-ingredient:iron_oxide_yellow,
dailymed-ingredient:lactose_monohydrate,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol_3350,
dailymed-ingredient:polyvinyl_alcohol,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:water
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dailymed-instance:precautio... |
General: 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.<br/>Electrolyte Imbalance: 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 anychloride 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 isthe therapy of choice.<br/>Risk of Renal Impairment: 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 ofACE 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.<br/>Information for Patients: Pregnancy: Female patients of childbearing
age should be told about the consequences of second- and third-trimester
exposure to drugs that act on the renin-angiotensin system, and they
should also be told that these consequences do not appear to have
resulted from intrauterine drug exposure that has been limited to
the first trimester. These patients should be asked to report pregnancies
to their physicians as soon as possible so that treatmentmay be discontinued
under medical supervision. Symptomatic Hypotension: A patient
receiving TEVETEN HCT should be cautioned that lightheadedness
can occur, especially during the first days of therapy, and that it
should be reported to the prescribing physician. The patient should
be told that if syncope occurs, TEVETEN HCT should
be discontinued until the physician has been consulted. All patients
should be cautioned that inadequate fluid intake, excessive perspiration,
diarrhea, or vomiting can lead to an excessive fall in blood pressure,
with the same consequences of lightheadedness and possible syncope. Potassium Supplements: A patient
receiving TEVETEN HCT should be told not to use potassium
supplements or salt substitutes containing potassium without consulting
the prescribing physician .<br/>Drug Interactions: Eprosartan Mesylate: Eprosartan
has been shown to have no effect on the pharmacokinetics of digoxin
and the pharmacodynamics of warfarin and glyburide. Thus, no dosing
adjustments are necessary during concomitant use with these agents.
Because eprosartan is not metabolized by the cytochrome P450 system,
inhibitors of CYP450 enzyme would not be expected to affect its metabolism,
and ketoconazole and fluconazole, potent inhibitors of CYP3A and 2C9,
respectively, have been shown to have no effect on eprosartan pharmacokinetics.
Ranitidine also has no effect on eprosartan pharmacokinetics. Eprosartan
(up to 400 mg b.i.d. or 800 mg q.d.) doses have been safely used concomitantly
with a thiazide diuretic (hydrochlorothiazide). 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. As with other drugs that block angiotensin
II or its effects, concomitant use of potassium-sparing diuretics
(e.g., spironolactone, triamterene, amiloride), potassium supplements
or salt substitutes containing potassium may lead to increases in
serum potassium . Hydrochlorothiazide: When administered
concurrently the following drugs may interact with thiazide diuretics: Alcohol, barbiturates, or narcotics���potentiation of orthostatic hypotension may occur. Antidiabetic drug (oral agents and insulin)���dosage adjustment of the antidiabetic drug may be required. Other antihypertensive drugs���additive effect or potentiation. Cholestyramine
and colestipol resins���Absorption of hydrochlorothiazide
is impaired in the presence of anionic exchange resins. Single doses
of either cholestyramine or colestipol resins bind the hydrochlorothiazide
and reduce its absorption from the gastrointestinal tract by up to
85% and 43%, respectively. Corticosteroids,
ACTH���intensified electrolyte depletion, particularly
hypokalemia. Pressor amines (e.g., norepinephrine)���possible decreased response to pressor amines but not sufficient
to preclude their use. Skeletal muscle
relaxants, nondepolarizing (e.g., tubocurarine)���possible increased responsiveness to the muscle relaxant. Lithium���should not generally
be given with diuretics. Diuretic agents reduce the renal clearance
of lithium and add a high risk of lithium toxicity. Refer to the package
insert for lithium preparations before use of such preparations with
TEVETEN HCT. Nonsteroidal
Anti-Inflammatory Drugs���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 HCT
and nonsteroidal anti-inflammatory agents are used concomitantly,
the patient should be observed closely to determine if the desired
effect of the diuretic is obtained.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: 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 hydrochlorothiazidewas not mutagenic in vitro in
bacteria (Ames test) and did not cause structural chromosomal damage invivo (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 assaysusing 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.<br/>Pregnancy: Pregnancy Category C (first trimester) and
D (second and third trimesters): See WARNINGS:
Fetal/Neonatal Morbidity and Mortality.<br/>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. 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.<br/>Pediatric Use: Safety and effectiveness
in pediatric patients have not been established.<br/>Geriatric Use: 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 mg treatment according to age. However, following single
oral dose administration of eprosartan to healthy elderly men, (aged
68 to 78 years), AUC, C, and Teprosartan
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).
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dailymed-instance:overdosag... |
Eprosartan Mesylate: 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. Hydrochlorothiazide: The most
common signs and symptoms observed are those caused by electrolyte
depletion (hypokalemia, hypochloremia, and hyponatremia) and dehydration
resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias. The degree to which
hydrochlorothiazide is removed by hemodialysis has not been established.
The oral LDof hydrochlorothiazide is greater than 10
g/kg in both mice and rats.
|
dailymed-instance:genericMe... |
eprosartan mesylate and hydrochlorothiazide
|
dailymed-instance:fullName |
Teveten HCT (Tablet)
|
dailymed-instance:adverseRe... |
TEVETEN HCT
600/12.5 mg 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 mg 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 mg discontinued therapy due to clinical
adverse experiences.<br/>Adverse Events Occurring at an Incidence of Greater Than 3%
Among TEVETEN HCT Treated Patients: The following table
lists adverse events that occurred at an incidence of>3% among TEVETEN HCT 600/12.5 mg- or monotherapy-treated patients who
participated in the controlled clinical trials. Of the 268 patients
who received TEVETEN HCT 600/12.5 mg 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. Eprosartan Mesylate: In addition
to the adverse events above, potentially important adverse events
that are included in the current labeling for TEVETEN monotherapy are listed below. Most of these adverse events occurred
in<1% of patients, or were as frequent or more frequent in the
placebo group. It is not known if these events were related to eprosartan
usage: Body as a Whole: alcohol intolerance, asthenia, substernal chest pain, dependent
edema, peripheral edema, facial edema, fatigue, fever, hot flushes,
influenza-like symptoms, injury, malaise, pain, rigors, viral infection; Cardiovascular: angina pectoris,
bradycardia, abnormal ECG, specific abnormal ECG, extrasystoles, atrial
fibrillation, hypotension (including orthostatic hypotension), tachycardia,
palpitations; Gastrointestinal:
abdominal pain, anorexia, constipation, diarrhea, dry
mouth, dyspepsia, 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, hypertriglyceridemia; Musculoskeletal: arthralgia, arthritis, aggravated arthritis,
arthrosis, skeletal pain, tendinitis; Nervous System/Psychiatric: anxiety, ataxia, depression,
dizziness, insomnia, migraine, neuritis, nervousness, paresthesia,somnolence, tremor, vertigo; Resistance
Mechanism: herpes simplex, otitis externa, otitis media,
upper respiratory tract infection; Respiratory: asthma, bronchitis, coughing, epistaxis, pharyngitis,
rhinitis; 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, urinary tractinfection; Vascular: leg cramps, peripheral ischemia. Hydrochlorothiazide: Other adverse events
that have been reported for hydrochlorothiazide, without regard to
causality, are listed below: Body
as a Whole: weakness; Cardiovascular: hypotension (including orthostatic hypotension); Digestive: pancreatitis, jaundice
(intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis,
cramping, constipation, gastric irritation, nausea, anorexia; Hematologic: aplastic anemia, agranulocytosis,
leukopenia, hemolytic anemia, thrombocytopenia; Hypersensitivity: anaphylactic
reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis),
respiratory distress including pneumonitis, and pulmonary edema, photosensitivity,
fever, urticaria, rash, purpura; Metabolic: electrolyte imbalance including hyponatremia,
hypokalemia, and hypochloremic alkalosis, hyperglycemia, glycosuria,
hyperuricemia; Musculoskeletal:
muscle spasm; Nervous
System/Psychiatric: vertigo, paresthesias, restlessness; Renal: renal failure, renal dysfunction,
interstitial nephritis, azotemia; Skin: erythema multiform, including Stevens-Johnson syndrome,
exfoliative dermatitis, including toxic epidermal necrolysis, alopecia; Special Senses: transient blurred
vision, xanthopsia; Urogenital: impotence.<br/>Laboratory Test Findings:: 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 listed 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 10/mmoccurred
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 10/mmoccurred 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 10/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.<br/>Additional Information:: 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.<br/>OVERDOSAGE: Eprosartan Mesylate: 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. Hydrochlorothiazide: The most
common signs and symptoms observed are those caused by electrolyte
depletion (hypokalemia, hypochloremia, and hyponatremia) and dehydration
resulting from excessive diuresis. If digitalis has also been administered,
hypokalemia may accentuate cardiac arrhythmias. The degree to which
hydrochlorothiazide is removed by hemodialysis has not been established.
The oral LDof hydrochlorothiazide is greater than 10
g/kg in both mice and rats.
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dailymed-instance:warning |
Fetal/Neonatal Morbidity and Mortality: 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. Motherswhose 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.<br/>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 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.<br/>Hydrochlorothiazide: Impaired Hepatic Function: 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. Hypersensitivity Reactions: Hypersensitivity
reactions to hydrochlorothiazide may occur in patients with or without
a history of allergy or bronchial asthma, but are more likely in patients
with such a history. Systemic Lupus Erythematosus: Thiazide
diuretics have been reported to cause exacerbation or activation of
systemic lupus erythematosus. Lithium Interaction: Lithium generally
should not be given with thiazides .
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dailymed-instance:indicatio... |
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 .
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dailymed-instance:represent... | |
dailymed-instance:routeOfAd... | |
dailymed-instance:name |
Teveten HCT
|