Teveten HCT

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 AT₁ receptor found in many tissues (e.g., vascular smooth muscle, adrenal gland). There is also an AT₂ receptor found in many tissues but it is not known to be associated with cardiovascular homeostasis. Eprosartan does not exhibit any partial agonist activity at the AT₁ receptor. Its affinity for the AT₁ receptor is 1,000 times greater than for the AT₂ receptor. In vitro binding studies indicate that eprosartan is a reversible, competitive inhibitor of the AT₁ receptor. Blockade of the AT₁ receptor 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, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-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.

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 [¹⁴C] eprosartan in human subjects. Eprosartan was the only drug-related compound found in the plasma and feces. Following intravenous [¹⁴C] eprosartan, about 61% of the material is recovered in the feces and about 37% in the urine. Following an oral dose of [¹⁴C] 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.

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.

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_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. 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 C_max in 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_HD<1L/hr) (see DOSAGE AND ADMINISTRATION).

Hepatic Insufficiency: Eprosartan AUC (but not C_max) 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.

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.

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 AT₁ agonist 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.

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 to ACE 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 reported cough 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 HCT^®/(Eprosartan Mesylate/ 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.

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.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

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 (see PRECAUTIONS, Drug Interactions, Hydrochlorothiazide, Lithium).

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 treatment may 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 (see PRECAUTIONS, Drug Interactions, Eprosartan Mesylate).

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 (see PRECAUTIONS, Information for Patients, Potassium Supplements).

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including eprosartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving eprosartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including eprosartan may be attenuated by NSAIDs including selective COX-2 inhibitors.

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.

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 tract infection; 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.

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 LD₅₀ of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

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.