Diovan HCT (Valsartan / Hydrochlorothiazide) - Description and Clinical Pharmacology

DESCRIPTION

Diovan HCT (valsartan and hydrochlorothiazide, USP) is a combination of valsartan, an orally active, specific angiotensin II receptor blocker (ARB) acting on the AT₁ receptor subtype, and hydrochlorothiazide, a diuretic.

Valsartan, a nonpeptide molecule, is chemically described as N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-Valine. Its empirical formula is C₂₄H₂₉N₅O₃, its molecular weight is 435.5, and its structural formula is

Valsartan is a white to practically white fine powder. It is soluble in ethanol and methanol and slightly soluble in water.

Hydrochlorothiazide USP is a white, or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is chemically described as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

Hydrochlorothiazide is a thiazide diuretic. Its empirical formula is C₇H₈ClN₃O₄S₂, its molecular weight is 297.73, and its structural formula is

Diovan HCT tablets are formulated for oral administration to contain valsartan and hydrochlorothiazide, USP 80/12.5 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg. The inactive ingredients of the tablets are colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxides, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT₁ receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.

There is also an AT₂ receptor found in many tissues, but AT₂ is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the AT₁ receptor than for the AT₂ receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT₁ receptor about one 200th that of valsartan itself.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II) it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.

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.

Pharmacodynamics

Valsartan : Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available.

Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed.

In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.

In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.

Hydrochlorothiazide: After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.

Pharmacokinetics

Valsartan : Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) by about 50%. AUC and C_max values of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.

Hydrochlorothiazide : Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours.

Geriatric : Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary [see Dosage and Administration (2.1 )].

Gender : Pharmacokinetics of valsartan does not differ significantly between males and females.

Race : Pharmacokinetic differences due to race have not been studied.

Renal Insufficiency : There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinine clearance <10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan [see Dosage and Administration (2.1)].

In a study of patients with impaired renal function (mean creatinine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.

Hepatic Insufficiency : On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex, and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease [see Dosage and Administration (2.1)].

Distribution

Valsartan : The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.

Hydrochlorothiazide : Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Metabolism

Valsartan : The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism.

Hydrochlorothiazide : Is not metabolized.

Excretion

Valsartan : Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites.

Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).

Hydrochlorothiazide: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half-life is between 5.8 and 18.9 hours.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Valsartan-Hydrochlorothiazide : No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of valsartan and hydrochlorothiazide. However, these studies have been conducted for valsartan as well as hydrochlorothiazide alone. Based on the preclinical safety and human pharmacokinetic studies, there is no indication of any adverse interaction between valsartan and hydrochlorothiazide.

Valsartan : There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for up to 2 years at doses up to 160 and 200 mg/kg/day, respectively. These doses in mice and rats are about 2.6 and 6 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Mutagenicity assays did not reveal any valsartan-related effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella  (Ames) and E. coli; a gene mutation test with Chinese hamster V79 cells; a cytogenetic test with Chinese hamster ovary cells; and a rat micronucleus test.

Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is about 6 times the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Hydrochlorothiazide : 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.

Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella Typhimurium strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 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 only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 to 1300 mcgm/mL, and in the Aspergillus Nidulans non-disjunction assay at an unspecified concentration.

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, respectively, prior to mating and throughout gestation. These doses of hydrochlorothiazide in mice and rats represent 19 and 1.5 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

Developmental Toxicity Studies

Valsartan-Hydrochlorothiazide : There was no evidence of teratogenicity in mice, rats, or rabbits treated orally with valsartan at doses up to 600, 100 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide at doses up to 188, 31 and 3 mg/kg/day. These non-teratogenic doses in mice, rats and rabbits, respectively, represent 9, 3.5 and 0.5 times the maximum recommended human dose (MRHD) of valsartan and 38, 13 and 2 times the MRHD of hydrochlorothiazide on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

Fetotoxicity was observed in association with maternal toxicity in rats and rabbits at valsartan doses of ≥200 and 10 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of ≥63 and 3 mg/kg/day. Fetotoxicity in rats was considered to be related to decreased fetal weights and included fetal variations of sternebrae, vertebrae, ribs and/or renal papillae. Fetotoxicity in rabbits included increased numbers of late resorptions with resultant increases in total resorptions, postimplantation losses and decreased number of live fetuses. The no observed adverse effect doses in mice, rats and rabbits for valsartan were 600, 100 and 3 mg/kg/day, respectively, in combination with hydrochlorothiazide doses of 188, 31 and 1 mg/kg/day. These no adverse effect doses in mice, rats and rabbits, respectively, represent 9, 3 and 0.18 times the MRHD of valsartan and 38, 13 and 0.5 times the MRHD of hydrochlorothiazide on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

Valsartan : No teratogenic effects were observed when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones were observed in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was observed at doses of 5 and 10 mg/kg/day. The no observed adverse effect doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6 and 0.1 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 320 mg/day and a 60-kg patient.)

Hydrochlorothiazide : Under the auspices of the National Toxicology Program, pregnant mice and rats that received hydrochlorothiazide via gavage at doses up to 3000 and 1000 mg/kg/day, respectively, on gestation days 6 through 15 showed no evidence of teratogenicity. These doses of hydrochlorothiazide in mice and rats represent 608 and 405 times, respectively, the maximum recommended human dose on a mg/m² basis. (Calculations assume an oral dose of 25 mg/day and a 60-kg patient.)

CLINICAL STUDIES

Hypertension

Valsartan-Hydrochlorothiazide : In controlled clinical trials including over 7600 patients, 4372 patients were exposed to valsartan (80, 160 and 320 mg) and concomitant hydrochlorothiazide (12.5 and 25 mg). Two factorial trials compared various combinations of 80/12.5 mg, 80/25 mg, 160/12.5 mg, 160/25 mg, 320/12.5 mg and 320/25 mg with their respective components and placebo. The combination of valsartan and hydrochlorothiazide resulted in additive placebo-adjusted decreases in systolic and diastolic blood pressure at trough of 14-21/8-11 mmHg at 80/12.5 mg to 320/25 mg, compared to 7-10/4-5 mmHg for valsartan 80 mg to 320 mg and 5-11/2-5 mmHg for hydrochlorothiazide 12.5 mg to 25 mg, alone.

Three other controlled trials investigated the addition of hydrochlorothiazide to patients who did not respond adequately to valsartan 80 mg to valsartan 320 mg, resulted in the additional lowering of systolic and diastolic blood pressure by approximately 4-12/2-5 mmHg.

The maximal antihypertensive effect was attained 4 weeks after the initiation of therapy, the first time point at which blood pressure was measured in these trials.

In long-term follow-up studies (without placebo control) the effect of the combination of valsartan and hydrochlorothiazide appeared to be maintained for up to two years. The antihypertensive effect is independent of age or gender. The overall response to the combination was similar for Black and non-Black patients.

There was essentially no change in heart rate in patients treated with the combination of valsartan and hydrochlorothiazide in controlled trials.

Valsartan : The antihypertensive effects of valsartan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide.

Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control) the effect of valsartan appeared to be maintained for up to two years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin II blockers) have generally been found to be less effective in low-renin hypertensives (frequently Blacks) than in high-renin hypertensives (frequently Whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 Blacks and 830 Whites, valsartan and an ACE-inhibitor control were generally at least as effective in Blacks as Whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The 7 studies of valsartan monotherapy included over 2000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg.

Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups.

In another 4-week study, 1876 patients randomized to valsartan 320 mg once daily had an incremental blood pressure reduction 3/1 mmHg lower than did 1900 patients randomized to valsartan 160 mg once daily.

In controlled trials, the antihypertensive effect of once daily valsartan 80 mg was similar to that of once daily enalapril 20 mg or once daily lisinopril 10 mg.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

Initial T herapy - Hypertension

The safety and efficacy of Diovan HCT as initial therapy for patients with severe hypertension (defined as a sitting diastolic blood pressure ≥110 mmHg and systolic blood pressure ≥140 mmHg off all antihypertensive therapy) was studied in a 6-week multicenter, randomized, double-blind study. Patients were randomized to either Diovan HCT (valsartan and hydrochlorothiazide 160/12.5 mg once daily) or to valsartan (160 mg once daily) and followed for blood pressure response. Patients were force-titrated at 2-week intervals. Patients on combination therapy were subsequently titrated to 160/25 mg followed by 320/25 mg valsartan/hydrochlorothiazide. Patients on monotherapy were subsequently titrated to 320 mg valsartan followed by a titration to 320 mg valsartan to maintain the blind.

The study randomized 608 patients, including 261 (43%) females, 147 (24%) Blacks, and 75 (12%) ≥65 years of age. The mean blood pressure at baseline for the total population was 168/112 mmHg. The mean age was 52 years. After 4 weeks of therapy, reductions in systolic and diastolic blood pressure were 9/5 mmHg greater in the group treated with Diovan HCT compared to valsartan. Similar trends were seen when the patients were grouped according to gender, race or age.