The combination of valsartan [an angiotensin II type 1 (AT1) receptor blocker] and hydrochlorothiazide (a thiazide diuretic), administered once daily, has been evaluated in the treatment of patients with hypertension in clinical trials ranging in duration from 8 weeks to 3 years. These studies showed that combination treatment with valsartan 80 or 160mg and hydrochlorothiazide 12.5 or 25mg induced significant reductions from baseline in systolic blood pressure (SBP) and diastolic BP (DBP) in patients with mild to severe hypertension.
Clinical trials have demonstrated that the combination of valsartan 80 or 160mg with hydrochlorothiazide 12.5 or 25mg is significantly more effective than either drug alone. Furthermore, valsartan plus hydrochlorothiazide was effective at reducing BP in patients unresponsive to monotherapy with either agent alone. Effective BP control with valsartan plus hydrochlorothiazide was maintained in long-term studies, with reductions observed after 3 months of treatment being similar to those seen after 1, 2 or 3 years.
Fixed-dose valsartan/hydrochlorothiazide showed similar BP reductions to amlodipine and to valsartan plus benazepril. Valsartan/hydrochlorothiazide also provided effective 24-hour ambulatory SBP/DBP control.
Headache, dizziness and fatigue were the most common adverse events occurring in clinical trials; the incidence of these events in valsartan plus hydrochlorothiazide recipients was not significantly different to that in placebo recipients. Hypokalaemia occurred in 4.5% of valsartan plus hydrochlorothiazide recipients; valsartan attenuated the hydrochlorothiazide-associated decrease in serum potassium concentrations.
Conclusions: the combination of valsartan and hydrochlorothiazide is an effective treatment for patients with hypertension. Clinical trials have demonstrated that the combination is more effective than either drug alone, and is effective in patients not responding to monotherapy with either agent. Furthermore, the adverse event profile of valsartan/hydrochlorothiazide is similar to that of placebo. Unless there are compelling or specific indications for other drugs, current data support the use of valsartan/hydrochlorothiazide when patients are unresponsive to monotherapy with either agent. Results from clinical trials evaluating the effects of valsartan/hydrochlorothiazide on cardiovascular morbidity and mortality will help to further define the role of the combination in the management of hypertension.
Valsartan is an angiotensin II receptor blocker with affinity for the type I (AT1) receptor subtype, which is responsible for most of the known effects of angiotensin II. In vitro studies have shown that valsartan is a partially insurmountable antagonist with a relatively long dissociation half-life (17 minutes) from the AT1 receptor. This may contribute to its prolonged hypotensive effect in the clinical setting. Indeed, recent results showed 51% AT1 receptor blockade 24 hours after a single dose of valsartan 160mg in healthy volunteers.
Hydrochlorothiazide therapy in patients with hypertension produces changes in plasma volume, cardiac output, mean arterial pressure, stroke volume, heart rate and total peripheral resistance. Although the mechanism by which thiazide diuretics exert their hypotensive effects is not fully understood, it has been recently suggested that thiazides reduce peripheral resistance during long-term therapy via a direct vascular effect.
In spontaneously hypertensive rats, the hypotensive effects of valsartan were potentiated by the addition of hydrochlorothiazide. Indeed, when rats were administered subcutaneous valsartan 3 mg/kg/day with hydrochlorothiazide 10 mg/kg/day, the hypotensive effect was synergistic.
A peak plasma concentration (Cmax) of 1.64 mg/L was achieved 2 hours (tmax) after oral administration of a single dose of valsartan 80mg to healthy volunteers; the area under the plasma concentration-time curve from 0 to 24 hours (AUC24h) was 8.54 mg · h/L. A higher valsartan dose (200mg) produced a proportionately higher Cmax (3.46 mg/L) with a similar tmax. The bioavailability of valsartan was 23%.
Valsartan is extensively bound to plasma proteins (85 to 99%); the estimated volume of distribution and plasma clearance are 17L and 2.2 L/h. The mean elimination half-life (t½) after a single dose of valsartan 80mg was 7.05 hours. Faecal excretion accounts for ≈86% of an orally administered dose of valsartan, whereas ≈13% is excreted renally. Renal excretion is largely complete 2 days postdose but substantial faecal elimination continues until day 4. The drug is predominantly excreted unchanged.
After 15 days of treatment with oral valsartan 80mg, the AUC24h of valsartan was 52% higher in patients with hypertension on haemodialysis than in those with hypertension and normal renal function. Mild or moderate hepatic impairment approximately doubled the AUC of valsartan compared with that seen in healthy volunteers. Compared with younger volunteers (mean age 23 years), elderly volunteers (mean age 76 years) experienced higher systemic exposure to a given dose of valsartan; however, dosage adjustment based solely on age is not considered necessary.
After administration of a single dose of hydrochlorothiazide 12.5mg to healthy adults, a Cmax of 0.075 mg/L was achieved 1.9 hours postdose; Cmax after administration of hydrochlorothiazide 12.5mg once daily for 5 days was 0.091 mg/L, and tmax was 2 hours. The bioavailability of orally administered hydrochlorothiazide is 66 to 75%, and 40 to 58% is protein-bound. Hydrochlorothiazide does not undergo metabolism, and ≥61% of an oral dose is excreted unchanged in the urine within 24 hours of the dose; reports of the t½ range from 2.5 to 18.9 hours.
Hydrochlorothiazide has no effect on the pharmacokinetics of valsartan, but valsartan does modify hydrochlorothiazide pharmacokinetics. The mean AUC24h, Cmax and t½ after a single dose of hydrochlorothiazide 25mg were reduced by 22, 26 and 35% when administered with valsartan 160mg; the amount of hydrochlorothiazide excreted in the urine was reduced by 15%.
Cmax and AUC48h values for valsartan and hydrochlorothiazide after the administration of fixed-combination tablets or each drug alone to 37 volunteers were within the limits of bioequivalence.
Results from a dose-response study demonstrated that the combination of valsartan 80 or 160mg with hydrochlorothiazide 12.5 or 25mg, administered once daily, was significantly more effective than either drug alone in the treatment of patients with mild to moderate essential hypertension. The greatest reductions in blood pressure (BP) were seen in the valsartan plus hydrochlorothiazide 80 plus 25mg and 160 plus 25mg group [reductions in systolic/diastolic BP (SBP/DBP) of 21.2/15.7 and 22.5/15.3mm Hg]. Reductions in SBP/DBP in patients who received valsartan plus hydrochlorothiazide 80 plus 12.5mg or 160 plus 12.5mg were 16.5/11.8 and 17.8/13.5mm Hg.
Valsartan plus hydrochlorothiazide was also effective at reducing BP in patients who did not respond to monotherapy with either valsartan or hydrochlorothiazide. Among nonresponders to monotherapy with valsartan 80mg, SBP/DBP reductions in patients who recieved valsartan 80mg in combination with hydrochlorothiazide 12.5 (9.8/8.2mm Hg) or 25mg (16.0/10.8mm Hg) were significantly higher than those seen in patients who received monotherapy with valsartan 80 (3.9/5.1mm Hg) or 160mg (6.5/6.2mm Hg). Similarly, nonresponders to hydrochlorothiazide 12.5mg achieved significantly better BP control with fixed-dose valsartan/hydrochlorothiazide 80/12.5mg (14.9/11.2mm Hg) than with hydrochlorothiazide 12.5 (5.2/2.9mm Hg) or 25mg (6.8/5.7mm Hg).
Effective BP control with valsartan plus hydrochlorothiazide was maintained in long-term studies, with reductions observed after 3 months of treatment being similar to those seen after 1, 2 or 3 years. Reductions from baseline in SBP/DBP after 3 years of treatment with valsartan 80mg plus hydrochlorothiazide 12.5mg or 25mg were 11.7/12.5 and 16.4/12.6mm Hg.
Fixed-dose valsartan/hydrochlorothiazide 80/12.5mg showed similar BP reductions to amlodipine 10mg (in patients who did not respond to valsartan 80mg or amlodipine 5mg, respectively), and to valsartan 80mg plus benazepril 10mg in patients not responding to valsartan 80mg. Both valsartan/hydrochlorothiazide and amlodipine provided effective 24-hour ambulatory SBP/DBP control, with trough-to-peak ratio of 0.61/0.57 and 0.56/0.56. However, when only responders to treatment were considered, night-time BP was controlled more effectively with valsartan/hydrochlorothiazide than with amlodipine 5 or 10mg.
Valsartan plus hydrochlorothiazide is well tolerated. Headache, dizziness and fatigue were the most common adverse events occurring in clinical trials; however, the incidence of these events in valsartan plus hydrochlorothiazide recipients was not significantly different to that in placebo recipients. Moreover, the overall incidence of adverse events in patients who received valsartan plus hydrochlorothiazide was similar to that in placebo recipients, and 3.6 vs 4.3% of patients discontinued treatment because of adverse events. There was no increase in the incidence of adverse events in long-term (1 to 3 years’ duration) studies.
The incidence of hypokalaemia in patients who received valsartan plus hydrochlorothiazide in clinical trials was 4.5%. Data from one study showed valsartan attenuated the hydrochlorothiazide-associated decrease in serum potassium concentrations. Orthostatic hypotension has been reported in two patients receiving valsartan plus hydrochlorothiazide. There have been no cases of treatment-related angioneurotic oedema.
Valsartan was similarly well tolerated in combination with either hydrochlorothiazide or benazepril. Valsartan/hydrochlorothiazide was, however, associated with significantly fewer adverse events than amlodipine, predominantly because of a higher rate of lower-limb oedema in amlodipine recipients.
Dosage and Administration
The fixed combination of valsartan/hydrochlorothiazide is indicated for the treatment of patients with hypertension who have not achieved adequate BP control after receiving monotherapy with either drug. The recommended initial starting dosage is valsartan/hydrochlorothiazide 80/12.5mg administered once daily. If BP remains uncontrolled after 3 to 4 weeks, the dosage of valsartan or both components can be titrated to valsartan/hydrochlorothiazide 160/25mg.
Valsartan/hydrochlorothiazide can be administered to patients with renal impairment, as long as creatinine clearance is >1.8 L/h (30 ml/min). Patients with hepatic insufficiency receiving valsartan/hydrochlorothiazide should be monitored for alterations in fluid volume and electrolyte imbalance.
Because of the hydrochlorothiazide component, valsartan/hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
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