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.
Hydrochlorothiazide is a thiazide diuretic. It affects the renal tubular mechanisms of electrolyte reabsorption, directly increasing the excretion of sodium and chloride. 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 a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist (Valsartan) tends to reverse the potassium loss associated with thiazide diuretics.
Absorption: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Absolute bioavailability for Valsartan is about 25%. Food decreases the exposure (as measured by AUC) to Valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of Valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of the dose) and urine (about 13% of the dose). The recovery is mainly as unchanged drug, with only about 20% of the dose recovered as metabolites. The enzymes responsible for Valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes.
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.
Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Hydrochlorothiazide crosses the placenta but not the blood-brain barrier and is excreted in breast milk.
Hypertension: Disys® (Valsartan), Disys® Plus (Valsartan 80 mg & Hydrochlorothiazide 12.5 mg), and Disys® Plus DS (Valsartan 160 mg & Hydrochlorothiazide 12.5 mg) are indicated for the treatment of hypertension. Disys® may be used alone or in combination with other antihypertensive agents.
Heart Failure: Disys® is indicated for the treatment of heart failure (NYHA class II-IV). In a controlled clinical trial, Valsartan significantly reduced hospitalizations for heart failure.
Post-Myocardial Infarction: In clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction, Valsartan is indicated to reduce cardiovascular mortality.
Hypertension: The recommended starting dose of Valsartan is 80 mg or 160 mg once daily when used as monotherapy in patients who are not volume-depleted. Patients requiring greater reductions may be started at the higher dose. Valsartan may be used over a dose range of 80 mg to 320 mg daily, administered once daily.
Hydrochlorothiazide is effective in doses of 12.5 mg to 50 mg once daily and can be given at doses of 12.5 mg as Disys® Plus. 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.
Heart Failure: The recommended starting dose of Valsartan is 40 mg twice daily. Up-titration to 80 mg and 160 mg twice daily should be done to the highest dose, as tolerated by the patient.
Post-Myocardial Infarction: Disys® may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose is 20 mg twice daily. Patients may be up-titrated within 7 days to 40 mg twice daily, with subsequent titrations to a target maintenance dose of 160 mg twice daily, as tolerated by the patient.
Disys®, Disys® Plus, and Disys® Plus DS are contraindicated in patients who are hypersensitive to any component of the product.
Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. The overall incidence of adverse experiences with Valsartan and Hydrochlorothiazide was comparable to placebo. Some adverse reactions such as dizziness, fatigue, pharyngitis, coughing, diarrhea, nausea, etc., may be observed.
Pediatric: The pharmacokinetics of Valsartan has not been investigated in patients under 18 years of age.
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.
Gender: Pharmacokinetics of Valsartan does not differ significantly between males and females.
Heart Failure: The average time to peak concentration and elimination half-life of Valsartan in heart failure patients are similar to that observed in healthy volunteers. AUC and Cmax values of Valsartan increase linearly and are almost proportional with increasing dose over the clinical dosing range (40 to 160 mg twice a day). The average accumulation factor is about 1.7. The apparent clearance of Valsartan following oral administration is approximately 4.5 L/h. Age does not affect the apparent clearance in heart failure patients.
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. Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5-15 hours. In 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: In patients with mild to moderate hepatic impairment without cholestasis, no dosage adjustment is required. However, Valsartan should be used with caution. Liver disease does not significantly alter the pharmacokinetics of Hydrochlorothiazide.
Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to ACE inhibitors given to pregnant women during the 2nd and 3rd trimesters has been reported to cause injury and death to the developing fetus. As for any drug that also acts directly on the renin-angiotensin-aldosterone system, Valsartan should not be used during pregnancy. If pregnancy is detected during therapy, Valsartan should be discontinued as soon as possible.
Because no information is available regarding the use of Valsartan during breastfeeding, Valsartan is not recommended, and alternative treatments with a better-established safety profile during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide crosses the placenta and is excreted in human milk. Thus, it is not advisable to use this combination in lactating mothers.
No clinically significant pharmacokinetic interactions were observed when Valsartan was co-administered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide, hydrochlorothiazide, or indomethacin.
Store at a temperature not exceeding 30ºC in a dry place. Protect from light and moisture.
Medicine: Keep out of reach of children.
