Absorption: The peak plasma concentration of Valsartan is reached 2 to 4 hours after dosing. The absolute bioavailability of Valsartan is approximately 25%. Food decreases the exposure (as measured by AUC) to Valsartan by about 40% and the peak plasma concentration (Cmax) by about 50%. AUC and Cmax values of Valsartan increase approximately linearly with increasing doses over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.
Metabolism and Elimination: When administered as an oral solution, Valsartan is primarily recovered in feces (about 83% of the dose) and urine (about 13% of the dose). The recovery is mainly in the form of 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 appear to be CYP 450 isozymes.
Hydrochlorothiazide is not metabolized but is rapidly eliminated by the kidneys. At least 61% of the oral dose is eliminated as unchanged drug within 24 hours. The elimination half-life ranges between 5.8 and 18.9 hours.
Valsartan is highly bound to serum proteins (95%), mainly serum albumin. Hydrochlorothiazide crosses the placenta but does not cross 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 a 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 a 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 a dose of 12.5 mg as Disys® Plus. To minimize dose-independent side effects, it is usually appropriate to initiate 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 and have only infrequently required discontinuation of therapy. The overall incidence of adverse experiences with Valsartan and Hydrochlorothiazide was comparable to that of placebo. Some adverse reactions, such as dizziness, fatigue, pharyngitis, coughing, diarrhea, and nausea, may occur.
Pediatric: The pharmacokinetics of Valsartan has not been investigated in patients under 18 years of age.
Geriatric: Exposure (measured by AUC) to Valsartan is 70% higher, and the half-life is 35% longer in elderly patients compared to younger individuals. However, no dosage adjustment is necessary.
Gender: The pharmacokinetics of Valsartan do 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 those observed in healthy volunteers. AUC and Cmax values of Valsartan increase linearly and are nearly proportional with increasing doses over the clinical dosing range (40 to 160 mg twice daily). 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 kidneys, 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 is prolonged 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 to the fetus cannot be excluded. In utero exposure to ACE inhibitors during the second and third trimesters has been reported to cause injury and death to the developing fetus. As with any drug that 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, it is not recommended. Alternative treatments with a better-established safety profile during breastfeeding should be preferred, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide crosses the placenta and is excreted in human milk; therefore, its use in lactating mothers is not advisable.
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.
Keep medicine out of reach of children.
