Diovan^® (Tablets) Instructions for Use

ATC Code

C09CA03 (Valsartan)

Active Substance

Valsartan (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Angiotensin II receptor antagonist

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system, angiotensin II receptor antagonists (ARBs)

Pharmacological Action

Antihypertensive agent. It is a specific antagonist of angiotensin II receptors. It exerts selective antagonistic action on AT₁ receptors, which are responsible for the realization of the effects of angiotensin II.

Due to the blockade of AT₁ receptors, the plasma concentration of angiotensin II increases, which may stimulate unblocked AT₂ receptors. It has no agonistic activity towards AT₁ receptors. The affinity of valsartan for AT₁ receptors is approximately 20,000 times higher than for AT₂ receptors.

It does not inhibit ACE. It does not interact with or block receptors of other hormones or ion channels important for the regulation of cardiovascular functions. It does not affect the plasma levels of total cholesterol, triglycerides, glucose, and uric acid.

The onset of the antihypertensive effect of valsartan after a single oral dose is observed within 2 hours after administration, with the maximum effect achieved within 4-6 hours.

Pharmacokinetics

After oral administration, Valsartan is rapidly absorbed from the gastrointestinal tract, with the extent of absorption characterized by individual variations. The absolute bioavailability averages 23%. The pharmacokinetic curve of valsartan is multiexponential (T_1/2 in the α-phase < 1 hour and T_1/2 in the β-phase – about 9 hours), with linear kinetics.

No changes in pharmacokinetic parameters were noted during course administration.

When valsartan is taken with food, the AUC decreases by 48%, while approximately 8 hours after administration, plasma concentrations of valsartan are the same in patients who took it with food and on an empty stomach. The decrease in AUC is not accompanied by a clinically significant reduction in the therapeutic effect.

When valsartan is taken once daily, accumulation is minimal. Plasma concentrations of valsartan were similar in women and men.

Plasma protein binding, primarily to albumin, is 94-97%. The V_d at steady state is about 17 L.

The plasma clearance of valsartan is about 2 L/h. It is excreted in feces – 70% and in urine – 30%, predominantly unchanged.

In biliary cirrhosis or obstruction of the biliary tract, the AUC of valsartan increases approximately 2-fold.

Indications

Treatment of arterial hypertension.

Treatment of chronic heart failure (NYHA functional class II-IV) in patients receiving conventional therapy with diuretics, digitalis preparations, as well as ACE inhibitors or beta-blockers.

ICD codes

Dosage Regimen

For arterial hypertension, initiate therapy at 80 mg or 40 mg taken orally once daily. Administer the dose at the same time each day, with or without food. If the antihypertensive effect is inadequate after a suitable evaluation period, titrate the dose upward.

Alternatively, for some patients, a regimen of 40 mg twice daily may be used. The total daily dose may be increased to a maximum of 160 mg administered once daily. For doses exceeding 160 mg per day, administer in two divided doses.

The maximum recommended daily dose is 320 mg. For chronic heart failure (NYHA class II-IV), the recommended starting dose is 40 mg twice daily. Titrate the dose gradually to 80 mg twice daily and then to the target maintenance dose of 160 mg twice daily, as tolerated by the patient.

When titrating the dose for heart failure, double the dose at intervals of no less than two weeks. The highest dose administered in clinical trials was 160 mg twice daily. Closely monitor blood pressure and renal function during any dose titration period.

For patients with mild to moderate hepatic impairment (Child-Pugh A and B), exercise caution and do not exceed a daily dose of 80 mg. In patients with volume depletion, correct this condition prior to administration to reduce the risk of symptomatic hypotension.

No initial dosage adjustment is required for patients with renal impairment; however, monitor renal function periodically. For elderly patients, no initial dosage adjustment is necessary. Adhere to the prescribed regimen and do not discontinue therapy without consulting a physician.

Adverse Reactions

From the cardiovascular system arterial hypotension, postural dizziness, postural hypotension.

From the central nervous system dizziness, headache.

From the digestive system diarrhea, nausea, increased bilirubin level.

From the urinary system rarely – impaired renal function, increased levels of creatinine and blood urea nitrogen (especially in chronic heart failure).

From metabolism hyperkalemia.

From the hematopoietic system neutropenia, decreased hemoglobin and hematocrit.

Allergic reactions rarely – angioedema, rash, pruritus, serum sickness, vasculitis.

Other fatigue, general weakness, cough, pharyngitis, increased risk of viral infections.

Contraindications

Pregnancy, hypersensitivity to valsartan.

Use in Pregnancy and Lactation

Valsartan is contraindicated for use during pregnancy.

It is not known whether Valsartan is excreted in human breast milk. Use during lactation (breastfeeding) is not recommended.

In experimental studies, it has been shown that Valsartan is excreted in the breast milk of rats.

Use in Renal Impairment

In patients with renovascular hypertension secondary to renal artery stenosis, serum urea and creatinine levels should be regularly monitored during treatment. Data on the safety of use in patients with CrCl less than 10 ml/min are not available.

Due to the inhibition of the RAAS, changes in renal function are possible in predisposed patients.

Pediatric Use

The safety and efficacy of valsartan in children have not been established.

Special Precautions

In cases of hyponatremia and/or reduced blood volume, as well as during therapy with high doses of diuretics, Valsartan may, in rare cases, cause pronounced arterial hypotension. Correction of water and electrolyte balance disorders should be performed before starting treatment.

In patients with renovascular hypertension secondary to renal artery stenosis, serum urea and creatinine levels should be regularly monitored during treatment. Data on the safety of use in patients with CrCl less than 10 ml/min are not available.

Use with particular caution in patients with biliary tract obstruction.

Due to the inhibition of the RAAS, changes in renal function are possible in predisposed patients. When using ACE inhibitors and angiotensin receptor antagonists in patients with severe chronic heart failure, oliguria and/or increasing azotemia have been observed, and rarely, acute renal failure with a risk of fatal outcome has developed.

The safety and efficacy of valsartan in children have not been established.

Effect on the ability to drive vehicles and operate machinery

When using valsartan, caution is recommended when driving vehicles and operating machinery.

Drug Interactions

Concomitant use of diuretics in high doses may lead to arterial hypotension.

Concomitant use of potassium-sparing diuretics, heparin, dietary supplements, or salt substitutes containing potassium may lead to hyperkalemia.

Concomitant use with indomethacin may reduce the antihypertensive effect of valsartan.

A case of lithium intoxication has been described with concomitant use with lithium carbonate.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.