Valsartan is (S)-N-valeryl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-valine.
Excipients/Inactive Ingredients: Microcrystalline cellulose, crospovidone, anhydrous colloidal silica, magnesium stearate, hypromellose, titanium dioxide (E171), macrogol 8000, red iron oxide (E172), yellow iron oxide (E172) and black iron oxide (E172; 160-mg tablet only).
Angiotensin II antagonist.
Pharmacology: Pharmacodynamics: The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from angiotensin I through angiotensin-converting enzyme (ACE). Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular, both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.
Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype which is responsible for the known actions of Ang II. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 20,000-fold) greater affinity for the AT1 receptor than for the AT2 receptor.
Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, Ang II antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly less (p<0.05) in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% vs 7.9%, respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (p<0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Administration of Tareg to patients with hypertension results in reduction of blood pressure without affecting pulse rate.
In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hrs, and the peak reduction of blood pressure is achieved within 4-6 hrs. The antihypertensive effect persists over 24 hrs after dosing. During repeated dosing, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of Tareg has not been associated with rebound hypertension or other adverse clinical events.
In multiple-dose studies in hypertensive patients, Tareg had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose or uric acid.
Heart Failure: Hemodynamics and Neurohormones: Hemodynamics and plasma neurohormones were measured in NYHA class II-IV heart failure patients with pulmonary capillary wedge pressure ≥15 mmHg in 2 short-term, chronic therapy studies. In 1 study, which included patients chronically treated with ACE inhibitors, single and multiple doses of valsartan given in combination with an ACE inhibitor improved hemodynamics, including pulmonary capillary wedge pressure (PCWP), pulmonary artery diastolic pressure (PAD) and systolic blood pressure (SBP). Reductions were observed in plasma aldosterone (PA) and plasma norepinephrine (PNE) levels after 28 days of treatment. In the 2nd study, which included only patients untreated with ACE inhibitors for at least 6 months prior to enrollment, valsartan significantly improved PCWP, systemic vascular resistance (SVR), cardiac output (CO) and SBP after 28 days of treatment. In the long-term Valsartan Heart Failure Trial (Val-HeFT) study, plasma norepinephrine and brain natriuretic peptide (BNP) were significantly reduced from baseline in the valsartan group compared to placebo.
Morbidity and Mortality: Val-HeFT was a randomized, controlled, multinational clinical trial of valsartan compared with placebo on morbidity and mortality in NYHA class II (62%), III (36%) and IV (2%) heart failure patients receiving usual therapy with LVEF <40% and left ventricular internal diastolic diameter (LVIDD) >2.9 cm/m2. The study enrolled 5010 patients in 16 countries who were randomized to receive either valsartan or placebo in addition to all other appropriate therapy including ACE inhibitors (93%), diuretics (86%), digoxin (67%) and β-blockers (36%). The mean duration of follow-up was nearly 2 years. The mean daily dose of Tareg in Val-HeFT was 254 mg. The study had 2 primary endpoints: All-cause mortality (time to death) and heart failure morbidity (time to 1st morbid event) defined as death, sudden death with resuscitation, hospitalization for heart failure, or administration of IV inotropic or vasodilator drugs for ≥4 hrs without hospitalization. All-cause mortality was similar in the valsartan and placebo groups. Morbidity was significantly reduced by 13.2% with valsartan compared with placebo. The primary benefit was a 27.5% reduction in risk for time to 1st heart failure hospitalization. The benefits were greatest in patients not receiving either an ACE inhibitor or a β-blocker. However, risk ratios favoring placebo were observed for those patients treated with the triple combination of a β-blocker, an ACE inhibitor and an ARB (angiotensin II receptor blocker), valsartan. Subgroup analyses can be difficult to interpret and it is not known whether these represent true differences or chance effects.
Exercise Tolerance and Capacity: The effects of valsartan in addition to usual heart failure therapy on exercise tolerance using the Modified Naughton Protocol were measured in NYHA class II-IV heart failure patients with left ventricular dysfunction (LVEF ≤40%). Increased exercise time from baseline was observed for all treatment groups. Greater mean increases from baseline in exercise time were observed for the valsartan groups compared to the placebo group, although statistical significance was not achieved. The greatest improvements were observed in the subgroup of patients not receiving ACE inhibitor therapy where mean changes in exercise time were 2 times greater for the valsartan groups compared to the placebo group. The effects of valsartan compared to enalapril on exercise capacity using the 6-min walk test were determined in NYHA class II and III heart failure patients with left ventricular ejection fraction ≤45% who had been receiving ACE inhibitor therapy for at least 3 months prior to study entry. Valsartan 80-160 mg once daily was at least as effective as enalapril 5-10 mg twice daily, with respect to exercise capacity, as measured by the 6-min walk test in patients previously stabilized on ACE inhibitors and directly switched to valsartan or enalapril.
NYHA Class, Signs and Symptoms, Quality of Life, Ejection Fraction: In Val-HeFT, valsartan-treated patients showed significant improvement in NYHA class, and heart failure signs and symptoms, including dyspnea, fatigue, oedema and rales compared to placebo. Patients on valsartan had a better quality of life as demonstrated by change in the Minnesota Living with Heart Failure Quality of Life score from baseline at endpoint than placebo. Ejection fraction in valsartan-treated patients was significantly increased and LVIDD significantly reduced from baseline at endpoint compared to placebo.
Pharmacokinetics: Absorption of valsartan after oral administration is rapid, although the amount absorbed varies widely. Mean absolute bioavailability for Tareg is 23%. Valsartan shows multiexponential decay kinetics (t½α <1 hr and t½β about 9 hrs).
The pharmacokinetics of valsartan are linear in the dose range tested. There is no change in the kinetics of valsartan on repeated administration, and little accumulation when dosed once daily. Plasma concentrations were observed to be similar in males and females.
Valsartan is highly bound to serum protein (94-97%), mainly serum albumin. Steady-state volume of distribution is low (about 17 L). Plasma clearance is relatively slow (about 2 L/hr) when compared with hepatic blood flow (about 30 L/hr). Of the absorbed dose of valsartan, 70% is excreted in the faeces and 30% in the urine, mainly as unchanged compound.
When Tareg is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hrs postdosing, plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect, and Tareg can therefore, be given either with or without food.
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 (40-160 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/hr. Age does not affect the apparent clearance in heart failure patients.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance.
Impaired Renal Function: As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, no correlation was seen between renal function and systemic exposure to valsartan. Dose adjustment is therefore not required in patients with renal impairment. No studies have been performed in patients undergoing dialysis. However, valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic Impairment: About 70% of the absorbed dose is excreted in the bile mainly as unchanged compound. Valsartan does not undergo extensive biotransformation, and as expected, systemic exposure to valsartan is not correlated with the degree of liver dysfunction. No dose adjustment for valsartan is therefore necessary in patients with hepatic insufficiency of nonbiliary origin and without cholestasis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction (see Precautions).
Treatment of hypertension.
Treatment of heart failure (NYHA class II-IV) in patients receiving usual therapy eg, diuretics, digitalis and either ACE inhibitors or β-blockers but not both; presence of all these standard therapies is not mandatory.
In these patients, Tareg improves morbidity, primarily via reduction in hospitalization for heart failure. Tareg also slows the progression of heart failure, improves NYHA functional class, ejection fraction and signs and symptoms of heart failure, and improves quality of life vs placebo (see Pharmacology under Actions).
Post-Myocardial Infarction: To improve survival following myocardial infarction in clinically stable patients with signs, symptoms or radiological evidence of left ventricular failure and/or with left ventricular systolic dysfunction.
Hypertension: Recommended Dose: 80 or 160 mg once daily, irrespective of race, age or gender. The antihypertensive effect is substantially present within 2 weeks and maximal effects are seen after 4 weeks. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 320 mg or a diuretic may be added.
Renal Impairment/Hepatic Insufficiency: No dosage adjustment is required for patients with renal impairment or for patients with hepatic insufficiency of nonbiliary origin and without cholestasis.
Tareg may also be administered with other antihypertensive agents.
Heart Failure: Recommended Starting Dose: 40 mg twice daily. Uptitration to 80 and 160 mg twice daily should be done to the highest dose, as tolerated by the patient. Consideration should be given to reducing the dose of concomitant diuretics. The maximum daily dose administered in clinical trials is 320 mg in divided dose.
Evaluation of patients with heart failure should always include assessment of renal function.
Post-Myocardial Infarction: Therapy may be initiated as early as 12 hrs after a myocardial infarction. After an initial dose of 20 mg twice daily, valsartan therapy should be titrated to 40, 80 and 160 mg twice daily over the next few weeks. The starting dose is provided by the 40-mg divisible tablet. Achievement of the target dose of 160 mg twice daily should be based on the patient's tolerability to valsartan during titration. If symptomatic hypotension or renal dysfunction occur, consideration should be given to a dosage reduction.
Valsartan may be used in patients treated with other post-myocardial infarction therapies eg, thrombolytics, acetylsalicylic acid, β-blockers and statins.
Children: The safety and efficacy of Tareg have not been established in children.
Although there is no experience of overdosage with Tareg, the major sign that might be expected is marked hypotension. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be IV infusion of normal saline solution. Valsartan is unlikely to be removed by hemodialysis.
Hypersensitivity to any of the components of Tareg.
Use in Pregnancy & Lactation: Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to angiotensin-converting enzyme (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 (RAAS), Tareg should not be used during pregnancy. If pregnancy is detected during therapy, Tareg should be discontinued as soon as possible.
It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Thus, it is not advisable to use Tareg in lactating mothers.
Sodium- and/or Volume-Depleted Patients: In severely sodium- and/or volume-depleted patients eg, those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Tareg. Sodium and/or volume depletion should be corrected before starting treatment with Tareg eg, by reducing the diuretic dose.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an IV infusion of normal saline. Treatment can be continued once the blood pressure has stabilized.
Renal Artery Stenosis: Short-term administration of Tareg to 12 patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal haemodynamics, serum creatinine or blood urea nitrogen (BUN). However, since other drugs that affect the renin-angiotensin-aldosterone system may increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring is recommended as a safety measure.
Impaired Renal Function: No dosage adjustment is required for patients with renal impairment. However, in severe cases (creatinine clearance <10 mL/min), no data are available, and therefore caution is advised.
Hepatic Impairment: No dosage adjustment is required for patients with hepatic insufficiency. Valsartan is mostly eliminated unchanged in the bile, and patients with biliary obstructive disorders showed lower valsartan clearance (see Pharmacology: Pharmacokinetics under Actions). Particular caution should be exercised when administering valsartan to these patients.
Heart Failure: Patients with heart failure given Tareg commonly have some reduction in blood pressure, but discontinuation therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. Caution should be observed when initiating therapy in patients with heart failure (see Dosage & Administration).
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Evaluation of patients with heart failure should always include assessment of renal function.
In patients with heart failure, the triple combination of an ACE inhibitor, a β-blocker and an ARB (angiotensin II receptor blocker), valsartan is not recommended (see Pharmacology under Actions).
Effects on the Ability to Drive or Operate Machinery: As with other antihypertensive agents, it is advisable to exercise caution when driving or operating machinery.
Use in Children: The safety and efficacy of Tareg have not been established in children.
Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to angiotensin-converting enzyme (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 (RAAS), Tareg should not be used during pregnancy. If pregnancy is detected during therapy, Tareg should be discontinued as soon as possible.
It is not known whether valsartan is excreted in human milk. Valsartan was excreted in the milk of lactating rats. Thus, it is not advisable to use Tareg in lactating mothers.
In the placebo-controlled trials involving 2316 patients with hypertension who have been treated with Tareg, the study drug showed an overall incidence of adverse experiences (AEs) comparable with that of placebo.
The following table of AEs is based on 10 placebo-controlled trials in patients treated with various doses of valsartan (10-320 mg) for up to 12 weeks. Of the 2316 patients, 1281 and 660 received 80 or 160 mg, respectively. With none of the AEs did their incidence appear to be related to dose or duration of treatment; therefore, AEs occurring on all doses of valsartan were pooled. The incidence of AEs also showed no association with gender, age or race. All adverse experiences showing an incidence of ≥1% in the Tareg treatment group are included in the following table, irrespective of their causal association with the study drug. (See table.)
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Other adverse experiences with a frequency <1% included oedema, asthenia, insomnia, rash, decreased libido and vertigo. It is unknown whether these effects were causally related to valsartan therapy.
Post-marketing data revealed very rare cases of angioedema, rash, pruritus and other hypersensitivity/allergic reactions including serum sickness and vasculitis. Very rare cases of impaired renal function have also been reported.
In double-blind, short-term heart failure trials, including the first 4 months of the Val-HeFT, the following drug-related adverse events were observed with an incidence >1% and more frequent in valsartan-treated patients than placebo-treated patients: Dizziness (excluding vertigo), hypotension, postural dizziness, postural hypotension, fatigue, diarrhoea, headache, nausea, renal impairment, hyperkalemia and vertigo. All patients received standard drug therapy for heart failure, frequently as multiple medications which could include diuretics, digitalis, β-blockers or ACE inhibitors.
From the long-term data in Val-HeFT, there did not appear to be any significant adverse events not already identified during short-term exposure.
In rare cases, valsartan may be associated with decreases in haemoglobin and haematocrit. In controlled clinical trials, 0.8% and 0.4% of patients receiving Tareg showed significant decreases (>20%) in haematocrit and haemoglobin, respectively.
In comparison, 0.1% of patients receiving placebo showed decreases in both haematocrit and haemoglobin.
Neutropenia was observed in 1.9% of patients treated with valsartan vs 1.6% of patients treated with an ACE inhibitor.
In controlled clinical trials in hypertensive patients, significant increases in serum creatinine, potassium and total bilirubin were observed, respectively, in 0.8%, 4.4% and 6% of patients treated with valsartan vs 1.6%, 6.4% and 12.9% of those treated with an ACE inhibitor. Occasional elevations of liver function values were reported in patients treated with valsartan.
No special monitoring of laboratory parameters is necessary for patients with essential hypertension receiving valsartan therapy.
In heart failure patients, >50% increases in serum creatinine were observed in 3.9% of Tareg-treated patients compared to 0.9% of placebo-treated patients. In these patients, >20% increases in serum potassium were observed in 10% of Tareg-treated patients compared to 5.1% of placebo-treated patients.
In heart failure trials, >50% increases in blood urea nitrogen (BUN) were observed in 16.6% of patients treated with valsartan as compared to 6.3% of patients treated with placebo.
No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide.
As Tareg is not metabolized to a significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P-450 system are not expected with valsartan. Although valsartan is highly bound to plasma proteins, in vitro studies have not shown any interaction at this level with a range of molecules which are also highly protein-bound eg, diclofenac, furosemide and warfarin.
Concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements or salt substitutes containing potassium may lead to increases in serum potassium and in heart failure patients to increases in serum creatinine. If co-medication is considered necessary, caution is advisable.
Instructions for Use and Handling: No specific instructions for use and handling.
Incompatibilities: None known.
Do not store above 30°C. Store in the original package.
C09CA03 - valsartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Tab 80 mg x 28's. 160 mg x 28's. 320 mg x 28's.