Each film-coated tablet contains: Valsartan 80 mg and 160 mg.
Pharmacology: Pharmacodynamics: The active hormone of the RAAS angiotensin II, which is formed from angiotensin I through ACE. Angiotensin II binds to a specific receptors located in the cell membranes of various tissues. It has 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 angiotensin 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 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, angiotensin II antagonists are unlikely to be associated with cough. Valsartan does not bind or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Pharmacokinetics: Absorption: Following oral administration of valsartan alone, peak plasma concentrations are reached in 2-4 hours. Mean absolute bioavailability is 23%. When valsartan is given with food, the area under the plasma concentration curve (AUC) of valsartan is reduced by 48%, although from about 8 hours post dosing, plasma valsartan concentrations are similar to fed and fasted group. This reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without foods.
Distribution: Steady-state volume of distribution of valsartan after intravenous administration is about 17 liters, indicating that valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly as serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the valsartan AUC). This metabolite pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t1/2 α <1 h and t1/2 β about 9 h). Valsartan is primarily eliminated in feces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
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.
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.
Special Populations: Elderly: A somewhat higher systemic exposure to valsartan was observed in some elderly subjects compared to the 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 non-biliary origin and without cholestatis. The AUC with valsartan has been observed to approximately double in patients with biliary cirrhosis or biliary obstruction.
Pediatric population: In a study of 26 pediatric hypertensive patients (aged 1 to 16 years) given a single dose of suspension of valsartan (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the clearance (liters/h/kg) of valsartan was comparable across the age range 1 to 16 years and similar to that of adults receiving the same formulation.
Hypertension: Treatment of hypertension in adults and in children and adolescents 6-18 years of age.
Heart failure: Treatment of heart failure (NYHA class II-IV) in patients receiving standard therapy such as diuretics, digitalis and either angiotensin-converting enzyme (ACE) inhibitors or beta-blockers but not both; presence of all these standard therapies is not mandatory.
Valsartan improves morbidity in these patients, primarily via reduction in hospitalization for heart failure. It 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 versus placebo.
Post-myocardial infarction: Valsartan is indicated 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.
Hypertensive adult patients with impaired Glucose Tolerance (IGT) at cardiovascular risk: Valsartan is indicated in addition to lifestyle modifications to delay the progression to type 2 diabetes in hypertensive adult patients with impaired glucose tolerance at cardiovascular risk.
Adult Population: Hypertension:
The recommended dose is 80 mg or 160 mg once daily, irrespective of race, age or gender. The antihypertensive effect is substantially present within 2 weeks and maxima 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.
Valsartan may also be administered with other antihypertensive agents.
The recommended dose is 40 mg twice daily. Up-titration to 80 mg to 160 mg twice daily should be done to the highest dose 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 doses.
Evaluation of patients with heart failure should always include assessment of renal function.
Therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg twice daily, valsartan therapy should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next few weeks. The starting dose is provided by the 40 mg divisible tablet.
The target maximum dose is 160 mg twice daily. In general, it is recommended that patients achieve a dose level of 80 mg twice daily by two weeks after treatment initiation and that the target maximum dose be achieved by three months, based on the patients tolerability to valsartan during titration. If symptomatic hypotension or renal dysfunction occurs, 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, beta blockers or statins.
Evaluation of post-myocardial infarction patients should always include assessment of renal function.
Hypertensive adult patients with Impaired Glucose Tolerance at cardiovascular risk:
The recommended starting is 80 or 160 mg film-coated tablet once daily. For those patients starting on 80 mg, up-titration to 160 mg once daily should be done, as tolerated by the patient. If hypertension remains uncontrolled, please refer to Hypertension as previously mentioned.
Note for all indications:
No dosage adjustment is required for patients with renal impairment or to patients with hepatic insufficiency of non-billiary origin and without cholestatis.
Special populations: Pediatric population (Pediatric Hypertension): Children and adolescents 6-18 years of age:
The initial dose is a 40 mg tablet once daily for children and adolescents below 35 kg of weight and 80 mg once daily for those weighing 35 kg or more. The dose should be adjusted based on blood pressure response.
Doses higher than those listed have not been studied and are therefore not recommended. (See Table 1.)
Click on icon to see table/diagram/image
Children less than 6 years of age:
Safety and efficacy of Valsartan in children less than 6 years of age have not been established.
Pediatric heart failure and recent myocardial infarction:
Valsartan is not recommended for the treatment of heart failure or recent myocardial infarction in children and adolescents below the age of 18 years due to the lack of data on safety and efficacy.
Use in children and adolescents:
The safety and efficacy of Valsartan have not been established in children and adolescents (below the age of 18 years).
Method of Administration:
Valsartan may be taken independently of a meal and should be administered with water.
Overdosage may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. If the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be i.v. infusion of normal saline. Valsartan is unlikely to be removed by hemodialysis.
Known hypersensitivity to valsartan or to any of the excipients.
Concomitant use of angiotensin receptor antagonist (ARBs) - Valsartan or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with Type 2 diabetes.
Patients with sodium-and/or volume-depletion: In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with valsartan. Sodium and/or volume depletion should be corrected before starting treatment, for example by reducing the diuretic dose.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an i.v. infusion of normal saline. Treatment can be continued once blood pressure has been stabilized.
Patients with renal artery stenosis: Short-term administration of valsartan to twelve patients with renovascular hypertension secondary to unilateral renal artery stenosis did not induce any significant changes in renal hemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, since other drugs that affect the renin-angiotensin-aldosterone system (RAAS) may increase blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis, monitoring of both parameters is recommended as a safety measure.
Patients with impaired renal function: No dosage adjustment is required for patients with renal impairment. However, no data is available for severe cases (creatinine clearance <10 mL/min), and caution is therefore advised.
The use of ARBs - including Valsartan - or of ACEIs with aliskiren should be avoided in patients with severe renal impairment (GFR <30 mL/min).
Patients with hepatic impairment: No dosage adjustment is required for patients with hepatic insufficiency. Valsartan is mostly eliminated unchanged in bile, and patients with biliary obstructive disorders showed lower valsartan clearance. Particular caution should be exercised when administering valsartan to patients with biliary obstructive disorders.
Patients with heart failure/post myocardial infarction: Use in patients with heart failure or post-myocardial infarction commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed.
Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction.
As a consequence of the inhibition of the RAAS, 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 RAAS, treatment with ACE inhibitors or angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. Evaluation of patients with heart failure or post-myocardial infarction should always include assessment of renal function.
In patients with heart failure, caution should be observed with the triple combination of an ACE inhibitor, a beta blocker and valsartan.
Angioedema: Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips, pharynx, and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should be immediately discontinued in patients who develop angioedema, and should not be re-administered.
Dual blockade of the Renin-Angiotensin System (RAS): Caution is required while co-administering ARBs with other agents blocking the RAS such as ACEIs or aliskiren.
Use in Children: Patients with impaired renal function: Use in pediatric patients with a glomerular filtration rate of <30 mL/min/1.73 m2 and pediatric patients undergoing dialysis has not been studied, therefore valsartan is not recommended in these patients. No dose adjustment is required for pediatric patients with a glomerular filtration rate of >30 mL/min/1.73 m2. Renal function and serum potassium should be closely monitored during treatment with valsartan. This applies particularly when valsartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function.
Patients with impaired hepatic function: As in adults, particular caution should be exercised when administering valsartan to pediatric patients with biliary obstructive disorders. There is a limited clinical experience with Valsartan in pediatric patients with mild to moderate hepatic impairment.
Woman of child-bearing potential: As for any drug that also acts directly on the RAAs, valsartan should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women childbearing potential about the potential risk of these agents during pregnancy.
Pregnancy: As for any drug that also acts directly on the RAAS, valsartan should not be used during pregnancy. Due to the mechanism of action of angiotensin II antagonists, a risk for the fetus cannot be excluded. In utero exposure to ACE inhibitors (a specific class of drugs acting on the RAAS) during the second and third trimesters has been reposted to cause injury and death to the developing fetus. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction, when pregnant women have inadvertently taken valsartan. If pregnancy is detected during therapy, valsartan should be discontinued as soon as possible.
Breast Feeding: It is not known whether valsartan is excreted in human milk. Since valsartan was excreted in the milk of lactating rats, its use is not advisable in breast-feeding mothers.
Fertility: There is no information on the effects of valsartan on human fertility. Studies in rats did not show any effects of valsartan on fertility.
In controlled clinical studies in patients with hypertension, the overall incidence of adverse reactions (ADRs) were comparable with placebo and is consistent with the pharmacology of valsartan. The incidence of ADRs did not appear to be related to dose or treatment duration and also showed no association with gender, age or race.
The ADRs reported from clinical studies, post marketing experience and laboratory findings are listed as follows, according to system organ class.
Adverse reactions are ranked by frequency, the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000) including isolated reports. With each frequency grouping adverse reactions are ranked in order of decreasing seriousness.
For all the ADRs reported from post-marketing experience and laboratory findings, it is not possible to apply any ADR frequency and therefore they are mentioned with a "not known" frequency. (See Table 2.)
Click on icon to see table/diagram/image
The following events have also been observed during clinical trials in hypertensive patients, irrespective of their causal association with the study drug: Arthralgia, asthenia, back pain, diarrhea, dizziness, headache, insomnia, libido decrease, nausea, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Hyperkalemia has been observed in children and adolescents aged 6 to 18 years with underlying chronic kidney disease.
Heart failure and/or post myocardial infarction:
The safety profile seen in controlled-clinical studies in patients with heart failure and/or post myocardial infarction varies from the overall safety profile seen in hypertensive patients. This may relate to the patients underlying disease. ADRs that occurred in heart failure and/or post-myocardial infarction patients are listed as follows: (See Table 3.)
Click on icon to see table/diagram/image
The following events have also been observed during clinical trials in patients with heart failure and/or post-myocardial infarction irrespective of their causal association with the study drug: Arthralgia, abdominal pain, back pain, insomnia, libido decrease, neutropenia, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Dual blockade of the Renin-Angiotensin-System (RAS) with ARBs, ACEIs, or aliskerin: The concomitant use of ARBs, including Valsartan, with other agents acting on the RAS is associated with an increased incidence of hypotension, hyperkalemia, and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS.
The concomitant use of ARBs - including valsartan or of ACEIs with aliskerin, should be avoided in patients with severe renal impairment (GFR <30 mL/min).
The concomitant use of ARBs - including valsartan or ACEIs with aliskerin is contraindicated in patients with Type 2 diabetes.
Potassium: 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, monitoring of serum potassium is advisable.
Non-Steroidal Anti-Inflammatory Agents (NSAIDS) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): When angiotensin II antagonists are administered simultaneously with NSAIDS, attenuation of the antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including those on diuretic therapy), or have compromised renal function, concomitant use of angiotensin II antagonists and NSAIDS may lead to an increased risk of worsening of renal function. Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on valsartan who are taking NSAIDS concomitantly.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists, including valsartan. Therefore, careful monitoring of serum lithium level is recommended during concomitant use. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further with valsartan.
Transporters: Co-administration of inhibitor of the uptake transporter (rifampicin, ciclosporin) or efflux transporter (ritonavir) may increase the systemic exposure to valsartan.
No drug interactions of clinical significance have been found. Compounds which have been studied in clinical trials include, cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorthiazide, amlodipine and glibenclamide.
As valsartan is not metabolized to significant extent, clinically relevant drug-drug interactions in the form of metabolic induction or inhibition of the cytochrome P450 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, such as diclofenac, furosemide and warfarin.
Pediatric Population: In hypertension in children and adolescents, where underlying renal abnormalities are common, caution is recommended with the concomitant use of valsartan and other substances that inhibit the renin angiotensin aldosterone system which may increase serum potassium. Renal function and serum potassium should be closely monitored in these patients.
Store at temperature not exceeding 30°C. Protect from light and moisture.
C09CA03 - valsartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Torval-80: FC tab 80 mg (brick red coloured oval shaped, biconvex with breakline on both sides) x 30's.
Torval-160: FC tab 160 mg (yellow coloured oval shaped, biconvex with breakline on both sides) x 30's.