RiteMED Valsartan

RiteMED Valsartan

valsartan

Manufacturer:

Sun Pharma Industries

Distributor:

RiteMED
Full Prescribing Info
Contents
Valsartan.
Description
Each 80/160 mg film coated tablet contains: Valsartan USP 80/160 mg.
Excipients/Inactive Ingredient: Cellulose Microcrystalline (Avicel PH 101 and Avicel PH 102), Crospovidone (PPXL), Colloidal Anhydrous Silica, Magnesium Stearate, Starch Pregelatinised, Purified Talc, Purified Water, Opadry 03G52389 (Yellow) [Hypromellose 6cP, Titanium Dioxide, Macrogol/PEG 400, Macrogol/PEG 4000, Purified Talc, Iron oxide Yellow, Iron oxide Red].
Each tablet contain valsartan a nonpeptide, orally active, and specific angiotensin II receptor blocker acting on the AT1 receptor subtype. Valsartan is chemically described as N-(1- 1 oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1, 1'-biphenyl]-4-yl] methyl]-L-valine. Its empirical formula is C24H29N5O3, its molecular weight is 435.5.
Action
Pharmacology: Pharmacodynamics: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. 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 1 smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis.
There is also an AT2 receptor found in many tissues, but AT2 is not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20000-fold) for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. The primary metabolite of valsartan is essentially inactive with an affinity for the AT1 receptor about one 200th that of valsartan itself.
Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.
Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is reported.
Removal of the negative feedback of angiotensin II is reported is reported to cause a 2- to 3- fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone have been reported after administration of valsartan; with very little effect on serum potassium.
In reported multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, there was no clinically significant effects reported with valsartan on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow.
In reported multiple-dose studies in hypertensive patients, no notable effects were reported with valsartan on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid.
Pharmacokinetics: Valsartan peak plasma concentration is reported to reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for valsartan is about 25% (range 10% to 35%). With the tablet, food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%. AUC max and Cmax values of valsartan increase approximately linearly with increasing dose over the max 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 dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and co-administered drugs are unlikely because of the low extent of metabolism. 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).
Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.
Special Populations: Pediatric: In a reported study of pediatric hypertensive patients (1 to 16 years of age) given single doses of a suspension of valsartan (mean: 0.9 to 2 mg/kg), the clearance (L/h/kg) of valsartan for children was reported to be similar to that of adults receiving the same formulation.
Geriatric: Exposure (measured by AUC) to valsartan is reported to be higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary (see DOSAGE & ADMINISTRATION).
Gender: Pharmacokinetics of valsartan is not reported to 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 reported in healthy volunteers. AUC and Cmax values of max 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 reported correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. No studies have been reported in patients with severe impairment of renal function (creatinine clearance <10 ml/min). Valsartan is not removed from the plasma by hemodialysis. Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤30 ml/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 ml/min) or moderate (CrCl 30 to 60 ml/min) renal impairment. In the case of severe renal disease, exercise care with dosing of valsartan (see DOSAGE & ADMINISTRATION).
Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease are reported to have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). Valsartan is contraindicated in patients with severe hepatic impairment; biliary cirrhosis and cholestasis (see CONTRAINDICATIONS). In patients with mild to moderate hepatic impairment without cholestasis, it should be used with caution and the dose of valsartan should not exceed 80 mg (see DOSAGE & ADMINISTRATION).
Toxicology: Preclinical Safety Data: Non-clinical data have not reported any special hazard for humans based on reported studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In reported non-clinical safety studies in rats, high doses of valsartan (200 to 600 mg/kg body weight) which are approximately 6 and 18 times the maximum recommended human dose, caused a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal hemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). In marmosets at similar doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised urea and creatinine. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Daily oral dosing of neonatal/juvenile rats with valsartan at doses as low as 1 mg/kg/day (about 10 to 35% of the maximum recommended pediatric dose of 4 mg/kg/day on systemic exposure basis) reportedly produced persistent, irreversible kidney damage. These effects represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers and are reported in rats treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. Functional renal maturation is an ongoing process within the first year of life in humans. Consequently, a clinical relevance in children <1 year of age cannot be excluded, while reported preclinical data does not indicate a safety concern for children older than 1 year.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of carcinogenicity reported when valsartan was administered to mice and rats for up to 2 years at doses up to 2.6 and 6 times, respectively, the maximum recommended human dose. on a mg/m2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).
Mutagenicity assays have not reported any valsartan-related effects at either the gene or chromosome level.
Valsartan had no reported adverse effects on the reproductive performance of male or female rats at oral doses up to 6 times the maximum recommended human dose on a mg/m2 basis (Calculations assume an oral dose of 320 mg/day and a 60-kg patient).
No teratogenic effects have been reported when valsartan was administered to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses up to 10 mg/kg/day. However, significant decreases in fetal weight, pup birth weight, pup survival rate, and slight delays in developmental milestones have been reported in studies in which parental rats were treated with valsartan at oral, maternally toxic (reduction in body weight gain and food consumption) doses of 600 mg/kg/day during organogenesis or late gestation and lactation. In rabbits, fetotoxicity (i.e., resorptions, litter loss, abortions, and low body weight) associated with maternal toxicity (mortality) was reported at doses of 5 and 10 mg/kg/day. The adverse effect reported at doses of 600, 200 and 2 mg/kg/day in mice, rats and rabbits represent 9, 6, and 0.1 times, respectively, the maximum recommended human dose on a mg/m2 basis.
Indications/Uses
Hypertension: Valsartan is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been reported in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which valsartan principally belongs. There are no controlled trials reported in hypertensive patients demonstrating risk reduction with valsartan.
Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients do require more than one drug to achieve blood pressure goals. For specific advice on goals and management, refer to published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).
Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.
Valsartan may be used alone or in combination with other antihypertensive agents.
Heart Failure: Valsartan is indicated for the treatment of heart failure (NYHA class II to IV). Valsartan significantly reduced hospitalizations for heart failure in a reported clinical trial. There is no evidence reported that valsartan provides added benefits when it is used with an adequate dose of an ACE inhibitor.
Post-Myocardial Infarction: Valsartan is indicated to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Dosage/Direction for Use
Valsartan 80 mg / 160 mg tablets may not be suitable to deliver all dosage regimens of valsartan; and therefore other suitable available approved dosage forms and/or strengths of valsartan should be used in such cases.
The general dosage recommendations of valsartan are given as follows.
Hypertension: Adult 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 a day.
The antihypertensive effect is substantially present within 2 weeks and maximal reduction is generally attained after 4 weeks. If additional antihypertensive effect is required over the starting dose range, the dose may be increased to a maximum of 320 mg or a diuretic may be added. Addition of a diuretic has a greater effect than dose increases beyond 80 mg.
No initial dosage adjustment is required for elderly patients, for patients with mild or moderate renal impairment. Care should be exercised with dosing of valsartan in patients with severe renal impairment. Valsartan is contraindicated in patients with severe hepatic impairment; biliary cirrhosis and cholestasis (see CONTRAINDICATIONS). In patients with mild to moderate hepatic impairment without cholestasis, it should be used with caution and the dose of valsartan should not exceed 80 mg.
Valsartan may be administered with other antihypertensive agents. Valsartan may be administered with or without food.
Pediatric Hypertension (6 to 18 years of age): For children who can swallow tablets, the usual recommended starting dose is 1.3 mg/kg once daily (up to 40 mg total). The dosage should be adjusted according to blood pressure response. Doses higher than 2.7 mg/kg (up to 160 mg) once daily have not been reported in pediatric patients 6 to 16 years old.
For children who cannot swallow tablets, or children for whom the calculated dosage (mg/kg) does not correspond to the available strengths of valsartan tablets, may be prescribed other alternative suitable available formulation (e.g. suspension) of valsartan.
No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate <30 ml/min/1.73 m2 (see PRECAUTIONS).
Valsartan is not recommended for patients <6 years old.
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. 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.
Valsartan may be administered with other heart failure therapies. However, the triple combination of an ACE inhibitor, a beta blocker and valsartan is not recommended.
Evaluation of patients with heart failure should always include assessment of renal function.
Post-Myocardial Infarction: Valsartan may be initiated as early as 12 hours after a myocardial infarction. The recommended starting dose of valsartan 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. If symptomatic hypotension or renal dysfunction occurs, consideration should be given to a dosage reduction. Valsartan may be given with other standard post-myocardial infarction treatment, including thrombolytics, aspirin, beta-blockers, statins and diuretics. The combination with ACE inhibitors is not recommended.
Evaluation of post-myocardial infarction patients should always include assessment of renal function.
Method of Administration: Valsartan tablet may be taken independently of a meal and should be administered with water.
Special Populations: Renal Impairment: (see PRECAUTIONS).
Hepatic Impairment: (see PRECAUTIONS).
Elderly: No initial dose adjustment is required in elderly patients.
Pediatrics: (see PRECAUTIONS).
Overdosage
Limited data has been reported related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. Depressed level of consciousness, circulatory collapse and shock has been reported.
The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms; stabilization of the circulatory condition is of prime importance. If hypotension occurs, supportive treatment should be instituted, the patient should be placed in a supine position and blood volume correction should be undertaken.
Valsartan is not reported to be removed from the plasma by hemodialysis.
Valsartan was not reported for grossly observable adverse effects at single oral doses up to 2000 mg/kg in rats and up to 1000 mg/kg in marmosets (60 and 31 times, respectively, the maximum recommended human dose on a mg/m2 basis), except for salivation and diarrhea in the rat and vomiting in the marmoset at the highest dose .
Contraindications
Valsartan tablets are contraindicated in patients with: Hypersensitivity to valsartan or to any of the excipients of the product.
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Do not co-administer aliskiren with valsartan in patients with diabetes.
Warnings
Fetal Toxicity: When pregnancy is detected, discontinue valsartan as soon as possible (see CONTRAINDICATIONS and PRECAUTIONS).
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (see SPECIAL POPULATIONS under Actions).
Special Precautions
Hypotension: Excessive hypotension is rarely reported in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume and/ or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision.
Caution should be observed when initiating therapy in patients with heart failure or postmyocardial infarction patients. Patients with heart failure or post-myocardial infarction patients given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In reported controlled trials in heart failure patients, the incidence of hypotension in valsartan treated patients was 5.5% compared to 1.8% in placebo-treated patients. In a reported clinical study, hypotension in post-myocardial infarction patients led to permanent discontinuation of therapy in 1.4% of valsartan-treated patients and 0.8% of captopril-treated patients.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Impaired Hepatic Function: Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and cholestasis (see CONTRAINDICATIONS). In patients with mild to moderate hepatic impairment without cholestasis, it should be used with caution and the dose of valsartan should not exceed 80 mg.
Pediatrics with Impaired Hepatic Function:
As in adults, valsartan is contraindicated in pediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see CONTRAINDICATIONS). There is limited clinical experience with valsartan in pediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.
As in adults, valsartan is contraindicated in pediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see CONTRAINDICATIONS). There is limited clinical data reported with valsartan in pediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.
Valsartan is not recommended for treatment of children with glomerular filtration rates <30 ml/min/1.73 m2, as no data has been reported.
Impaired Renal Function / Other Conditions with Stimulation of the Renin-Angiotensin System: In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been reportedly associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of valsartan may be associated with impairment of the renal function.
Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤ 30 ml/min) have not been established.
Pediatrics with Impaired Renal Function: Use in pediatric patients with a creatinine clearance <30 ml/min and pediatric patients undergoing dialysis has not been reported, therefore valsartan is not recommended in these patients. No dose adjustment is required for pediatric patients with a creatinine clearance >30 ml/min. Renal function and serum potassium should be closely monitored This applies particularly when valsartan is given in the presence of other conditions (fever, dehydration) likely to impair renal function. (SPECIAL POPULATIONS under Actions).
Sodium and/or Volume Depleted Patients: 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 with valsartan, for example by reducing the diuretic dose.
Kidney Transplantation: There is currently no experience reported on the safe use of valsartan in patients who have recently undergone kidney transplantation.
Hyperkalemia: Some patients with heart failure reportedly developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended. Monitoring of potassium should be undertaken as appropriate.
Primary Hyperaldosteronism: Patients with primary hyperaldosteronism should not be treated with valsartan as their renin-angiotensin system is not activated.
Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
History of 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 valsartan should not be re-administered.
Recent Myocardial Infarction: The combination of captopril and valsartan has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies. Therefore, the combination of valsartan with an ACE inhibitor is not recommended.
Caution should be observed when initiating therapy in post-myocardial infarction patients. Evaluation of post-myocardial infarction patients should always include assessment of renal function (see DOSAGE & ADMINISTRATION).
Use of valsartan in post-myocardial infarction patients reportedly 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.
Heart Failure: In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and valsartan has not been reported to show any clinical benefit. This combination apparently increases the risk for adverse events and is therefore not recommended.
Caution should be observed when initiating therapy in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function (see DOSAGE & ADMINISTRATION).
Use of valsartan in patients with heart failure reportedly 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.
In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of valsartan may be associated with impairment of the renal function.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive have been reported. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur.
Renal Impairment:
Safety and effectiveness of valsartan in patients with severe renal impairment (CrCl ≤ 30 ml/min) have not been established. No dose adjustment is required in patients with mild (CrCl 60 to 90 ml/min) or moderate (CrCl 30 to 60 ml/min) renal impairment.
Hepatic Impairment: Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and cholestasis (see CONTRAINDICATIONS). In patients with mild to moderate hepatic impairment without cholestasis, should be used with caution and the dose of valsartan should not exceed 80 mg.
Use in Children:
Valsartan is not recommended for patients <6 years old.
Use in pediatric patients aged 6 to 18 years with renal impairment: (see as follows).
Use in pediatric patients aged 6 to 18 years with hepatic impairment: As in adults, valsartan is contraindicated in pediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see CONTRAINDICATIONS). There is limited clinical data reported with valsartan in pediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.
Valsartan is not recommended for treatment of children with glomerular filtration rates <30 ml/min/1.73 m2, as no data has been reported.
Pediatric patients with 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 safety and efficacy data reported.
The antihypertensive effects of valsartan have been reported in two randomized, double-blind clinical studies in pediatric patients from 1 to 5 years and 6 to 16 years of age. The pharmacokinetics of valsartan have been reported in pediatric patients 1 to 16 years of age (see PHARMACOLOGY: PHARMACODYNAMICS and PHARMACOKINETICS under ACTIONS). Valsartan was reported to be well tolerated in children 6 to 16 years and the adverse experience profile was similar to that described for adults.
Neonates with a history of in utero exposure to valsartan: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required for reversing hypotension and/or substituting for disordered renal function.
Use in the Elderly: In the reported controlled clinical trials of valsartan, no overall difference in the efficacy or safety of valsartan was reported in hypertensive patients ≥65 years of age patient population.
In two separate reported randomized studies for patients (65 years of age or older) with heart failure treated with valsartan and valsartan + captopril, no notable difference in efficacy or safety was reported between older and younger patients.
Use in Pregnancy: Fetal Toxicity: (See WARNINGS).
Unless continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use during pregnancy.
US FDA Pregnancy Category D.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios are reportedly associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue valsartan as soon as possible (see USE IN PREGNANCY & LACTATION).
Use In Pregnancy & Lactation
Pregnancy: US FDA Pregnancy Category D.
The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third trimester of pregnancy (see CONTRAINDICATIONS).
Epidemiological evidence reported regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive, however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data reported on the risk with AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be administered an alternative anti-hypertensive treatments with an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate therapy should be started.
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. AIIRAs therapy exposure during the second and third trimesters is reported to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia). Resulting oligohydramnios is reportedly associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Therefore, when pregnancy is detected, valsartan/AIIRA should be discontinued as soon as possible and, if appropriate, alternative therapy should be started.
If exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
If there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue valsartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Close observation of infants with histories of in utero exposure to valsartan for hypotension, oliguria, and hyperkalemia is recommended.
Lactation: It is not known whether valsartan is excreted in human milk. Valsartan was reported to be excreted in the milk of lactating rats; however, animal breast milk drug levels may not accurately reflect human breast milk levels. Since many drugs are excreted into human milk and have the potential to cause adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue valsartan, based on the importance of the drug to the mother.
Fertility: Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day which is 6 times the maximum recommended human dose.
Adverse Reactions
Clinical Studies Experience: Since clinical studies are conducted under widely varying conditions, adverse reactions rates reported in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Adult Hypertension: Safety evaluation of valsartan has been reported for more than 4000 patients, including over 400 treated for over 6 months, and more than 160 for over 1 year. Adverse reactions were reportedly mild and transient in nature and only infrequently required discontinuation of therapy. The overall incidence of adverse reactions with valsartan was reported to be similar to placebo.
The overall frequency of adverse reactions was reported to be neither dose-related nor related to gender, age, race, or regimen. Discontinuation of therapy due to side effects was reported in 2.3% of valsartan patients and 2.0% of placebo patients. The most common reasons for discontinuation of therapy with valsartan were headache and dizziness.
The adverse reactions reported placebo-controlled clinical trials in at least 1% of patients treated with valsartan and at a higher incidence in valsartan than placebo patients included viral infection, fatigue, and abdominal pain.
Headache, dizziness, upper respiratory infection, cough, diarrhea, rhinitis, sinusitis, nausea, pharyngitis, edema, and arthralgia reported at a more than 1% rate but at about the same incidence in placebo and valsartan patients.
In reported trials in which valsartan was compared to an ACE inhibitor with or without placebo, the incidence of dry cough was reported to be significantly greater in the ACE-inhibitor group than in the groups who received valsartan or placebo. In a reported study limited to patients who had had dry cough when they had previously received ACE inhibitors, the incidences of cough in patients who received valsartan, HCTZ, or lisinopril were 20%, 19%, and 69% respectively (p<0.001).
Dose-related orthostatic effects were seen in less than 1% of patients. An increase in the incidence of dizziness has been reported in patients treated with valsartan 320 mg as compared to 10 to 160 mg.
Valsartan has been used concomitantly with hydrochlorothiazide without evidence of clinically important adverse interactions.
Other adverse reactions that occurred in reported controlled clinical trials of patients treated with valsartan (>0.2%) are listed as follows. It cannot be determined whether these events were causally related to valsartan.
Body as a Whole: Allergic reaction and asthenia.
Cardiovascular: Palpitations.
Dermatologic: Pruritus and rash.
Digestive: Constipation, dry mouth, dyspepsia, and flatulence.
Musculoskeletal: Back pain, muscle cramps, and myalgia.
Neurologic and Psychiatric: Anxiety, insomnia, paresthesia, and somnolence.
Respiratory: Dyspnea.
Special Senses: Vertigo.
Urogenital: Impotence.
Other reported events seen less frequently in clinical studies include chest pain, syncope, anorexia, vomiting, and angioedema.
Pediatric Hypertension: With the exception of isolated gastrointestinal disorders (like abdominal pain, nausea, vomiting) and dizziness, no relevant differences in terms of type, frequency and severity of adverse reactions were identified between the safety profile for hypertensive pediatric patients aged 6 to 18 years and that previously reported for adult patients.
Valsartan has been reported for safety in over 400 pediatric patients aged 6 to 17 years and more than 160 pediatric patients aged 6 months to 5 years. No relevant differences were reported between the adverse experience profile for pediatric patients aged 6 to 16 years and that previously reported for adult patients. Headache and hyperkalemia were the most commonly reported adverse events suspected to be study drug-related in older children (6 to 17 years old) and younger children (6 months to 5 years old), respectively. Hyperkalemia was mainly reported in children with underlying renal/chronic kidney disease.
Valsartan is not recommended for pediatric patients under 6 years of age. In a study of pediatric patients (1 to 5 years), two deaths and three cases of on-treatment liver transaminase elevations were reported in a one-year open-label extension phase. These 5 events occurred in a study population in which patients frequently had significant comorbidities. A causal relationship to valsartan has not been reported. In a another 1 year open-label extension randomized study involving children aged 1 to 6 years, one case of marked liver transaminase elevations was reported.
Heart Failure: The adverse experience profile of valsartan in heart failure patients is reported to be consistent with the pharmacology of the drug and the health status of the patients. In a reported clinical study, comparing valsartan in total daily doses up to 320 mg to placebo, 10% of valsartan-treated patients reportedly discontinued for adverse reactions vs. 7% of placebo-treated patients.
The table as follows shows adverse reactions in reported double-blind short-term heart failure studies, including the first 4 months of the clinical study, with an incidence of at least 2% that were more frequent in valsartan-treated patients than in placebo-treated patients. All patients reportedly received standard drug therapy for heart failure including multiple medications, which could include diuretics, digitalis, beta-blockers, or ACE inhibitors. Majority of patients reported to have received concomitant ACE inhibitors. (See Table 1.)

Click on icon to see table/diagram/image

Discontinuations occurred in 0.5% of valsartan-treated patients and 0.1% of placebo patients for each of the following: elevations in creatinine and elevations in potassium.
Other adverse reactions reported with a greater incidence than 1% and greater than placebo included headache NOS, nausea, renal impairment NOS, syncope, blurred vision, upper abdominal pain and vertigo (NOS = not otherwise specified).
From the long-term data in the reported clinical study, there did not appear to be any significant adverse reactions not previously identified.
Post-Myocardial Infarction: The safety profile of valsartan was consistent with the pharmacology of the drug and the background diseases, cardiovascular risk factors, and clinical course of patients treated in the post-myocardial infarction setting. The table as follows shows the percentage of patients discontinued in the valsartan and captopril-treated groups in a reported clinical study with a rate of at least 0.5% in either of the treatment groups.
Discontinuations due to renal dysfunction have been reported in 1.1% of valsartan-treated patients and 0.8% of captopril-treated patients. (See Table 2.)

Click on icon to see table/diagram/image

Post-Marketing Experience: The following additional adverse reactions have been reported in innovator's post-marketing experience: Hypersensitivity: Hypersensitivity including serum sickness has been reported. There are rare reports of angioedema. Some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Valsartan should not be re-administered to patients who have had angioedema.
Digestive: Elevated liver enzymes/liver function values including serum bilirubin and very rare reports of hepatitis.
Renal: Impaired renal function, renal failure and impairment.
Clinical Laboratory Tests: Hyperkalemia.
Dermatologic: Alopecia, Bullous Dermatitis.
Blood and Lymphatic: There are very rare reports of thrombocytopenia.
Vascular: Vasculitis.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Since these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Other adverse events: reported include decrease in hemoglobin, decrease in hematocrit, neutropenia, hyponatremia, cardiac failure, orthostatic hypotension, acute renal failure and increase in blood urea nitrogen.
Drug Interactions
No clinically significant pharmacokinetic interactions have been reported when valsartan was coadministered with amlodipine, atenolol, cimetidine, digoxin, furosemide, glyburide/glibenclamide, hydrochlorothiazide, or indomethacin. The valsartan-atenolol combination was reported to be more antihypertensive than either component, but it did not lower the heart rate more than atenolol alone.
Coadministration of valsartan and warfarin did not change the pharmacokinetics of valsartan or the time-course of the anticoagulant properties of warfarin.
CYP 450 Interactions: In vitro metabolism studies report that CYP 450 mediated drug interactions between valsartan and co-administered drugs are unlikely due to low extent of metabolism.
Transporters: The results from an in vitro study with human liver tissue indicated that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (e.g. rifampin, cyclosporine) or efflux transporter (e.g. ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
Potassium: Concomitant use of valsartan with other agents that block the renin-angiotensin system, potassium sparing diuretics (e.g. 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 a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors), Acetylsalicylic Acid >3 g/day, and Non-selective NSAIDs: In elderly patients, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including valsartan, may reportedly result in deterioration of renal function, including possible acute renal failure and an increase in serum potassium. These effects are reported to be reversible. Therefore, monitoring of renal function at the beginning of the treatment and periodically as well as adequate hydration of the patient is recommended in patients receiving valsartan and NSAID therapy.
The antihypertensive effect of angiotensin II receptor antagonists, including valsartan may be attenuated by NSAIDs including selective COX-2 inhibitors.
Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is reportedly associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Close monitoring of blood pressure, renal function and electrolytes in patients on valsartan and other agents that affect the RAS is advised.
Do not co-administer aliskiren with valsartan in patients with diabetes (see CONTRAINDICATIONS). Avoid use of aliskiren with valsartan in patients with renal impairment (GFR <60 ml/min).
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including valsartan. Monitoring of serum lithium levels during concomitant use is recommended.
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.
Clinical Laboratory Test Findings: In reported controlled clinical trials, clinically important changes in standard laboratory parameters were rarely associated with administration of valsartan.
Creatinine: In reported controlled clinical trials of hypertensive patients, minor elevations in creatinine have been reported to occur in a smaller percentage of patients taking valsartan. In reported heart failure trials, ≥ 50% increases in creatinine were observed in 3.9% of valsartan-treated patients compared to 0.9% of placebo-treated patients. In post-myocardial infarction patients, doubling of serum creatinine was reported in 4.2% of valsartan-treated patients and 3.4% of captopril-treated patients.
Hemoglobin and Hematocrit: Greater than 20% decreases in hemoglobin and hematocrit were reported in 0.4% and 0.8%, respectively, of valsartan patients, compared with 0.1% and 0.1% in placebo-treated patients. One valsartan patient reportedly discontinued treatment for microcytic anemia.
Liver Function Tests: Occasional elevations (≥150%) of liver chemistries reported in valsartan-treated patients.
Neutropenia: Neutropenia has been reported in patients treated with valsartan.
Serum Potassium: In hypertensive patients, >20% increases in serum potassium have been reported in 4.4% of valsartan-treated patients compared to 2.9% of placebo-treated patients. In heart failure patients, greater than 20% increases in serum potassium have been reported in 10.0% of valsartan-treated patients compared to 5.1% of placebo-treated patients.
Blood Urea Nitrogen (BUN): In reported heart failure trials, greater than 50% increases in BUN have been reported in 16.6% of valsartan-treated patients as compared to 6.3% of placebo-treated patients.
Storage
Store at temperatures not exceeding 30°C.
Patient Counseling Information
Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to valsartan during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.
ATC Classification
C09CA03 - valsartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 80 mg x 28's. 160 mg x 28's.
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