Tareg

Tareg

valsartan

Manufacturer:

Sandoz

Distributor:

Sandoz
Full Prescribing Info
Contents
Valsartan.
Description
Valsartan 80 mg: Each film-coated tablet contains 80 mg of Valsartan.
Valsartan 160 mg: Each film-coated tablet contains 160 mg of Valsartan.
Action
Pharmacotherapeutic Group: Angiotensin II Antagonists, plain.
Pharmacology: Pharmacodynamics: 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 the AT1 receptor and has much (about 20,000 fold) greater affinity for the AT1 receptor than for the AT2 receptor. Valsartan is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.
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 coughing. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 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 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (P<0.05).
Hypertension: Administration of valsartan 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 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks and persist during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 μmol/L). At 24 weeks, UAE was reduced (p<0.001) by 42% (-24.2 μg/min; 95% CI: -40.4 to -19.1) with valsartan and approximately 3% (-1.7 μg/min; 95% CI: -5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups.
The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 μg/min; 20-700 μg/min) and preserved renal function (mean serum creatinine=80 μmol/L). Patients were randomized to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), and by 44% with valsartan 320 mg (95% CI: 31 to 54%). It was concluded that 160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.
Recent Myocardial Infarction Hypertension: Administration of valsartan 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 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated dosing, the antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks and persist during long-term therapy. Combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.
Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (valsartan: 58 μg/min; amlodipine: 55.4 μg/min), normal or high blood pressure and with preserved renal function (blood creatinine <120 μmol/L). At 24 weeks, UAE was reduced (p<0.001) by 42% (-24.2 μg/min; 95% CI: -40.4 to -19.1) with valsartan and approximately 3% (-1.7 μg/min; 95% CI: -5.6 to 14.9) with amlodipine despite similar rates of blood pressure reduction in both groups.
The Diovan Reduction of Proteinuria (DROP) study further examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg) with type 2 diabetes, albuminuria (mean=102 μg/min; 20-700 μg/min) and preserved renal function (mean serum creatinine=80 μmol/L). Patients were randomized to one of 3 doses of valsartan (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg (95% CI: 22 to 47%), and by 44% with valsartan 320 mg (95% CI: 31 to 54%). It was concluded that 160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.
The VALsartan In Acute myocardial INfarcTion trial (VALIANT) was a randomised, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and signs, symptoms or radiological evidence of congestive heart failure and/or evidence of left ventricular systolic dysfunction (manifested as an ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomised within 12 hours to 10 days after the onset of myocardial infarction symptoms to valsartan, captopril, or the combination of both. The mean treatment duration was two years. The primary endpoint was time to all-cause mortality.
Valsartan was as effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the valsartan (19.9%), captopril (19.5%), and valsartan + captopril (19.3%) groups. Combining valsartan with captopril did not add further benefit over captopril alone. There was no difference between valsartan and captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying disease. Valsartan was also effective in prolonging the time to and reducing cardiovascular mortality, hospitalisation for heart failure, recurrent myocardial infarction, resuscitated cardiac arrest, and non-fatal stroke (secondary composite endpoint).
The safety profile of valsartan was consistent with the clinical course of patients treated in the post-myocardial infarction setting. Regarding renal function, doubling of serum creatinine was observed in 4.2% of valsartan-treated patients, 4.8% of valsartan + captopril-treated patients, and 3.4% of captopril-treated patients. Discontinuations due to various types of renal dysfunction occurred in 1.1% of valsartan-treated patients, 1.3% in valsartan + captopril patients, and 0.8% of captopril patients. An assessment of renal function should be included in the evaluation of patients post-myocardial infarction.
There was no difference in all-cause mortality, cardiovascular mortality or morbidity when beta blockers were administered together with the combination of valsartan + captopril, valsartan alone, or captopril alone. Irrespective of treatment, mortality was lower in the group of patients treated with a beta blocker, suggesting that the known beta blocker benefit in this population was maintained in this trial.
Heart Failure: Val-HeFT was a randomised, controlled, multinational clinical trial of valsartan compared with placebo on morbidity and mortality in 5,010 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. Baseline therapy included ACE inhibitors (93%), diuretics (86%), digoxin (67%) and beta blockers (36%). The mean duration of follow-up was nearly two years. The mean daily dose of Valsartan in Val-HeFT was 254 mg. The study had two primary endpoints: All cause mortality (time to death) and composite mortality and heart failure morbidity (time to first morbid event) defined as death, sudden death with resuscitation, hospitalisation for heart failure, or administration of intravenous inotropic or vasodilator agents for four hours or more without hospitalisation.
All cause mortality was similar (p=NS) in the valsartan (19.7%) and placebo (19.4%) groups. The primary benefit was a 27.5% (95% CI: 17 to 37%) reduction in risk for time to first heart failure hospitalisation (13.9% vs. 18.5%).
Results appearing to favour placebo (composite mortality and morbidity was 21.9% in placebo vs. 25.4% in valsartan group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and valsartan.
In a subgroup of patients not receiving an ACE inhibitor (n=366), the morbidity benefits were greatest. In this subgroup all-cause mortality was significantly reduced with valsartan compared to placebo by 33% (95% CI: -6% to 58%) (17.3% valsartan vs 27.1% placebo) and the composite mortality and morbidity risk was significantly reduced by 44% (24.9% valsartan vs. 42.5% placebo). In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the valsartan (21.8%) and placebo (22.5%) groups. Composite mortality and morbidity risk was significantly reduced by 18.3% (95% CI: 8% to 28%) with valsartan compared with placebo (31.0% vs. 36.3%).
In the overall Val-HeFT population, valsartan treated patients showed significant improvement in NYHA class, and heart failure signs and symptoms, including dyspnoea, fatigue, oedema and rales compared to placebo. Patients treated with 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: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. 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 food.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres, indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation: Valsartan is not biotransformed to a high extent as only about 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 is pharmacologically inactive.
Excretion: Valsartan shows multiexponential decay kinetics (t½α <1 h and t½β about 9 h). Valsartan is primarily eliminated by biliary excretion in feces (about 83% of dose) and renally in 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.
In Heart Failure Patients: 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 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 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 (creatinine clearance >10 mL/min). There is currently no experience on the safe use in patients with a creatinine clearance <10 mL/min and patients undergoing dialysis, therefore valsartan should be used with caution in these patients (see Dosage & Administration and Precautions). Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.
Hepatic Impairment: Approximately 70% of the dose absorbed is eliminated in the bile, essentially in the unchanged form. Valsartan does not undergo any noteworthy biotransformation. A doubling of exposure (AUC) was observed in patients with mild to moderate hepatic impairment compared to healthy subjects. However, no correlation was observed between plasma valsartan concentration versus degree of hepatic dysfunction. Valsartan has not been studied in patients with severe hepatic dysfunction (see Dosage & Administration, Contraindications and Precautions).
Toxicology: Preclinical Safety Data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential.
In rats, maternally toxic doses (600 mg/kg/day) during the last days of gestation and lactation led to lower survival, lower weight gain and delayed development (pinna detachment and ear-canal opening) in the offspring (see Use in Pregnancy & Lactation). These doses in rats (600 mg/kg/day) are approximately 18 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).
In non-clinical safety studies, high doses of valsartan (200 to 600 mg/kg body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, haemoglobin, haematocrit) and evidence of changes in renal haemodynamics (slightly raised plasma urea, and renal tubular hyperplasia and basophilia in males). These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/mg2 basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
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.
Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Indications/Uses
Hypertension: Treatment of essential hypertension.
Recent Myocardial Infarction: Treatment of clinically stable patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours 10 days) myocardial infarction (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Heart Failure: Treatment of symptomatic heart failure when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta blockers cannot be used (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Dosage/Direction for Use
Hypertension: The recommended starting dose of valsartan is 80 mg once daily. The antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose can be increased to 160 mg and to a maximum of 320 mg.
Valsartan may also be administered with other antihypertensive agents. The addition of a diuretic such as hydrochlorothiazide will decrease blood pressure even further in these patients.
Recent Myocardial Infarction: In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg twice daily, valsartan 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, 160 mg twice daily, be achieved by three months, based on the patient's tolerability. 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, e.g. thrombolytics, acetylsalicylic acid, beta blockers, statins, and diuretics. The combination with ACE inhibitors is not recommended (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Evaluation of post-myocardial infarction patients should always include assessment of renal function.
Heart Failure: The recommended starting dose of valsartan is 40 mg twice daily. Uptitration to 80 mg and 160 mg twice daily should be done at intervals of at least two weeks 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 (see Pharmacology: Pharmacodynamics under Actions and Precautions).
Evaluation of patients with heart failure should always include assessment of renal function.
Additional Information on Special Populations: Elderly: No dose adjustment is required in elderly patients.
Renal Impairment: No dosage adjustment is required for patients with a creatinine clearance >10 mL/min (see Pharmacology: Pharmacokinetics under Actions and Precautions).
Hepatic Impairment: In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg. Valsartan Sandoz is contraindicated in patients with severe hepatic impairment and in patients with cholestasis (see Pharmacology: Pharmacokinetics under Actions, Contraindications and Precautions).
Pediatric Patients: Valsartan is not recommended for use in children below the age of 18 years due to a lack of data on safety and efficacy.
Administration: Valsartan (Tareg) may be taken independently of a meal and should be administered with water.
Overdosage
Overdosage with valsartan 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 solution.
Valsartan is unlikely to be removed by hemodialysis.
Contraindications
Known hypersensitivity to valsartan or to any of the excipients.
Pregnancy (see Use in Pregnancy & Lactation).
Special Precautions
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 with valsartan, 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.
Patients with 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 patients with biliary obstructive disorders.
Patients with Heart Failure/Post-Myocardial Infarction: Use of valsartan in patients with heart failure or post-myocardial infarction commonly results in some reduction in blood pressure, but discontinuation of valsartan therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are allowed.
Caution should be observed when initiating therapy in patients with heart failure or post-myocardial infarction (see Dosage & Administration).
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 (see Pharmacology: Pharmacodynamics under Actions).
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.
Effects on Ability to Drive and Use Machines: Not applicable.
Use in Children: Patients with Impaired Renal Function: Use in pediatric patients with a glomerular filtration rate <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 >30 mL/min/1.73 m2 (see Pharmacology: Pharmacokinetics under Actions). 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 (see Pharmacology: Pharmacokinetics under Actions). There is limited clinical experience with valsartan in pediatric patients with mild to moderate hepatic impairment.
Use In Pregnancy & Lactation
Use in Pregnancy: As for any drug that also acts directly on the RAAS, valsartan should not be used during pregnancy (see Contraindications). 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 reported 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 (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Women 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 of childbearing potential about the potential risk of these agents during pregnancy.
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 (see Pharmacology: Toxicology: Preclinical Safety Data under Actions).
Use in Lactation: It is not known whether valsartan is excreted in human milk. Since valsartan was excreted in the milk of lactating rats, it is not advisable to use valsartan in breast-feeding mothers.
Adverse Reactions
In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse reactions (ADRs) was 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. Within 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 an therefore they are mentioned with a "not known" frequency.
Adverse Drug Reactions in Hypertension: Blood and Lymphatic System Disorders: Not Known: Decrease in hemoglobin, decrease in hematocrit, neutropenia, thrombocytopenia.
Immune System Disorders: Not Known: Hypersensitivity including serum sickness.
Metabolism and Nutrition Disorders: Not Known: Increase of serum potassium.
Ear and Labyrinth System Disorders: Uncommon: Vertigo.
Vascular Disorders: Not Known: Vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough.
Gastrointestinal Disorders: Uncommon: Abdominal pain.
Hepatobiliary Disorders: Not Known: Elevation of liver function values including increase of serum bilirubin.
Skin and Subcutaneous Tissue Disorders: Not Known: Angioedema, rash, pruritus.
Musculoskeletal and Connective Tissue Disorders: Not Known: Myalgia.
Renal and Urinary Disorders: Not Known: Renal failure and impairment, evaluation of serum creatinine.
General Disorders and Administration Site Conditions: Uncommon: Fatigue.
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, diarrhoea, dizziness, headache, insomnia, libido decrease, nausea, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Hypertensive Adult Patients with Impaired Glucose Tolerance at Cardiovascular Risk: In the NAVIGATOR study, adverse events with valsartan were similar to those reported previously for patients with hypertension.
Pediatric Population (Hypertension): The antihypertensive effect of valsartan has been evaluated in two randomized, double-blind clinical studies in 561 pediatric patients from 6 to 18 years of age. No relevant differences in terms of type, frequency and severity of adverse reactions were identified between the safety profile for pediatric patients aged 6 to 18 years and that previously reported for adult patients.
Neurocognitive and developmental assessment of pediatric patients aged 6 to 16 years of age revealed no overall clinically relevant adverse impact after treatment with valsartan for up to one year.
In a double-blind randomized study in 90 children aged 1 to 6 years, which was followed by a one-year open-label extension, two deaths and isolated cases of marked liver transaminases elevations were observed. In a second study in which 75 children aged 1 to 6 years were randomized, no deaths and one case of marked liver transaminase elevations occurred during a one year open-label extension. These cases occurred in a population who has significant comorbidities. A casual relationship to valsartan has not been established.
Hyperkalaemia 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.
Adverse Drug Reactions in Heart Failure and/or Post-Myocardial Infarction: Blood and Lymphatic System Disorders: Not Known: Thrombocytopenia.
Immune System Disorders: Not Known: Hypersensitivity including serum sickness.
Metabolism and Nutrition Disorders: Uncommon: Hyperkalaemia. Not Known: Increase of serum potassium.
Nervous System Disorders: Common: Dizziness, postural dizziness. Uncommon: Syncope, headache.
Ear and Labyrinth System Disorders: Uncommon: Vertigo.
Cardiac Disorders: Uncommon: Cardiac failure.
Vascular Disorders: Common: Hypotension, orthostatic hypotension. Not Known: Vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Cough.
Gastrointestinal Disorders: Uncommon: Nausea, diarrhea.
Hepatobiliary Disorders: Not Known: Elevation of liver function values.
Skin and Subcutaneous Tissue Disorders: Uncommon: Angioedema. Not Known: Rash, pruritus.
Musculoskeletal and Connective Tissue Disorders: Not Known: Myalgia.
Renal and Urinary Disorders: Common: Renal failure and impairment. Uncommon: Acute renal failure, elevation of serum creatinine. Not Known: Increase in blood urea nitrogen.
General Disorders and Administration Site Conditions: Uncommon: Asthenia, fatigue.
The following events have also been observed during clinical trials in patients with heart failure and/or post-myocardial infarction irrespective of their casual association with the study drug: Arthralgia, abdominal pain, back pain, insomnia, libido decrease, neutropenia, oedema, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, viral infections.
Drug Interactions
Potassium: Concomitant use of 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 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 with 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.
Transporters: The results from an in vitro study with human liver tissue indicate that valsartan is a substrate of the hepatic uptake transporter OATP1B1 and the hepatic efflux transporter MRP2. Co-administration of inhibitors of the uptake transporter (rifampin, 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, hydrochlorothiazide, amlodipine and glibenclamide.
As valsartan is not metabolized to a 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.
Caution For Usage
Incompatibilities: Not applicable.
Storage
Store at temperatures not exceeding 30°C.
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 (pale-red, round with bevelled edges, scored on one side with debossing "D" on one side of the score and "V" on the other side of the score and "NVR" on the reverse side; can be divided into equal halves) x 28's. 160 mg (grey-orange, ovaloid, slightly convex, scored on one side with debossing "DX" on one side of the score and "DX" on the other side of the score and "NVR" on the reverse side; can be divided into equal halves) x 14's, 28's.
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