Valvex 80/Valvex 160

Valvex 80/Valvex 160

valsartan

Manufacturer:

Vexxa Lifesciences

Distributor:

VE Pharma
Full Prescribing Info
Contents
Valsartan.
Description
Valvex 80: Each film coated tablet contains: Valsartan USP 80 mg.
Valvex 160: Each film coated tablet contains: Valsartan USP 160 mg.
Valsartan is a white or almost white, hygroscopic powder and Freely soluble in anhydrous ethanol, sparingly soluble in methylene chloride, practically insoluble in water. It's chemical name is L-Valine, N-(1-oxopentyl)-N-[[2c-(1H-tetrazol-5-yl) [1,1c-biphenyl]-4-yl]methyl]-N-[p-(o-1H-Tetrazol-5-ylphenyl)benzyl]-N-valeryl-L-valine. And it's molecular formula is C24H29N5O3 and molecular weight 435.52 mg.
Action
Pharmacotherapeutic Group: Angiotensin II Receptor Blocker.
Pharmacology: 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 AT 1 receptor. Valsartan does not exhibit any partial agonist activity at the A T 1 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).
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 transformed 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.
Elimination: Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan is primarily eliminated in faeces (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.
Special populations: Paediatric population (age below 18 years): No pharmacokinetic data are available in the paediatric population.
Elderly (age 65 years or over): Time to peak plasma amlodipine concentrations is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to decline, causing increases in the area under the curve (AUC) and elimination half-life. Mean systemic AUC of valsartan is higher by 70% in the elderly than in the young, therefore caution is required when increasing the dosage.
Renal impairment: The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. 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.
Hepatic impairment: Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Caution should be exercised in patients with liver disease.
Indications/Uses
Hypertension: Treatment of essential hypertension in adults, and hypertension in children and adolescents 6 to 18 years of age.
Recent myocardial infarction: Treatment of clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours-10 days) myocardial infarction.
Heart failure: Treatment of symptomatic heart failure in adult patients when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used, or as add-on therapy to ACE inhibitors when beta blockers cannot be used.
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 dose 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.
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. 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 dose adjustment is required for adult patients with a creatinine clearance >10 ml/min.
Hepatic impairment: Valsartan is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis.
In patients with mild to moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg.
Paediatric population: Paediatric hypertension, Children and adolescents 6 to 18 years of age: The initial dose is 40 mg once daily for children weighing below 35 kg and 80 mg once daily for those weighing 35 kg or more. The dose should be adjusted based on blood pressure response. For maximum doses studied in clinical trials please refer to the table below. Doses higher than those listed have not been studied and are therefore not recommended. (See Table 3).

Click on icon to see table/diagram/image

Children less than 6 years of age: However safety and efficacy of valsartan in children aged 1 to 6 years have not been established.
Use in paediatric patients aged 6 to 18 years with renal impairment: Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore valsartan is not recommended in these patients. No dose adjustment is required for paediatric patients with a creatinine clearance >30 ml/min. Renal function and serum potassium should be closely monitored.
Use in paediatric patients aged 6 to 18 years with hepatic impairment: As in adults, valsartan is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis.There is limited clinical experience with valsartan in paediatric patients with mild to moderate hepatic impairment.
The dose of valsartan should not exceed 80 mg in these patients.
Paediatric 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.
Method of administration: Valsartan may be taken independently of a meal and should be administered with water.
Overdosage
Symptoms: Overdose with valsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock.
Treatment:
The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms; stabilisation of the circulatory condition is of prime importance. If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken. Valsartan is unlikely to be removed by haemodialysis.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Second and third trimesters of pregnancy.
Warnings
Hyperkalaemia: 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.
Impaired renal function: 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. No dose adjustment is required for adult patients with creatinine clearance >10 ml/min.
Hepatic impairment: In patients with mild to moderate hepatic impairment without cholestasis, valsartan should be used with caution.
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.
Renal artery stenosis: In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of valsartan has not been established.
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 haemodynamics, serum creatinine, or blood urea nitrogen (BUN). However, other agents that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis, therefore monitoring of renal function is recommended when patients are treated with valsartan.
Kidney transplantation: There is currently no experience on the safe use of valsartan in patients who have recently undergone kidney transplantation.
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).
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.
Use of valsartan in post-myocardial infarction patients 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.
Heart Failure: In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and valsartan has not shown 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.
Use of valsartan in patients with heart failure 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.
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 azotaemia 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.
Paediatric population: Impaired renal function: Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore valsartan is not recommended in these patients. No dose adjustment is required for paediatric patients with a creatinine clearance >30 ml/min.
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.
Impaired hepatic function: As in adults, valsartan is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis. There is limited clinical experience with valsartan in paediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients. 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.
Use In Pregnancy & Lactation
Pregnancy: Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Adverse Reactions
See Table 2.

Click on icon to see table/diagram/image

See Table 3.

Click on icon to see table/diagram/image
Drug Interactions
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. Due to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels If a medicinal product that affects potassium levels is considered necessary in combination with valsartan, monitoring of potassium plasma levels is advised.
Caution required with concomitant use: Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid >3 g/day), and non-selective NSAIDs.
When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.
Others: In drug interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.
Paediatric 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.
Storage
Store at temperatures not exceeding 30ºC. Shelf-Life: 3 years from the date of manufacturing.
ATC Classification
C09CA03 - valsartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Presentation/Packing
Valvex 80: FC tab 80 mg (maroon, biconvex, film-coated, round) x 30's. Valvex 160: FC tab 160 mg (maroon, biconvex, film-coated, round) x 30's.
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