Valsartan Tablets USP 320mg  (Taj Pharma)

1. Name of the medicinal product

Valsartan Tablets USP 40mg  (Taj Pharma)
Valsartan Tablets USP 80mg  (Taj Pharma)
Valsartan Tablets USP 160mg (Taj Pharma)
Valsartan Tablets USP 320mg  (Taj Pharma)

   2. Qualitative and quantitative composition

a) Each film-coated tablet contains:
Valsartan USP                                  40mg
Excipients:                                         q.s.
Colours: Red Oxide Iron & Titanium Dioxide USP

b) Each film-coated tablet contains:
Valsartan USP                                 80mg
Excipients:                                         q.s.
Colours: Red Oxide Iron & Titanium Dioxide USP

c) Each film-coated tablet contains:
Valsartan USP                                 160mg
Excipients:                                         q.s.
Colours: Red Oxide Iron & Titanium Dioxide USP

d) Each film-coated tablet contains:
Valsartan USP                                 320mg
Excipients:                                         q.s.
Colours: Red Oxide Iron & Titanium Dioxide USP

For the full list of excipients, see section 6.1.

1. Pharmaceutical form

Film-coated tablet

1. Clinical particulars

4.1 Therapeutic indications

Hypertension (40 mg only)

Treatment of hypertension in children and adolescents 6 to 18 years of age.

Hypertension (80 mg, 160 mg and 320 mg only)

Treatment of essential hypertension in adults, and hypertension in children and adolescents 6 to 18 years of age.

Recent myocardial infarction (40 mg, 80 mg and 160 mg only)

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 (see sections 4.4 and 5.1).

Heart failure (40 mg, 80 mg and 160 mg only)

Treatment of adult patients with symptomatic heart failure when ACE-inhibitors are not tolerated or in beta-blocker intolerant patients as add-on therapy to ACE-inhibitors when mineralocorticoid receptor antagonists cannot be used (see sections 4.2, 4. 4, 4.5 and 5.1).

4.2 Posology and method of administration

Posology

Hypertension (only 80 mg, 160 mg and 320 mg)

The recommended starting dose of Valsartan Taj Pharma 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 Taj Pharma may also be administered with other antihypertensive agents (see sections 4.3, 4.4, 4.5 and 5.1). The addition of a diuretic such as hydrochlorothiazide will decrease blood pressure even further in these patients.

Recent myocardial infarction (only 40 mg, 80 mg and 160 mg)

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 Taj Pharma 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 Taj Pharma 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 sections 4.4 and 5.1).

Evaluation of post-myocardial infarction patients should always include assessment of renal function.

Heart failure (only 40 mg, 80 mg and 160 mg)

The recommended starting dose of Valsartan Taj Pharma 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 Taj Pharma may be administered with other heart failure therapies. However, the triple combination of an ACE-inhibitor, Valsartan Taj Pharma and a beta-blocker or a potassium-sparing diuretic is not recommended (see sections 4.4 and 5.1).

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 (see sections 4.4 and 5.2). Concomitant use of Valsartan Taj Pharma with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²) (see section 4.3).

Diabetes Mellitus

Concomitant use of Valsartan Taj Pharma with aliskiren is contraindicated in patients with diabetes mellitus (see section 4.3).

Hepatic impairment

Valsartan Taj Pharma is contraindicated in patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3, 4.4 and 5.2). In patients with mild to moderate hepatic impairment without cholestasis, the dose of Valsartan Taj Pharma 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.

Children less than 6 years of age

Available data are described in sections 4.8, 5.1 and 5.2. However safety and efficacy of Valsartan Taj Pharma 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 Taj Pharma 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 (see sections 4.4 and 5.2).

Use in paediatric patients aged 6 to 18 years with hepatic impairment

As in adults, Valsartan Taj Pharma is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3, 4.4 and 5.2). There is limited clinical experience with Valsartan Taj Pharma in paediatric patients with mild to moderate hepatic impairment. The dose of Valsartan Taj Pharma should not exceed 80 mg in these patients.

Paediatric heart failure and recent myocardial infarction

Valsartan Taj Pharma 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 Taj Pharma may be taken independently of a meal and should be administered with water.

4.3 Contraindications

– Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

– Severe hepatic impairment, biliary cirrhosis and cholestasis.

– Second and third trimester of pregnancy (see sections 4.4 and 4.6).

– The concomitant use of Valsartan Taj Pharma with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

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 Taj Pharma should be used with caution in these patients. No dose adjustment is required for adult patients with a creatinine clearance >10 ml/min (see sections 4.2 and 5.2).

The concomitant use of ARBs – including Valsartan Taj Pharma – or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²) (see sections 4.3 and 4.5).

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Valsartan Taj Pharma should be used with caution (see sections 4.2 and 5.2).

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 Taj Pharma. Sodium and/or volume depletion should be corrected before starting treatment with Valsartan Taj Pharma, 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 Taj Pharma has not been established.

Short-term administration of Valsartan Taj Pharma 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 Taj Pharma.

Kidney transplantation

There is currently no experience on the safe use of Valsartan Taj Pharma in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Valsartan Taj Pharma 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).

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. 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 in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Recent myocardial infarction (only 40 mg, 80 mg and 160 mg)

The combination of captopril and Valsartan Taj Pharma has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies (see sections 4.2 and 5.1). Therefore, the combination of Valsartan Taj Pharma 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 section 4.2).

Use of Valsartan Taj Pharma 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 (see section 4.2).

Heart Failure (only 40 mg, 80 mg and 160 mg)

The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Valsartan Taj Pharma is used in combination with an ACE-inhibitor. In patients with heart failure, the triple combination of an ACE inhibitor, a beta-blocker and Valsartan Taj Pharma has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and Valsartan Taj Pharma is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

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 section 4.2).

Use of Valsartan Taj Pharma 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 (see section 4.2).

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone-system (e.g patients with severe congestive heart failure), treatment with ACE-inhibitors has been associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As Valsartan Taj Pharma is an angiotensin II receptor blocker, it cannot be excluded that the use of Valsartan Taj Pharma may be associated with impairment of the renal function.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

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 associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As Valsartan Taj Pharma is an angiotensin II antagonist, it cannot be excluded that the use of Valsartan Taj Pharma may be associated with impairment of the renal function.

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 Taj Pharma; some of these patients previously experienced angioedema with other drugs including ACE inhibitors.

Valsartan Taj Pharma should be immediately discontinued in patients who develop angioedema, and Valsartan Taj Pharma should not be re-administered.

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Paediatric population

Renal function

Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore Valsartan Taj Pharma is not recommended in these patients. No dose adjustment is required for paediatric patients with a creatinine clearance >30 ml/min (see sections 4.2 and 5.2). Renal function and serum potassium should be closely monitored during treatment with Valsartan Taj Pharma. This applies particularly when Valsartan Taj Pharma is given in the presence of other conditions (fever, dehydration) likely to impair renal function. The concomitant use of ARBs – including Valsartan Taj Pharma – or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m^2. ) (see sections 4.3 and 4.5).

Hepatic function

As in adults, Valsartan Taj Pharma is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis (see sections 4.3 and 5.2). There is limited clinical experience with Valsartan Taj Pharma in paediatric patients with mild to moderate hepatic impairment. The dose of Valsartan Taj Pharma should not exceed 80 mg in these patients.

Valsartan Taj Pharma Film-coated Tablets contain sodium

This medicine contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

4.5 Interaction with other medicinal products and other forms of interaction

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Dual blockade of the Renin-Angiotensin – System (RAS) with ARBs, ACEIs, or aliskiren:

Concomitant use of angiotensin receptor antagonists (ARBs) – including Valsartan Taj Pharma – or of angiotensin- converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR< 60 mL/min/1.73 m²) is contraindicated (see sections 4.3 and 4.4).

Concomitant use not recommended

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 Taj Pharma 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 Taj Pharma, 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.

Transporters

In vitro data indicates that Valsartan Taj Pharma 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. Rifampicin, ciclosporin) or efflux transporter (e.g. ritonavir) may increase the systemic exposure to Valsartan Taj Pharma. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.

Others

In drug interaction studies with Valsartan Taj Pharma, no interactions of clinical significance have been found with Valsartan Taj Pharma 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 Taj Pharma and other substances that inhibit the renin angiotensin aldosterone system which may increase serum potassium. Renal function and serum potassium should be closely monitored.

4.6 Fertility, pregnancy and lactation

Pregnancy

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data 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 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.

AIIRAs therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia); see also section 5.3 ‘Preclinical safety data’.

Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also sections 4.3 and 4.4).

Breast-feeding

Because no information is available regarding the use of Valsartan Taj Pharma during breastfeeding, Valsartan Taj Pharma is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

Valsartan Taj Pharma had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day. This dose is 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).

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive have been performed. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or weariness may occur when taking Valsartan Taj Pharma.

4.8 Undesirable effects

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 Taj Pharma. 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 below 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 and therefore they are mentioned with a ‘not known’ frequency.

– Hypertension

Paediatric population

Hypertension

The antihypertensive effect of Valsartan Taj Pharma has been evaluated in two randomised, double-blind clinical studies (each followed by an extension period or study) and one open-label study. These studies include 771 paediatric patients from 6 to less than 18 years of age with and without chronic kidney disease (CKD), of which 560 patients received Valsartan Taj Pharma. With the exception of isolated gastrointestinal disorders (such as 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 paediatric patients aged 6 to less than 18 years and that previously reported for adult patients.

A pooled analysis of 560 paediatric hypertensive patients (aged 6-17 years) receiving either Valsartan Taj Pharma monotherapy [n=483] or combination antihypertensive therapy including Valsartan Taj Pharma [n=77] was conducted. Of the 560 patients, 85 (15.2%) had CKD (baseline GFR <90 mL/min/1.73m2). Overall, 45 (8.0%) patients discontinued a study due to adverse events. Overall 111 (19.8%) patients experienced an adverse drug reaction (ADR), with headache (5.4%), dizziness (2.3%) and hyperkalaemia (2.3%) being the most frequent. In patients with CKD, the most frequent ADRs were hyperkalaemia (12.9%), headache (7.1%), blood creatinine increased (5.9%) and hypotension (4.7%). In patients without CKD, the most frequent ADRs were headache (5.1%) and dizziness (2.7%). ADRs were observed more frequently in patients receiving Valsartan Taj Pharma in combination with other antihypertensive medications than Valsartan Taj Pharma alone.

Neurocognitive and developmental assessment of paediatric patients aged 6 to 16 years of age revealed no overall clinically relevant adverse impact after treatment with Valsartan Taj Pharma 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. These cases occurred in a population who had significant comorbidities. A causal relationship to Valsartan Taj Pharma has not been established. In a second study in which 75 children aged 1 to 6 years were randomised, no significant liver transaminase elevations or death occurred with Valsartan Taj Pharma treatment.

Hyperkalaemia was more frequently observed in children and adolescents aged 6 to 18 years with underlying chronic kidney disease.

The safety profile seen in controlled-clinical studies in adult patients with post-myocardial infarction and/or heart failure varies from the overall safety profile seen in hypertensive patients. This may relate to the patients underlying disease. ADRs that occurred in adult patients with post-myocardial infarction and/or heart failure patients are listed below.

– Post-myocardial infarction and/or heart failure (studied in adult patients only)

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

Symptoms

Overdose with Valsartan Taj Pharma 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 Taj Pharma is unlikely to be removed by haemodialysis.

1. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II Antagonists, plain.

Mechanism of action

Valsartan Taj Pharma 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 Taj Pharma may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the AT₁ receptor.

Valsartan Taj Pharma 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 Taj Pharma is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Valsartan Taj Pharma 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 Taj Pharma was compared with an ACE inhibitor, the incidence of dry cough was significantly (P<0.05) less in patients treated with Valsartan Taj Pharma 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 Taj Pharma 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).

Clinical efficacy and safety

Recent myocardial infarction (only 40 mg, 80 mg and 160 mg)

The Valsartan Taj Pharma 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 Taj Pharma, captopril, or the combination of both. The mean treatment duration was two years. The primary endpoint was time to all-cause mortality.

Valsartan Taj Pharma was as effective as captopril in reducing all-cause mortality after myocardial infarction. All cause mortality was similar in the Valsartan Taj Pharma (19.9%), captopril (19.5%), and Valsartan Taj Pharma + captopril (19.3%) groups. Combining Valsartan Taj Pharma with captopril did not add further benefit over captopril alone. There was no difference between Valsartan Taj Pharma and captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying disease. Valsartan Taj Pharma 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 Taj Pharma was consistent with the clinical course of patients treated in the postmyocardial infarction setting. Regarding renal function, doubling of serum creatinine was observed in 4.2% of Valsartan Taj Pharma-treated patients, 4.8% of Valsartan Taj Pharma + captopril-treated patients, and 3.4% of captopril-treated patients. Discontinuations due to various types of renal dysfunction occurred in 1.1% of Valsartan Taj Pharma-treated patients, 1.3% in Valsartan Taj Pharma + 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 Taj Pharma + captopril, Valsartan Taj Pharma 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 (only 40 mg, 80 mg and 160 mg)

Val-HeFT was a randomised, controlled, multinational clinical trial of Valsartan Taj Pharma 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 Taj Pharma 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 Taj Pharma (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 Taj Pharma group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and Valsartan Taj Pharma.

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 Taj Pharma compared to placebo by 33% (95% CI: 6% to 58%) (17.3% Valsartan Taj Pharma vs. 27.1% placebo) and the composite mortality and morbidity risk was significantly reduced by 44% (24.9% Valsartan Taj Pharma vs. 42.5% placebo).

In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the Valsartan Taj Pharma (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 Taj Pharma compared with placebo (31.0% vs. 36.3%).

In the overall Val-HeFT population, Valsartan Taj Pharma 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 Taj Pharma 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 Taj Pharma treated patients was significantly increased and LVIDD significantly reduced from baseline at endpoint compared to placebo.

Hypertension (only 80 mg, 160 mg and 320 mg)

Administration of Valsartan Taj Pharma 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 Taj Pharma has not been associated with rebound hypertension or other adverse clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, Valsartan Taj Pharma has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Valsartan Taj Pharma) study assessed the reduction in urinary albumin excretion (UAE) with Valsartan Taj Pharma (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 Taj Pharma: 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of Valsartan Taj Pharma 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 Taj Pharma 160 mg (95%CI: 22 to 47%), and by 44% with Valsartan Taj Pharma 320 mg (95%CI: 31 to 54%). It was concluded that 160-320 mg of Valsartan Taj Pharma produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Paediatric population

Hypertension

The antihypertensive effect of Valsartan Taj Pharma have been evaluated in four randomized, double-blind clinical studies in 561 paediatric patients from 6 to 18 years of age and 165 paediatric patients 1 to 6 years of age. Renal and urinary disorders, and obesity were the most common underlying medical conditions potentially contributing to hypertension in the children enrolled in these studies.

Clinical experience in children at or above 6 years of age

In a clinical study involving 261 hypertensive paediatric patients 6 to 16 years of age, patients who weighed <35 kg received 10, 40 or 80 mg of Valsartan Taj Pharma tablets daily (low, medium and high doses), and patients who weighed 35 kg received 20, 80, and 160 mg of Valsartan Taj Pharma tablets daily (low, medium and high doses). At the end of 2 weeks, Valsartan Taj Pharma reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of Valsartan Taj Pharma (low, medium and high) significantly reduced systolic blood pressure by 8, 10, 12 mm Hg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of Valsartan Taj Pharma or were switched to placebo. In patients who continued to receive the medium and high doses of Valsartan Taj Pharma, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of Valsartan Taj Pharma, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of Valsartan Taj Pharma was consistent across all the demographic subgroups.

In another clinical study involving 300 hypertensive paediatric patients 6 to 18 years of age, eligible patients were randomized to receive Valsartan Taj Pharma or enalapril tablets for 12 weeks. Children weighing between 18 kg and <35 kg received Valsartan Taj Pharma 80 mg or enalapril 10 mg; those between _35 kg and <80 kg received Valsartan Taj Pharma 160 mg or enalapril 20 mg; those _80 kg received Valsartan Taj Pharma 320 mg or enalapril 40 mg. Reductions in systolic blood pressure were comparable in patients receiving Valsartan Taj Pharma (15 mmHg) and enalapril (14 mm Hg) (non-inferiority p-value <0.0001). Consistent results were observed for diastolic blood pressure with reductions of 9.1 mmHg and 8.5 mmHg with Valsartan Taj Pharma and enalapril, respectively.

In a third, open label clinical study, involving 150 paediatric hypertensive patients 6 to 17 years of age, eligible patients (systolic BP ≥95th percentile for age, gender and height) received Valsartan Taj Pharma for 18 months to evaluate safety and tolerability. Out of the 150 patients participating in this study, 41 patients also received concomitant antihypertensive medication. Patients were dosed based on their weight categories for starting and maintenance doses. Patients weighing >18 to < 35 kg, ≥35 to < 80 kg and ≥ 80 to < 160 kg received 40 mg, 80 mg and 160 mg and the doses were titrated to 80 mg, 160 mg and 320 mg respectively after one week. One half of the patients enrolled (50.0%, n=75) had CKD with 29.3% (44) of patients having CKD Stage 2 (GFR 60 – 89 mL/min/1.73m2) or Stage 3 (GFR 30-59 mL/min/1.73m2). Mean reductions in systolic blood pressure were 14.9 mmHg in all patients (baseline 133.5 mmHg), 18.4 mmHg in patients with CKD (baseline 131.9 mmHg) and 11.5 mmHg in patients without CKD (baseline 135.1 mmHg). The percentage of patients who achieved overall BP control (both systolic and diastolic BP <95th percentile) was slightly higher in the CKD group (79.5%) compared to the non-CKD group (72.2%).

Clinical experience in children less than 6 years of age

Two clinical studies were conducted in patients aged 1 to 6 years with 90 and 75 patients, respectively. No children below the age of 1 year were enrolled in these studies. In the first study, the efficacy of Valsartan Taj Pharma was confirmed compared to placebo but a dose-response could not be demonstrated. In the second study, higher doses of Valsartan Taj Pharma were associated with greater BP reductions, but the dose response trend did not achieve statistical significance and the treatment difference compared to placebo was not significant. Because of these inconsistencies, Valsartan Taj Pharma is not recommended in this age group (see section 4.8).

The European Medicines Agency has waived the obligation to submit the results of studies with Valsartan Taj Pharma in all subsets of the paediatric population in heart failure and heart failure after recent myocardial infarction. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties

Absorption:

Following oral administration of Valsartan Taj Pharma alone, peak plasma concentrations of Valsartan Taj Pharma are reached in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) to Valsartan Taj Pharma by about 40% and peak plasma concentration (C_max) by about 50%, although from about 8 h post dosing plasma Valsartan Taj Pharma 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 Taj Pharma can therefore be given either with or without food.

Distribution:

The steady-state volume of distribution of Valsartan Taj Pharma after intravenous administration is about 17 litres, indicating that Valsartan Taj Pharma does not distribute into tissues extensively. Valsartan Taj Pharma is highly bound to serum proteins (94–97%), mainly serum albumin.

Biotransformation:

Valsartan Taj Pharma 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 Taj Pharma AUC). This metabolite is pharmacologically inactive.

Excretion:

Valsartan Taj Pharma shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Valsartan Taj Pharma is primarily eliminated by biliary excretion in faeces (about 83% of dose) and renally in urine (about 13% of dose), mainly as unchanged drug. Following intravenous administration, plasma clearance of Valsartan Taj Pharma is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of Valsartan Taj Pharma is 6 hours.

In Heart failure patients (only 40 mg, 80 mg and 160 mg):

The average time to peak concentration and elimination half-life of Valsartan Taj Pharma in heart failure patients are similar to that observed in healthy volunteers. AUC and C_max values of Valsartan Taj Pharma 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 Taj Pharma 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 Taj Pharma 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 Taj Pharma. 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 Taj Pharma should be used with caution in these patients (see sections 4.2 and 4.4).

Valsartan Taj Pharma 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 Taj Pharma 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 Taj Pharma concentration versus degree of hepatic dysfunction. Valsartan Taj Pharma has not been studied in patients with severe hepatic dysfunction (see sections 4.2, 4.3 and 4.4).

Paediatric population

In a study of 26 paediatric hypertensive patients (aged 1 to 16 years) given a single dose of a suspension of Valsartan Taj Pharma (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the clearance (litres/h/kg) of Valsartan Taj Pharma was comparable across the age range of 1 to 16 years and similar to that of adults receiving the same formulation.

Renal function

Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore Valsartan Taj Pharma 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 (see sections 4.2 and 4.4).

5.3 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 section 4.6). 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 Taj Pharma (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/m² 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 Taj Pharma which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of Valsartan Taj Pharma in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.

Paediatric population

Daily oral dosing of neonatal/juvenile rats (from a postnatal day 7 to postnatal day 70) with Valsartan Taj Pharma at doses as low as 1 mg/kg/day (about 10-35% of the maximum recommended paediatric dose of 4 mg/kg/day on systemic exposure basis) produced persistent, irreversible kidney damage. These effects above mentioned represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are 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. The rats in the juvenile Valsartan Taj Pharma study were dosed up to day 70, and effects on renal maturation (postnatal 4-6 weeks) cannot be excluded. 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 preclinical data do not indicate a safety concern for children older than 1 year.

1. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Microcrystalline cellulose, Crospovidone, Povidone, Croscarmellose Sodium, Silica, colloidal anhydrous

Magnesium stearate

Tablet coating

Hypromellose, Titanium dioxide, Macrogol, Iron oxide yellow, Iron oxide black .mg tablets], Iron oxide red

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Valsartan Taj Pharma film-coated tablets are presented in the following pack types.

• HDPE bottle pack (marketable pack) comprises of white HDPE bottle with white opaque polypropylene closure with induction sealing liner.
• Cold form blister pack (marketable pack) comprises of cold form laminate (aluminium foil laminated to oriented polyamide on one side and to PVC on the other side i.e. OPA/Al/PVC) on one side and hard tempered aluminium foil coated with heat seal lacquer on the other side.
• PVC/PE/PVDC-Aluminium triplex blister pack.

Valsartan  is available in blister packs of 7, 10, 14, 28, 30, 56, 90, 98, 100 tablets, and HDPE bottles containing 28, 56, 98, 500 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

7. Manufactured By:
   Taj Pharmaceuticals Ltd. (Mumbai, India)
   Unit No. 214, Old Bake House,
   Maharashtra Chambers of commerce Lane,Fort,
   Mumbai-400001 at: Ahmedabad- Gujarat, INDIA.

Valsartan Tablets USP 40mg  (Taj Pharma)
Valsartan Tablets USP 80mg  (Taj Pharma)
Valsartan Tablets USP 160mg (Taj Pharma)
Valsartan Tablets USP 320mg  (Taj Pharma)

Package leaflet: Information for the user

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1 What Valsartan Tablets are and what they are used for
2 What you need to know before you take Valsartan Tablets
3 How to take Valsartan Tablets
4 Possible side effects
5 How to store Valsartan Tablets
6 Contents of the pack and other information

1. What Valsartan Tablets are and what they are used for

Valsartan  Tablets contain the active substance Valsartan  and belongs to a class of medicines known as angiotensin II receptor antagonists, which help to control high blood pressure. Angiotensin II is a substance in the body that causes the blood vessels to tighten, causing your blood pressure to increase.

Valsartan  Tablets work by blocking the effect of angiotensin II. As a result, blood vessels relax and blood pressure is lowered.

Valsartan  40mg Tablets can be used for three different conditions:

• to treat high blood pressure in children and adolescents 6 to 18 years of age. High blood pressure increases the workload on the heart and arteries. If not treated it can damage the blood vessels of the brain, heart, and kidneys, and may result in a stroke, heart failure, or kidney failure. High blood pressure increases the risk of heart attacks. Lowering your blood pressure to normal reduces the risk of developing these disorders.
• to treat adult patients after a recent heart attack (myocardial infarction). “Recent” here means between 12 hours and 10 days.
• to treat symptomatic heart failure in adult patients. Valsartan  40mg Tablets are used when a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors (a medication to treat heart failure) cannot be used or it may be used in addition to ACE-inhibitors when other medications to treat heart failure cannot be used. Heart failure symptoms include shortness of breath, and swelling of the feet and legs due to fluid build-up. It is caused when the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body.

Valsartan  80mg and 160mg Tablets can be used for three different conditions:

• to treat high blood pressure in adults and in children and adolescents 6 to 18 years of age. High blood pressure increases the workload on the heart and arteries. If not treated it can damage the blood vessels of the brain, heart, and kidneys, and may result in a stroke, heart failure, or kidney failure.

High blood pressure increases the risk of heart attacks. Lowering your blood pressure to normal reduces the risk of developing these disorders.

• to treat adult patients after a recent heart attack (myocardial infarction). “Recent” here means between 12 hours and 10 days.
• to treat symptomatic heart failure in adult patients. Valsartan  80mg and 160mg Tablets is used when a group of medicines called Angiotensin Converting Enzyme (ACE) inhibitors (a medication to treat heart failure) cannot be used or it may be used in addition to ACE-inhibitors when other medications to treat heart failure cannot be used.

Heart failure symptoms include shortness of breath, and swelling of the feet and legs due to fluid build-up. It is caused when the heart muscle cannot pump blood strongly enough to supply all the blood needed throughout the body.

2. What you need to know before you take Valsartan Tablets

Do not take Valsartan  Tablets:

• if you are allergic to Valsartan  or any of the other ingredients of this medicine (listed in section 6).
• if you have severe liver disease.
• if you are more than 3 months pregnant (it is also better to avoid Valsartan  Tablets in early pregnancy – see pregnancy section).
• if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.

Warnings and precautions

Talk to your doctor before taking Valsartan  Tablets

• if you have liver disease.
• if you have severe kidney disease or if you are undergoing dialysis.
• if you are suffering from a narrowing of the kidney artery.
• if you have recently undergone kidney transplantation (received a new kidney).
• if you have severe heart disease other than heart failure or heart attack.
• if you are being treated after a heart attack or heart failure, your doctor may check your kidney function.
• if you have ever experienced swelling of the tongue and face caused by an allergic reaction called angioedema when taking another drug (including ACE inhibitors), tell your doctor. If these symptoms occur when you are taking Valsartan  Tablets, stop taking Valsartan  Tablets immediately and never take it again. See section 4, “Possible side effects”
• if you are taking medicines that increase the amount of potassium in your blood. These include potassium supplements or salt substitutes containing potassium, potassium-sparing medicines and heparin. It may be necessary to check the amount of potassium in your blood at regular intervals.
• if you suffer from aldosteronism. This is a disease in which your adrenal glands make too much of the hormone aldosterone. If this applies to you, the use of Valsartan  Tablets is not recommended.
• if you have lost a lot of fluid (dehydration) caused by diarrhoea, vomiting, or high doses of water tablets (diuretics).
• if you are taking any of the following medicines used to treat high blood pressure:
  • an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems.
  • aliskiren
• if you are being treated with an ACE-inhibitor together with certain other medicines to treat your heart failure, which are known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone, eplerenone) or betablockers (for example metoprolol).

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Valsartan  Tablets“

Other medicines and Valsartan  Tablets

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

The effect of the treatment can be influenced if Valsartan  Tablets are taken together with certain other medicines. Your doctor may need to change your dose and/or take other precautions, or in some cases to stop taking one of the medicines. This applies to both prescription and non-prescription medicines, especially:

• other medicines that lower blood pressure, especially “water tablets” (diuretics).
• medicines that increase the amount of potassium in your blood. These include potassium supplements or salt substitutes containing potassium, potassium-sparing medicines and heparin.
• certain type of pain killers called non-steroidal anti-inflammatory medicines (NSAIDs).
• some antibiotics (rifamycin group), a drug used to protect against transplant rejection (ciclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs may increase the effect of Valsartan  Tablets.
• lithium, a medicine used to treat some types of psychiatric illness.
• if you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Valsartan  Tablets” and “Warnings and precautions”).

In addition:

• if you are being treated with an ACE-inhibitor together with certain other medicines to treat your heart failure, which are known as mineralocorticoid receptors antagonists (MRA) (for example spironolactone, eplerenone) or betablockers (for example metoprolol).
• if you are being treated after a heart attack, a combination with ACE inhibitors (a medication to treat heart attack) is not recommended.

Valsartan  Tablets with food and drink

You can take Valsartan  Tablets with or without food.

Pregnancy and breast-feeding

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

You must tell your doctor if you think that you are (or might become) pregnant.

Your doctor will normally advise you to stop taking Valsartan  Tablets before you become pregnant or as soon as you know you are pregnant, and will advise you to take another medicine instead of Valsartan  Tablets.

Valsartan  Tablets are not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as they may cause serious harm to your baby if they are used after the third month of pregnancy.

Tell your doctor if you are breast-feeding or about to start breast-feeding.

Valsartan  Tablets are not recommended if you are breast-feeding. Your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is newborn, or was born prematurely.

Driving and using machines

Before you drive a vehicle, use tools or operate machines, or carry out other activities that require concentration, make sure you know how this medicine affects you. Like many other medicines used to treat high blood pressure, Valsartan  Tablets may in rare cases cause dizziness and affect the ability to concentrate.

3. How to take Valsartan Tablets

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

People with high blood pressure often do not notice any signs of this problem. Many may feel quite normal. This makes it all the more important for you to keep your appointments with the doctor even if you are feeling well.

Take Valsartan  Tablets at about the same time each day. Swallow the Tablets with a glass of water. You can take the Tablets with or without food.

Dosage:

Children and adolescents (6 to 18 years of age) with high blood pressure

In patients who weigh less than 35kg the recommended dose is 40mg of valsartan once daily.

In patients who weigh 35kg or more the recommended starting dose is 80mg of Valsartan  once daily.

In some cases your doctor may prescribe higher doses (the dose can be increased to 160mg and to a maximum of 320mg).

Adult patients with high blood pressure:

The recommended dose is 80mg capsule daily. In some cases your doctor may prescribe higher doses (e.g. 160mg or 320mg). You may also be prescribed an additional medicine to take e.g. “water tablets” (a diuretic).

Adult patients after a recent heart attack:

After a heart attack the treatment is generally started as early as after 12 hours, usually at a low dose of 20mg twice daily. You obtain the 20mg dose by dividing a 40mg tablet (obtained from a different source). Your doctor will increase this dose gradually over several weeks to a maximum of 160mg twice daily. The final dose depends on what you as an individual patient can tolerate.

Valsartan Tablets can be given together with certain other treatments for heart attack, and your doctor will decide which treatment is suitable for you.

Adult patients with heart failure:

Treatment starts generally with 40mg capsule twice daily. Your doctor will increase the dose gradually over several weeks to a maximum of 160mg capsule twice daily. The final dose depends on what you as an individual patient can tolerate.

Valsartan Tablets can be given together with other treatments for heart failure, and your doctor will decide which treatment is suitable for you.

If you take more Valsartan Tablets than you should

If you experience severe dizziness and/or fainting, contact your doctor immediately and lie down. If you have accidentally taken too many tablets, contact your doctor, pharmacist or hospital.

If you forget to take Valsartan Tablets

If you forget to take a dose, take it as soon as you remember. However, if it is almost time for your next dose, skip the dose you missed.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Valsartan Tablets

Stopping your treatment with Valsartan Tablets may cause your disease to get worse. Do not stop taking your medicine unless your doctor tells you to.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Some side effects can be serious and need immediate medical attention:

You may experience symptoms of angioedema (a specific allergic reaction), such as

• swollen face, lips, tongue or throat
• difficulty in breathing or swallowing
• hives, itching

If you get any of these symptoms, stop taking Valsartan Tablets and contact your doctor straight away.

Other side-effects include:

Common (may affect up to 1 in 10 people):

• dizziness
• low blood pressure with or without symptoms such as dizziness and fainting when standing up
• decreased kidney function (signs of renal impairment)

Uncommon (may affect up to 1 in 100 people):

• sudden loss of consciousness (syncope)
• spinning sensation (vertigo)
• severely decreased kidney function (signs of acute kidney failure)
• muscle spasms, abnormal heart rhythm (signs of hyperkalaemia)
• breathlessness, difficulty breathing when lying down, swelling of the feet or legs (signs of cardiac failure)
• headache
• cough
• abdominal pain
• nausea (feeling sick)
• diarrhoea
• tiredness
• weakness

Not known (frequency cannot be estimated from the available data):

• blistering skin (sign of dermatitis bullous)
• rash
• itching
• allergic reactions with rash, itching and hives together with some of the following signs or symptoms; fever, swollen joints and joint pain, muscle pain, swollen lymph nodes and/or flu-like symptoms may occur (signs of serum sickness)
• purplish-red spots, fever, itching (signs of inflammation of blood vessels also called vasculitis)
• unusual bleeding or bruising (signs of thrombocytopenia)
• muscle pain (myalgia)
• fever, sore throat or mouth ulcers due to infections (symptoms of low level of white blood cells also called neutropenia)
• decrease in level of haemoglobin and decrease of the percentage of red blood cells in the blood (which can, in severe cases, lead to anaemia)
• increase in level of potassium in the blood (which can, in severe cases, trigger muscle spasms, abnormal heart rhythm)
• elevation of liver function values (which can indicate liver damage) including an increase of bilirubin in the blood (which can, in severe cases, trigger yellow skin and eyes)
• increase in level of blood urea nitrogen and increase of level of serum creatinine (which can indicate abnormal kidney function)
• low level of sodium in the blood (which can trigger tiredness, confusion, muscle twitching and/or convulsions in severe cases)

The frequency of some side effects may vary depending on your condition. For example, side effects such as dizziness, and decreased kidney function, were seen less frequently in adult patients treated with high blood pressure than in adult patients treated for heart failure or after a recent heart attack.

Side effects in children and adolescents are similar to those seen in adults.

Reporting of side effects

If you get any side effects, talk to your doctor, or pharmacist. This includes any possible side effects not listed in this leaflet.

By reporting side effects you can help provide more information on the safety of this medicine

5. How to store Valsartan Tablets

Store below 30°C.

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the pack after EXP. The expiry date refers to the last day of that month.

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Valsartan Tablets contain

The active substance is Valsartan. Each capsule contains 40mg, 80mg, 160mg or 320mg of valsartan.

The other ingredients in Tablets are Microcrystalline cellulose, Croscarmellose Sodium, Sodium laurilsulfate, Povidone , Magnesium stearate, Gelatin, Titanium dioxide , Red iron oxide and Black iron oxide.

The black printing ink contains Shellac, Ethanol, Isopropanol, butanol, propylene glycol, purified water, strong ammonia solution, potassium hydroxide and black iron oxide.

What Valsartan Tablets look like and contents of the pack

The Tablets are packed in aluminium foil blisters.

Pack sizes: 7, 28, 30, 50,98, 100 and 500 tablets.

Not all pack sizes may be marketed.

7. Manufactured By:
   Taj Pharmaceuticals Ltd. (Mumbai, India)
   Unit No. 214, Old Bake House,
   Maharashtra Chambers of commerce Lane,Fort,
   Mumbai-400001 at: Ahmedabad- Gujarat, INDIA.