Biorax

Hypertension

Treatment of 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 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.

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

Posology

Hypertension

The recommended starting dose of Biorax 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.

Biorax 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, Biorax should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next few weeks. It is not possible to obtain the 20 mg dose with Biorax Capsules. The starting dose should be obtained by dividing a 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.

Biorax 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 Biorax 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.

Biorax may be administered with other heart failure therapies. However, the triple combination of an ACE-inhibitor, Biorax and a beta-blocker or a potassium-sparing diuretic 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 dosage adjustment is required for adult patients with a creatinine clearance >10 ml/min.

Concomitant use of Biorax with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m²).

Diabetes Mellitus

Concomitant use of Biorax with aliskiren is contraindicated in patients with diabetes mellitus.

Hepatic impairment

Biorax 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 Biorax 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

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 Biorax 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, Biorax is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis. There is limited clinical experience with Biorax in paediatric patients with mild to moderate hepatic impairment. The dose of Biorax should not exceed 80 mg in these patients.

Paediatric heart failure and recent myocardial infarction

Biorax 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

Biorax may be taken independently of a meal and should be administered with water.

Posology

Children and adolescents 6 to 18 years of age

For children and adolescents who are unable to swallow tablets, the use of the Biorax oral solution is recommended. The systemic exposure and peak plasma concentration of valsartan is about 1.7-fold and 2.2-fold higher with the solution compared to the tablets.

The initial dose for the Biorax oral solution is 20 mg (corresponding to 7 ml of the solution) once daily for children and adolescents below 35 kg of weight and 40 mg (corresponding to 13 ml of the solution) once daily for those weighing 35 kg or more. The dose should be adjusted based on blood pressure response up to a maximum dose of 40 mg valsartan once daily (corresponding to 13 ml of the solution) for children and adolescents with body weight below 35 kg and 80 mg valsartan (corresponding to 27 ml of the solution) for children and adolescents with body weight of 35 kg or more.

Switching between Biorax tablets and Biorax Oral Solution

It is not recommended to switch between Biorax tablets and Biorax oral solution unless clinically required.

If switching from Biorax tablets to Biorax oral solution is considered essential on clinical grounds, the valsartan dose should be adjusted as described in the table below and blood pressure should be carefully monitored. The dose should be titrated based on blood pressure response and tolerability.

If switching from Biorax oral solution to Biorax tablets is considered clinically essential, initially the same dose in milligrams should be given. Subsequently, frequent blood pressure monitoring should be performed taking into account potential under-dosing and dose should be titrated further based on blood pressure response and tolerability.

Children less than 6 years of age

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, Biorax is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis. There is limited clinical experience with Biorax 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

Biorax 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

Biorax may be taken independently of a meal.

-Severe hepatic impairment, biliary cirrhosis and cholestasis.

-Second and third trimester of pregnancy.

-The concomitant use of Biorax with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m²).

- Severe hepatic impairment, biliary cirrhosis and cholestasis.

- Second and third trimester of pregnancy.

- Concomitant use of Biorax with aliskiren containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m²).

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 Biorax should be used with caution in these patients. No dosage adjustment is required for adult patients with a creatinine clearance >10 ml/min.

The concomitant use of ARBs - including Biorax - or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73m²).

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Biorax 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 Biorax. Sodium and/or volume depletion should be corrected before starting treatment with Biorax, 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 Biorax has not been established.

Short-term administration of Biorax 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 Biorax.

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Biorax 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.

Recent myocardial infarction

The combination of captopril and Biorax has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies. Therefore, the combination of Biorax 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 Biorax 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

The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when [Product name] is used in combination with an ACE-inhibitor. In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and Biorax has not shown any clinical benefit. 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 Biorax 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.

Use of Biorax 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-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 Biorax is an angiotensin II antagonist, it cannot be excluded that the use of Biorax 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.

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 Biorax; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Biorax should be immediately discontinued in patients who develop angioedema, and Biorax 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.

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.

Concomitant use of angiotensin receptor antagonists (ARBs) - including Biorax - or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m²) is contraindicated.

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 Biorax 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 Biorax. This applies particularly when Biorax is given in the presence of other conditions (fever, dehydration) likely to impair renal function.

The concomitant use of ARBs - including Biorax - or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73m²).

Impaired hepatic function

As in adults, Biorax is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis. There is limited clinical experience with Biorax in paediatric patients with mild to moderate hepatic impairment. The dose of Biorax should not exceed 80 mg in these patients.

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

Short-term administration of Biorax 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 Biorax in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Biorax 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).

Diabetes

Biorax oral solution contains 0.3 g sucrose per milliliter. This should be taken into account in patients with diabetes mellitus.

Hereditary fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take Biorax oral solution as it contains sucrose.

Methyl parahydroxybenzoate

Biorax oral solution contains methyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Biorax oral solution contains poloxamer (188) which may cause softened stools.

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.

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

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 is an angiotensin II antagonist, it cannot be excluded that the use of Biorax may be associated with impairment of the renal function.

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 the RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

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

Change of pharmaceutical form

Biorax oral solution is not bioequivalent to the tablet formulation and patients should not be switched unless clinically essential.

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, Biorax is contraindicated in paediatric patients with severe hepatic impairment, biliary cirrhosis and in patients with cholestasis. There is limited clinical experience with Biorax in paediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.

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.

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.

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 Biorax. 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 Biorax has been evaluated in two randomised, double-blind clinical studies in 561 paediatric patients from 6 to 18 years of age. With the exception of isolated gastrointestinal disorders (like abdominal pain, nausea, vomiting) and dizziness, no relevant differences in terms of type, frequency and severity of adverse reactions were identified between the safety profile for paediatric patients aged 6 to 18 years and that previously reported for adult patients.

Neurocognitive and developmental assessment of paediatric patients aged 6 to 16 years of age revealed no overall clinically relevant adverse impact after treatment with Biorax 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 Biorax 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 Biorax 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse drug 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 below according to system organ class.

Adverse Drug Reactions

Adverse drug 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); not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse drug 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 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 included 711paediatric patients from 6 to less than 18 years of age with and without chronic kidney disease (CKD), of which 560 patients received valsartan. 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.

Neurocognitive and developmental assessment of paediatric patients aged 6 to 16 years of age revealed no overall clinically relevant adverse impact after treatment with Biorax 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 Biorax 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 treatment.

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

A pooled analysis of 560 paediatric hypertensive patients (aged 6-17 years) receiving either valsartan monotherapy [n=483] or combination antihypertensive therapy including valsartan [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 in combination with other antihypertensive medications than valsartan alone.

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 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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

Symptoms

Overdose with Biorax 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 the supine position and blood volume correction should be undertaken.

Biorax is unlikely to be removed by haemodialysis.

Symptoms

Overdose with Biorax 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.

Pharmacotherapeutic group: angiotensin II antagonists, plain, ATC code: C09C A03

Mechanism of action

Biorax 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 Biorax may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the AT₁ receptor. Biorax 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. Biorax is not known to bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Biorax 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.

Clinical efficacy and safety

In clinical trials where Biorax was compared with an ACE inhibitor, the incidence of dry cough was significantly (P < 0.05) less in patients treated with Biorax 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 Biorax 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).

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.

Hypertension

Administration of Biorax 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 Biorax has not been associated with rebound hypertension or other adverse clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, Biorax has been shown to reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with Biorax) study assessed the reduction in urinary albumin excretion (UAE) with Biorax (80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years; 265 men) with microalbuminuria (Biorax: 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 Biorax 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 Biorax Reduction of Proteinuria (DROP) study further examined the efficacy of Biorax 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 Biorax (160, 320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal dose of Biorax 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 Biorax 160 mg (95%CI: 22 to 47%), and by 44% with Biorax 320 mg (95%CI: 31 to 54%). It was concluded that 160-320 mg of Biorax produced clinically relevant reductions in UAE in hypertensive patients with type 2 diabetes.

Recent myocardial infarction

The Biorax 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 randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to Biorax, captopril, or the combination of both. The mean treatment duration was two years. The primary endpoint was time to all-cause mortality.

Biorax was as effective as captopril in reducing all-cause mortality after myocardial infarction. All-cause mortality was similar in the Biorax (19.9 %), captopril (19.5 %), and Biorax + captopril (19.3 %) groups. Combining Biorax with captopril did not add further benefit over captopril alone. There was no difference between Biorax and captopril in all-cause mortality based on age, gender, race, baseline therapies or underlying disease. Biorax was also effective in prolonging the time to and reducing cardiovascular mortality, hospitalisation for heart failure, recurrent myocardial infarction and resuscitated cardiac arrest and non-fatal stroke (secondary composite endpoint).

The safety profile of Biorax 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 Biorax-treated patients, 4.8% of Biorax+captopril-treated patients, and 3.4% of captopril-treated patients. Discontinuations due to various types of renal dysfunction occurred in 1.1% of Biorax-treated patients, 1.3% in Biorax+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 or cardiovascular mortality or morbidity when beta-blockers were administered together with the combination of Biorax + captopril, Biorax 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 Biorax 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 betablockers (36%). The mean duration of follow-up was nearly two years. The mean daily dose of Biorax 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 Biorax (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 Biorax group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and Biorax. 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 Biorax compared to placebo by 33% (95% CI: -6% to 58%) (17.3% Biorax vs. 27.1% placebo) and the composite mortality and morbidity risk was significantly reduced by 44% (24.9% Biorax vs. 42.5% placebo). In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the Biorax (21.8%) and placebo (22.5%) groups. Composite mortality and morbidity risk was significantly reduced by 18.3% (95% CI: 8% to 28%) with Biorax compared with placebo (31.0% vs. 36.3%).

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

Paediatric population

Hypertension

The antihypertensive effect of Biorax 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 Biorax tablets daily (low, medium and high doses), and patients who weighed >35 kg received 20, 80, and 160 mg of Biorax tablets daily (low, medium and high doses). At the end of 2 weeks, Biorax reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of Biorax (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 Biorax or were switched to placebo. In patients who continued to receive the medium and high doses of Biorax, 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 Biorax, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of Biorax 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 Biorax or enalapril tablets for 12 weeks. Children weighing between >18 kg and <35 kg received Biorax 80 mg or enalapril 10 mg; those between >35 kg and <80 kg received Biorax 160 mg or enalapril 20 mg; those >80 kg received Biorax 320 mg or enalapril 40 mg. Reductions in systolic blood pressure were comparable in patients receiving Biorax (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 Biorax and enalapril, respectively.

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 Biorax was confirmed compared to placebo but a dose-response could not be demonstrated. In the second study, higher doses of Biorax 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, Biorax is not recommended in this age group.

The European Medicines Agency has waived the obligation to submit the results of studies with Biorax in all subsets of the paediatric population in heart failure and heart failure after recent myocardial infarction.

Pharmacotherapeutic group: Angiotensin II Antagonists, plain, ATC code: C09CA03

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).

Use in adults

Administration of Biorax 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 Biorax 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 Biorax 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.

Other: dual blockade of the renin-angiotensin-aldosterone system (RAAS)

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.

Hypertension (paediatric population)

The antihypertensive effect of valsartan have been evaluated in four randomized, double-blind clinical studies in 561 paediatric patients from 6 to less than 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 tablets daily (low, medium and high doses), and patients who weighed >35 kg received 20, 80, and 160 mg of valsartan tablets daily (low, medium and high doses). At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by 8, 10, 12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, 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, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

In a second clinical study involving 300 hypertensive paediatric patients 6 to less than 18 years of age, eligible patients were randomized to receive valsartan or enalapril tablets for 12 weeks. Children weighing between >18 kg and <35 kg received valsartan 80 mg or enalapril 10 mg; those between >35 kg and <80 kg received valsartan 160 mg or enalapril 20 mg; those >80 kg received valsartan 320 mg or enalapril 40 mg. Reductions in systolic blood pressure were comparable in patients receiving valsartan (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 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 >95^th percentile for age, gender and height) received valsartan 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 <95^th 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 was confirmed compared to placebo but a dose-response could not be demonstrated. In the second study, higher doses of valsartan 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 is not recommended in this age group.

The European Medicines Agency has waived the obligation to submit the results of studies with Biorax in all subsets of the paediatric population in heart failure and heart failure after recent myocardial infarction.

Absorption

Following oral administration of Biorax alone, peak plasma concentrations of Biorax are reached

in 2-4 hours with tablets and 1-2 hours with solution formulation. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC) and 39% with tablets and solution formulation, respectively to Biorax by about 40% and peak plasma concentration (C_max) by about 50%, although from about 8 h post dosing plasma Biorax 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 Biorax can therefore be given either with or without food.

Distribution

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

Biotransformation

Biorax 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 Biorax AUC). This metabolite is pharmacologically inactive.

Excretion

Biorax shows multiexponential decay kinetics (t_½α <1 h and t_½ß about 9 h). Biorax 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 Biorax is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of Biorax is 6 hours.

In Heart failure patients

The average time to peak concentration and elimination half-life of Biorax in heart failure patients are similar to that observed in healthy volunteers. AUC and C_max values of Biorax 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 Biorax 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 Biorax was observed in some elderly subjects than in with 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 Biorax. Dose adjustment is therefore not required in patients with renal impairment (creatinine clearance >10ml/min). There is currently no experience on the safe use in patients with a creatinine clearance <10 ml/min and patients undergoing dialysis, therefore Biorax should be used with caution in these patients. Biorax 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. Biorax 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 Biorax concentration versus degree of hepatic dysfunction. Biorax has not been studied in patients with severe hepatic dysfunction.

Paediatric population

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

Impaired renal function

Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore Biorax 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.

Absorption:

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours with tablets and 1-2 hours with solution formulation. Mean absolute bioavailability is 23% and 39% with tablets and solution formulation, respectively. Food decreases exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) 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.

Elimination:

Valsartan shows multiexponential decay kinetics (t_½α <1 h and t_½ß about 9 h). Valsartan 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 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

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.

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. Biorax has not been studied in patients with severe hepatic dysfunction.

Paediatric population

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

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.

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. 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 Biorax (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 Biorax which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of Biorax 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 Biorax 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 Biorax 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.

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. 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/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 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.

Paediatric population

Daily oral dosing of neonatal/juvenile rats (from a postnatal day 7 to postnatal day 70) with valsartan 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 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.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements.