DIOVAN

Posology For children and adolescents who are unable to swallow tablets, the use of the Diovan oral solution is recommended. 2-fold higher with the solution compared to the tablets. Children 1 to less than 6 years of age The usual starting dose is 1 mg/kg once daily.

The table below shows the corresponding volume of Diovan oral solution to some selected doses. 5 ml 30 kg 30 mg 10 ml A higher starting dose 2 mg/kg may be considered in some selected cases when a faster reduction of blood pressure is needed.

The dose should be adjusted based on blood pressure response and tolerability up to a maximum dose of 4 mg/kg once daily. Doses above 4 mg/kg have not been studied in children between 1 and less than 6 years old. When reaching the age of six years, transition to the posology for children 6-17 years old is recommended.

However, some children may have a higher valsartan dose than the highest recommended dose for children 6-17 years of age. If this dose is well- tolerated, the dose may be retained under close monitoring of blood-pressure and tolerability.

Children and adolescents 6 to lessthan 18 years of age The initial dose for the Diovan 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.

For children already started on valsartan prior to the age of six years, please refer to the posology for Children 1 to less than 6 years of age. Switching between Diovan tablets and Diovan Oral Solution It is not recommended to switch between Diovan tablets and Diovan oral solution unless clinically required.

If switching from Diovan tablets to Diovan 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.

Tablets Solution Valsartan dose Valsartan dose to provide when switching Volume to take 40 mg 20 mg 7 ml 80 mg 40 mg 13 ml 160 mg 80 mg 27 ml 320 mg Due to the high volume of solution that would be necessary, the use of the solution is not recommended Not applicable If switching from Diovan oral solution to Diovan 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. Diovan tablets are not suitable for children aged 1 to 5 years of age and for those having difficulties swallowing the tablets.

2. However, the safety and efficacy of Diovan in children aged below 1 year of age have not been established. Use in paediatric patients aged 1 to less than 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. 2). 2). There is limited clinical experience with Diovan 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 Diovan 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 Diovan may be taken independently of a meal.

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 Blood and lymphatic system disorders Not known Decrease in haemoglobin, Decrease in haematocrit, Neutropenia Immune system disorders Not known Hypersensitivity including serum sickness Metabolism and nutrition disorders Not known Increase of serum potassium, Hyponatraemia Ear and labyrinth disorders Uncommon Vertigo Vascular disorders Not known Vasculitis Respiratory, thoracic and mediastinal disorders Uncommon Cough Gastrointestinal disorders Uncommon Abdominal pain Hepato-biliary disorders Not known Elevation of liver function values including increase of serum bilirubin Skin and subcutaneous tissue disorders Not known Angioedema, Dermatitis bullous, Rash, Pruritus Musculoskeletal and connective tissue disorders Not known Myalgia Renal and urinary disorders Not known Renal failure and impairment, Elevation of serum creatinine General disorders and administration site conditions Uncommon Fatigue 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 Diovan for up to one year. 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.

73m2). 0%) patients discontinued a study due to adverse events. 3%) being the most frequent. 7%). 7%). ADRs were observed more frequently in patients receiving valsartan in combination with other antihypertensive medications than valsartan alone.

The antihypertensive effect of valsartan in children 1 to less than 6 years of age has been evaluated in three randomised, double-blind clinical studies (each followed by an extension period). In the first study in 90 children aged 1 to less than 6 years, 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 Diovan has not been established. In the two subsequent studies in which 202 children aged 1 to less than 6 years were randomised, no significant liver transaminase elevations or death occurred with valsartan treatment.

In a pooled analysis of the two subsequent studies in 202 hypertensive children (aged 1 to less than 6 years), all patients received valsartan monotherapy in the double blind periods (excluding the placebo withdrawal period). Of these, 186 patients continued in either extension study or open label period.

3%) had CKD (baseline eGFR <90 ml/min). 1%) discontinued due to an adverse event. 0%) patients experienced at least one ADR. 1%). There was one ADR (diarrhoea) in the CKD group. 4% patients (10/186) had at least one ADR. 1%). In both the double blind period and the open label periods, hyperkalaemia was reported for one patient in each period.

There were no cases of hypotension or dizziness in either double blind or open label periods. Hyperkalaemia was more frequently observed in children and adolescents aged 1 to less than 18 years with underlying chronic kidney disease (CKD).

The risk of hyperkalaemia may be higher in children aged 1 to 5 years compared to children aged 6 to less than 18 years The safety profile seen in controlled-clinical studies in adult patients with post- […]

) 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.

2). 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 Diovan.

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

Short-term administration of Diovan 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 Diovan in patients who have recently undergone kidney transplantation. Primary hyperaldosteronism Patients with primary hyperaldosteronism should not be treated with Diovan 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).

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 Diovan oral solution as it contains sucrose.

Methyl parahydroxybenzoate Diovan oral solution contains methyl parahydroxybenzoate which may cause allergic reactions (possibly delayed). Poloxamer Diovan oral solution contains poloxamer (188) which may cause softened stools. 186% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

6). 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.

8). 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 Diovan 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).

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 Change of pharmaceutical form Diovan oral solution is not bioequivalent to the tablet formulation and patients should not be switched unless clinically essential. 2. 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.

2). […]

1. - Severe hepatic impairment, biliary cirrhosis and cholestasis. 6). 1).