Hypertension (only 40 mg)

Treatment of hypertension in children and adolescents 6 to 18 years of age. Hypertension (only 80 mg, 160 mg and 320 mg)

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

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

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 (only 40 mg, 80 mg and 160 mg)

Treatment of symptomatic heart failure in adult patients when Angiotensin Converting Enzyme (ACE) inhibitors cannot be used

1.1   Posology

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

The recommended starting dose of Arbaval 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.

Arbaval 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 (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, Arbaval   should be titrated to 40 mg, 80 mg, and 160 mg twice daily over the next few weeks. The starting dose is provided by the 40 mg divisible tablet.

The target maximum dose is 160 mg twice daily. In general, it is recommended that patients achieve a dose level of 80 mg twice daily by two weeks after treatment initiation and that the target maximum dose, 160 mg twice daily, be achieved by three months, based on the patient's tolerability. If symptomatic hypotension or renal dysfunction occur, consideration should be given to a dose reduction.

Arbaval 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 Arbaval 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.

Arbaval may be administered with other heart failure therapies. However, the triple combination of an ACE inhibitor, a beta blocker and Arbaval 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).

Hepatic impairment

Arbaval 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 Arbaval 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. Weight                                              Maximum dose studied in clinical trials

≥18 kg to <35 kg                  80 mg

≥35 kg to <80 kg                  160 mg

≥80 kg to ≤160 kg                320 mg

For children who cannot swallow tablets, or children for whom the calculated dosage (mg/kg) does not correspond to the available tablet strengths of Arbaval, the use of a suspension is recommended. Follow the suspension preparation instructions below (see Preparation of Suspension) to administer Valsartan as a suspension. When the suspension is replaced by a tablet, the dose of Valsartan may have to be increased. The exposure to Valsartan with the suspension is 1.6 times greater than with the tablet. No data are available in pediatric patients either undergoing dialysis or with a glomerular filtration rate

<30 mL/min/1.73 m2.

Preparation of Suspension (for 160 mL of a 4 mg/mL suspension)

Add 80 mL of Ora-Plus®* oral suspending vehicle to an amber glass bottle containing 8 Arbaval 80 mg tablets, and shake for a minimum of 2 minutes. Allow the suspension to stand for a minimum of 1 hour. After the standing time, shake the suspension for a minimum of 1 additional minute. Add 80 mL of Ora-Sweet SF®* oral sweetening vehicle to the bottle and shake the suspension for at least 10 seconds to disperse the ingredients. The suspension is homogenous and can be stored for either up to 30 days at room temperature (below 30°C/86°F) or up to 75 days at refrigerated conditions (2-8°C/35-46°F) in the glass bottle with a child-resistant screw-cap closure. Shake the bottle well (at least 10 seconds) prior to dispensing the suspension.

*Ora-Sweet SF® and Ora-Plus® are registered trademarks of Paddock Laboratories, Inc.

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 Arbaval 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 Arbaval 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, Arbaval 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 Arbaval in paediatric patients with mild to moderate hepatic impairment. The dose of Arbaval should not exceed 80 mg in these patients.

Paediatric heart failure and recent myocardial infarction

Arbaval 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

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

1.1   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 Arbaval should be used with caution in these patients. No dose adjustment is required for adult patients with creatinine clearance

>10 ml/min (see sections 4.2 and 5.2).

Hepatic impairment

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

Short-term administration of Arbaval 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 Arbaval .

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Arbaval 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 Arbaval 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 Arbaval 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 Arbaval 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)

In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and Arbaval has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended.

Caution should be observed when initiating therapy in patients with heart failure. Evaluation of patients with heart failure should always include assessment of renal function (see section 4.2).

Use of Arbaval 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 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 Arbaval is an angiotensin II antagonist, it cannot be excluded that the use of Arbaval 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 Arbaval ; some of these patients previously experienced angioedema with other drugs including ACE inhibitors. Arbaval should be immediately discontinued in patients who develop angioedema, and Arbaval should not be re-administered (see section 4.8).

Other conditions with stimulation of the renin-angiotensin system (only 320 mg)

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

Paediatric population

Impaired renal function

Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore Arbaval 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 Arbaval . This applies particularly when Arbaval is given in the presence of other conditions (fever, dehydration) likely to impair renal function.

Impaired hepatic function

As in adults, Arbaval 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 Arbaval in paediatric patients with mild to moderate hepatic impairment. The dose of Arbaval should not exceed 80 mg in these patients.

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 Arbaval 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 Arbaval , 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 Arbaval 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 (eg. rifampin, ciclosporin) or efflux transporter (eg. ritonavir) may increase the systemic exposure to Arbaval . Exercise appropriate care when initiating or ending concomitant treatment with such drugs.

Others

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

Pregnancy category (D)

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 fetotoxicity (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).

Lactation

Because no information is available regarding the use of Arbaval during breastfeeding, Arbaval 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

Arbaval 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).

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.

1.1   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 Arbaval. 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 Arbaval 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 Arbaval 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 Arbaval 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 Arbaval 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) Blood and lymphatic system disorders

Not known            Thrombocytopenia Immune system disorders

Not known            Hypersensitivity including serum sickness Metabolism and nutrition disorders

Uncommon           Hyperkalaemia

Not known            Increase of serum potassium, hyponatraemia Nervous system disorders

Common               Dizziness, Postural dizziness Uncommon           Syncope, Headache

Ear and labyrinth system disorders Uncommon           Vertigo

Cardiac disorders

Uncommon            Cardiac failure Vascular disorders

Common                Hypotension, Orthostatic hypotension Not known                     Vasculitis

Respiratory, thoracic and mediastinal disorders Uncommon            Cough

Gastrointestinal disorders Uncommon Nausea, Diarrhoea Hepato-biliary disorders

Not known              Elevation of liver function values Skin and subcutaneous tissue disorders

Uncommon            Angioedema

Not known              Rash, Pruritis Musculoskeletal and connective tissue disorders Not known Myalgia

Renal and urinary disorders

Common                Renal failure and impairment

Uncommon            Acute renal failure, Elevation of serum creatinine Not known                     Increase in Blood Urea Nitrogen

General disorders and administration site conditions Uncommon            Asthenia, Fatigue

-  To reports any side effect(s):

·         Saudi Arabia

·         Other GCC States:

Symptoms

Overdose with Arbaval 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.

Arbaval is unlikely to be removed by haemodialysis.

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

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

Arbaval 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 Arbaval was compared with an ACE inhibitor, the incidence of dry cough was significantly (p<0.05) less in patients treated with Arbaval 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 Arbaval and 19.0% of those receiving a thiazide diuretic experienced cough compared to 68.5% of those treated with an ACE inhibitor (p<0.05).

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

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

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

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

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

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

+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 Arbaval + captopril, Arbaval 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 Arbaval 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 Arbaval 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 Arbaval (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 Arbaval group) were observed for those patients receiving the triple combination of an ACE inhibitor, a beta blocker and Arbaval .

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

In patients receiving an ACE inhibitor without a beta-blocker, all cause mortality was similar (p=NS) in the Arbaval (21.8%) and placebo (22.5%) groups. Composite mortality and morbidity risk was significantly reduced by 18.3% (95% CI: 8% to 28%) with Arbaval compared with placebo (31.0% vs. 36.3%).

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

Paediatric population Hypertension

The antihypertensive effect of Arbaval 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 Arbaval tablets daily (low, medium and high doses), and patients who weighed ≥35 kg received 20, 80, and 160 mg of Arbaval tablets daily (low, medium and high doses). At the end of 2 weeks, Arbaval reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of Arbaval (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 Arbaval or were switched to placebo. In patients who continued to receive the medium and high doses of Arbaval , 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 Arbaval, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of Arbaval 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 Arbaval or enalapril tablets for 12 weeks. Children weighing between ≥18 kg and <35 kg received Arbaval 80 mg or enalapril 10 mg; those between ≥35 kg and <80 kg received Arbaval 160 mg or enalapril 20 mg; those ≥80 kg received Arbaval 320 mg or enalapril 40 mg. Reductions in systolic blood pressure were comparable in patients receiving Arbaval (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 Arbaval 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 Arbaval was confirmed compared to placebo but a dose-response could not be demonstrated. In the second study, higher doses of Arbaval 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, Arbaval 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 Arbaval 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.

Absorption:

Following oral administration of Arbaval alone, peak plasma concentrations of Arbaval 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 Arbaval by about 40% and peak plasma concentration (Cmax) by about 50%, although from about 8 h post dosing plasma Arbaval 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 Arbaval can therefore be given either with or without food.

Distribution:

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

Biotransformation:

Arbaval 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 Arbaval AUC). This metabolite is pharmacologically inactive.

Excretion:

Arbaval shows multiexponential decay kinetics (t½α <1 h and t½ß about 9 h). Arbaval 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 Arbaval is about 2 l/h and its renal clearance is 0.62 l/h (about 30% of total clearance). The half-life of Arbaval 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 Arbaval in heart failure patients are similar to that observed in healthy volunteers. AUC and Cmax values of Arbaval 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 Arbaval 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 Arbaval 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 Arbaval . 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 Arbaval should be used with caution in these patients (see sections 4.2 and 4.4).

Arbaval 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. Arbaval 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 Arbaval concentration versus degree of hepatic dysfunction. Arbaval 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 Arbaval (mean: 0.9 to 2 mg/kg, with a maximum dose of 80 mg), the clearance (litres/h/kg) of Arbaval   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 Arbaval 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).

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

Silicified microcrystalline cellulose, Crospovidone, Magnesium stearate.
The tablet coating contains hypromellose, PEG 4000, Talc, Titanium dioxide, Red iron oxide,
Yellow Iron oxide, Carmoisine, and FD&C Blue #2 Aluminum Lake
 

Not applicable.
 

Store below 30°C.
Store in the original package in order to protect from moisture.
 

Forming Aluminium / Aluminium blister pack
Pack sizes: 28 film-coated tablets
 

No special requirements.