Valsartan Viatris 320 mg Film-coated Tablets

6.5 Nature and contents of container

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

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

Valsartan is available in blister packs of 7, 10, 14, 28, 30, 56, 90, 98, 100 tablets and HDPE bottles containing 28, 56, 98, 500, 1000 tablets. Valsartan 320 mg is also available in blister multipack containing 98 (2 packs of 49) tablets.

4.2 Posology and method of administration


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 Vvalsartan in children aged 1 to 6 years have not been established.

Use in paediatric patients aged 6 to 18 years with hepatic impairment
As in adults, Vvalsartan 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 Vvalsartan in paediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe hepatic impairment, biliary cirrhosis and cholestasis.
- Second and third trimester of pregnancy (see sections 4.4 and 4.6).
- The concomitant use of Vvalsartan Mylan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Hyperkalaemia
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended.
Monitoring of potassium should be undertaken as appropriate.

Impaired rRenal functionimpairment
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 a creatinine clearance >10 ml/min (see sections 4.2 and 5.2).

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

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

Sodium- and/or volume-depleted patients
In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with Valsartan. Sodium and/or volume depletion should be corrected before starting treatment with Valsartan, for example by reducing the diuretic dose.

Renal artery stenosis
In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of Vvalsartan has not been established.
Short-term administration of Vvalsartan 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 Vvalsartan in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism
Patients with primary hyperaldosteronism should not be treated with Vvalsartan 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
The combination of captopril and valsartan has shown no additional clinical benefit, instead the risk for adverse events increased compared to treatment with the respective therapies (see sections 4.2 and 5.1). Therefore, the combination of valsartan with an ACE inhibitor is not recommended.
Caution should be observed when initiating therapy in post-myocardial infarction patients. Evaluation of post-myocardial infarction patients should always include assessment of renal function (see section 4.2).
Use of Vvalsartan 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
The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when Vvalsartan Mylan is used in combination with an ACE-inhibitor. In patients with heart failure, the triple combination of an ACE inhibitor, a beta blocker and Vvalsartan has not shown any clinical benefit (see section 5.1). This combination apparently increases the risk for adverse events and is therefore not recommended. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and valsartan is also not recommended. Use of these combinations should be under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

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

Use of Vvalsartan in patients with heart failure commonly results in some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension is not usually necessary provided dosing instructions are followed (see section 4.2).

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone- system (e.g. patients with severe congestive heart failure), treatment with ACE inhibitors has been associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II receptor blocker, it cannot be excluded that the use of  Vvalsartan 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 valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors.
Valsartan should be immediately discontinued in patients who develop angioedema, and valsartan should not be re-administered.

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

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

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

Paediatric population

Impaired rRenal functionimpairment
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 (see sections 4.2 and 5.2). 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. The concomitant use of ARBs – including valsartan – or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m2 ) (see sections 4.3 and 4.5)

Impaired hHepatic impairmentfunction
As in adults, Vvalsartan 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 Vvalsartan in paediatric patients with mild to moderate hepatic impairment. The dose of valsartan should not exceed 80 mg in these patients.

4.5 Interaction with other medicinal products and other forms of interaction

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

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

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

Concomitant use not recommended

Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors or angiotensin II receptor antagonists including with valsartanconcurrent use of ACE inhibitors. If the combination proves necessary, a careful monitoring ofDue to the lack of experience with concomitant use of valsartan and lithium, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may presumably be increased further.

Transporters
In vitro data indicates that valsartan is a substrate of the hepatic uptake transporter OATP1B1/OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this finding is unknown. Co-administration of inhibitors of the uptake transporter (e.g. Rrifampicin, ciclosporin) or efflux transporter (e.g ritonavir) may increase the systemic exposure to valsartan. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse reactions (ADRs) was comparable with placebo and is consistent with the pharmacology of valsartan. 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) 
vVery rare (< 1/10,000),
not known (frequency cannot be estimated from the available data)
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

Blood and lymphatic system disorders
Not known	Decrease in haemoglobin, Decrease in haematocrit, Neutropenia, Thrombocytopenia
Immune system disorders
Not known	Hypersensitivity including serum sickness
Metabolism and nutrition disorders
Not known	Increase of serum potassium, hyponatraemia
Ear and labyrinth system 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 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 Vvalsartan 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 Vvalsartan 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 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	Dermatitis bullous, Rash, Pruritus
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

4.9 Overdose

 

Symptoms
Overdose with Vvalsartan may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock.

ManagementTreatment
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.

5.2 Pharmacokinetic properties

EliminationExcretion:
Valsartan shows multiexponential decay kinetics (t½α <1 h and t½ß 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 rRenal impairmentfunction
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 (see sections 4.2 and 4.4). 
Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis.

Paediatric population

Impaired rRenal impairmentfunction
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 (see sections 4.2 and 4.4).

Section 4.2:

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

Section 4.3:

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe hepatic impairment, biliary cirrhosis and cholestasis.
- Second and third trimester of pregnancy (see sections 4.4 and 4.6).
- The concomitant use of Valsartan Mylan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2) (see sections 4.5 and 5.1).Concomitant use of angiotensin receptor antagonists (ARBs) – including valsartan – or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.4 and 4.5).

Section 4.4:

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

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

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

Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system.

Caution is required while co-administering ARBs, including valsartan, with other agents blocking the RAS such as ACEIs or aliskiren (see sections 4.3 and 4.5).

Concomitant use of angiotensin receptor antagonists (ARBs) – including valsartan – or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR< 60 mL/min/1.73 m2) is contraindicated (see sections 4.3 and 4.5).

Section 4.5:

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

Section 5.1:
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.

Section 3:
Dark grey violet, oval- shaped, beveled edged, biconvex, film-coated tablets (17.7 x 8.2 mm) debossed with “VN 4” on one side and “M” on the other side.


Section 4.8:
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


HPRA Pharmacovigilance,
Earlsfort Terrace,
IRL - Dublin 2;
Tel: +353 1 6764971;
Fax: +353 1 6762517.
Website: www.hpra.ie
E-mail: medsafety@hpra.ie

Section 6.5:

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

Section 4.2:
Renal impairment
No dose adjustment is required for adult patients with a creatinine clearance >10 ml/min (see sections 4.4 and 5.2). Concomitant use of valsartan with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m2) (see section 4.3).

Diabetes Mellitus
Concomitant use of valsartan with aliskiren is contraindicated in patients with diabetes mellitus (see section 4.3).

Section 4.3:


- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe hepatic impairment, biliary cirrhosis and cholestasis.
- Second and third trimester of pregnancy (see sections 4.4 and 4.6).
- Concomitant use of angiotensin receptor antagonists (ARBs) – including valsartan – or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2) (see sections 4.4 and 4.5).

Section 4.4:
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 a creatinine clearance >10 ml/min (see sections 4.2 and 5.2).

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


History of angioedema
Angioedema, including swelling of the larynx and glottis, causing airway obstruction and/or swelling of the face, lips pharynx, and/or tongue has been reported in patients treated with valsartan; some of these patients previously experienced angioedema with other drugs including ACE inhibitors.
Valsartan should be immediately discontinued in patients who develop angioedema, and valsartan should not be re-administered.

Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS)
Hypotension, syncope, stroke, hyperkalaemia, and changes in renal function (including acute renal failure) have been reported in susceptible individuals, especially if combining medicinal products that affect this system.

Caution is required while co-administering ARBs, including valsartan, with other agents blocking the RAS such as ACEIs or aliskiren (see sections 4.3 and 4.5).

Concomitant use of angiotensin receptor antagonists (ARBs) – including valsartan – or of angiotensin-converting-enzyme inhibitors (ACEIs) with aliskiren in patients with diabetes mellitus or renal impairment (GFR< 60 mL/min/1.73 m2) is contraindicated (see sections 4.3 and 4.5).

Paediatric population

Impaired renal function
Use in paediatric patients with a creatinine clearance <30 ml/min and paediatric patients undergoing dialysis has not been studied, therefore valsartan is not recommended in these patients. No dose adjustment is required for paediatric patients with a creatinine clearance >30 ml/min (see sections 4.2 and 5.2). 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. The concomitant use of ARBs – including valsartan – or of ACEIs with aliskiren is contraindicated in patients with renal impairment (GFR < 60 mL/min/1.73 m2 ) (see sections 4.3 and 4.5)

Section 4.5:
Dual blockade of the Renin-Angiotensin – System (RAS) with ARBs, ACEIs, or aliskiren:

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

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

Section 4.8:

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 preferably through the online reporting option (preferred method) accessible from the IMB homepage (www.imb.ie). A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’ (see details below). Alternatively, the traditional post-paid ‘yellow card’ option may also continue to be used.

FREEPOST
Pharmacovigilance Section
Irish Medicines Board
Kevin O’Malley House
Earlsfort Centre
Earlsfort Terrace
Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.imb.ie
e-mail: imbpharmacovigilance@imb.ie

Section 2, 3, 4.3, 4.4, 4.6 and 5.1 updated in line with QRD template
Section 4.8 updated with CSP updates as follows

In controlled clinical studies in adult patients with hypertension, the overall incidence of adverse reactions (ADRs) was comparable with placebo and is consistent with the pharmacology of valsartan. 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

 

Blood and lymphatic system disorders
Not known	Decrease in haemoglobin, Decrease in haematocrit, Neutropenia, Thrombocytopenia
Immune system disorders
Not known	Hypersensitivity including serum sickness
Metabolism and nutrition disorders
Not known	Increase of serum potassium, hyponatraemia
Ear and labyrinth system 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, 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 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 Valsartan for up to one year.

 

In a double-blind randomized study in 90 children aged 1 to 6 years, which was followed by a one-year open-label extension, two deaths and isolated cases of marked liver transaminases elevations were observed. These cases occurred in a population who had significant comorbidities. A causal relationship to Valsartan 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 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, Pruritus
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

 
In section 6.5 additional pack sizes approved

Valsartan is available in blister packs of 7, 10, 14, 28, 30, 56, 90, 98, 100 tablets, and HDPE bottles containing 28, 56, 98, 500, 1000 tablets. Not all pack sizes may be marketed.

None provided