Valazyd 40, 80 & 160 40 mg, 80 mg, 160 mg Tablet

Hypertension: Treatment of mild to moderate hypertension.

Post-myocardial infarction: To improve survival following myocardial infarction in clinically stable patients with signs, symptoms, or radiological evidence of left ventricular failure and/or with left ventricular systolic dysfunction.

Heart failure: VALAZYD is indicated for the treatment of heart failure (NYHA class II u2013 IV).

Posology

Hypertension

The recommended dose of VALAZYD is 80 mg or 160 mg once daily, irrespective of race, age, or gender. The antihypertensive effect is substantially present within 2 weeks and maximal effects are seen after 4 weeks. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 320 mg, or a diuretic may be added. VALAZYD may also be administered with other antihypertensive medicines.

Post-myocardial infarction

Therapy may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg twice daily, VALAZYD therapy 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 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 be achieved by three months, based on the patientu2019s tolerability to valsartan during titration. If symptomatic hypotension or renal dysfunction occurs, consideration should be given to a dosage reduction.

VALAZYD may be used in patients treated with other post-myocardial infarction therapies, e.g. thrombolytics, aspirin (acetylsalicylic acid), beta blockers, or statins. Evaluation of post-myocardial infarction patients should always include assessment of renal function.

Heart failure

The recommended starting dose of VALAZYD is 40 mg twice daily. Up-titration to 80 mg and 160 mg twice daily should be done to the highest dose, 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. Evaluation of patients with heart failure should always include assessment of renal function.

Note for all indications: No dosage adjustment is required for patients with mild renal impairment (where the creatinine clearance is above 70 mL/min) or for patients with hepatic insufficiency of nonbiliary origin and without cholestasis.

Paediatric population

The safety and efficacy of VALAZYD have not been established in children and adolescents (below the age of 18 years).

Method of administration

For oral administration.

• Hypersensitivity to valsartan or to any of the ingredients of VALAZYD listed in section 6.1.
• Pregnancy and lactation (see section 4.6).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers: These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic stenosis.
• Concomitant therapy with potassium sparing diuretics, such as spirinolactone, triamterene and amiloride (see section 4.5).
• Porphyria.
• Lithium therapy: concomitant administration with VALAZYD may lead to toxic blood concentrations of lithium (see section 4.5).
• The concomitant use of VALAZYD with aliskiren-containing products (see sections 4.4 and 4.5).
• Concomitantly using fluoroquinolones in moderate to severe renal impairment (creatinine clearance u2264 30 mL/min), and in the elderly.

Pregnancy

Should a woman become pregnant while receiving VALAZYD, the treatment should be stopped promptly and switched to a different class of antihypertensive medicine (see sections 4.3 and 4.6).

Hyperkalaemia

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium, or other medicines that may increase potassium levels (heparin, etc.) is contraindicated (see section 4.3). Monitoring of potassium should be undertaken as appropriate.

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 after initiation of therapy with VALAZYD. Sodium and/or volume depletion should be corrected before starting treatment with VALAZYD, for example by reducing the diuretic dose. If hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has stabilised.

Renal artery stenosis

In patients with bilateral renal artery stenosis or stenosis to a solitary kidney, the safe use of VALAZYD has not been established. Short-term administration of VALAZYD to 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 medicines that affect the renin-angiotensin system may increase blood urea and serum creatinine in patients with unilateral renal artery stenosis and monitoring of renal function is recommended when patients are treated with VALAZYD (see section 4.3).

Kidney transplantation

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with VALAZYD as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

VALAZYD is contraindicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM) (see section 4.3).

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 VALAZYD should be used with caution in these patients. No dose adjustment is required for adult patients with mild renal impairment (see sections 4.2 and 5.2). The concomitant use of angiotensin receptor blockers (ARBs), including VALAZYD, with aliskiren is contraindicated, as well as use of VALAZYD in patients with severe renal impairment (GFR < 30 mL/min) (see section 4.3).

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, VALAZYD should be used with caution (see section 5.2). Valsartan is mostly eliminated unchanged in the bile, and patients with biliary obstructive disorders showed lower valsartan clearance (see section 5.2). Particular caution should be exercised when administering VALAZYD to patients with biliary obstructive disorders.

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 section 5.1). Therefore, the combination of VALAZYD with an ACE inhibitor is not recommended. Caution should be observed when initiating therapy in heart failure or post-myocardial infarction patients. Evaluation of post-myocardial infarction and heart failure patients should always include assessment of renal function (see section 4.2).

Use of VALAZYD 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 VALAZYD is used in combination with an ACE inhibitor. The combination of VALAZYD, an ACE inhibitor and a beta-blocker apparently increases the risk for adverse events and is therefore not recommended. Triple combination of an ACE-inhibitor, a mineralocorticoid receptor antagonist and VALAZYD 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 VALAZYD 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).

Other conditions with stimulation of renin-angiotension system

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 ureamia and in rare cases with acute renal failure and/or death. As VALAZYD is an angiotensin II receptor blocker, it cannot be excluded that the use of VALAZYD 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 medicines including ACE inhibitors. VALAZYD should be immediately discontinued in patients who develop angioedema, and VALAZYD should not be re-administered (see section 4.3).

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 VALAZYD and aliskiren is therefore contraindicated (see sections 4.3 and 4.5).

Fluoroquinolones and ARBs

Concomitant use of fluoroquinolones and ARBs may precipitate acute kidney injury in patients, especially those with moderate to severe renal impairment and elderly patients (see section 4.3). Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ARBs whether used separately and/or concomitantly.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with ARBs, ACE inhibitors, or aliskiren

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) (see sections 4.3 and 4.4).

Concomitant use of ARBs, including VALAZYD, with aliskiren is contraindicated (see sections 4.3).

Lithium

Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use of ACE inhibitors. The concomitant use of VALAZYD and lithium is contraindicated (see section 4.3).

Fluoroquinolones

Concomitant use of ARBs and fluoroquinolones may precipitate acute kidney injury. The mechanism of the possible interaction between the different classes of medicines, over and above different mechanisms of kidney damage, is unknown (see section 4.3).

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other substances that may increase potassium levels

If a medicine that affects potassium levels is considered necessary in combination with VALAZYD, monitoring of potassium plasma levels is advised.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, aspirin (acetylsalicylic acid) >3 g/day), and non-selective NSAIDs

When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function and an increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment is recommended, as well as adequate hydration of the patient.

Transporters

In vitro data indicates that valsartan 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 VALAZYD. Exercise appropriate care when initiating or ending concomitant treatment with such medicines.

Others

No interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indometacin, hydrochlorothiazide, amlodipine, glibenclamide.

Women of childbearing potential

Women of childbearing age should use effective contraception.

Pregnancy

Safety in pregnancy has not been established (see sections 4.3 and 4.4). When pregnancy is planned or confirmed, VALAZYD should be discontinued. Medicines affecting the renin-angiotensin system, such as VALAZYD, can cause embryonal toxicity, foetal and neonatal morbidity and mortality when administered in pregnant women.

Breastfeeding

Safety during lactation has not been established (see sections 4.3 and 4.4). Because no information is available regarding the use of VALAZYD during breastfeeding, VALAZYD is contraindicated (see section 4.3). Alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.

Fertility

No data are available on the effects of VALAZYD on fertility.

VALAZYD may cause side effects, such as dizziness or weariness. Caution is advised before driving a vehicle or operating until the effects of VALAZYD are known.

Listed summary of adverse reactions

The following adverse reactions have been reported in hypertension, post-myocardial infarction and heart failure.

Infections and infestations

• Frequent: viral infections
• Less frequent: upper respiratory tract infection, pharyngitis, sinusitis, rhinitis

Blood and lymphatic system disorders

• Frequent: neutropenia
• Less frequent: thrombocytopenia
• Frequency unknown: decreased haemoglobin, decreased hematocrit

Immune system disorders

• Less frequent: hypersensitivity (including serum sickness)

Metabolism and nutrition disorders

• Less frequent: hyperkalaemia 1, 2
• Frequency unknown: increased serum potassium, hyponatraemia

Psychiatric disorders

• Less frequent: insomnia, libido decreased

Nervous system disorders

• Frequent: postural dizziness 2 , dizziness 3
• Less frequent: syncope 1 , headache 3

Ear and labyrinth disorders

• Less frequent: vertigo

Cardiac disorders

• Less frequent: cardiac failure 1

Vascular disorders

• Frequent: hypotension 3 , orthostatic hypertension 2
• Less frequent: vasculitis

Respiratory, thoracic and mediastinal disorders

• Less frequent: cough

Gastrointestinal disorders

• Less frequent: diarrhoea, abdominal pain, nausea 3

Hepatobiliary disorders

• Frequency unknown: elevation of liver function values including increase of serum bilirubin

Skin and subcutaneous tissue disorders

• Less frequent: angioedema 4 , rash, pruritis, dermatitis bullous

Musculoskeletal and connective tissue disorders

• Less frequent: back pain, arthralgia, myalgia

Renal and urinary disorders

• Frequent: renal failure 1, 2
• Less frequent: renal impairment 3, 4 , acute renal failure 4 , renal insuffiency 4 , elevation of serum creatinine
• Frequency unknown: increase in blood urea nitrogen 1, 2

General disorders and administration site conditions

• Less frequent: fatigue, asthenia, oedema.

1 Reported in post-myocardial infarction indication.

2 Reported in heart failure indication.

3 Reported more frequently in heart failure indication than in post-myocardial infarction indication.

4 Reported more frequently in post-myocardial infarction than in heart failure indication.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of VALAZYD is important. It allows continued monitoring of the benefit/risk balance of VALAZYD . Health care providers are asked to report any suspected adverse reactions via the u201c 6.04 Adverse Drug Reaction Reporting Form u201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

Overdose with VALAZYD may result in marked hypotension, which could lead to depressed level of consciousness, circulatory collapse and/or shock. 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 the ingestion is recent, vomiting should be induced. Otherwise, the usual treatment would be intravenous infusion of normal saline solution. If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken. VALAZYD is unlikely to be removed by haemodialysis.