Valgen 40 mg, 80 mg, 160 or 320 mg FC tablets

Hypertension: Treatment of mild to moderate essential hypertension in adult patients 18 years and older.

Post-myocardial infarction: To improve survival following a recent (12 hours u2013 10 days) 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: VALGEN is indicated for the treatment of heart failure (NYHA class II u2013 IV).

Posology: Hypertension: The recommended dose of VALGEN 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. VALGEN may also be administered with other antihypertensive medicines.

Post-myocardial infarction: Treatment may be initiated as early as 12 hours after a myocardial infarction. After an initial dose of 20 mg twice daily, VALGEN treatment 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. VALGEN may be used in patients treated with other post-myocardial infarction medicines, e.g. thrombolytics, 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 VALGEN 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.

Special populations

Renal impairment: NOTE for all indications: No dosage adjustment is required for patients with mild to moderate renal impairment (where the creatinine clearance is 30 to less than 90 mL/min).

Hepatic impairment: NOTE for all indications: No dosage adjustment is required for patients with hepatic insufficiency of non-biliary origin and without cholestasis. A lower dose should be considered for patients with a history of hepatic impairment (see section 4.4).

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

Method of administration

Oral use. VALGEN is given orally with or without food.

• Known hypersensitivity to valsartan or to any of the excipients of VALGEN (see section 6.1).
• A history of angioedema related to previous treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs): These patients must never again be given these medicines.
• Hereditary or idiopathic angioedema.
• Hypertrophic obstructive cardiomyopathy (HOCM).
• Severe renal function impairment (creatinine clearance less than 30 mL/min).
• Bilateral renal artery stenosis.
• Renal artery stenosis in patients with a single kidney.
• Aortic valve stenosis.
• Mitral valve stenosis.
• Concomitant treatment with potassium sparing diuretics such as spironolactone, triamterene, amiloride (see section 4.5).
• Concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min) and in elderly patients.
• Porphyria.
• Lithium treatment: Concomitant administration with VALGEN may lead to toxic blood concentrations of lithium (see section 4.5).
• Pregnancy and lactation (see section 4.6).
• The concomitant use of VALGEN with aliskiren-containing medicines is contraindicated (see section 4.4).
• Concomitant use of VALGEN with aliskiren in patients with Type 2 diabetes mellitus (see section 4.5, subsection dual blockade of the RAAS).
• Concomitant use of VALGEN with aliskiren-containing medicines in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73 m2) (see sections 4.5 and 5.1).

Pregnancy: Should a woman become pregnant while receiving VALGEN 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 not recommended. Monitoring of potassium should be undertaken as appropriate.

Impaired renal function: No dosage adjustment is required for patients with mild to moderate renal impairment (where the creatinine clearance is above 30 to u2264 90 mL/min). VALGEN is contraindicated in patients with severe renal function impairment (CrCI < 30mL/min). The use of VALGEN with aliskiren should be avoided in patients with renal impairment (GFR < 60 mL/min) (see section 4.5, subsection dual blockade of the RAAS).

Hepatic impairment: In patients with mild to moderate hepatic impairment without cholestasis, VALGEN should be used with caution (see sections 4.2 and 5.2). No dosage adjustment is required for patients with hepatic insufficiency of non-biliary origin and without cholestasis. (see sections 4.2 and 5.2). VALGEN is mostly eliminated unchanged in the bile, and patients with biliary obstructive disorders showed lower VALGEN clearance (see section 5.2). Particular caution should be exercised when administering valsartan to patients with biliary obstructive disorders.

Sodium- and/or volume-depleted patients: In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of diuretics, and/or patients with moderate to severe renal impairment, symptomatic hypotension may occur after initiation of treatment with VALGEN. Sodium and/or volume depletion should be corrected before starting treatment with VALGEN, 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 VALGEN has not been established.

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

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

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: VALGEN is contraindicated in patients suffering from aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy (HOCM). See section 4.3.

Recent myocardial infarction (only 40 mg, 80 mg and 160 mg): 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 as in VALGEN 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 VALGEN 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): The risk of adverse reactions, especially hypotension, hyperkalaemia and decreased renal function (including acute renal failure), may increase when VALGEN is used in combination with an ACE-inhibitor. In patients with heart failure, the triple combination of an ACE inhibitor, a beta-blocker and valsartan 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 as in VALGEN are 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 VALGEN 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 the renin-angiotensin system: In patients whose renal function may depend on the activity of the renin-angiotensin system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and/or progressive azotaemia and in rare cases with acute renal failure and/or death. As valsartan is an angiotensin II antagonist, it cannot be excluded that the use of VALGEN 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 valsartan; some of these patients previously experienced angioedema with other medicines including ACE inhibitors. VALGEN 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 VALGEN and aliskiren is therefore contraindicated (see sections 4.3). VALGEN should not be used concomitantly with aliskiren (see section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers: The concomitant use of fluoroquinolones with ACE inhibitors/Angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min) and in elderly patients. Renal function should be assessed before initiating treatment and monitored during treatment with fluoroquinolones or ACE inhibitors/Angiotensin receptor blockers whether used separately and/or concomitantly. Patients currently treated with concomitant use of ACE inhibitors/Angiotensin receptor blockers and fluoroquinolones should contact their doctor to re-evaluate their treatment.

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.

Impaired Hepatic function: As in adults, VALGEN 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 VALGEN in paediatric patients with mild to moderate hepatic impairment.

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS) with ARB, ACEIs, 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 (see sections 4.3, 4.4 and 5.1). Concomitant use of angiotensin receptor antagonists (ARBs) u2013 including valsartan u2013 or of angiotensin-converting enzyme inhibitors (ACEIs) with aliskiren is contraindicated (see sections 4.3 and 4.4). The concomitant use of VALGEN, with other medicines acting on the RAAS is associated with an increased incidence of hypotension, hyperkalaemia, and changes in renal function compared to monotherapy. It is recommended to monitor blood pressure, renal function, and electrolytes in patients on VALGEN and other medicines that affect the RAAS (see section 4.4). The concomitant use of VALGEN with aliskiren, should be avoided in patients with renal impairment (GFR < 60 mL/min) (see section 4.4). The concomitant use of VALGEN with aliskiren is contraindicated in patients with Type 2 diabetes mellitus or renal impairment (GFR < 60 mL/min/1,73 m2) (see section 4.3).

Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers: Concomitant use of fluoroquinolones and ACE inhibitors/Angiotensin receptor blockers 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).

Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported. Concurrent use of lithium and valsartan as contained in VALGEN, is contraindicated. Therefore, monitoring of serum lithium levels is recommended, if needed (see section 4.3).

Potassium: Concomitant use of potassium-sparing diuretics (e.g. spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium that may lead to increases in serum potassium, and in patients with heart failure to increase in serum creatinine, are contraindicated. If needed, serum potassium to be monitored.

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective Cyclooxygenase-2 Inhibitors (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, in elderly patients, volume-depleted (including those on diuretic treatment), or with compromised renal function, 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 is recommended, when initiating or modifying the treatment in patients on valsartan who are taking NSAIDs concomitantly, 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 (e.g. rifampicin, 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 medicines.

Others: In interaction studies with valsartan, no interactions of clinical significance have been found with valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine and glibenclamide. As VALGEN is not metabolised to a significant extent, clinically relevant interactions in the form of metabolic induction or inhibition of the cytochrome P450 system are not expected with valsartan. Although valsartan is highly bound to plasma proteins, in vitro studies have not shown any interaction at this level with a range of molecules which are also highly protein-bound, such as diclofenac, furosemide, and warfarin.

Paediatric population: In hypertension in children and adolescents, where underlying renal abnormalities are common, caution is recommended with the concomitant use of valsartan and other medicines that inhibit the renin-angiotensin-aldosterone system which may increase serum potassium. Renal function and serum potassium should be closely monitored.

Women of childbearing potential: Women of childbearing age should ensure effective contraception. VALGEN acts directly on the RAAS and therefore should not be used in women planning to become pregnant. Healthcare providers prescribing VALGEN should counsel women of childbearing potential about the potential risk during pregnancy.

Pregnancy: When pregnancy is detected, VALGEN should be discontinued as soon as possible. Not to be used in pregnancy as teratogenicity has been shown in experimental animals. Safety in pregnancy and lactation has not been established (see section 4.3). In case of accidental exposure to ARB treatment, appropriate foetal monitoring should be considered. Infants whose mothers have taken VALGEN should be closely observed for hypotension. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan.

Breastfeeding: It is not known whether valsartan is excreted in human milk. Since valsartan was excreted in the milk of lactating rats, mothers taking VALGEN should not breastfeed their infants.

Fertility: There is no information on the effects of VALGEN on human fertility. Valsartan 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 when taking VALGEN.

Tabulated summary of adverse reactions

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Symptoms: Overdose with VALGEN 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 the ingestion is recent, vomiting should be induced if the patient is conscious. If hypotension occurs, the patient should be placed in a supine position and blood volume correction should be undertaken. Otherwise, the usual treatment would be intravenous infusion of normal saline. VALGEN is unlikely to be removed by haemodialysis.