Valsartan

Registered South African indications:

• Essential hypertension - mild to moderate
• Post myocardial infarction
• Heart failure

Contraindications

South African recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl<30ml/min)
• Porphyria
• History of angioedema related to previous therapy with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs)
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Aortic valve stenosis
• Mitral valve stenosis
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Coadministration with potassium sparing diuretics such as spironolactone, triamterene and amiloride
• Coadministration with lithium
• Coadministration with aliskiren-containing agents in patients with type 2 diabetes mellitus or renal impairment (GFR<60ml/min/1.73 m²)
• Coadministration with fluoroquinolones in those with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients

Recommendations in other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients
• Second and third trimester of pregnancy
• Severe hepatic impairment
• Biliary cirrhosis
• Cholestasis
• Coadministration with aliskiren-containing agents in patients with diabetes mellitus or renal impairment (GFR<60ml/min/1.73m²)

Cautions

South African recommendations

• Women of childbearing potential
• Severe hepatic impairment (Child-Pugh class C)
• Chronic hepatic disease
• History of hepatic impairment
• Biliary cirrhosis
• Biliary obstructive disorders
• Sodium depleted patients
• Volume depleted patients
• Initiation of therapy in those with heart failure or post myocardial infarction
• Severe heart failure
• History of angioedema
• Coadministration of ACE inhibitors and beta-blockers in heart failure
• Coadministration of agents blocking the renin-angiotensin-aldosterone system (RAAS)
• Coadministration with non-steroidal anti-inflammatory drugs (NSAIDs) in the elderly, volume-depleted or those with compromised renal function
• May impair ability to drive and operate machinery

Recommendations in other jurisdictions

• First trimester of pregnancy
• Breastfeeding
• Renal impairment
  - Adult population: CrCl<10ml/min
  - Paediatric population: CrCl<30ml/min and those undergoing dialysis
  - Patients on dialysis
• Mild to moderate hepatic impairment
  - Without cholestasis
• Sodium depleted patients
• Volume depleted patients
• Bilateral renal artery stenosis
• Renal artery stenosis with single kidney
• Recent kidney transplantation 
• Primary hyperaldosteronism
• Aortic and mitral valve stenosis
• Obstructive hypertrophic cardiomyopathy
• Post myocardial infarction
• Initiation of therapy in those with heart failure
• History of angioedema
• Those whose renal function may depend on the activity of the renin-angiotensin system e.g. patients with severe congestive heart failure
• Coadministration of ACE-inhibitors and angiotensin II receptor blockers in those with diabetic nephropathy 
• Coadministration of agents blocking the renin-angiotensin-aldosterone system (RAAS)
• Coadministration with an ACE inhibitor in recent myocardial infarction
• Coadministration with an ACE-inhibitor and a mineralocorticoid receptor antagonist
• Coadministration with an ACE-inhibitor and a beta-blocker
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

Essential hypertension - mild to moderate (Additional agent(s) may be required)

• Oral (fct, tab): 80-160mg, dly; Titrate up to 320mg, dly in those whose blood pressure is not adequately controlled

---

The antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks

---

Post myocardial infarction (Additional agent(s) may be required)
- To improve survival following a recent (12hrs – 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

• Oral (fct, tab): Initial: 20mg, 12hrly; Titrate up to 40mg, 80mg, and 160mg, 12hrly over the next few weeks; Recommended dose level 2 weeks after initiation: 80mg, 12hrly; Target at 3 months: 160mg, 12hrly, based on the patient’s tolerability; Max: 320mg/24hrs

---

Therapy may be initiated as early as 12 hours after a myocardial infarction

---

Evaluation of post myocardial infarction patients should always include assessment of renal function. If symptomatic hypotension or renal dysfunction occurs, consideration should be given to a dosage reduction

---

Heart failure (Additional agent(s) may be required)
- NYHA class II–IV

• Oral (fct, tab):  Initial: 40mg, 12hrly; Titrate up to 80-160mg, 12hrly to the highest dose tolerated; Max: 320mg/24hrs

---

Evaluation of patients with heart failure should always include assessment of renal function

---

Consideration should be given to reducing the dose of coadministered diuretics

---

Indications and dosages registered in other jurisdictions

Essential hypertension (Additional agent(s) may be required)

• Oral (fct): Initial: 80mg, dly; Titrate up to 160mg, dly, for those whose blood pressure is not adequately controlled; Max: 320mg/24hrs

---

The antihypertensive effect is substantially present within 2 weeks, and maximal effects are attained within 4 weeks

---

Post myocardial infarction (Additional agent(s) may be required)
- In clinically stable adult patients with symptomatic heart failure or asymptomatic left ventricular systolic dysfunction after a recent (12 hours-10 days) myocardial infarction

• Oral (fct):  Initial: 20mg, 12hrly; Titrate up to 40mg, 80mg, and 160mg, 12hrly over the next few weeks; Recommended dose level 2 weeks after initiation: 80mg, 12hrly; Target at 3 months: 160mg, 12hrly, based on the patient’s tolerability; Max: 320mg/24hrs

---

In clinically stable patients, therapy may be initiated as early as 12 hours after a myocardial infarction

---

Valsartan 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

---

If symptomatic hypotension or renal dysfunction occur, consideration should be given to a dosage reduction

---

Heart failure (Additional agent(s) may be required)
- In those with symptomatic heart failure when angiotensin converting enzyme (ACE) inhibitors are not tolerated or in beta-blocker intolerant patients as add-on therapy to ACE-inhibitors when mineralocorticoid receptor antagonists cannot be used

• Oral (fct): Initial: 40mg, 12hrly; Titrate up to 80-160mg, 12hrly at intervals of 2 weeks, to the highest dose tolerated; Max: 320mg/24hrs

---

Valsartan may be administered with other heart failure therapies. However, the triple combination of an ACE-inhibitor, valsartan and a beta-blocker or a potassium-sparing diuretic is not recommended

---

Evaluation of patients with heart failure should always include assessment of renal function

Paed. forms avail. in SA and covered in this monograph: fct, tab

Dosages below include:

• South African registered indications and dosages
• Indications and dosages registered in other jurisdictions

South African registered indications and dosages

• Not established for use in children below 18 years

---

Indications and dosages registered in other jurisdictions

Paediatric hypertension

Younger than 1 year

• Not established for use

Between 1-5 years

• Not recommended for use

Between 6-18 years

• ≥18kg to <35kg: Oral (fct): Initial: 40mg, dly; Titrated to blood pressure response and tolerability; Max: 80mg/24hrs
• ≥35kg to <80kg: Oral (fct): Initial: 80mg, dly; Titrated to blood pressure response and tolerability; Max: 160mg/24hrs
• ≥80kg to ≤160kg: Oral (fct): Initial: 80mg, dly; Titrated to blood pressure response and tolerability; Max: 320mg/24hrs

Paediatric heart failure and recent myocardial infarction

• Not established for use in children below 18 years

---

Renal function and serum potassium should be closely monitored

---

Dose should not exceed 80mg in paediatric patients with mild to moderate hepatic impairment (See Special Populations) 

Pregnancy

South African recommendations

• Contraindicated
• Safety in pregnancy has not been established
• When pregnancy is detected, valsartan should be discontinued as soon as possible
• Not to be used in pregnancy as teratogenicity has been shown in experimental animals
• In case of accidental exposure to angiotensin II receptor antagonist therapy, appropriate foetal monitoring should be considered
• Infants whose mothers have taken valsartan 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
• Valsartan acts directly on the renin-angiotensin-aldosterone system (RAAS) and therefore should not be used in women planning to become pregnant. Healthcare professionals prescribing valsartan should counsel women of childbearing potential about the potential risk during pregnancy
• Women of childbearing age should ensure adequate contraception

Recommendations in other jurisdictions

• First trimester: Caution; not recommended
• Second and third trimester: Contraindicated
• 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
• 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 agents
• AIIRAs therapy exposure during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). 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

Breastfeeding

South African recommendations

• Contraindicated
• Safety in breastfeeding has not been established
• It is not known whether valsartan is excreted in human milk
• Since valsartan was excreted in the milk of lactating rats, mothers taking valsartan should not breastfeed their infants

Recommendations in other jurisdictions

• Caution; not recommended
• Because no information is available regarding the use of valsartan during breastfeeding, valsartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or preterm infant

Fertility

South African recommendations

• There is no information on the effects of valsartan on human fertility
• Studies in rats did not show any effects of valsartan on fertility
• Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200mg/kg/day, approximately 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320mg/day and a 60kg patient)

Recommendations in other jurisdictions

• Valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200mg/kg/day. This dose is 6 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320mg/day and a 60kg patient)

Renal Impairment

South African recommendations

• Mild to moderate (CrCl≥30-≤90ml/min): No dose adjustment recommended 
• Severe (CrCl<30ml/min): Contraindicated 
  No studies have been performed in patients undergoing dialysis. However, valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing agents: Contraindicated 

Recommendations in other jurisdictions

Adult population

• CrCl≥10ml/min: No dose adjustment recommended 
• CrCl<10ml/min and in those undergoing dialysis: Caution; no information available 
  Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated

Paediatric population (Between 6-18 years)

• CrCl>30ml/min: No dose adjustment recommended
• CrCl<30ml/min and those undergoing dialysis: Caution; not recommended
  Valsartan is highly bound to plasma protein and is unlikely to be removed by dialysis
• GFR<60ml/min/1.73m² and coadministration of aliskiren-containing products: Contraindicated 

Hepatic Impairment

South African recommendations

• Mild to moderate (Child-Pugh class A and B): No dose adjustment recommended 
• Severe (Child-Pugh class C) or chronic hepatic disease: Caution, no dose adjustment recommended 
  Caution should be exercised in biliary obstructive disorders and a lower dose should be considered with a history of hepatic impairment

Recommendations in other jurisdictions

• Mild to moderate (without cholestasis): Caution; dose adjustment recommended
  Max: 80mg/24hrs 
• Severe: Contraindicated 
• Biliary cirrhosis and in patients with cholestasis: Contraindicated 

Elderly

• No dose adjustment recommended
  A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in young subjects; however, this has not been shown to have any clinical significance

Porphyria Information

South African recommendations

• Contraindicated

Recommendations in other jurisdictions

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Fatigue
• Syncope
• Headache
• Dizziness
  - Postural dizziness
• Insomnia

Cardiovascular Disorders

• Cardiac failure
• Hypotension
  - Orthostatic hypotension
• Vasculitis

Respiratory Disorders

• Cough
• Upper respiratory tract infection
  - Pharyngitis
  - Rhinitis
  - Sinusitis

Gastrointestinal Disorders

• Abdominal pain
• Nausea
• Diarrhoea

Hepatobiliary Disorders

• Abnormal liver function tests
• Increased serum bilirubin

Genitourinary Disorders

• Renal failure
  - Renal impairment
  - Acute renal failure
• Elevated serum creatinine
• Increased serum urea
• Decreased libido

Endocrine and Metabolic Disorders

• Hyperkalaemia

Musculoskeletal Disorders

• Myalgia
• Arthralgia
• Back pain

Skin and Subcutaneous Tissue Disorders

• Angioedema
• Rash
• Pruritis
• Bullous dermatitis

Immune, Blood and Lymphatic System Disorders

• Decreased haematocrit
• Decreased haemoglobin
• Neutropenia
• Thrombocytopenia
• Hypersensitivity reactions
  - Serum sickness
• Viral infections
• Oedema

Sensory Disorders

• Vertigo

• Agents that increase serum potassium levels
• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• Amiloride
• Potassium supplements
• Lithium
• Aliskiren
• Agents that act on the renin-angiotensin-aldosterone system
• Angiotensin-converting enzyme inhibitors
• Non-steroidal anti-inflammatory drugs
• Selective cyclooxygenase-2 Inhibitors
• OATP1B1 transporter inhibitors
• Rifampicin
• Ciclosporin
• Hepatic efflux transporter MRP2 inhibitors
• Ritonavir
• Heparin

Other interactions

• Salt substitutes containing potassium

• Blood pressure
• Electrolytes
• Renal function

Method of administration

• Valsartan may be taken independently of a meal and should be administered with water

Valsartan is an orally active, specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the angiotensin 1 (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 valsartan may stimulate the unblocked AT₂ receptor, which appears to counterbalance the effect of the AT₁ receptor. Valsartan does not exhibit any partial agonist activity at the AT₁ receptor and has much greater affinity (about 20 000 fold) for the AT₁ receptor than for the AT₂ receptor. The angiotensin 2 (AT₂) receptor subtype is unrelated to cardiovascular effect. 

Film-coated tablet 40mg 

• Diovan (Novartis) originator
• Valant (Pharmaplan)

Film-coated tablet 80mg

• Adco Valsartan (Adcock Ingram)
• Diovan (Novartis) originator
• Dynaval (Pharma Dynamics)
• Migroben (Novartis)
• Regoval (Pharma Dynamics)
• Tareg (Novartis)
• Valant (Litha Pharma)
• Valheft (Jubilant Pharma)
• Zomevek (Sandoz)

Tablet 80mg

• Diolo (Ranbaxy)
• Valsartan Unicorn (Ranbaxy)
• Vasovan (Unicorn)

Film-coated tablet 160mg 

• Adco Valsartan (Adcock Ingram)
• Diovan (Novartis) originator
• Dynaval (Pharma Dynamics)
• Migroben (Novartis)
• Regoval (Pharma Dynamics)
• Tareg (Novartis)
• Valant (Litha Pharma)
• Valheft (Jubilant Pharma)
• Zomevek (Sandoz)

Tablet 160mg

• Diolo (Ranbaxy)
• Valsartan Unicorn (Ranbaxy)
• Vasovan (Unicorn)

Film-coated tablet

• Diovan (Novartis) originator

Tablet 320mg 

• Regoval 320mg (Pharma Dynamics)

COMBINATION PREPARATIONS

Valsartan/ Hydrochlorothiazide

Tablet 80mg/12.5mg

• Co-Diovan (Novartis)
• Co-Migroben (Adcock)
• Co-Tareg (Novartis)
• Co-Zomevek (Sandoz)
• Diolo Co (Ranbaxy)
• Dynaval Co (Pharma Dynamic) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 160mg/12.5mg

• Co-Diovan Plus (Novartis)
• Co-Migroben (Adcock))
• Co-Tareg (Novartis)
• Co-Zomevek (Sandoz)
• Diolo Co (Ranbaxy)
• Dynaval Co (Pharma Dynamic) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 160mg/25mg

• Co-Diovan Plus (Novartis)
• Co-Migroben (Adcock))
• Co-Tareg Plus (Novartis)
• Co-Zomevek (Sandoz)
• Dynaval Co (Pharma Dynamic) Discontinued: 25/06/2020
• Regoval Co (Pharma Dynamics)

Tablet 320mg/12.5mg 

• Co-Diovan (Novartis) originator

Tablet 320mg/25mg 

• Co-Diovan (Novartis) originator