Sacubitril/ Valsartan

Registered South African indications:

• Symptomatic heart failure (NYHA class I-IV) with systolic dysfunction

Contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy (second and third trimester)
• Severe hepatic impairment
• Biliary cirrhosis
• Cholestasis
• Known history of angioedema related to previous angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy
• Hereditary or idiopathic angioedema
• Coadministration with angiotensin-converting enzyme inhibitors, or within 36hrs of their use
• Coadministration with aliskiren-containing medicinal products in patients with diabetes mellitus or in patients with renal impairment (eGFR <60ml/min/1.73m²)

Cautions

• Pregnancy (first trimester)
• Breastfeeding
• Moderate to severe renal impairment
• Moderate hepatic impairment (Child-Pugh Classes B & C)
• Elderly
• Salt and/or volume depletion
  - Diuretic therapy
  - Dietary salt restriction
  - Diarrhoea
  - Vomiting
  - Dehydration 
• Systolic blood pressure of <100mmHg
• Serum potassium level >5.4 mmol/l
• Risk factors for hypokalaemia
  - Diabetes mellitus
  - Hypoaldosteronism
  - High potassium diet
  - Coadministration with mineralocorticoid antagonists
• Black patients
• Bilateral or unilateral renal artery stenosis
• NYHA functional classification IV
• Coadministration with non-steroidal anti-inflammatory agents
• Coadministration with other angiotensin receptor blocker agents
• May impair the ability to drive or operate machinery

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

Symptomatic chronic heart failure with reduced ejection fraction

Sacubitril/ Valsartan
24/26 (mg) - 50mg tab
49/51 (mg) - 100mg tab
97/103 (mg) - 200mg tab

• Oral (tab): Initial: 100mg tab, 12hrly; Titrate by doubling dose at intervals of 2-4 weeks; Maintenance: 200mg tab, 12hrly

Sacubitril/valsartan should not be co-administered with an ACE-inhibitor or an angiotensin receptor blocker. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, it must not be started for at least 36 hours after discontinuing ACE-inhibitor therapy

For patients previously taking low dose ACE-inhibitor or angiotensin receptor blocker, initiate with 50mg tab, 12hrly and slow dose titration (doubling every 3-4 weeks) is recommended

If patients experience tolerability issues (systolic blood pressure ≤95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down-titration or discontinuation of sacubitril/valsartan is recommended

Treatment should not be initiated in patients with serum potassium level >5.4mmol/l or with systolic blood pressure <100mmHg. A starting dose of 50mg, 12hrly should be considered for patients with systolic blood pressure ≥100mmHg

The valsartan contained within the sacubitril/valsartan combination is more bioavailable than the valsartan in other marketed tablet formulations

If a dose is missed, the patient should take the next dose at the scheduled time

May be administered with or without food and swallowed with a glass of water

Not established for use in children below 18 years

Pregnancy

• First trimester: Caution; not recommended
  Second the third trimester: Contraindicated
• Sacubitril/valsartan: There are no data from the use of sacubitril/valsartan in pregnant women. Animal studies with sacubitril/valsartan have shown reproductive toxicity
• Valsartan: 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 ARBs, similar risks may exist for this class of medicinal product. Unless continued ARB therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ARBs should be stopped immediately and, if appropriate, alternative therapy should be started. Exposure to ARB therapy 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 ARBs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ARBs should be closely observed for hypotension
• Sacubitril: There are no data from the use of sacubitril in pregnant women. Studies in animals have shown reproductive toxicity

Breastfeeding

• Caution; not recommended
• It is not known whether sacubitril/valsartan is excreted in human milk. The components, sacubitril and valsartan, were excreted in the milk of lactating rats
• Because of the potential risk for adverse reactions in breastfed newborns/infants, it is not recommended during breastfeeding. A decision should be made whether to abstain from breastfeeding or to discontinue sacubitril/valsartan while breastfeeding, taking into account the importance of sacubitril/valsartan to the mother

Fertility

• There are no available data on the effect of sacubitril/valsartan on human fertility. No impairment of fertility was demonstrated in studies with it in male and female rats

Renal Impairment

• Mild (eGFR: 60-90 ml/min/1.73m²): No dose adjustment recommended
• Moderate (eGFR: 30-60 ml/min/1.73m²): Caution; dose adjustment recommended
  Initial dose of 50mg, 12hrly should be considered
• Severe (eGFR: <30 ml/min/1.73m²): Caution; dose adjustment recommended
  Initial dose of 50mg, 12hrly recommended
  There is very limited clinical experience in patients with severe renal impairment
• End stage renal disease: Use not recommended
  There is no experience in patients with end-stage renal disease and use of sacubitril/valsartan is not recommended

Hepatic Impairment

• Mild (Child-Pugh Class A): No dose adjustment recommended
• Moderate (Child-Pugh Class B): Caution; dose adjustment recommended
  Initial dose of 50mg, 12hrly is recommended
  There is limited clinical experience with moderate hepatic impairment or with AST/ALT values more than twice the upper limit of the normal range
• Severe (Child-Pugh Class C): Contraindicated

Elderly

• Caution; No dose adjustment recommended
  The dose should be in line with the renal function of the elderly patient

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders

• Dizziness
• Headache
• Syncope
• Postural dizziness
• Fatigue

Cardiovascular Disorders

• Hypotension
• Orthostatic hypotension

Respiratory Disorders

• Cough

Gastrointestinal Disorders

• Diarrhoea
• Nausea
• Gastritis

Genitourinary Disorders

• Renal impairment
• Renal failure

Endocrine and Metabolic Disorders

• Hyperkalaemia
• Hypokalaemia
• Hypoglycaemia

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Angioedema

Immune, Blood and Lymphatic System Disorders

• Anaemia
• Hypersensitivity

Sensory Disorders

• Vertigo

• Angiotensin-converting enzyme inhibitors
• Aliskiren-containing products
• Angiotensin receptor blockers
• OATP1B1 substrates
• OATP1B3 substrates
• Statins
• Atorvastatin
• Phosphodiesterase type 5 inhibitors
• Sildenafil
• Potassium-sparing diuretics
• Triamterene
• Amiloride
• Mineralocorticoid antagonists
• Spironolactone
• Eplerenone
• Potassium supplements
• Salt substitutes containing potassium
• Heparin
• Non-steroidal anti-inflammatory drugs
• Selective cyclooxygenase-2 (COX-2) inhibitors
• Lithium
• Furosemide
• OATP1B1 inhibitors
• OATP1B3 inhibitors
• OAT3 inhibitors
• Rifampicin
• Ciclosporin
• OAT1 inhibitors
• Tenofovir
• Cidofovir
• MRP2 inhibitors
• Ritonavir
• Metformin 

Other

• B-type natriuretic peptide (BNP) (See additional prescribing points)

• Blood pressure
• Serum potassium
• Renal function

Biomarker interactions

• B-type natriuretic peptide (BNP) is not a suitable biomarker of heart failure in patients treated with sacubitril/valsartan because it is a neprilysin substrate

Sacubitril/valsartan exhibits the mechanism of action of an angiotensin receptor neprilysin inhibitor by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and by blocking the angiotensin II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits of sacubitril/valsartan in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by LBQ657 and the simultaneous inhibition of the effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), which could result in vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release. This prevents sustained activation of the renin-angiotensin-aldosterone system that would result in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodelling.

COMBINATION PREPARATIONS

Sacubitril/ Valsartan

Tablet 24mg/26mg

• Entresto (Novartis) originator
• Vymada (Novartis)

Tablet 49mg/51mg

• Entresto (Novartis) originator
• Vymada (Novartis)

Tablet 97mg/103mg

• Entresto (Novartis) originator
• Vymada (Novartis)