sacubitril/valsartan (Rx)

>10%

Hypotension (18%)

Hyperkalemia (12%)

1-10%

Cough (9%)

Dizziness (6%)

Orthostasis (2.1%)

Falls (1.9%)

<1%

Angioedema, all patients (0.5%); in black patients (2.4%)

Hypersensitivity (rash, pruritus, anaphylaxis)

Contraindications

Hypersensitivity to any component

History of angioedema related to previous ACE inhibitor or ARB therapy

Coadministration of neprilysin inhibitors (eg, sacubitril) with ACE inhibitors may increase angioedema risk; do not administer ACE inhibitors within 36 hr of switching to or from sacubitril/valsartan

Concomitant use with aliskiren in patients with diabetes

Cautions

Can cause fetal harm when administered to a pregnant woman; use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death (see Black Box Warnings)

Not for use in patients with hereditary angioedema; observe for signs and symptoms of angioedema; if angioedema occurs, discontinue drug immediately, provide appropriate therapy, and monitor for airway compromise

Sacubitril/valsartan lowers blood pressure and may cause symptomatic hypotension; patients who are volume-depleted or salt-depleted, or those taking diuretics, are at greater risk

Drug interaction overview

• Dual blockade of the renin-angiotensin-aldosterone system

  • Coadministration with an ACE inhibitor is contraindicated because of the increased risk of angioedema
  • Avoid use with an ARB, because drug contains the angiotensin II receptor blocker valsartan
  • Concomitant use with aliskiren is contraindicated in patients with diabetes

• Potassium-sparing diuretics

  • As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium

• Nonsteroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)

  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with sacubitril/valsartan may result in worsening of renal function, including possible acute renal failure
  • Effects are usually reversible; monitor renal function periodically

• Lithium

  • Increases in serum lithium concentrations and lithium toxicity have been reported during coadministration of lithium with angiotensin II receptor antagonists; monitor serum lithium levels
  • Monitor renal function and potassium levels in susceptible patients (eg, diabetes, hypoaldosteronism, high-potassium diet, renal artery stenosis); dosage reduction or interruption may be required

Pregnancy

Discontinue as soon as pregnancy detected; during the second and third trimesters of pregnancy, resulting oligohydramnios may cause fetal injury (eg, hypotension, neonatal skull hypoplasia, anuria, reversible and irreversible renal failure) and death

Neonates with a history of in utero exposure: Direct attention toward support of blood pressure and renal perfusion; exchange transfusions or dialysis may be required

Animal data

• Treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively)
• Drug is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day
• The adverse embryo-fetal effects are attributed to the angiotensin receptor antagonist activity;
• Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment during organogenesis, gestation, and lactation may affect pup development and survival

Lactation

Unknown if distributed in human breast milk; not recommended

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Combination is an angiotensin receptor-neprilysin inhibitor (ARNi)

Sacubitril: Neprilysin inhibitor; neprilysin is responsible for degradation of atrial and brain natriuretic peptide; the cardiovascular and renal effects of sacubitril’s active metabolite (LBQ657) in heart failure are attributed to the increased levels of peptides that are degraded by neprilysin (eg, natriuretic peptide); administration results in increased natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP

Valsartan: Angiotensin II receptor type I inhibitor; decreases blood pressure and blocks vasoconstrictor and aldosterone-secreting effects of angiotensin II

Absorption

Absolute bioavailability

• Sacubitril: ≥60%
• Valsartan in Entresto is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in Entresto is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively

Steady-state

• Reached in 3 days
• At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold

Peak plasma concentration

• Sacubitril: 0.5 hr
• LBQ657: 2 hr
• Valsartan: 1.5 hr

Distribution

Protein bound

• Sacubitril: 94-97%
• LBQ657: 94-97%; LBQ657 crosses the blood-brain barrier to a limited extent (0.28%)
• Valsartan: 94-97%

Vd

• Sacubitril: 103 L
• Valsartan: 75 L

Metabolism

Sacubitril is a prodrug that is metabolized by esterases to the active metabolite LBQ657

LBQ657 is not further metabolized to a significant extent

Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites; a hydroxyl metabolite has been identified in plasma at low concentrations (<10%)

Elimination

Half-life

• Sacubitril: 1.4 hr
• LBQ657: 11.5 hr
• Valsartan: 9.9 hr

Excretion

• Sacubitril: 52-68% (primarily as LBQ657) in urine; 37-48% (primarily as LBQ657) in feces
• Valsartan: 13% in urine; 86% in feces

Oral Suspension Preparation

Oral suspension can be substituted in patients unable to swallow tablets

Prepare an oral suspension in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL)

Transfer eight 49/51-mg tablets into a mortar

Crush tablets into a fine powder using a pestle

Add 60 mL of Ora-Plus into mortar and triturate gently with pestle for 10 min, to form a uniform suspension

Add 140 mL of Ora-Sweet into mortar and triturate with pestle for another 10 min, to form a uniform suspension; resulting in a final concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL)

Transfer entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle

Place a press-in bottle adapter and close the bottle with a child resistant cap

Oral Administration

May take with or without food

Use oral suspension for the following

• Pediatric patients <40 kg
• Pediatric patients 40-50 kg who are not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents
• Pediatric patients 40-50 kg who are renally or hepatically impaired

Storage

Prepared oral suspension

• Store <25ºC (77ºF) for up to 15 days and do not refrigerate
• Shake before each use

Tablets

• Store at controlled room temperature (25ºC [77ºF]), with excursions between 15-30ºC (59-86ºF) permitted
• Protect from moisture
• Store in the original package