Side Effects of Entresto (sacubitril and valsartan)

Entresto (sacubitril and valsartan) is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker (ARB) used to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV). Entresto is combined with other heart failure medications and in place of an ACE inhibitor or other ARBs.

Common side effects of Entresto include

• low blood pressure,
• increased potassium levels,
• cough, and
• dizziness.

Serious side effects of Entresto include

• hives (angioedema),
• kidney failure,
• serious allergic reactions,
• severe low blood pressure,
• reduced number of white blood cells,
• reduced number of platelets,
• hepatitis,
• muscle breakdown, and
• fetal toxicity.

Drug interactions of Entresto include ACE inhibitors, because the combination increases the risk of angioedema and other side effects.

• Combining aliskiren with Entresto increases the risk of kidney failure, high blood potassium, and low blood pressure. Aliskiren should not be combined with Entresto.
• Combining Entresto with potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.
• Increases in blood lithium levels and lithium toxicity have occurred when lithium and ARBs were combined. Blood lithium levels should be monitored if lithium is combined with Entresto.
• Combining Entresto with nonsteroidal anti-inflammatory drugs (NSAIDs) in patients who are elderly, fluid-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure.

Entresto can cause fetal harm when administered to a pregnant woman.

There is no information regarding the presence of sacubitril/valsartan in breast milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for serious adverse reactions in breastfed infants from exposure to Entresto, breastfeeding is not recommended during treatment with Entresto.

The most common side effects of Entresto are:

• Low blood pressure
• Increased potassium levels
• Cough
• Dizziness

Possible serious side effects include:

• Hives (angioedema)
• Kidney failure
• Serious allergic reactions
• Severe low blood pressure
• Reduced number of white blood cells
• Reduced number of platelets
• Hepatitis
• Muscle breakdown
• Fetal toxicity

Clinically significant adverse reactions that appear in other sections of the labeling include:

• Angioedema
• Hypotension
• Impaired Renal Function
• Hyperkalemia

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Heart Failure

• In the PARADIGM-HF trial, subjects were required to complete sequential enalapril and Entresto run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing Entresto and enalapril.
• During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly
  • renal dysfunction (1.7%),
  • hyperkalemia (1.7%) and
  • hypotension (1.4%).
• During the Entresto run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly
  • renal dysfunction (1.8%),
  • hypotension (1.7%) and
  • hyperkalemia (1.3%).
• Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.
• In the double-blind period, safety was evaluated in 4,203 patients treated with Entresto and 4,229 treated with enalapril.
• In PARADIGM-HF, patients randomized to Entresto received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.
• Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of Entresto treated patients and 516 (12.2%) of patients receiving enalapril.
• Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with Entresto in the double-blind period are shown in Table 2.

Table 2: Adverse Reactions Reported in ≥ 5% of Patients Treated with Entresto in the Double-Blind Period

• In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and Entresto run-in periods.
• In the double-blind period, the incidence of angioedema was higher in patients treated with Entresto than enalapril (0.5% and 0.2%, respectively).
• The incidence of angioedema in Black patients was 2.4% with Entresto and 0.5% with enalapril.
• Orthostasis was reported in 2.1% of patients treated with Entresto compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF.
• Falls were reported in 1.9% of patients treated with Entresto compared to 1.3% of patients treated with enalapril.

Pediatric Heart Failure

• The adverse reactions observed in pediatric patients 1 to <18 years old who received treatment with Entresto were consistent with those observed in adult patients.

Laboratory Abnormalities

Hemoglobin and Hematocrit

• Decreases in hemoglobin/hematocrit of > 20% were observed in approximately 5% of both Entresto-and enalapriltreated patients in the double-blind period in PARADIGM-HF.

Serum Creatinine

• Increases in serum creatinine of > 50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the Entresto run-in period.
• During the double-blind period, approximately 16% of both Entresto-and enalapril-treated patients had increases in serum creatinine of > 50%.

Serum Potassium

• Potassium concentrations > 5.5 mEq/L were observed in approximately 4% of patients in both the enalapril and Entresto run-in periods.
• During the double-blind period, approximately 16% of both Entresto-and enalapriltreated patients had potassium concentrations > 5.5 mEq/L.

Postmarketing Experience

The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity including

• rash,
• pruritus, and
• anaphylactic reaction

Dual Blockade Of The Renin-Angiotensin-Aldosterone System

• Concomitant use of Entresto with an ACE inhibitor is contraindicated because of the increased risk of angioedema.
• Avoid use of Entresto with an ARB, because Entresto contains the angiotensin II receptor blocker valsartan.
• The concomitant use of Entresto with aliskiren is contraindicated in patients with diabetes. Avoid use with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

Potassium-Sparing Diuretics

• As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., 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 Entresto may result in worsening of renal function, including possible acute renal failure.
• These effects are usually reversible. Monitor renal function periodically.

Lithium

• Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with Entresto.