Greta Staubly 

The combination medication sacubitril and valsartan (Entresto) is indicated for use in adult patients with 

 (HF) to reduce the risk of hospitalization and death related to cardiovascular complications. In pediatric patients 1 year of age or older, sacubitril/valsartan treats symptomatic HF with systolic left ventricular systolic dysfunction.

In both populations, sacubitril/valsartan reduces negative cardiovascular outcomes. The 

Sacubitril/valsartan is an angiotensin receptor neprilysin inhibitor (ARNI). Sacubitril prevents breakdown of natriuretic peptides by blocking neprilysin.

 Valsartan is an angiotensin receptor blocker (ARB), halting the function of the renin-angiotensin-aldosterone-system.

Neprilysin breaks down angiotensin II, which is why sacubitril is formulated with an ARB to block the buildup of excess angiotensin II.

The PARADIGM-HF trial reported that sacubitril/valsartan significantly reduced mortality and hospitalization in HF patients with a reduced ejection fraction.

 Sacubitril/valsartan therapy reduced cardiovascular hospitalization rates and mortality by 20% and prolonged survival by approximately 1-2 years in patients who had HF with reduced ejection fraction compared with enalapril.

Upon the study’s publication, the American College of Cardiology, American Heart Association, and the Heart Failure Association of America updated their guidelines. Sacubitril/valsartan further reduces morbidity and mortality in patients with the above indications.

Several ongoing trials are investigating sacubitril/valsartan in other cardiovascular and non-cardiovascular conditions. The trials are examining sacubitril/valsartan’s efficacy in advanced HF, arrhythmias, chronic kidney disease, diabetes mellitus, end-stage renal disease, and hypertension.

One study that is examining the effects on chemotherapy-induced left ventricular dysfunction will have results in September 2025.

Sacubitril/valsartan is available in 3 different strength combinations: sacubitril 24 mg/valsartan 26 mg, sacubitril 49 mg/valsartan 51 mg, and sacubitril 97 mg/valsartan 103 mg.

The starting dose for patients on low dose angiotensin-converting enzyme (ACE) inhibitors (ACEIs) or ARBs or not previously on ACEI or ARB is sacubitril 24 mg/valsartan 26 mg twice daily. Patients should discontinue their previous ACE inhibitor or ARB when transitioning to this drug.

For patients on moderate- to high-dose ACEIs or ARBs, the starting dose is sacubitril 49 mg/valsartan 51 mg twice daily. In both instances, patients should double their dose every 2-4 weeks as tolerated, with a maximum dose of sacubitril 97 mg/valsartan 103 mg twice daily.

For patients with moderate hepatic impairment or an eGFR less than 30 mL/minute, the starting dose should be sacubitril 24 mg/valsartan 26 mg twice daily. Patients with severe hepatic impairment should not take sacubitril/valsartan.

 for full pediatric dosing information. Pharmacists should provide oral suspensions to pediatric patients less than 40 kg or those unable to swallow tablets. Sacubitril/valsartan oral suspension 800 mg/200 mL (1.96/2.06 mg/mL) can be prepared using eight tablets of 49/51 mg tablets. See the package insert for full preparation instructions.

Adverse reactions to sacubitril/valsartan include cough, dizziness, hyperkalemia, hypotension, and renal failure.

Patients with hypersensitivity to any ingredients of sacubitril/valsartan should not use this drug. Pharmacists should counsel patients to not use sacubitril/valsartan concomitantly with ACE inhibitors or history of angioedema related to previous ARB or ACE inhibitor use.

If switching from an ACE inhibitor to sacubitril/valsartan, patients must allow 36 hours before starting sacubitril/valsartan. In patients with diabetes, concomitant use of aliskiren is contraindicated.

At each visit, pharmacists should observe patients for signs and symptoms of angioedema and hypotension. In susceptible patients, providers should monitor renal function and potassium levels while on this medication.

Sacubitril/valsartan can cause fetal harm when administered to pregnant women.

 Pregnant patients must discontinue sacubitril/valsartan as soon as possible.

Use of this medication, especially in the second and third trimesters of pregnancy, will affect the fetal renal function which can lead to renal failure, skeletal deformations, and/or death. However, if the medication is lifesaving for the mother, advise the patient of the potential risk to the fetus.

Pharmacists should counsel patients to not breastfeed during treatment with sacubitril/valsartan due to the potential presence in breast milk.

Greta Staubly is a 2024 PharmD candidate at the University of Connecticut.

Highlights of Prescribing Information: Entresto

. Novartis United States of America. Retrieved April 29, 2022, from https://www.novartis.us/

Diala, N., Kerndt, C. C., & Reed, M. (2021, July 26). 

. National Library of Medicine. Retrieved April 30, 2022, from https://www.ncbi.nlm.nih.gov/books/NBK507904/

Mann, D. L., Greene, S. J., Givertz, M. M., et. al. (2020). SACUBITRIL/Valsartan in advanced heart failure with reduced ejection fraction. 

https://doi.org/10.1016/j.jchf.2020.05.005

Hubers, S. A., & Brown, N. J. (2016). Combined angiotensin receptor antagonism and NEPRILYSIN inhibition. 

(11), 1115–1124. https://doi.org/10.1161/circulationaha.115.018622

Badreldin, H.A.; Aldosari, N.; Alnashwan, L.; Almutairi, T.; Yousif, N.; Alsulaiman, K.; Aljuhani, O.; Hafiz, A.; Alshaya, O. What the near Future Holds for Sacubitril/ Valsartan: A Summary of Major Ongoing Studies. 

,54. https://doi.org/ 10.3390/jcdd9020054

Articles

Sacubitril/valsartan (Entresto)reduces the risk of hospitalization and death related to cardiovascular complications in patients with heart failure.

Clinical Overview: Sacubitril/Valsartan (Entresto) for Chronic Heart Failure

The FDA has authorized the use of Evusheld for pre-exposure prophylaxis for prevention of 

 under an Emergency Use Authorization (EUA).

Tixagevimab co-packaged with cilgavimab (Evusheld) is a SARS-CoV-2 spike protein-directed attachment inhibitor. 

The EUA does not allow tixagevimab/cilgavimab to treat COVID-19 or for post-exposure prophylaxis of COVID-19.

Adults and children 12 years of age or older who weigh at least 40 kg may receive tixagevimab/cilgavimab. Individuals must not have COVID-19 or have been in contact with an individual with COVID-19. They must be moderately to severely immunocompromised with an inadequate immune response to COVID-19 vaccination or unable to complete their vaccination series due to a severe adverse reaction to a COVID-19 vaccine or any components.

Tixagevimab/cilgavimab is not a substitute for any COVID-19 vaccinations in unvaccinated individuals who are able to receive and respond appropriately to COVID-19 vaccination.

The phase 3 trial, PROVENT, supports the EUA. PROVENT is a randomized (2:1), double-blind, placebo controlled clinical trial studying tixagevimab/cilgavimab’s efficacy for pre-exposure prophylaxis of COVID-19.

All subjects selected had at least 1 elevated risk factor for COVID-19, including age (over 60 years), comorbidities, or residential or occupational status. Of the 3441 patients given 150 mg of tixagevimab plus 150 mg cilgavimab, only 8 (0.2%) developed symptomatic COVID-19. Seventeen (1.0%) of the 1731 patients administered placebo developed symptomatic COVID-19. The results show a relative risk reduction of 77%.

Detailed results from the pre-exposure prophylaxis trial showed that the treatment reduced the risk of developing symptomatic COVID-19 by 77% in the primary analysis and by 83% in the 6-month follow-up analysis, versus placebo. There were no cases of severe disease or COVID-19 related deaths in the tixagevimab/cilgavimab group through the 6-month follow-up.

Tixagevimab and cilgavimab are both human immunoglobulin G1 (IgG1k) monoclonal antibodies. The antibodies are produced in Chinese hamster ovary cells via recombinant DNA technology.

In combination, tixagevimab and cilgavimab bind to the receptor binding domain of spike protein and block its interaction with human ACE2 (the SARS-CoV-2 receptor), which prevents virus attachment to the receptor.

Tixagevimab/cilgavimab consists of 2 separate consecutive intramuscular injections of 300 mg of tixagevimab and 300 mg of cilgavimab. Currently, there are no recommendations to repeat dosages. A qualified health care provider must prepare and administer both injections, and monitor the patient for at least an hour after injections.

The provider must inspect the vials to ensure proper color and absence of particulates before withdrawal. The solutions are colorless to slightly yellow and clear to opalescent, and must not be shaken.

Tixagevimab and cilgavimab are packaged separately in 150 mg/1.5 mL (100 mg/mL) single-dose vials. The injection requires 2 vials of each drug, for a total of 3 mL (300 mg).

Providers must use a separate syringe for each drug. Both products contain no preservatives, so they require immediate administration and must be discarded if they are not administered within 4 hours.

Providers should administer tixagevimab and cilgavimab as 2 separate, consecutive intramuscular injections. The provider should give the injections in different injection sites, preferably 1 in each gluteal muscle to account for the appropriate volume of 3 mL per injection.

A health care professional must monitor the patient for at least 1 hour after the injections. Patients who have received a COVID-19 vaccination must wait at least 2 weeks before they can receive tixagevimab/cilgavimab.

Some individuals have initially received 150 mg of tixagevimab and 150 mg of cilgavimab from the previously authorized dose. Those patients should receive a second dose of 150 mg tixagevimab and 150 mg cilgavimab as soon as possible. All other individuals should receive an initial dose of 300 mg of tixagevimab and 300 mg of cilgavimab.

The most common AEs include headache, fatigue, and cough. Local injection site reactions including pain, bruising of the skin, and soreness are possible.

A health care professional should monitor the patient for at least an hour after the injections in case of serious hypersensitivity reactions. This includes anaphylaxis, which can occur with IgG1 monoclonal antibody use.

Providers should use caution when administering to patients with thrombocytopenia or other coagulation disorder. They must consider the benefit/risk ratio in patients who are at high risk for cardiovascular AEs, as clinical trials have reported a higher proportion of subjects who experienced cardiovascular AEs.

There are insufficient data to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

 Patients should only use Evusheld during pregnancy if the potential benefit outweighs the potential risk factors. It is unknown whether tixagevimab or cilgavimab are present in breastmilk.

Fact Sheet for Healthcare Providers: Emergency Use Authorization for Evusheld (tixagevimab co-packaged with cilgavimab). AstraZeneca. Accessed March 7, 2022. 

https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2/6d1d5fea-2532-46e9-a1d4-1504f6dd41b2_viewable_rendition__v.pdf

Prevention of SARS-CoV-2 Infection. National Institutes of Health. Accessed March 7, 2022. 

https://www.covid19treatmentguidelines.nih.gov/overview/prevention-of-sars-cov-2/

EVUSHELD™ significantly protected against symptomatic COVID-19 for at least six months in PROVENT Phase III trial in high-risk populations. AstraZeneca. April 20, 2022. 

https://finance.yahoo.com/news/evusheld-significantly-protected-against-symptomatic-221200107.html

Evusheld has been found to significantly reduce the risk of developing symptomatic COVID-19.