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Safety in Lactation: Drugs for hypertension

23 September 2020Additional information relating to breastfeeding To be used in conjunction with individual drug entries for specific information and guidance. Many of the drugs covered by…
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Lactation Safety Information

Captopril; Enalapril
(with appropriate infant monitoring)
Sacubitril is a neprilysin inhibitor only available in combination with valsartan and indicated for heart failure
No published evidence of safety for either component
Monitor infants for hypotension
13 January 2017

New Medicines

EntrestoHeart failure with reduced ejection fraction - first-line in children

Information

Entresto
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

None
Phase III Clinical Trials
Launched
Mar 20EU filing planned for 2022 [6].
Oct 19Oct 19: Approved in the US for the treatment symptomatic heart failure with systemic left ventricular systolic dysfunction in paediatric patients 1 to <18 years. The approval was based on an analysis at 12 weeks from the 52-week PANORAMA-HF trial which demonstrated reductions in the cardiac biomarker N-terminal pro-B-type natriuretic peptide (NT-proBNP) [5].

Category

A first-in-class compound comprising a neprilysin inhibitor (sacubitril) with an angiotensin receptor antagonist (valsartan). Sacubitril augments natriuretic peptides. This is not a fixed-dose combination, rather a new molecular entity.
In children, the causes of HF are significantly different from adults and many cases are due to congenital malformations which usually result in high output cardiac failure. Some children suffer from low output cardiac failure such as cardiomyopathy. CHD occurs in around 8 per 1,000 live births. HF associated with congenital heart disease occurs in approximately 20% of all patients [1].
Heart failure with reduced ejection fraction - first-line in children
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Trial or other data

Oct 18PIII PANORAMA-HF study (NCT02678312) still recruiting, with an estimated primary completion date of Apr 2021 [4].
Feb 18PIII study (NCT02678312) still recruiting [3].
Nov 16PII/III trial to assess the safety, tolerability, pharmacokinetics (Part 1) and efficacy (Part 2) of sacubitril/valsartan as compared with enalapril in paediatric patients with heart failure due to systemic left ventricle systolic dysfunction starts (NCT02678312). The open-label, single-dose (Part 1) followed by 52-week, randomised, parallel, double-blind, placebo-controlled (Part 2) trial will enrol approximately 360 patients (aged 1 month to 17 years) in the US, Canada, Italy, Puerto Rico, South Korea, Singapore and Taiwan. Collection of primary outcome is expected to complete Apr 21 [2,3].

EntrestoChronic heart failure with preserved ejection fraction

Information

Entresto
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Phase III Clinical Trials
Phase III Clinical Trials
Launched
Feb 21Approved by the FDA in the US where the licensed indication will be "to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal" [18,19].
Dec 20US FDA Advisory committee vote in favour of approving sacubitril/valsartan as a treatment of patients with heart failure with preserved ejection fraction (HFpEF) [17].
Jun 20Filing accepted in the US. Filing is based primarily on PIII data from the PARAGON-HF trial, [15].
Mar 20Company pipeline updated; filings for CHF with preserved ejection fraction now planned for 2020 [12].
Dec 18Filings will go ahead 2019 [9].
Nov 17Novartis remains on course to file in 2019 [7].
Dec 15PIII. Filings planned 2019 [1].

Category

A first-in-class compound comprising a neprilysin inhibitor (sacubitril) with an angiotensin receptor antagonist (valsartan). Sacubitril augments natriuretic peptides. This is not a fixed-dose combination, rather a new molecular entity.
Chronic heart failure affects 2% of adults in developed nations, and nearly half have preserved ejection fraction [2].
Chronic heart failure with preserved ejection fraction
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Trial or other data

Aug 21Post hoc analysis of the PIII PARAGON-HF trial (n=4,795) found sacubitril/valsartan was more effective than valsartan alone for achieving controlled systolic blood pressure in those with resistant hypertension at study entry (47.9% vs 34.3%, OR 1.78, 95%CI 1.30-2.43).
Nov 20PIII PARAGLIDE-HF study is due to complete collection of primary outcome data in Mar 22 [16].
Sep 20PIII PARAGLIDE-HF (NCT03988634) study to assess the effect of sacubitril/valsartan (LCZ696) vs. valsartan on changes in NT-proBNP and outcomes, safety and tolerability in patients with HFpEF (left ventricular ejection fraction (LVEF) >40%) who have been stabilised during hospitalisation for acute decompensated heart failure and initiated in-hospital or within 30 days post discharge is ongoing [14].
Sep 19PIII PARAGON-HF study (n=4822) is published in the NEJM; it reports that addition of sacubitril to valsartan did not reduce hospitalisations for heart failure and death from cardiovascular causes vs valsartan (rate ratio, 0.87; 95% CI, 0.75 to 1.01; P=0.06) [11].
Jul 19Novartis announce PIII PARAGON-HF study (n=4,822) fails to meet primary endpoint [10].
Dec 18The phase PIII PERSPECTIVE trial (NCT02884206) is still recruiting subjects, with an estimated primary completion date of July 2021. [8]
Jan 18The phase PIII PERSPECTIVE trial (NCT02884206) is still recruiting subjects, with an estimated primary completion date of July 2021. [8]
Nov 16Novartis initiates the PIII PERSPECTIVE trial to assess the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction (NCT02884206). The randomised, double-blind, parallel, placebo-controlled trial will enrol approximately 520 patients in the US and EU [6]
Jul 14Novartis initiates a global PIII trial, which will evaluate safety and efficacy of sacubitril/valsartan, compared with valsartan, in patients with heart failure with preserved ejection fraction (PARAGON-HF; NCT01920711). Enrolment of approximately 4,300 patients in ongoing in the US and Spain, and is expected to expand to Hungary, Italy, the Philippines, Romania, Slovakia and South Africa. Primary outcome is cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations; collection of these data is expected to complete in May 19 [4].
Aug 12PII PARAMOUNT study published early online in the Lancet. 301 pts with NYHA class II—III heart failure were randomised to LCZ696 (200 mg twice daily) or valsartan (160 mg twice daily) and treated for 36 weeks. The primary endpoint was change in NT-proBNP, a marker of left ventricular wall stress, from baseline to 12 weeks and was significantly reduced in the LCZ696 group (LCZ696: baseline, 783 pg/mL [95% CI 670—914], 12 weeks, 605 pg/mL [512—714]; valsartan: baseline, 862 pg/mL [733—1012], 12 weeks, 835 [710—981]; ratio LCZ696/valsartan, 0.77, 95% CI 0.64—0.92, p=0.005). The reduction in NT-proBNP in pts receiving LCZ696 became evident at 4 weeks and appeared to be sustained to 36 weeks, although the between-group difference was no longer significant. LCZ696 had adverse effects similar to those of valsartan; 22 pts (15%) on LCZ696 and 30 (20%) on valsartan had one or more serious adverse event [5].
Dec 11Novartis completes the PII PARAMOUNT trial, which assessed effects of sacubitril/valsartan on N-terminal pro-Brain Natriuretic Peptide, compared with valsartan, in patients with chronic heart failure and preserved left-ventricular ejection fraction (pEF) (NCT00887588; EudraCT2009-010208-27). This 36-week, randomised, double-blind, parallel group study met its primary endpoint [23] . The trial enrolled 301 patients in the US, Europe (Italy, Netherlands, Poland, Romania, Spain), Canada, Argentina, Brazil, Venezuela, Russia, Singapore and India [3].

Evidence based evaluations

EntrestoPost-myocardial infarction, to reduce adverse cardiac outcomes in patients with evidence of LV systolic dysfunction and/or pulmonary congestion.

Information

Entresto
Licence extension / variation
Novartis
Novartis

Development and Regulatory status

Discontinued
Discontinued
Discontinued
May 21Development discontinued. Although the initial results of PARADISE-MI showed beneficial trends in favour of sacubitril/valsartan over ramipril across the primary and secondary endpoints, statistical significance was not met. Given these results, Novartis do not plan to file with regulatory authorities for the post-acute myocardial infarction indication at this time [9].

Category

A first-in-class compound comprising a neprilysin inhibitor (sacubitril) with an angiotensin receptor antagonist (valsartan). Sacubitril augments natriuretic peptides. This is not a fixed-dose combination, rather a new molecular entity.
After acute MI, about 25% of patients will have signs and symptoms of heart failure and about 40% will have some left ventricular systolic dysfunction [2].
Post-myocardial infarction, to reduce adverse cardiac outcomes in patients with evidence of LV systolic dysfunction and/or pulmonary congestion.
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Evidence based evaluations