June 29, 2020
Otsuka Pharmaceutical Co., Ltd.
Novartis Pharma obtains manufacturing and marketing approval in Japan for Entresto® tablet as angiotensin receptor neprilysin inhibitor (ARNI) for chronic heart failure
Otsuka Pharmaceutical Co., Ltd. (Otsuka), announces that Novartis Pharma K.K. (Novartis Pharma) has obtained manufacturing and marketing approval in Japan for Entresto® tablet as an Angiotensin Receptor Neprilysin Inhibitor (ARNI; generic name: Sacubitril Valsartan Sodium Hydrate) for patients undergoing standard treatment for chronic heart failure.
Heart failure is a disease that leads to shortness of breath and swelling as a result of the heart's compromised ability to pump blood, gradually worsening and shortening the patient's life in many cases. Heart failure often progresses chronically and progressively becomes more severe with repeated acute exacerbations.1
Newly approved 'Entresto' suppresses excessive activation of the renin-angiotensin-aldosterone system (RAAS), one of the neurohumoral factors that exacerbate the pathology of heart failure. Additionally, it acts compensatory for RAAS by enhancing the endogenous natriuretic peptide system and correcting imbalanced neurohumoral factors as a single agent. As such, the drug represents a new approach in the treatment of chronic heart failure.
Entresto was compared to enalapril, an angiotensin converting enzyme (ACE) inhibitor, in an overseas phase-III PARADIGM-HF trial involving heart failure (HFrEF) patients suffering from decreased left-ventricular ejection fraction. The trial demonstrated a significant 20% reduction in the combined risks of hospitalization for cardiovascular death and heart failure2. Entresto is the first drug to show a statistically significant improvement over enalapril in terms of life prognosis. Based on the successful results of this trial in overseas, a domestic phase-III PARALLEL-HF trial was conducted with HFrEF patients in Japan. Manufacturing and marketing approval was granted in Japan based mainly on the results of these two trials.
Although the primary goals of heart-failure treatment are to improve life prognosis, prevent/reduce hospitalization, control medical condition and improve quality of life, nevertheless, mortality and hospitalization rates for heart failure remain high, even in cases of treatment based on currently recommended guidelines.3,4 Accordingly, a therapeutic method using a new mechanism of action, different from conventional heart failure therapeutic agents, has been sought.1
Novartis Pharma and Otsuka Pharmaceutical Co., Ltd. will jointly provide information on Entresto to medical professionals in Japan.
Entresto is a single crystal complex containingsacubitril, which is a neprilysin inhibitor, and valsartan, which is an angiotensin receptor blocker (ARB), as active ingredients in a molar ratio of 1:1. It reduces the strain on the failing heart by enhancing the protective neurohormonal systems (natriuretic peptide system) while simultaneously inhibiting the harmful effects of the overactive renin-angiotensin-aldosterone system (RAAS) . Other common heart failure medicines, called angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), only block the harmful effects of the overactive RAAS. Entresto has been approved in more than 100 countries worldwide. In the United States, Entresto is indicated for the treatment of heart failure (New York Heart Association class II-IV) in patients with systolic dysfunction. In Europe, Entresto is indicated in adult patients for the treatment of symptomatic chronic heart failure with reduced ejection fraction.
About heart failure
Under Japan's guidelines for treating acute and chronic heart failure, the disease is defined as a type of cardiac dysfunction, namely, an organic and/or functional abnormality of the heart, resulting in failure of the compensatory mechanism of the cardiac pump function and leading to dyspnea, malaise and/or edema and an accompanying decrease in exercise tolerance. It is a clinical syndrome.1
Although there are various criteria for classifying heart failure, left ventricular dysfunction is often involved in the pathophysiology of heart failure. The classification based on left ventricular contractility is often used in clinical practice guidelines.1 Left ventricular contractility has classifications according to left ventricular ejection fraction (LVEF), of which the main two are LVEF-decreased heart failure (HFrEF, defined as LVEF <40%), and LVEF-maintained heart failure (HfpEF, defined as LVEF 50% or more).
- The Japanese Circulation Society/Japanese Heart Failure Association Joint Guidelines: Acute and Chronic Heart Failure Clinical Practice Guidelines (revised 2017)
- 2JJ McMurray, M Packer, AS Desai, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. New England Journal of Medicine: 2014, 371: 993-1004.
- 3Ministry of Health, Labor and Welfare (2017), Table 7. Number of Deaths and Mortality by Gender by Simple Classification of Causes of Death (in Population 100,000): p. 16.
- 4Japanese Circulation Society. Cardiovascular disease medical condition survey report (implemented/announced in FY2016)
Entresto® Tablet 50mg, Entresto® Tablet 100mg, Entresto® Tablet 200mg
SacubitrilValsartan Sodium Hydrate
|Efficacy or effect*||
Chronic heart failure, but only in patients undergoing standard treatment for chronic heart failure
|Usage and dose*||
The usual adult dosage is 50 mg of sacubitril valsartan, starting at 50 mg orally twice daily. If tolerated, the dose should be increased stepwise to 200 mg every 2 to 4 weeks. The single dose is 50 mg, 100 mg or 200 mg, administered orally twice a day. The dose should be reduced according to tolerability.
|Date of approval in Japan||
June 29, 2020
|Manufacturing and sales||
Novartis Pharma K.K.
- Please see the package insert for precautions related to efficacy or effect and precautions related to dosage and administration.
Information in this news release was current as of the original release date.