Summary of the Safety Profile: The most commonly reported adverse reactions during treatment with Entresto were hypotension, hyperkalaemia and renal impairment (see Precautions). Angioedema was reported in patients treated with Entresto (see Description of Selected Adverse Reactions).
The safety of Entresto in patients with chronic heart failure was evaluated in the pivotal phase 3 study PARADIGM-HF, which compared patients treated twice daily with Entresto 200 mg (n=4,203) or enalapril 10 mg (n=4,229). Patients randomised to the Entresto group received treatment for a median duration of exposure of 24 months; 3,271 patients were treated for more than one year.
In the PARADIGM-HF study, subjects were previously treated with ACE inhibitors and/or ARBs and also had to successfully complete sequential enalapril and Entresto run-in periods (median drug exposure of 15 and 29 days, respectively) prior to the randomised double-blind period. During the enalapril run-in period, 1,102 patients (10.5%) permanently discontinued from the study, 5.6% because of an adverse reaction, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). During the Entresto run-in period, 10.4% of patients permanently discontinued, 5.9% because of an adverse reaction, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%). Due to discontinuations during the run-in period, the adverse reaction rates as presented in table below may be lower than the adverse reaction rates expected in clinical practice.
Discontinuation of therapy due to an adverse reaction in the double-blind period of the PARADIGM-HF study occurred in 450 Entresto-treated patients (10.7%) and 516 enalapril-treated patients (12.2%).
Tabulated List of Adverse Reactions: Adverse reactions are ranked by system organ class and then by frequency with the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 2.)
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Description of Selected Adverse Reactions: Angioedema: Angioedema has been reported in patients treated with Entresto. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with Entresto, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with Entresto (2.4%) and enalapril (0.5%) (see Precautions).
Hyperkalaemia and Serum Potassium: In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/L were reported in 11.6% and 19.7% of Entresto-treated patients and 14.0% and 21.1% of enalapril-treated patients, respectively.
Blood Pressure: In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 4.76% of Entresto-treated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively.
Renal Impairment: In PARADIGM-HF, renal impairment was reported in 10.1% of Entresto-treated patients and 11.5% of enalapril-treated patients.
Reporting of Suspected Adverse Reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.