Date of approval.
Date of revision.
Sacubitril sodium valsartan tablets instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name]
Generic name: Sacubitril valsartan sodium tablets
Trade name: Entresto® (Entresto®)
English name: Sacubitril Valsartan Sodium Tablets
Hanyu Pinyin: Shakubaqu Xieshatan Na Pian
Ingredients
The active ingredient: Shakubaqu Valsartan Sodium
Chemical name: sodium octadecanoate
Hexa(4-{[(1S,3R)-1-([1,1′-biphenyl)-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoic acid) Hexa(N-pentanoyl-N-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-L-valine)-water (1/15)
Chemical structure formula.
Molecular formula: C24H28NNaO5・C24H27N5Na2O3・2½ H2O
Molecular weight: 957.99
【Properties】.
This product is a purple-white oval film-coated tablet with “LZ” engraved on one side and “NVR” engraved on the other side (50mg specification), or a light yellow oval film-coated tablet with “L1” engraved on one side and “NVR” engraved on the other side (100mg specification), or a light pink oval film-coated tablet with “L11” engraved on one side and “NVR” engraved on the other side. The word “L11” is engraved on one side and the word “NVR” is engraved on the other side (200mg specification).
Indications
For adult patients with chronic heart failure (NYHA class II-IV, LVEF ≤40%) with reduced ejection fraction, to reduce the risk of cardiovascular death and hospitalization for heart failure.
Sacubitril sodium valsartan tablets can be used in place of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonists (ARB) in combination with other heart failure therapeutic agents (e.g., beta-blockers, diuretics, and salt corticosteroid antagonists).
【Specifications】.
In terms of sakubatril valsartan: (1) 50mg (sakubatril 24mg/valsartan 26mg).
(2) 100mg (sacubitril 49mg/valsartan 51mg).
(3) 200mg (Shakubatra 97mg/valsartan 103mg).
【Dosage】.
This product can be taken with food or on an empty stomach (see [Pharmacokinetics]).
The combination of this product with ACEI is prohibited due to the potential risk of angioedema when combined with ACE inhibitors. If switching from ACEI to this product, it must not be started until at least 36 hours after discontinuation of ACE inhibitor therapy (see [Contraindications]).
The recommended starting dose of this product is 100 mg twice daily. In patients not currently taking an ACEI or angiotensin II receptor antagonist (ARB) or in patients with limited experience with low doses of these agents, a starting dose of 50 mg twice daily is recommended. Depending on patient tolerance, the dose should be doubled every 2 to 4 weeks until a target maintenance dose of 200 mg twice daily is achieved.
It should not be started in patients with potassium levels >5.4 mmol/l. It should be started with caution in patients with SBP <100 mmHg, and blood pressure should be monitored for changes. For patients with 100 mmHg ≤ SBP to 110 mmHg, a starting dose of 50 mg twice daily should be considered.
If patients develop intolerance to this product (systolic blood pressure ≤95 mmHg, symptomatic hypotension, hyperkalemia, renal impairment), it is recommended to adjust the combination, temporarily reduce the dose or discontinue the product (see [Precautions]).
This product has antagonistic activity at the angiotensin II receptor and should not be used in combination with ARB (see [Precautions] and [Drug Interactions]).
Special Populations
Patients with renal impairment.
Patients with mild renal impairment (eGFR 60-90 mL/min/1.73 m2) do not require starting dose adjustment.
Patients with moderate renal impairment (eGFR 30-60 mL/min/1.73 m2) should consider a starting dose of 50 mg twice daily. Because of the very limited experience with dosing in patients with severe renal impairment (eGFR <30 ml/min/1.73 m2), this product should be used with caution in these patients and the recommended starting dose is 50 mg twice daily.
There is no experience with this product in patients with end-stage renal disease and therefore it is not recommended for use in such patients.
Hepatic Impairment.
Patients with mild hepatic impairment (Child-Pugh Class A) do not require an adjustment to the starting dose.
The recommended starting dose for patients with moderate hepatic impairment (Child-Pugh Class B) is 50 mg twice daily. The dose may be multiplied every 2-4 weeks until the target maintenance dose of 200 mg twice daily is reached, as tolerated by the patient.
This product is not recommended for patients with severe hepatic impairment (Child-Pugh Class C) (see [Pharmacology and Toxicology]).
Geriatric patients (65 years of age or older).
No dose adjustment is required for patients over 65 years of age.
Adverse reactions]
This product may cause the following clinically significant adverse reactions: angioedema, hypotension, renal impairment, hyperkalemia, see Precautions for details.
Clinical trial experience.
Because clinical trials are conducted under different conditions, the incidence of adverse reactions observed in clinical trials for one drug cannot be directly compared with the incidence of adverse reactions observed in other clinical trials for another drug, and the incidence of adverse reactions observed in clinical trials for this drug may not reflect the incidence observed in actual application.
In trial PARADIGM-HF, subjects were asked to complete a sequential 15-day and 29-day (median) introductory phase of enalapril and enalapril, respectively, before entering a randomized, double-blind phase comparing sakubatril valsartan sodium tablets (nocinto) to enalapril. The study was permanently terminated in 1102 patients (10.5%) during the enalapril introductory phase, 5.6% due to adverse events, most commonly renal impairment (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). An additional 10.4% of patients permanently discontinued treatment during the introductory period of Nocinta, 5.9% due to adverse events, most commonly renal impairment (1.8%), hypotension (1.7%), and hyperkalemia (1.3%). As a result of this introductory phase design, the incidence of adverse reactions described below was lower than expected in actual application.
The double-blind phase evaluated the safety of 4203 nociceptor-treated patients and 4229 enalapril-treated patients. in the PARADIGM-HF study, patients randomized to the nociceptor group received treatment for up to 4.3 years with a median exposure duration of 24 months; 3271 patients received treatment for more than one year. 450 (10.7%) nociceptor-treated patients, 516 (12.2%) enalapril-treated patients discontinued treatment in the double-blind phase due to adverse events.
The adverse events that occurred in ≥5% of nociceptor-treated patients in the double-blind phase are shown in Table 1.
Table 1. Adverse reactions reported in ≥5% of nociceptor-treated patients in the double-blind phase
Norcindol
(n = 4,203)
% Enalapril
(n = 4,229)
% hypotension 1812 hyperkalemia 1214 cough 913 dizziness 65 renal failure/acute renal failure 55
In the trial PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril introduction phase and the nocinto introduction phase. In the double-blind phase, the incidence of angioedema was higher in nocinto-treated patients than in enalapril-treated patients (0.5% and 0.2%, respectively). The incidence of angioedema was 2.4% in nociceptor-treated black patients and 0.5% in enalapril-treated black patients (see [Caution]).
In the double-blind phase of the PARADIGM-HF study, the incidence of Orthostasis was 1.1% and 2.1% in the enalapril and nocinto groups, respectively. Falls were reported in 1.9% of nocinto-treated patients compared to enalapril-treated patients (1.3%).
Laboratory abnormalities.
Hemoglobin and erythrocyte pressure
During the double-blind phase of the PARADIGM-HF study, a decrease in hemoglobin/erythrocyte pressure product of >20% was observed in approximately 5% of treated patients in both the nocinto and enalapril groups.
Serum creatinine
Elevated serum creatinine was observed in 1.4% of patients during the enalapril introduction phase and 2.2% of patients during the nocinto introduction phase >50%. During the double-blind treatment phase, serum creatinine was elevated in approximately 16% of patients in both the nociceptor and enalapril groups>50%.
Serum potassium
Potassium concentrations >5.5 mEq/L were observed in approximately 4% of patients during the introductory phase of both enalapril and nocintaur. In the double-blind treatment phase, potassium concentrations >5.5 mEq/L were observed in approximately 16% of patients in both the nocintaur and enalapril groups.
[Contraindications].
Contraindicated in patients with hypersensitivity to the active ingredients of this product (sakubatril, valsartan) or any excipients.
Combination with ACEI is prohibited (see [Precautions], [Dosage] and [Drug Interactions]). This product must be taken only 36 hours after discontinuation of ACEI therapy.
Contraindicated in patients with a prior history of angioedema associated with ACEI or ARB therapy.
Contraindicated in patients with hereditary or idiopathic angioedema.
Combination of nocicept with aliskiren is contraindicated in patients with type 2 diabetes mellitus (see [Precautions] and [Drug Interactions]).
Contraindicated in severe hepatic impairment, biliary cirrhosis and cholestasis.
Contraindicated in patients with mid- and late-term pregnancy (see [Pregnancy and Lactation]).
[Precautions].
Warning: Embryotoxicity
The application of this product in pregnant women may cause fetal damage. Application of drugs acting on the renin-angiotensin system in mid- and late-pregnancy may decrease fetal renal function and increase fetal and neonatal morbidity and mortality. Alternative drug therapy and discontinuation of this product should be considered when pregnancy is detected. However, if no suitable alternative therapy (substitution of drugs affecting the renin-angiotensin system) is available and the product is thought to save the mother’s life, inform the pregnant woman of the potential risk of the product to the fetus.
Angioedema.
Nocinto may cause angioedema. In the double-blind phase of the study PARADIGM-HF, angioedema occurred in 0.5% of Norcindol-treated patients and 0.2% of enalapril-treated patients (see [ADVERSE REACTIONS]). If angioedema occurs, discontinue Norcintol immediately, administer appropriate therapy and monitor for airway involvement. Reapplication of Nocinto is prohibited. Confirmed cases of angioedema confined to the face and lips generally resolve without treatment, although antihistamines may help.
Angioedema with laryngeal edema may be fatal. If the edema involves the tongue, vocal cords, or larynx, it may lead to airway obstruction, and appropriate treatment, such as subcutaneous epinephrine solution 1:1000 (0.3 mL-0.5 mL) and the necessary measures to ensure the patient’s airway is open, is given.
The incidence of angioedema was higher in blacks than in non-blacks when Nocinto was administered.
Patients with a prior history of angioedema may be at increased risk of angioedema with nocinto (see [ADVERSE REACTIONS]). Patients with a known prior history of angioedema associated with ACEI or ARB therapy should not use nocinto (see [Contraindications]).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS).
Due to the risk of angioedema, nocinto should not be combined with ACEI. Norcindol must be started 36 hours after the last dose of ACEI. If Norcindol therapy is discontinued, ACEI must not be started until 36 hours after the last dose of Norcindol (see [Contraindications], [Dosage] and [Drug Interactions]).
Caution should be exercised when combining Norcindol with direct renin inhibitors (e.g., aliskiren) (see [Contraindications] and [Drug Interactions]). Combination of nocicept with aliskiren is contraindicated in patients with type 2 diabetes (see [Contraindications]).
Norcindol should not be used in combination with ARB because of its antagonistic activity on angiotensin II receptors (see [DOSAGE AND ADMINISTRATION] and [DRUG INTERACTIONS]).
Hypotension.
Norcindol may lower blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system (e.g., patients with hypovolemia or electrolyte deficiencies, such as those receiving high doses of diuretics) are at greater risk. In the double-blind phase of the study PARADIGM-HF, hypotensive adverse events were reported in 18% of nociceptor-treated patients and 12% of enalapril-treated patients (see [Adverse Reactions]), and severe adverse events of hypotension were reported in approximately 1.5% of patients in both treatment groups. Hypovolemia or electrolyte deficiencies should be corrected prior to administration of nociceptor or initiated at a lower dose. If hypotension occurs, consider adjusting the dose of diuretics, co-administered antihypertensives, and treating other causes of hypotension (e.g., hypovolemia). If hypotension persists despite these measures, reduce the dose of Nocinto or discontinue it temporarily. Permanent discontinuation of therapy is usually not required.
Renal impairment.
Due to inhibition of the renin-angiotensin-aldosterone system (RAAS), hyperalgesia may occur in susceptible individuals treated with nociceptor as expected. In the double-blind phase of the PARADIGM-HF study, adverse events of renal failure were reported in 5% of patients in both the nociceptor and enalapril groups (see [Adverse Reactions]). In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACEI and ARB can be associated with oliguria, progressive azotemia, rare acute renal failure, and death. If a patient develops clinically significant renal decompensation, closely monitor serum creatinine and reduce the dose of nociceptor or suspend its administration (see [Dosage and Administration] – Special Populations and [Pharmacokinetics]).
As with other drugs affecting the renin-angiotensin-aldosterone system, nociceptor may cause elevated blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Patients with renal artery stenosis need to use Nocinto with caution and renal function monitoring is recommended.
Hyperkalemia.
Hyperkalemia may occur with nociceptor treatment by acting on the RAAS. In the double-blind phase of the PARADIGM-HF study, hyperkalemia was reported in 12% of nociceptor-treated patients and 14% of enalapril-treated patients (see [ADVERSE REACTIONS]). Regular monitoring of serum potassium levels and appropriate therapy is required, especially in patients with risk factors for hyperkalemia (e.g., severe renal impairment, diabetes mellitus, hypoaldosteronism, or being on a high-potassium diet), which may require a reduction in the dose of nociceptor or suspension of dosing (see [Dosage]).
NYHA functional class IV patients.
Due to limited clinical experience in patients with NYHA functional class IV, caution should be exercised when starting nocinto therapy in such patients.
B-type natriuretic peptide (BNP).
B-type natriuretic peptide (BNP) is a substrate for enkephalinase. B-type natriuretic peptide (BNP) is not an appropriate biomarker for heart failure in patients treated with nociceptor.
Patients with hepatic impairment.
There is limited clinical experience with dosing in patients with moderate hepatic impairment (Child-Pugh Class B) or AST/ALT values greater than twice the upper limit of normal. In these patients, exposure may be elevated and a safety profile has not been established. Therefore, caution is advised in the use of this product in such patients. This product is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh Class C).
[For Pregnant and Lactating Women].
Pregnancy.
Animal Data.
During organogenesis, rats were administered doses ≥ sakubatril valsartan 100 mg/kg/day (as AUC, ≤ 0.14 times the maximum recommended human dose [MRHD] 200 mg twice daily [LBQ657, active metabolite] and 1.5 times [valsartan]) and rabbits were administered doses ≥ sakubatril valsartan 10 mg/kg daily (as valsartan and LBQ657 AUC, 4 and 0.06 times the MRHD, respectively), nocinto caused an increase in embryo-fetal lethality. Based on the low incidence of fetal hydrocephalus associated with maternal toxic doses observed with rabbit administration of nocinto at doses ≥ 10 mg/kg/day of sakubatril valsartan, nocinto was considered teratogenic. The adverse effects of nocinto on embryo-fetuses were attributed to its angiotensin receptor antagonist activity.
Pre- and postnatal developmental studies in rats (application of sacubitril at doses up to 750 mg/kg/day (4.5 times MRHD at LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86 times MRHD at AUC)) showed that the application of sacubitril valsartan during organogenesis, gestation and lactation may affect the development and survival of the pups .
Risk summary.
The application of nocinto in pregnant women may cause fetal damage. Application of drugs acting on the renin-angiotensin system during mid- and late pregnancy may reduce fetal renal function and increase fetal and neonatal morbidity and mortality. Most epidemiological studies (assessing fetal abnormalities following the application of antihypertensive drugs in early pregnancy) have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive drugs. In animal reproduction studies, application of nocinto during organogenesis in rats and rabbits resulted in increased embryo-fetal lethality and was teratogenic in rabbits. When pregnancy is detected, discontinuation of nocinto and switching to alternative drug therapy should be considered. However, if appropriate alternative drug therapy acting on the renin-angiotensin system is not available, and if the product is believed to save the mother’s life, inform the pregnant woman of the potential risk to the fetus.
Clinical Considerations.
Fetal/Neonatal Adverse Reactions: Hypohydramnios in pregnant women with mid- and late-pregnancy applications of drugs affecting the renin-angiotensin system can result in the following: fetal hyperalgesia leading to anuria and renal failure, fetal pulmonary hypoplasia, skeletal deformities (including craniosynostosis), hypotension, and death.
Serial ultrasonography is performed to assess the intra-amniotic cavity environment. Fetal testing may be appropriate based on the number of weeks of gestation. However, patients and physicians should be aware that it is possible for hypohydramnios to occur after the fetus has already developed ongoing irreversible damage. If hypohydramnios is observed, alternative drug therapy should be considered. Newborns with a history of intrauterine exposure to Nocinto should be closely monitored for hypotension, oliguria, and hyperkalemia. Elevate blood pressure and increase renal perfusion in neonates with a history of intrauterine exposure to Nocinto who develop oliguria or hypotension. Blood exchange therapy or dialysis may be required as a means of reversing hypotension and replacing renal function.
Lactation.
Transfer of LBQ657 into breast milk was observed in lactating rats following oral administration of [14C] sakubatril valsartan sodium (sakubatril 15 mg/valsartan 15 mg/kg). Transfer of valsartan into breast milk was observed in lactating rats after a single oral dose of [14C] valsartan 3 mg/kg.
RISK SUMMARY: There is no information on the occurrence of sakubatril/valsartan in human breast milk, no information on the effects on breastfed infants or lactation. Because of the potential for serious adverse reactions in breastfed infants exposed to sacubitril/valsartan, breastfeeding women should be advised that breastfeeding is not recommended during treatment with this product.
[Pediatric Use].
The safety and efficacy of Nocinto in pediatric patients under 18 years of age have not been established.
Geriatric use]
Clinically relevant pharmacokinetic differences between elderly (≥65 years) or elderly (≥75 years) patients and the overall population have not been observed (see [Pharmacokinetics]).
Drug Interactions
Contraindicated combinations.
ACEI: Combination of ACEI is contraindicated with nociceptor because concomitant application of ACEI with enkephalinase (NEP) inhibition may increase the risk of angioedema. The last dose of ACEI must be applied 36 hours before starting Nocinto. ACEI must not be started until 36 hours after the last dose of nocinto has been applied (see [Contraindications] and [Dosage]).
Aliskiren: Combination of nocicept with aliskiren is contraindicated in patients with type 2 diabetes (see [Contraindications]). Avoid combining aliskiren in patients with renal impairment (eGFR<60 mL/min/1.73 m²).
Combination is not recommended.
Avoid combining with ARB because it contains the angiotensin II receptor antagonist valsartan (see [Precautions]).
Combinations requiring caution.
Statins: In vitro data show that sakubatril inhibits OATP1B1 and OATP1B3 transport proteins, so nocicept may increase systemic exposure to OATP1B1 and OATP1B3 substrates (e.g., statins). The combination of nocinto may increase the peak concentration of atorvastatin and its metabolites up to 2-fold and the AUC up to 1.3-fold. Therefore, caution should be exercised when Norcintol is combined with statins.
Sildenafil: The addition of sildenafil for a single dose in hypertensive patients when nociceptor reaches steady state produces a more pronounced reduction in blood pressure than nociceptor alone. Therefore, caution should be exercised when starting sildenafil or other phosphodiesterase type 5 (PDE-5) inhibitors in patients on nociceptor.
Combination has predictable interactions with.
Potassium: In combination with potassium-preserving diuretics (e.g., aminoglutethimide, amiloride), salt corticosteroid receptor antagonists (e.g., spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium, may result in elevated serum potassium as well as elevated serum creatinine. If Nocinto is used in combination with these drugs, monitoring of serum potassium is recommended (see [Precautions]).
Nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)): In elderly patients, patients with hypovolemia (including those treated with diuretics), or patients with renal impairment, Nocinto in combination with NSAIDs may increase the risk of worsening renal impairment and may lead to deterioration of renal function, including the possibility of acute renal failure. Therefore, monitoring of renal function is recommended for patients on combined Norcindol and NSAID at the time of initiation of therapy or adjustment of therapy. These effects are usually reversible. Renal function should be monitored regularly.
Lithium: The potential for drug interactions between nocinto and lithium has not been studied. Reversible increases in serum lithium concentrations and toxicity have been reported during lithium co-administration with ACEI or ARB. The risk of lithium toxicity may be further increased if a diuretic is combined. Therefore, serum lithium levels should be closely monitored during the combination of nocinto and lithium.
Transporter proteins: The active metabolite of sakubatril (LBQ657) and valsartan are substrates of OATP1B1, OATP1B3, OAT1, and OAT3; valsartan is also an MRP2 substrate. Therefore, systemic exposure to LBQ657 or valsartan may be increased when Nocinto is co-administered with OATP1B1, OATP1B3, OAT3 inhibitors (e.g., rifampin, cyclosporine) or MRP2 inhibitors (e.g., ritonavir). Caution is required when initiating or ending the combination of these drugs.
No significant interactions.
No clinically significant drug interactions have been observed with Nocinto in combination with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, intravenous nitroglycerin, or concomitant levonorgestrel/ethinyl estradiol combination. No interactions are anticipated with atenolol, indomethacin, glibenclamide, or cimetidine.
The combination of nocinto with metformin resulted in a 23% decrease in both Cmax and AUC of metformin. The clinical significance of these results remains unknown. Therefore, the clinical status of the patient needs to be evaluated when starting nocinto in patients receiving metformin.
CYP 450 Interactions.
In vitro metabolism studies suggest a low potential for CYP 450-based drug interactions because of the limited metabolism of nociceptor via the CYP450 enzyme pathway. Norcindol does not induce or inhibit CYP450 enzymes.
Drug Overdose]
Data on overdose of nociceptor in human subjects are limited. Studies in healthy volunteers have shown that Norcindol is well tolerated with a single dose of 1200 mg and multiple doses of 900 mg (14 days).
Because of the blood pressure-lowering effect of nocinto, the most likely symptom of an overdose is hypotension. Symptomatic treatment should be given.
Due to the high protein binding rate of Nocinto, it is unlikely that Nocinto will be cleared by hemodialysis.
Clinical Trials]
Clinical trial dosing was based on the total amount of two components in Sacubitril valsartan sodium tablets, i.e. 50 mg, 100 mg and 200 mg.
Study PARADIGM-HF
Study PARADIGM-HF is a multi-country, randomized, double-blind study comparing the effects of sakubatril valsartan sodium tablets versus enalapril in 8,442 adult patients with chronic heart failure (NYHA Class II – IV) with symptomatic cardiac systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients must have received at least 4 weeks of ACEI or ARB therapy and be receiving the maximum tolerated dose of beta-blocker therapy. Patients with systolic blood pressure < 100 mmHg at baseline were excluded.
The primary objective of the study PARADIGM-HF is to determine whether sakubatril valsartan sodium tablets are superior to RAS inhibitors (enalapril) given alone in reducing the risk of the composite endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).
After discontinuation of current ACEI or ARB therapy, patients entered a sequential, single-blinded introductory phase during which they received enalapril 10 mg twice daily, followed by sakubatril valsartan sodium tablets 100 mg twice daily, and then increased to 200 mg twice daily. Patients who successfully completed the sequential introductory phase were randomized to receive sakubatril valsartan sodium tablets 200 mg (N=4209) twice daily or enalapril 10 mg (N=4233) twice daily. The primary endpoint was the first event in the composite endpoint of CV death or HF hospitalization. The median follow-up duration was 27 months, and patients were treated for up to 4.3 years.
The study population was 66% Caucasian, 18% Asian, and 5% black; mean age was 64 years, and 78% were male. At randomization, 70% of patients were NYHA class II, 24% were NYHA class III, and 0.7% were NYHA class IV. The mean left ventricular ejection fraction was 29%. 60% of patients had coronary heart disease as the underlying cause of heart failure; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had eGFR< 60 mL/min/1.73m2, and 35% had diabetes mellitus. Most patients were on beta-blockers (94%), salt corticosteroid receptor antagonists (58%), and diuretics (82%). A minority of patients were fitted with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) (15%).
Study PARADIGM-HF showed that sakubatril valsartan sodium tablets were superior to RAS inhibitors (enalapril) in reducing the risk of the composite endpoint of cardiovascular death or hospitalization for heart failure based on analysis to time to event (hazard ratio [HR]: 0.80, 95% confidence interval [CI], 0.73, 0.87, p <0.0001). The treatment effect was reflected by a reduction in both cardiovascular death and heart failure hospitalizations; see Table 2 and Figure 3. cardiovascular death accounted for 45% of sudden death, followed by pump failure at 26%.
Sacubitril valsartan sodium tablets also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p= 0.0009) (Table 2). This finding was solely due to the reduction in cardiovascular mortality when treated with sakubatril valsartan sodium tablets.
Table 2. treatment effects for the primary composite endpoint and its components and all-cause mortality
Sacubitril valsartan sodium tablets N=4187
n (%) Enalapril
N=4212
n (%) Risk ratio
(95% CI) p-value Primary composite endpoint of cardiovascular death or hospitalization for heart failure 914 (21.8)1,117 (26.5)0.80 (0.73, 0.87)<0.0001 Cardiovascular death as first event 377 (9.0)459 (10.9)Hospitalization for heart failure as first event 537 (12.8)658 ( 15.6)Number of patients with events:* Cardiovascular deaths**558 (13.3)693 (16.5)0.80 (0.71, 0.89)Heart failure hospitalizations537 (12.8)658 (15.6)0.79 (0.71, 0.89)All-cause deaths711 (17.0)835 (19.8)0.84 (0.76, 0.93)0.0009* No preplanned diversity adjustment for the primary composite endpoint component analysis.
**Including subjects who had been hospitalized for heart failure prior to death
The Kaplan-Meier curve below (Figure 1) shows the time until the first occurrence of the primary composite endpoint (A), the time from any time until the occurrence of cardiovascular death (B), and the time until the first occurrence of hospitalization for heart failure (C).
Figure 1 . Kaplan-Meier curves for the primary composite endpoint (A), cardiovascular death (B), and hospitalization for heart failure (C)
Figure A
Figure B Figure C
The impact of demographic characteristics, baseline disease characteristics, and baseline concomitant medications on outcomes was observed, and the data showed consistent results for the primary composite endpoint among the subgroups observed (Figure 2).
Figure 2. primary composite endpoint (CV death or HF hospitalization)-subgroup analysis
Total subgroup population (%) Nocinto n/N (%) Enalapril n/N (%) Risk ratio (95% CI) Total 100914/4,187 (21.8)1,117/4,212 (26.5) Age (years)<5724.3222/1,043 (21.3)248/ 994 (24.9)57 – < 6422.7182/ 917 (19.8)263/ 992 (26.5)64 – <7225.8229/1,084 (21.1)273/1,081 (25.3)≥7227.2281/1,143 (24.6)333/1,145 (29.1)Sex Male 78.2756/3,308 ( 22.9)902/3,259 (27.7)Female21.8158/ 879 (18.0)215/ 953 (22.6)Weight (kg)<67,525 0221/1,037 (21.3)269/1,061 (25.4)67.5 – <7924.8241/1,041 (23.2) 287/1,038 (27.6)79 – <91.725.2231/1,048 (22.0)283/1,069 (26.5)≥91.725.1221/1,060 (20.8)278/1,044 (26.6)Race White 66.0598/2,763 (21.6)717/2, 781 (25.8)Blacks5.158/ 213 (27.2)72/ 215 (33.5)Asians18.0179/ 759 (23.6)204/ 750 (27.2)Native Americans2.015/ 84 (17.9)22/ 88 (25.0)Other8.964/ 368 (17.4)102/ 378 (27.0 ) Region USA 5.258/ 225 (25.8)77/ 209 (36.8)Outside USA 94.8856/ 3,962 (21.6)1,040/ 4,003 (26.0)NYHA Classification NYHA Class II 70.5578/ 2,998 (19.3)742/ 2,921 (25.4)NYHA Class III 24.0292/ 969 (30.1)329/1,049 (31.4)NYHA Class IV 0.710/ 33 (30.3)11/ 27 (40.7)Estimated GFR (mL/mim/1.73m2)<5424.7280/1,021 (27.4)344/1,054 (32.6)54 – < ;6624.0218/1,018 (21.4)279/1,000 (27.9)66 – <7924 9205/1,037 (19.8)238/1,054 (22.6)≥7926.4211/1,111 (19.0)256/1,104 (23.2)diabetes no 65.4519/2, 736 (19.0)661/2,756 (24.0)with34.6395/1,451 (27.2456/1,456 31.3 Systolic blood pressure (mmHg)<11020.8208/ 834 (24.9)249/ 913 (27.3)110-<12023.0223/ 990 (22.5) 249/ 941 (26.5)120-<13024 5202/1.041 (19.4)264/1,018 (25.9)≥13031.7281/1,322 (21.3)355/1,340 (26.5)Ejection fraction (%)<2519.4215/ 784 (27.4)271/ 849 (31.9)25 – <3020.8191/ 861 (22.2)255/ 885 (28.8)30 – <3428.5243/1,229 (19.8)281/1,162 (24.2)≥3431.3265/1,313 (20.2)310/1,315 (23.6)Atrial fibrillation None63.2552/2,670 (20.7)637/2,638 (24.1)Yes36.8362/1,517 (23.9)480/1,574 (30.5)NT-proBNP≤median value49.9299/2,079 (14.4)403/2,116 (19.0)>median value49.9614/2 ,103 (29.2)711/2,087 (34.1)Hypertension no 29.3245/1,218 (20.1)303/1,241 (24.4)With 70.7669/2,969 (22.5)814/2,971 (27.4)Prior ACE inhibitor use no 22.2221/ 921 (24.0)246/ 946 (26.0) yes 77.8693/3,266 (21.2)871/3,266 ( 26.7) prior use of ARB no 77.5691/3,258 (21.2)866/3,249 (26.7) yes 22.5223/ 929 (24.0)251/ 963 (26.1) prior use of aldosterone antagonist no 44.4399/1,916 (20.8)494/1,812 (27.3) yes 55.6515/2,271 (22.7)623/2,400 (26.0) previous hospitalization for heart failure no 37.2262/1,580 (16.6)348/1,545 (22.5) yes 62.8652/2,607 ( 25.0)769/2,667 (28.8)Time since diagnosis of heart failure ≤1 year30.0202/1,275 (15.8)240/1,248 (19.2)>1-5 years38.5392/1,621 (24.2)447/1,611 (27.7)>5 years31.5320/1,291 (24.8)430/1,353 (31.8)Cause of heart failure non – ischemic 40.0339/1,681 (20.2)420/1,682 (25.0)Ischemic 60.0575/2,506 (22.9)697/2,530 (27.5)Any ICD (including CRT-D) No 85.2761/3, 564 (21.4)942/3,592 (26.2)yes14.8153/ 623 (24.6)175/ 620 (28.2)
Note: The above figure shows the effects of different subgroups, which are based on baseline characteristics. The 95% confidence intervals shown do not take into account the number of comparisons made and may not reflect the effect of a particular factor after correction for all other factors. The apparent homogeneity or heterogeneity shown between groups should not be over-interpreted.
In the PARADIGM-HF study, 353 patients were randomized in mainland China (n=177 in the nociceptor group and n=176 in the enalapril group). Of these 353 Chinese patients, 32% were 65 years of age or older. In the nocinto group, 86% of patients were still receiving the target dose of 200 mg twice daily (mean daily dose of 367 mg) at the end of the study. In the enalapril group, 79% of patients were still receiving the target dose of 10 mg twice daily (mean daily dose of 18.7 mg) at the end of the study. Subgroup analysis confirmed that the results of these 353 Chinese patients were generally consistent with the overall study results.
Pharmacology and Toxicology]
Pharmacological effects
Sacubitril valsartan sodium contains the enkephalinase inhibitor sacubitril and the angiotensin receptor antagonist valsartan. Sacubitril valsartan sodium inhibits enkephalinase (neutral peptide chain endonuclease; NEP) via LBQ657 (the active metabolite of the prodrug sacubitril) and blocks the type 1 receptor of angiotensin II (AT1) via valsartan. Increasing the levels of peptides degraded by enkephalinase (e.g., natriuretic peptide) via LBQ657, while inhibiting angiotensin II action via valsartan, produces cardiovascular and renal effects of sacubitril valsartan sodium in patients with heart failure. Valsartan inhibits angiotensin II action by selectively blocking AT1 receptors and also inhibits angiotensin II-dependent aldosterone release.
Toxicological studies
Genotoxicity.
Ames test, in vitro chromosomal aberration test and in vivo micronucleus test in rats were negative for sakubatril valsartan sodium and sakubatril. in vitro chromosomal aberration test for LBQ657 was negative.
Reproductive toxicity.
No significant effects on fertility or early embryonic development were observed with sakubatril valsartan sodium at doses up to 150 mg/kg/day [≤1.0 and ≤0.18 times the maximum recommended human dose (MRHD) for valsartan and LBQ657, respectively] in rats. No increase in embryo-fetal mortality was seen in pregnant rats administered at doses ≥ 100 mg/kg/day [≤ 0.72 times the MRHD in terms of AUC] and in pregnant rabbits administered at doses ≥ 10 mg/kg/day [2 and 0.03 times the MRHD in terms of valsartan and LBQ657 AUC, respectively]. Based on the low incidence of maternally toxic dose related hydrocephalus observed in fetuses at doses ≥ 10 mg/kg/day administered to rabbits, it is believed that sakubatril valsartan sodium has an effect on fetal growth and development. The embryo-fetal adverse effects of sacubitril valsartan sodium were attributed to its angiotensin receptor antagonistic activity (see [Use in Pregnant and Lactating Women]).
In perinatal toxicity tests in rats, effects on fetal/pup development and survival were seen during organogenesis, gestation and lactation at doses of up to 750 mg/kg/day [2.2 times MRHD in terms of AUC] for sakubatril and up to 600 mg/kg/day [0.86 times MRHD in terms of AUC] for valsartan.
Juvenile (2-4 years of age) crab-eating monkeys given oral sakubatril valsartan sodium 50 mg/kg/day for 2 weeks were evaluated for effects on amyloid-b concentrations in cerebrospinal fluid and brain tissue, and elevated levels of Aβ 1-40, 1-42, and 1-38 were seen in cerebrospinal fluid; no corresponding elevation in brain Ab levels was observed. No elevations in cerebrospinal fluid Aβ 1-40 and 1-42 were seen in a 2-week human study in healthy volunteers. No accumulation of amyloid-b in the brain was observed in crab-eating monkeys given oral sakubatril valsartan sodium at doses up to 300 mg/kg/day for 39 consecutive weeks.
Carcinogenicity.
The highest doses of sakubatril given to mice and rats were 1200 and 400 mg/kg/day (approximately 29 and 19 times the MRHD in mg/m2), respectively, and the highest doses of valsartan given to mice and rats were 160 and 200 mg/kg/day (approximately 4 and 10 times the MRHD in mg/m2), respectively, and no carcinogenic effects were seen for sakubatril and valsartan No carcinogenic effects were observed for sacubitril and valsartan.
[Pharmacokinetics].
Absorption.
After oral administration, nocicept is broken down into sakubatril (which is then further metabolized to LBQ657) and valsartan, which reach peak plasma concentrations at 0.5 h, 2 h and 1.5 h, respectively. The absolute oral bioavailability of sacubitril and valsartan is approximately ≥ 60% and 23%, respectively.
After twice-daily administration of nociceptor, steady-state levels of sacubitril, LBQ657, and valsartan were reached within 3 days. At steady-state, there was no significant accumulation of sacubitril and valsartan, while LBQ657 had a 1.6-fold accumulation. The effect of nocintaur with food on systemic exposure to sacubitril, LBQ657, and valsartan was not clinically significant. Although valsartan exposure was reduced when nocinto was administered with food, this reduced exposure did not result in a clinically meaningful reduction in efficacy. Therefore, nocinto can be taken with food or on an empty stomach.
Distribution.
Nocintaur has a high binding rate to plasma proteins (94-97%). Based on plasma exposure compared to cerebrospinal fluid exposure, LBQ657 crossed the blood-brain barrier to a limited extent (0.28%). The mean apparent volume of distribution ranges for valsartan and sacubitril were 75 L and 103 L, respectively.
Metabolism.
Sacubitril is rapidly converted to LBQ657 by esterases; no further metabolism of LBQ657 was evident. Valsartan metabolism was minimal, as recovery in the form of metabolites was only approximately 20% of the administered dose. Low concentrations of hydroxyl metabolites were observed in plasma (<10%). Because CYP450 enzymes rarely mediate the metabolism of sakubatril and valsartan, no effect on their pharmacokinetics is expected when combined with drugs that affect CYP450 enzymes.
Excretion.
After oral administration, 52-68% of sakubatril (mainly as LBQ657), ~13% of valsartan and its metabolites are excreted in the urine; 37-48% of sakubatril (mainly as LBQ657), 86% of valsartan and its metabolites are excreted in the feces.
The mean plasma elimination half-lives (T1/2) of sacubitril, LBQ657, and valsartan are approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.
Pharmacokinetic linearity.
The pharmacokinetics of sacubitril, LBQ657 and valsartan were linear over the dose range examined (Nocinto 50 ~ 400 mg).
Special Populations.
Elderly patients: compared to younger subjects, LBQ657 and valsartan exposure was increased by 42% and 30%, respectively, in subjects > 65 years of age.
Pediatric patients (under 18 years of age): Pharmacokinetic studies of this product have not been performed in pediatric patients.
Renal Impairment.
A correlation between renal function and LBQ657 systemic exposure was observed in patients with mild to severe renal impairment. With mild renal impairment (60 ml/min/1.73 m2
≤ eGFR < 90 ml/min/1.73 m2) (the group with the highest number of patients enrolled in the study PARADIGM-HF), compared to patients with moderate (30 ml/min/1.73 m2
≤ eGFR < 60 ml/min/1.73 m2) and severe (15 ml/min/1.73 m2
≤ eGFR < 30 ml/min/1.73 m2) had 1.4-fold and 2.2-fold higher LBQ657 exposure, respectively. Exposure to valsartan was similar in patients with moderate and severe renal impairment compared to patients with mild renal impairment.
Studies have not been conducted in patients receiving hemodialysis. However, the high plasma protein binding of LBQ657 and valsartan makes effective clearance by hemodialysis unlikely.
Hepatic Impairment.
Compared to matched healthy subjects, sakubatril exposure increased to 1.5-fold and 3.4-fold, LBQ657 exposure increased to 1.5-fold and 1.9-fold, and valsartan exposure increased to 1.2-fold and 2.1-fold, respectively, in patients with mild to moderate hepatic impairment. However, compared to matched healthy subjects, free LBQ657 exposure increased to 1.47-fold and 3.08-fold and free valsartan exposure increased to 1.09-fold and 2.20-fold, respectively, in patients with mild to moderate hepatic impairment.
Data from pharmacokinetic studies of this product in patients with severe liver injury, biliary cirrhosis, or cholestasis are not available.
Ethnicity.
The pharmacokinetic profile of Nocinto was similar between ethnic groups (Caucasian, Black, Asian (including Chinese)).
Effect of gender.
In male or female subjects, the pharmacokinetic characteristics of this product are similar.
Storage
Store in a dry place under 25℃.
Package
PVC/PVDC package; 14 tablets/box, 28 tablets/box.
Expiration date
24 months.
Executive Standard
Imported drug registration standard JX20150417
【Imported drug registration certificate number
50mg.
100mg.
200mg.
【Manufacturing Company
Company Name: Novartis Pharma Schweiz AG
Production plant: Novartis Pharma Stein AG
Production Address: Schaffhauserstrasse, 4332 Stein, Switzerland
Contact Address.
No. 31 Yong’an Road, Changping District, Beijing, China
Postal Code: 102200
Phone number: 400 621 3132
800 810 1555 (from a landline)
Fax number: 010 6505 7099
Web
Address:
www.novartis.com.cn