Product Overview
[Drug Name]
Generic Name: Sacubitril/Valsartan Sodium Tablets
Trade Name: Nosinto Sacubitril/Valsartan Sodium Tablets 50mg x 28 Tablets
[Main Ingredients]
Active ingredient: Sacubitril/Valsartan Sodium.
[Properties]
This product is a purple-white oval film-coated tablet debossed with "LZ" on one side and "NVR" on the other side (50mg strength), or a light yellow oval film-coated tablet debossed with "L1" on one side and "NVR" on the other side (100mg strength), or a light pink oval film-coated tablet debossed with "L1" on one side and "NVR" on the other side (200mg strength). Specifications).
[Indications/Main Functions]
For use in adult patients with chronic heart failure with reduced ejection fraction (NYHAI class IV, LVEF ≤ 40%) to reduce the risk of cardiovascular death and heart failure hospitalization. Sacubitril/valsartan sodium tablets can be used in place of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin I receptor blockers (ARBs) and in combination with other heart failure medications.
[Specifications]
50mg x 28 tablets
[Dosage and Administration]
This product can be taken with or without food (see [Pharmacokinetics]). Due to the potential risk of angioedema when used with ACE inhibitors, this product is contraindicated in combination with ACE inhibitors. If switching from an ACE inhibitor to this product, the ACE inhibitor must be discontinued. This product should not be started until at least 36 hours have passed since the start of treatment with a steroid (see [Contraindications]). The recommended starting dose of this product is 100 mg twice daily. In patients not currently taking ACE or angiotensin receptor blockers (ARBs) or those taking low doses of these drugs, experience with this product is limited, and the recommended starting dose is 50 mg twice daily. Based on patient tolerance, the dose of this product should be doubled every 2 to 4 weeks until a target maintenance dose of 200 mg twice daily is reached. Patients with serum potassium levels >5.4mmol/L should not be started on this product. Patients with SBP <100mmHg should be started with caution and blood pressure changes should be monitored carefully. For patients with SBP ≤100mmHg to 110 For patients with systolic blood pressure ≤95 mmHg, a starting dose of 50 mg twice a day should be considered. If the patient is intolerant to this product (systolic blood pressure ≤95 mmHg, symptomatic hypotension, hyperkalemia, renal impairment), it is recommended to adjust the concomitant medication, temporarily reduce the dose of this product or discontinue this product (see [Precautions]). This product has the activity of antagonizing angiotensin I receptors, so it should not be used in combination with ARBs (see [Precautions] and [Drug Interactions]). Special populations Patients with impaired renal function: Patients with mild renal impairment (eGFR 60~90 mL/min/1.73 m2) do not need to adjust the starting dose. Patients with moderate renal impairment (eGFR30~60 mL/min/1.73 m2) should consider a starting dose of 50 mg each time, twice a day. Because in patients with severe renal impairment (eGFR<30 ml/min/1.73 Experience with levofloxacin in patients with mild hepatic impairment (Child-Pugh class A) is very limited, so this drug should be used with caution in these patients. The recommended starting dose is 50 mg twice daily. There is no experience with levofloxacin in patients with end-stage renal disease, so its use is not recommended in these patients. Hepatic Impairment: No starting dose adjustment is required for patients with mild hepatic impairment (Child-Pugh class A). The recommended starting dose for patients with moderate hepatic impairment (Child-Pugh class B) is 50 mg twice daily. As tolerated, the dose can be doubled every 2-4 weeks to reach the target maintenance dose of 200 mg twice daily. This drug is not recommended for patients with severe hepatic impairment (Child-Pugh class C) (see [Pharmacology and Toxicology]). Elderly Patients (over 65 years): No dose adjustment is required for patients over 65 years of age.
[Adverse Reactions]
This product can cause the following clinically significant adverse reactions: angioedema, hypotension, renal impairment, and hyperkalemia. See [Precautions] for details. Clinical Trial Experience: Because clinical trials are conducted under diverse conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with those observed in other clinical trials of another drug. Furthermore, adverse reaction rates observed in clinical trials may not reflect the rates observed in actual use. In the PARADIGM-HF trial, before entering the randomized, double-blind phase comparing sacubitril/valsartan sodium tablets (Entresto®) and enalapril, subjects were required to complete sequential enalapril and Entresto® run-in periods of 15 and 29 days (median), respectively. During the enalapril run-in period, 1,102 patients (10.5%) permanently discontinued the study, 5.6% due to adverse events, the most common of which were renal impairment (1.7%), hyperkalemia (1.7%), and hypotension (1.4%). During the Entresto® run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% due to adverse events, the most common of which were renal impairment (1.8%), hypotension (1.7%), and hyperkalemia (1.3%). Due to this run-in design, the incidence of adverse reactions described below is lower than would be expected in real-world settings. The double-blind phase evaluated the safety of 4203 patients treated with Entresto® and 4229 patients treated with enalapril. In the PARADIGM-HF study, patients randomized to the Entresto® group received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3271 patients received treatment for more than one year. 450 (10.7%) Entresto®-treated patients and 516 (12.2%) enalapril-treated patients discontinued treatment due to adverse events during the double-blind phase of the PARADIGM-HF study. During the double-blind phase of the PARADIGM-HF study, the incidence of postural hypotension with orthostasis was 1.1% in the enalapril group and 2.1% in the Entresto® group. Falls were reported in 1.9% of patients treated with Entresto®, compared to 1.3% of patients treated with enalapril. Laboratory Abnormalities: Hemoglobin and Hematocrit: During the double-blind phase of the PARADIGM-HF study, decreases in hemoglobin/hematocrit greater than 20% were observed in approximately 5% of patients in both the Entresto® and enalapril groups. Serum Creatinine: Increases of greater than 50% were observed in 1.4% of patients during the enalapril run-in period and in 2.2% of patients during the Entresto® run-in period. During the double-blind treatment period, increases in serum creatinine greater than 50% were observed in approximately 16% of patients in both the Entresto® and enalapril groups. Serum Potassium: Potassium concentrations greater than 5.5 mEq/L were observed in approximately 4% of patients during the run-in period for both the enalapril and Entresto® groups. Potassium concentrations greater than 5.5 mEq/L were observed in approximately 16% of patients in both the Entresto® and enalapril groups during the double-blind treatment period.
[Contraindications]
This product is contraindicated in patients with hypersensitivity to the active ingredients (sacubitril, valsartan) or any of the excipients. It is contraindicated for use with ACE inhibitors (see [Precautions], [Dosage and Administration], and [Drug Interactions]). This product must be taken 36 hours after discontinuation of ACE inhibitor therapy. It is contraindicated in patients with a history of angioedema associated with ACE inhibitor or ARB therapy. It is contraindicated in patients with hereditary or idiopathic angioedema. In patients with type 2 diabetes, Entresto® is contraindicated for use with aliskiren (see [Precautions] and [Drug Interactions]). It is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, and cholestasis. It is contraindicated in patients during the second and third trimesters of pregnancy (see [Use in Pregnant and Lactating Women]).
[Drug Interactions]
Concomitant use of ACE inhibitors: Entresto® is contraindicated because concurrent use of ACE inhibitors, which inhibit neprilysin (NEP), may increase the risk of angioedema. Entresto® must be started 36 hours after the last dose of an ACE inhibitor. ACE inhibitors must be started 36 hours after the last dose of Entresto® (see [Contraindications] and [Dosage and Administration]). Aliskiren: Entresto® is contraindicated in patients with type 2 diabetes (see [Contraindications]). Avoid coadministration of aliskiren with this medication in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).
[Not recommended]
Because this medication contains the angiotensin I1 receptor antagonist valsartan, coadministration of an ARB should be avoided (see [Precautions]). Concomitant medications requiring caution: Statins: In vitro data indicate that sacubitril inhibits the OATP1B1 and OATP1B3 transporters. Therefore, Entresto® may increase the systemic exposure of OATP1B1 and OATP1B3 substrates (e.g., statins). Coadministration of Entresto® may increase peak concentrations of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised when Entresto® is coadministered with statins. No clinically significant drug interactions have been observed with Entresto® when used with simvastatin. Sildenafil: A single dose of sildenafil, added after Entresto® reaches steady-state, may produce a greater reduction in blood pressure in hypertensive patients compared to Entresto® alone. Therefore, caution should be exercised when initiating sildenafil or other phosphodiesterase type 5 (PDE-5) inhibitors in patients taking Entresto®. Predicted interactions with coadministration: Potassium: Concomitant use of potassium-sparing diuretics (e.g., triamterene, amiloride), mineralocorticoid receptor antagonists (e.g., spironolactone, eplerenone), potassium supplements, or potassium-containing salt substitutes may result in elevated serum potassium and serum creatinine. If Entresto® is coadministered with these medications, serum potassium monitoring is recommended (see Precautions). Nonsteroidal anti-inflammatory drugs (NSAIDs, including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors)): In elderly patients, those with volume depletion (including those taking diuretics), or those with impaired renal function, the concomitant use of Entresto® with NSAIDs may increase the risk of exacerbating renal impairment, potentially leading to worsening renal function, including the potential for acute renal failure. Therefore, renal function monitoring is recommended when coadministering Entresto® with NSAIDs during treatment initiation or adjustment. These effects are generally reversible. Renal function should be monitored regularly. Lithium: The potential for drug interactions between Entresto® and lithium has not been studied. Reversible increases in serum lithium concentrations and toxicity have been reported during the concomitant use of lithium with ACE inhibitors or ARBs. The risk of lithium toxicity may be further increased if a diuretic is used concomitantly. Therefore, serum lithium levels should be closely monitored during the concomitant use of Entresto® with lithium. Transporters: The active metabolite of sacubitril (LBQ657) and valsartan are substrates of OATP1B1, OATP1B3, OAT1, and OAT3; valsartan is also a substrate of MRP2. Therefore, coadministration of Entresto® with OATP1B1, OATP1B3, or OAT3 inhibitors (e.g., rifampin, cyclosporine) or MRP2 inhibitors (e.g., ritonavir) may increase systemic exposure to LBQ657 or valsartan. Caution should be exercised when coadministering these medications. No significant drug interactions have been observed with Entresto® when used with furosemide, digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, intravenous nitroglycerin, or levonorgestrel/ethinyl estradiol combination therapy. No interactions are expected with atenolol, indomethacin, glyburide, or cimetidine. Coadministration with metformin decreased both metformin Cmax and AUC by 23%. The clinical significance of these results remains unknown. Therefore, the patient's clinical status should be assessed before initiating Entresto® in patients receiving metformin. CYP450 Interactions: In vitro metabolism studies indicate that the potential for CYP450-based drug interactions is low due to limited metabolism of Entresto® via the CYP450 enzyme pathway. Entresto® does not induce or inhibit CYP450 enzymes.
[Precautions]
Warning: Embryotoxicity: This drug may cause fetal harm when used by pregnant women. Use of drugs that affect the renin-angiotensin system during the second and third trimesters can reduce fetal renal function and increase fetal and neonatal morbidity and mortality. Upon discovery of pregnancy, consider alternative drug therapy and discontinue this drug. However, if there is no appropriate alternative treatment (to drugs that affect the renin-angiotensin system) and this drug is considered life-saving for the mother, inform the pregnant woman of the potential risk to the fetus. Angioedema: Entresto® may cause angioedema. In the double-blind phase of the PARADIGM-HF study, angioedema occurred in 0.5% of patients treated with Entresto® and 0.2% of patients treated with enalapril (see Adverse Reactions). If angioedema occurs, immediately discontinue Entresto®, administer appropriate treatment, and monitor for respiratory tract involvement. Re-administration of Entresto® is contraindicated. Confirmed cases of angioedema limited to the face and lips generally resolve without treatment, although antihistamines may help relieve symptoms. Angioedema with laryngeal edema can be life-threatening. If edema involves the tongue, glottis, or larynx, airway obstruction may occur. Appropriate treatment should be administered, such as subcutaneous injection of epinephrine solution 1:1000 (0.3 mL to 0.5 mL), and necessary measures should be taken to ensure airway patency. The incidence of angioedema is higher in Black patients compared to non-Black patients using Entresto®. Patients with a history of angioedema may be at increased risk of angioedema when using Entresto® (see Adverse Reactions). Patients with a known history of angioedema associated with ACE inhibitor or ARB therapy should not use Entresto® (see Contraindications). Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Due to the risk of angioedema, Entresto® should not be used with ACE inhibitors. Entresto® must be started 36 hours after the last dose of the ACE inhibitor. If Entresto® is discontinued For treatment with Entresto, ACE inhibitors must be started 36 hours after the last dose of Entresto (see Contraindications, Dosage and Administration, and Drug Interactions). Entresto® should be used with caution with direct renin inhibitors (such as aliskiren) (see Contraindications and Drug Interactions). Entresto® is concomitantly used with aliskiren in patients with type 2 diabetes (see Contraindications). Due to its angiotensin II receptor antagonist activity, Entresto® should not be used with ARBs (see Dosage and Administration and Drug Interactions). Hypotension: Entresto® can lower blood pressure and may cause symptomatic hypotension. Patients with activated renin-angiotensin system (e.g., those with volume depletion or electrolyte depletion, such as those receiving high-dose diuretics) are at greater risk. In the double-blind phase of the PARADIGM-HF study, 18% of patients receiving Entresto® had hypotension. Hypotension was reported as an adverse event in 100% of patients treated with Entresto® and 12% of patients treated with enalapril (see Adverse Reactions). Serious adverse events of hypotension were reported in approximately 1.5% of patients in both treatment groups. Volume depletion or electrolyte deficiencies should be corrected before administering Entresto®, or the drug should be initiated at a lower dose. If hypotension occurs, consider adjusting the dose of diuretics and concomitant antihypertensive medications, and treating other causes of hypotension (e.g., volume depletion). If hypotension persists despite these measures, reduce the Entresto® dose or temporarily discontinue Entresto®. Permanent discontinuation of treatment is generally not necessary. Renal Impairment: Due to inhibition of the renin-angiotensin-aldosterone system (RAAS), treatment with Entresto® may result in decreased renal function in susceptible individuals. During the double-blind phase of the PARADIGM-HF study, adverse events of renal failure were reported in 5% of patients in both the Entresto® 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 ACE inhibitors and ARBs may be associated with oliguria, progressive azotemia, and rarely, acute renal failure and death. If a patient develops clinically significant renal decline, closely monitor serum creatinine and reduce or discontinue Entresto dose (see [Dosage and Administration] - Specific Populations and [Pharmacokinetics]). Like other drugs that affect the renin-angiotensin-aldosterone system, Entresto may cause elevations in blood urea and serum creatinine in patients with bilateral or unilateral renal artery stenosis. Entresto should be used with caution in patients with renal artery stenosis, and renal function monitoring is recommended. Hyperkalemia: Hyperkalemia may occur with Entresto therapy through its effects on the RAAS. In the double-blind phase of the PARADIGM-HF study, adverse events of hyperkalemia were reported in 12% of Entresto-treated patients and 14% of enalapril-treated patients (see [Adverse Reactions]). Monitor serum potassium levels regularly and administer appropriate treatment, especially in patients with risk factors for hyperkalemia (such as severe renal impairment, diabetes mellitus, hypoaldosteronism, or those on a high-potassium diet). A dose reduction or discontinuation of Entresto® may be necessary (see [Dosage and Administration]). Patients with NYHA functional class IV: Due to limited clinical experience in NYHA functional class IV patients, caution should be exercised when initiating Entresto® treatment in such patients. B-type natriuretic peptide (BNP): BNP is a substrate for neprilysin. BNP is not a suitable biomarker for heart failure in patients receiving Entresto®. Patients with hepatic impairment: There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh class B) or AST/ALT values greater than twice the upper limit of normal. Exposure may be increased in these patients, and the safety profile has not been established. Therefore, caution is advised when using this product in such patients. This product is contraindicated in patients with severe liver damage, biliary cirrhosis or bile accumulation (Child-Pugh C grade).
[Pediatric Use]
The safety and efficacy of Entresto® in pediatric patients under 18 years of age have not been established.
[Elderly Use]
No clinically relevant pharmacokinetic differences have been observed between elderly (≥65 years) or very elderly (≥75 years) patients and the general population (see [Pharmacokinetics]).
[Overdose]
Overdose data with Entresto® in human subjects are limited. Studies in healthy volunteers have shown that a single dose of 1200 mg and repeated doses of 900 mg (14 days) were well tolerated. Due to the blood pressure-lowering effect of Entresto®, the most likely symptom of an overdose is hypotension. Symptomatic treatment should be administered. Due to the high protein binding of Entresto®, hemodialysis clearance of Entresto® is unlikely.
[Pharmacology and Toxicology]
Pharmacological Action: Sacubitril/valsartan sodium contains the enkephalinase inhibitor sacubitril and the angiotensin receptor antagonist valsartan. Sacubitril/valsartan sodium inhibits neprilysin (neutral endopeptidase; NEP) through LBQ657 (the active metabolite of the prodrug sacubitril), while valsartan blocks the angiotensin II type 1 receptor (AT1). LBQ657 increases the levels of peptides degraded by neprilysin (such as natriuretic peptides), while valsartan inhibits the effects of angiotensin II. This combination can produce cardiovascular and renal effects in patients with heart failure. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor and also inhibits angiotensin II-dependent aldosterone release. Toxicological studies: Genotoxicity in sacubitril/valsartan sodium and sacubitril were negative in the Ames test, in vitro chromosome aberration test, and in vivo rat micronucleus test. LBQ657 was negative in the in vitro chromosome aberration test. Reproductive Toxicity: Sacubitril/valsartan sodium did not significantly affect fertility or early embryonic development in rats at doses up to 150 mg/kg/day (≤1.0 times and ≤0.18 times the maximum recommended human dose (MRHD) based on AUC for valsartan and LBQ657, respectively). No increase in embryo-fetal mortality was observed in pregnant rats at doses ≥100 mg/kg/day (≤0.72 times the MRHD based on AUC) or at a pregnancy-free dose ≥10 mg/kg/day (2 times and 0.03 times the MRHD based on AUC for valsartan and LBQ657, respectively). Based on the low incidence of fetal hydrocephalus associated with maternal toxicity observed at free doses ≥10 mg/kg/day, sacubitril/valsartan sodium is suspected to have an effect on fetal growth and development. Embryo-fetal adverse effects of sacubitril/valsartan sodium are due to its angiotensin receptor antagonist activity (see Use in Pregnant and Lactating Women). In perinatal toxicity studies in rats, sacubitril at doses up to 750 mg/kg/day (2.2 times the MRHD based on AUC) and valsartan at doses up to 600 mg/kg/day (0.86 times the MRHD based on AUC) affected fetal/pup development and survival during organogenesis, gestation, and lactation. The effects of oral administration of sacubitril/valsartan sodium 50 mg/kg/day for 2 weeks in cynomolgus monkeys (2-4 years of age) on cerebrospinal fluid and brain amyloid-β concentrations were assessed. Increased levels of Aβ1-40, 1-42, and 1-38 in CSF were observed; no corresponding increase in brain Aβ levels was observed. In a 2-week human study in healthy volunteers, no elevations in CSF Aβ1-40 and 1-42 were observed. In cynomolgus monkeys, oral administration of sacubitril and valsartan sodium for 39 weeks resulted in no accumulation of amyloid-β in the brain. Carcinogenicity: Sacubitril and valsartan were not observed in mice and rats at doses up to 1200 and 400 mg/kg/day (approximately 29 and 19 times the MRHD, respectively, on a mg/m2 basis) and 160 and 200 mg/kg/day (approximately 4 and 10 times the MRHD, respectively, on a mg/m2 basis) respectively.
