NOVARTIS NUOXINTUO Sacubitril Valsartan Sodium Tablets For Heart Disease 100mg*14

[Drug Name]
Generic Name: Sacubitril/Valsartan Sodium Tablets
Trade Name: Nosintoflavone Sacubitril/Valsartan Sodium Tablets 100mg x 14 Tablets

[Main Ingredients]
50mg of sacubitril/valsartan (24mg of sacubitril/26mg of valsartan).

[Appearance]
This product is a purple-white, oval film-coated tablet debossed with "LZ" on one side and "NVR" on the other side (50mg strength).

[Indications/Main Functions]
For adult patients with chronic heart failure with reduced ejection fraction (NYHAI class IV, LVEF <40%). It reduces the risk of cardiovascular death and hospitalization for heart failure. Nosintoflavone Sacubitril/Valsartan Sodium Tablets can be used in combination with other heart failure medications (e.g., beta-blockers, diuretics, and mineralocorticoid antagonists) as an alternative to angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin I receptor antagonists (ARBs).

[Specifications]
100mg*14 tablets

[Dosage and Administration]
The starting dose of this product is 100mg twice daily. Experience is limited in patients not currently taking ACE inhibitors or angiotensin receptor blockers (ARBs), or in those taking low doses of these drugs. The recommended starting dose is 50mg twice daily. Based on patient tolerance, the dose should be doubled every 2 to 4 weeks until a target dose of 200mg twice daily is reached.

[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, the incidence of adverse reactions observed in clinical trials of a drug cannot be directly compared with the incidence of adverse reactions observed in other clinical trials of another drug. Furthermore, the incidence of adverse reactions observed in clinical trials of a drug may not reflect the incidence observed in actual use. In the PARADIGM-HF trial, before entering the randomized, double-blind phase comparing sacubitril/valsartan sodium tablets (Entresto) with enalapril, patients were required to complete sequential run-in periods of 15 and 29 days (median), respectively, for enalapril and Entresto. During the enalapril run-in phase, 1,102 patients (10.5%) discontinued the study; 5.6% were due to adverse events, most commonly renal impairment (1.7%), hyperkalemia (1.7%), and hypotension (1.4%). During the Entresto run-in phase, an additional 10.4% of patients discontinued treatment; 5.9% were due to adverse events, most commonly 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. Safety was evaluated in 4,203 patients treated with Entresto and 4,229 patients treated with enalapril during the double-blind phase. In the PARADIGM-HF study, patients randomized to Entresto 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. During the double-blind phase, 450 (10.7%) Entresto-treated patients and 516 (12.2%) enalapril-treated patients discontinued treatment due to adverse events. Adverse reactions occurring in ≥5% of Entresto-treated patients during the double-blind phase are shown in Table 1. In the PARADIGM-HF trial, the incidence of angioedema was 0.1% during both the enalapril run-in period and the Entresto run-in period. During the double-blind phase, the incidence of angioedema was higher in Entresto-treated patients than in enalapril-treated patients (0.5% and 0.2%, respectively). The incidence of angioedema in black patients treated with Entresto and enalapril was 2.4% and 0.5%, respectively (see Precautions). In the double-blind phase of the PARADIGM-HF study, the incidence of 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% in patients treated with enalapril. Laboratory Abnormalities: (1) Hemoglobin and Hematocrit In the double-blind phase of the PARADIGM-HF study, a decrease in hemoglobin/hematocrit of >20% was observed in approximately 5% of patients treated with both the Entresto group and the enalapril group. (2) Serum Creatinine An increase in serum creatinine of >50% was 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, an increase in serum creatinine of >50% was observed in approximately 16% of patients in both the Entresto group and the enalapril group. (3) Serum Potassium A potassium concentration of >5.5 mEq/L was observed in approximately 4% of patients during the run-in period for both the enalapril and Entresto groups. During the double-blind treatment phase, approximately 16% of patients in both the Entresto and enalapril groups had potassium concentrations >5.5 mEq/L.

[Contraindications]
This product is contraindicated in patients with allergies 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 cessation 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, this product 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]
1. Contraindications: ACEI: Entresto is contraindicated with ACE inhibitors 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 ACE inhibitors (see [Contraindications] and [Dosage and Administration]). Aliskiren: Entresto is contraindicated with aliskiren in patients with type 2 diabetes (see [Contraindications]). Renal impairment (eGFR <60ml> 2. Co-administration is not recommended: Since this product contains angiotensin I receptor antagonist-grade sartan, co-administration with ARB should be avoided. (See Precautions). 3. Co-administration with caution: Statins: In vitro data show that sacubitril has the effect of inhibiting OATP1B1 and OATP1B3 transporters. Therefore, Entresto may increase the systemic exposure of OATP1B1 and OATP1B3 substrates (such as statins). When co-administered with Entresto, the peak concentration of atorvastatin and its metabolites can be increased by 2 times, and the AUC can be increased by 1.3 times. Therefore, caution should be exercised when Entresto is used in combination with statins. Sildenafil: Compared with Entresto alone, a single dose of sildenafil can produce a more significant lowering of blood pressure in patients with hypertension when Entresto reaches steady state. Therefore, patients using Entresto should start using sildenafil or other type 5 phosphodiesterase inhibitors (PD-1 inhibitors) Caution should be exercised when using Entresto with E-5 inhibitors. 4. Predictable 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 used 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, patients with volume depletion (including those receiving diuretics), or patients with impaired renal function, the combined 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 for patients taking Entresto and NSAIDs concomitantly when initiating or adjusting treatment. 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. There have been reports of reversible increases in serum lithium concentrations and toxicity during the combined use of ACE or ARB with lithium. The risk of lithium toxicity may be further increased if diuretics are used concomitantly. Therefore, serum lithium levels should be closely monitored during the co-administration of Entresto and lithium. Transporters: Sacubitril active metabolite (LBQ657) and valsartan are substrates of OATP1B1, OATP1B3, OAT1 and OAT3; valsartan is also an MRP2 substrate. Therefore, the systemic exposure of LBQ657 or valsartan may be increased when Entresto is used in combination with OATP1B1, OATP1B3, OAT3 inhibitors (such as rifampicin, cyclosporine) or MRP2 inhibitors (such as ritonavir). Be cautious when starting or ending co-administration of such drugs. 5. No significant drug interactions: No clinically significant drug interactions were observed when Entresto was coadministered with furosemide, digoxin, warfarin, hydrochlorothiazide, amiloride, omeprazole, carvedilol, intravenous nitroglycerin, or concomitant administration of levonorgestrel/estradiol combination products. No interactions are expected with atenolol, indomethacin, glyburide, or cimetidine. Entresto coadministration with metformin decreased both the Cmax and AUC of metformin by 23%. The clinical significance of these findings remains unknown. Therefore, the patient's clinical status should be assessed before initiating Entresto in patients receiving metformin. 6. CYP450 Interactions: In vitro metabolism studies indicate a low potential for CYP450-based drug interactions due to limited metabolism of Entresto via the CYP450 enzyme pathway. Entresto does not induce or inhibit CYP450 enzymes.

[Precautions]
1. Warning: Embryotoxicity This product may cause fetal harm when used by pregnant women. The use of drugs that act on the renin-angiotensin system during the second and third trimesters can reduce fetal renal function and increase fetal and neonatal morbidity and mortality. When pregnancy is discovered, alternative drug treatment should be considered and this product should be discontinued. However, if there is no appropriate alternative treatment (to replace drugs that affect the renin-angiotensin system) and it is believed that this product can save the mother's life, inform the pregnant woman of the potential risks of this product to the fetus. 2. Angioedema: Entresto may cause angioedema. In the double-blind phase of the PARADIGM-HF study, angioedema occurred in 0.5% of Entresto-treated patients and 0.2% of enalapril-treated patients (see [Adverse Reactions]). If angioedema occurs, discontinue Entresto immediately, administer appropriate treatment and monitor for respiratory tract involvement. Re-application of Entresto is prohibited. For confirmed cases limited to the face and lips Cases of angioedema generally resolve without treatment, although antihistamines can help relieve symptoms. Angioedema associated with laryngeal edema can be life-threatening. If edema involves the tongue, glottis, or larynx, airway obstruction may occur and appropriate treatment should be given, such as subcutaneous injection of epinephrine solution 1100 (0.3mL-0.5mL) and necessary measures to ensure airway patency. The incidence of angioedema in black patients using Entresto is higher than that in non-black patients. 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 ACEI or ARB therapy should not use Entresto (see [Contraindications]). 3. Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Due to the risk of angioedema, Entresto should not be used in combination with AC. Must Entresto should not be started until 36 hours after the last dose of AC. If Entresto treatment is discontinued, ACE 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 in combination with direct renin inhibitors (such as aliskiren) (see [Contraindications] and [Drug Interactions]. Entresto is contraindicated in patients with type 2 diabetes (see [Contraindications I]. Due to its activity in antagonizing angiotensin I receptors, Entresto should not be used in combination with ARBs (see Dosage and Administration] and [Drug Interactions]. 4. Hypotension: Entresto can lower blood pressure and may cause symptomatic hypotension. Patients with activated renin-angiotensin system (such as patients with insufficient blood volume or electrolytes, such as patients receiving high-dose diuretics) are at greater risk. In the double-blind phase of the PARADIGM-HF study, 18% Adverse events of hypotension were reported in 12% of patients treated with Entresto and 12% of patients treated with enalapril (see [Adverse Reactions]). Severe adverse events of hypotension were reported in approximately 1.5% of patients in both treatment groups. Before administering Entresto, hypovolemia or electrolyte insufficiency should be corrected or the drug should be started at a lower dose. If hypotension occurs, consider adjusting the dose of diuretics and concomitant antihypertensive drugs, and treating other causes of hypotension (such as hypovolemia). If hypotension persists after these measures, reduce the dose of Entresto or temporarily discontinue it. Discontinuation of treatment is usually not required. 5. Renal impairment: Due to the inhibition of the renin-angiotensin-aldosterone system (RAAS), it is expected that susceptible individuals may experience decreased renal function when treated with Entresto. In the double-blind phase of the PARADIGM-HF study, 5% of patients in both the Entresto group and the enalapril group reported adverse events of renal failure. Adverse events (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 may be associated with oliguria, progressive azotemia, rare acute renal failure, and death. If a patient develops clinically significant renal impairment, closely monitor serum creatinine and reduce the dose of Entresto or suspend administration (see [Dosage and Administration] - Special Populations and [Pharmacokinetics]). Like other drugs that affect the renin-angiotensin-aldosterone system, Entresto may cause increased blood urea and serum creatinine levels 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. 6. Hyperkalemia: Hyperkalemia may occur during treatment with Entresto by acting on RAAS. In the double-blind phase of the PARADIGM-HF study, 1 Hyperkalemia adverse events were reported in 2% of patients treated with Entresto and 14% of patients treated with enalapril (see [Adverse Reactions]). Serum potassium levels should be monitored regularly and treated appropriately, especially in patients with risk factors for hyperkalemia (such as severe renal impairment, diabetes, hypoaldosteronism, or those on a high-potassium diet). Entresto dose reduction or discontinuation may be necessary (see [Dosage and Administration]). Patients with NYHA functional class IV: Due to limited clinical experience in patients with NYHA functional class IV, caution should be exercised when starting Entresto treatment in such patients. B-type natriuretic peptide (BNP): B-type natriuretic peptide (BNP) is a substrate for neprilysin. B-type natriuretic peptide (BNP) is not a suitable biomarker for heart failure in patients receiving Entresto. 7. Patients with impaired liver function: In patients with moderate hepatic impairment (Child-Pugh B class) or AST Clinical experience with Entresto in patients with ALT values ​​exceeding twice the upper limit of normal is limited. Exposure may be increased in these patients, and a safety profile has not been established. Therefore, caution is advised in such patients. Entresto is contraindicated in patients with severe hepatic impairment, biliary cirrhosis, or cholestasis (Child-Pugh C).

[Pharmacology and Toxicology]
1. Pharmacological Action: Sacubitril/valsartan sodium contains the enkephalinase inhibitor sacubitril and the angiotensin receptor antagonist valsartan. Sacubitril/valsartan sodium inhibits enkephalinase (neutral endopeptidase NEP) via LBQ657 (the active metabolite of the prodrug sacubitril). Valsartan also blocks the angiotensin I type 1 receptor (AT1). LBQ657 increases the levels of peptides degraded by enkephalinase (e.g., natriuretic peptides), while valsartan inhibits the effects of angiotensin I. This may have a negative impact on patients with heart failure. Cardiovascular and renal effects. Valsartan can inhibit the action of angiotensin II by selectively blocking AT1 receptors, and can also inhibit angiotensin I-dependent aldosterone release. 2. Toxicological studies (1) Genotoxicity The results of the Ames test, in vitro chromosome aberration test, and in vivo micronucleus test of sacubitril-valsartan sodium and sacubitril were all negative. The in vitro chromosome aberration test result of LBQ657 was negative. (2) Reproductive toxicity When rats were given a dose of up to 150 mg/kg/day, which was 1.0 times and <0.18 times the maximum recommended human dose (MRHD) based on the AUC of valsartan and LBQ657, respectively, no significant effect of sacubitril-valsartan sodium on fertility or early embryonic development was observed. Pregnant rats were given a dose of ≥100 mg/kg/day [based on AUC, <0.72 times the MRHD], and the pregnancy-free dose was 210 mg/kg/day [based on the AUC of valsartan and LBQ657] No increase in embryonic-fetal mortality was observed at 2 times and 0.03 times the MRHD, respectively, based on AUC. Based on the low incidence of embryonic hydrocephalus related to maternal toxicity observed at doses ≥10 mg/day, sacubitril/valsartan sodium is believed to affect fetal growth and development. The embryonic-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, doses of sacubitril up to 750 mg/kg/day [2.2 times the MRHD based on AUC] and valsartan up to 600 mg/kg/day [0.86 times the MRHD based on AUC] were administered. Effects on fetal/juvenile development and survival were observed during organogenesis, pregnancy, and lactation. Young (2-4 years old) cynomolgus monkeys were given sacubitril orally for 2 weeks. The effect of sacubitril sodium 50 mg/day on the concentration of amyloid-B in cerebrospinal fluid and brain tissue was evaluated. Increased levels of AB1-40, 1-42 and 1-38 were observed in cerebrospinal fluid, but no corresponding increase in AB levels in the brain was observed. In a 2-week human study in healthy volunteers, no increase in cerebrospinal fluid A140 and 1-4 was observed. Sacubitril sodium 300 mg/day was orally administered to cynomolgus monkeys for 39 consecutive weeks, and no accumulation of amyloid-B in the brain was observed. (3) Carcinogenicity The highest doses of sacubitril administered to mice and rats were 1200 and 400 mg/day, respectively [approximately 29 times and 19 times the MRHD in mg/m2]. The highest doses of valsartan administered to mice and rats were 160 and 200 mg/day, respectively [approximately 4 times and 10 times the MRHD in mg/m2]. No teratogenic effects of sacubitril and valsartan were observed.