Generic Name
Valsartan
Brand Names
Sacubitril, Entresto, Amlodipine, Exforge, Diovan
FDA approval date: March 06, 1998
Classification: Dihydropyridine Calcium Channel Blocker
Form: Pellet, Tablet, Solution
What is Sacubitril (Valsartan)?
Sacubitril and valsartan tablets are a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker, and are indicated: to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction below normal.
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Brand Information
Sacubitril and Valsartan (Sacubitril and Valsartan)
WARNING: FETAL TOXICITY
• When pregnancy is detected, discontinue Sacubitril and Valsartan Tablets as soon as possible.
1DOSAGE FORMS AND STRENGTHS
Sacubitril and valsartan tablets are supplied as oval shaped, bioconvex, film-coated tablets in the following strengths:
2CONTRAINDICATIONS
Sacubitril and valsartan tablets are contraindicated:
3ADVERSE REACTIONS
Clinically significant adverse reactions that appear in other sections of the labeling include:
• Angioedema [see Warnings and Precautions (Hypotension [see Warnings and Precautions (Impaired Renal Function [see Warnings and Precautions (Hyperkalemia [see Warnings and Precautions (
3.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
In PARAGON-HF, no new adverse reactions were identified.
3.2Postmarketing Experience
The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
4OVERDOSAGE
Limited data are available with regard to overdosage in human subjects with sacubitril and valsartan tablets. In healthy volunteers, a single dose of sacubitril and valsartan tablets 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated.
5DESCRIPTION
Sacubitril and valsartan tablets is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker.
Sacubitril and valsartan tablets are available as film-coated tablets for oral administration, containing 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; and 97 mg of sacubitril and 103 mg of valsartan. The tablet inactive ingredients are microcrystalline cellulose, low-substituted hydroxypropylcellulose, colloidal silicon dioxide, magnesium stearate, crospovidone. The film-coat inactive ingredients are polyvinyl alcohol-part hydrolised, titanium dioxide, Macrogol 4000, talc. The film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet contains iron oxide yellow and iron oxide red.
6CLINICAL STUDIES
Dosing in clinical trials was based on the total amount of both components of sacubitril and valsartan, i.e., 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
6.1Adult Heart Failure
PARADIGM-HF
PARADIGM-HF was a multinational, randomized, double-blind trial comparing sacubitril and valsartan tablets and enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients had to have been on an ACE inhibitor or ARB for at least four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded.
The primary objective of PARADIGM-HF was to determine whether sacubitril and valsartan tablets, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).
After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by sacubitril and valsartan tablets 100 mg twice-daily, increasing to 200 mg twice-daily. Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril and valsartan tablets 200 mg (N = 4,209) twice-daily or enalapril 10 mg (N = 4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
The population was 66% Caucasian, 18% Asian, and 5% Black; the 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%. The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR less than 60 mL/min/1.73m2, and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter- defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%).
PARADIGM-HF demonstrated that sacubitril and valsartan tablets, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, p <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization; see Table 4 and Figure 3. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%.
Sacubitril and valsartan tablets also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 4). This finding was driven entirely by a lower incidence of cardiovascular mortality on sacubitril and valsartan tablets.
Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF
PARADIGM-HF was a multinational, randomized, double-blind trial comparing sacubitril and valsartan tablets and enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients had to have been on an ACE inhibitor or ARB for at least four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded.
The primary objective of PARADIGM-HF was to determine whether sacubitril and valsartan tablets, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).
After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by sacubitril and valsartan tablets 100 mg twice-daily, increasing to 200 mg twice-daily. Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril and valsartan tablets 200 mg (N = 4,209) twice-daily or enalapril 10 mg (N = 4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to 4.3 years.
The population was 66% Caucasian, 18% Asian, and 5% Black; the 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%. The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR less than 60 mL/min/1.73m2, and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter- defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%).
PARADIGM-HF demonstrated that sacubitril and valsartan tablets, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, p <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization; see Table 4 and Figure 3. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%.
Sacubitril and valsartan tablets also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 4). This finding was driven entirely by a lower incidence of cardiovascular mortality on sacubitril and valsartan tablets.
Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF
*Analyses of the components of the primary composite endpoint were not prospectively planned to be adjusted for multiplicity.
Figure C-
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the primary composite endpoint were consistent across the subgroups examined (Figure 4).
Figure 4: Primary Composite Endpoint (CV Death or HF Hospitalization) -Subgroup Analysis (PARADIGM-HF)Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.
PARAGON-HF
PARAGON-HF, was a multicenter, randomized, double-blind trial comparing sacubitril and valsartan tablets in 4,796 adult patients with symptomatic heart failure with left ventricular ejection fraction greater than or equal to 45%, and structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)]. Patients with a systolic blood pressure of less than 110 mmHg and patients with any prior echocardiographic LVEF less than 40% at screening were excluded.
The primary objective of PARAGON-HF was to determine whether sacubitril and valsartan tablets reduced the rate of the composite endpoint of total (first and recurrent) heart failure (HF) hospitalizations and cardiovascular (CV) death.
After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received valsartan 80 mg twice-daily, followed by sacubitril and valsartan tablets 100 mg twice-daily. Patients on prior low doses of an ACEi or ARB began the run-in period receiving valsartan 40 mg twice-daily for 1 to 2 weeks. Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril and valsartan tablets 200 mg (N =2,419) twice-daily or valsartan 160 mg (N = 2,403) twice-daily. The median follow-up duration was 35 months and patients were treated for up to 4.7 years.
The population was 81% Caucasian, 13% Asian, and 2% Black; the mean age was 73 years and 52% were female. At randomization, 77% of patients were NYHA Class II, 19% were NYHA Class III, and 0.4% were NYHA Class IV. The median left ventricular ejection fraction was 57%. The underlying cause of heart failure was of ischemic etiology in 36% of patients. Furthermore, 96% had a history of hypertension, 23% had a history of myocardial infarction, 46% had an eGFR less than 60 mL/min/1.73 m2, and 43% had diabetes mellitus. Most patients were taking beta-blockers (80%) and diuretics (95%).
PARAGON-HF demonstrated that sacubitril and valsartan tablets had a numerical reduction in the rate of the composite endpoint of total (first and recurrent) HF hospitalizations and CV death, based on an analysis using a proportional rates model (rate ratio [RR] 0.87; 95% CI [0.75, 1.01], p = 0.06); see Table 5. The treatment effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to sacubitril and valsartan tablets (RR 0.85; 95% CI [0.72, 1.00]).
Table 5: Treatment Effect for the Primary Composite Endpoint and Its Components in PARAGON-HF
Abbreviations: RR = rate ratio, HR = hazard ratio.
A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes (Figure 6).
Figure 6: Primary Composite Endpoint of Total HF Hospitalizations and CV Death – Subgroup Analysis (PARAGON-HF)
Note: The figure above presents effects in various subgroups, all of which are baseline characteristics. The 95% confidence limits that are shown do not take into account the number of comparisons made, and may not reflect the effect of a particular factor after adjustment for all other factors.
In an analysis of the relationship between LVEF and outcome in PARADIGM-HF and PARAGON-HF, patients with LVEF below normal treated with sacubitril and valsartan tablets experienced greater risk reduction (Figure 7).
Figure 7: Treatment Effect for the Composite Endpoint of Time to First HF Hospitalization or CV Death by LVEF in PARADIGM-HF and PARAGON-HF
6.2Pediatric Heart Failure
The efficacy of sacubitril and valsartan tablets was evaluated in a multinational, randomized, double-blind trial PANORAMA-HF comparing sacubitril and valsartan tablets (n = 187) and enalapril (n = 188) in pediatric patients aged 1 month to less than 18 years old due to systemic left ventricular systolic dysfunction (LVEF ≤ 45% or fractional shortening ≤ 22.5%). Patients with systemic right ventricle, single ventricle, restrictive cardiomyopathy or hypertrophic cardiomyopathy were excluded from the trial. Efficacy of sacubitril and valsartan tablets in patients less than 1 year old was not established. At Week 52, there were 144 sacubitril and valsartan tablets and 133 enalapril patients with a post-baseline assessment of NT-proBNP. The estimated least squares mean percent reduction from baseline in NT-proBNP was 65% and 62% in the sacubitril and valsartan and enalapril groups, respectively. While the between-group difference was not nominally statistically significant, the reductions for sacubitril and valsartan and enalapril were larger than what was seen in adults; these reductions did not appear to be attributable to post-baseline changes in background therapy.
Because sacubitril and valsartan tablets improved outcomes and reduced NT-proBNP in adults in PARADIGM-HF, the effect on NT-proBNP was the basis to infer improved cardiovascular outcomes in pediatric patients.
7HOW SUPPLIED/STORAGE AND HANDLING
Sacubitril and valsartan tablets (sacubitril/valsartan) is available as unscored, ovaloid, biconvex, film-coated tablets, containing 24 mg of sacubitril and 26 mg of valsartan; 49 mg of sacubitril and 51 mg of valsartan; and 97 mg of sacubitril and 103 mg of valsartan. All strengths are packaged in bottles as described below.
Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from moisture.
8PATIENT COUNSELING INFORMATION
Advise patients to read the FDA-approved patient labeling (Patient Information).
Medication Guide available at https://www.xlcarepharma.com/medication-guides
Manufactured for :
Manufactured by:
For more information, call 1-866-495-1995.
Revised: 09/2025
9SPL PATIENT PACKAGE INSERT SECTION
Patient Information
Sacubitril and valsartan tablets
What is the most important information I should know about sacubitril and valsartan tablets?
Sacubitril and valsartan tablets can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. Tell your doctor right away if you become pregnant during treatment with sacubitril and valsartan tablets.
What is sacubitril and valsartan tablet?
Sacubitril and valsartan tablet is a prescription medicine used to treat:
• adults with long-lasting (chronic) heart failure to help reduce the risk of death and hospitalization. Sacubitril and valsartan tablets works better when the heart cannot pump a normal amount of blood to the body.
• certain children 1 year of age and older who have symptomatic heart failure.
It is not known if sacubitril and valsartan tablet is safe and effective in children under 1 year of age.
Do not take sacubitril and valsartan tablets if you: • are allergic to any of the ingredients in sacubitril and valsartan tablets. See the end of this Patient Information leaflet for a complete list of ingredients in sacubitril and valsartan tablets.
• have had an allergic reaction, including swelling of your face, lips, tongue, throat, or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).
• take an ACE inhibitor medicine. Do not take sacubitril and valsartan tablets for at least 36 hours before or after you take an ACE inhibitor medicine. Talk with your doctor or pharmacist before taking sacubitril and valsartan tablet sif you are not sure if you take an ACE inhibitor medicine.
• have diabetes and take a medicine that contains aliskiren.
Before taking sacubitril and valsartan tablets, tell your doctor about all of your medical conditions, including if you:• have a history of hereditary angioedema
• have kidney or liver problems
• have diabetes
• are pregnant or plan to become pregnant. See “What is the most important information I should know about sacubitril and valsartan tablets?”
• are breastfeeding or plan to breastfeed. It is not known if sacubitril and valsartan passes into your breast milk. You should not breastfeed during treatment with sacubitril and valsartan tablets. You and your doctor should decide if you will take sacubitril and valsartan tablets or breastfeed.
Sacubitril and valsartan tablets
What is the most important information I should know about sacubitril and valsartan tablets?
Sacubitril and valsartan tablets can harm or cause death to your unborn baby. Talk to your doctor about other ways to treat heart failure if you plan to become pregnant. Tell your doctor right away if you become pregnant during treatment with sacubitril and valsartan tablets.
What is sacubitril and valsartan tablet?
Sacubitril and valsartan tablet is a prescription medicine used to treat:
• adults with long-lasting (chronic) heart failure to help reduce the risk of death and hospitalization. Sacubitril and valsartan tablets works better when the heart cannot pump a normal amount of blood to the body.
• certain children 1 year of age and older who have symptomatic heart failure.
It is not known if sacubitril and valsartan tablet is safe and effective in children under 1 year of age.
Do not take sacubitril and valsartan tablets if you: • are allergic to any of the ingredients in sacubitril and valsartan tablets. See the end of this Patient Information leaflet for a complete list of ingredients in sacubitril and valsartan tablets.
• have had an allergic reaction, including swelling of your face, lips, tongue, throat, or trouble breathing while taking a type of medicine called an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).
• take an ACE inhibitor medicine. Do not take sacubitril and valsartan tablets for at least 36 hours before or after you take an ACE inhibitor medicine. Talk with your doctor or pharmacist before taking sacubitril and valsartan tablet sif you are not sure if you take an ACE inhibitor medicine.
• have diabetes and take a medicine that contains aliskiren.
Before taking sacubitril and valsartan tablets, tell your doctor about all of your medical conditions, including if you:• have a history of hereditary angioedema
• have kidney or liver problems
• have diabetes
• are pregnant or plan to become pregnant. See “What is the most important information I should know about sacubitril and valsartan tablets?”
• are breastfeeding or plan to breastfeed. It is not known if sacubitril and valsartan passes into your breast milk. You should not breastfeed during treatment with sacubitril and valsartan tablets. You and your doctor should decide if you will take sacubitril and valsartan tablets or breastfeed.
Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking sacubitril and valsartan tablets with certain other medicines may affect each other. Taking sacubitril and valsartan tablets with other medicines can cause serious side effects. Especially tell your doctor if you take:
• potassium supplements or a salt substitute
• nonsteroidal anti-inflammatory drugs (NSAIDs)
• lithium
• other medicines for high blood pressure or heart problems, such as an ACE inhibitor, ARB, or aliskiren
Keep a list of your medicines to show your doctor and pharmacist when you get a new medicine.
How should I take sacubitril and valsartan tablets?• Take sacubitril and valsartan tablets exactly as your doctor tells you to take it.
• Take sacubitril and valsartan tablets 2 times each day. Your doctor may change your dose of sacubitril and valsartan tablets during treatment.
• If you or your child cannot swallow tablets, or if tablets are not available in the prescribed strength, you or your child may take sacubitril and valsartan tablets prepared as a liquid (oral) suspension.
• If you or your child switches between taking sacubitril and valsartan tablets and the liquid suspension prepared from sacubitril and valsartan tablets, your doctor will adjust the dose as needed.
• If you or your child are prescribed sacubitril and valsartan tablets to be prepared as a liquid suspension:
o Your pharmacist will prepare sacubitril and valsartan tablets for you or your child to take as a liquid suspension.
o Shake the bottle of suspension well before measuring the dose of medicine and before taking or giving the dose.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
• If you take too much sacubitril and valsartan tablets, call your doctor right away.
What are the possible side effects of sacubitril and valsartan tablets? See “What is the most important information I should know about sacubitril and valsartan tablets?” Get emergency medical help right away if you have symptoms of angioedema or trouble breathing. Do not take sacubitril and valsartan tablets again if you have had angioedema during treatment with sacubitril and valsartan tablets.
People who are Black and take sacubitril and valsartan tablets may have a higher risk of having angioedema than people who are not Black and take sacubitril and valsartan tablets.
• potassium supplements or a salt substitute
• nonsteroidal anti-inflammatory drugs (NSAIDs)
• lithium
• other medicines for high blood pressure or heart problems, such as an ACE inhibitor, ARB, or aliskiren
Keep a list of your medicines to show your doctor and pharmacist when you get a new medicine.
How should I take sacubitril and valsartan tablets?• Take sacubitril and valsartan tablets exactly as your doctor tells you to take it.
• Take sacubitril and valsartan tablets 2 times each day. Your doctor may change your dose of sacubitril and valsartan tablets during treatment.
• If you or your child cannot swallow tablets, or if tablets are not available in the prescribed strength, you or your child may take sacubitril and valsartan tablets prepared as a liquid (oral) suspension.
• If you or your child switches between taking sacubitril and valsartan tablets and the liquid suspension prepared from sacubitril and valsartan tablets, your doctor will adjust the dose as needed.
• If you or your child are prescribed sacubitril and valsartan tablets to be prepared as a liquid suspension:
o Your pharmacist will prepare sacubitril and valsartan tablets for you or your child to take as a liquid suspension.
o Shake the bottle of suspension well before measuring the dose of medicine and before taking or giving the dose.
• If you miss a dose, take it as soon as you remember. If it is close to your next dose, do not take the missed dose. Take the next dose at your regular time.
• If you take too much sacubitril and valsartan tablets, call your doctor right away.
What are the possible side effects of sacubitril and valsartan tablets? See “What is the most important information I should know about sacubitril and valsartan tablets?” Get emergency medical help right away if you have symptoms of angioedema or trouble breathing. Do not take sacubitril and valsartan tablets again if you have had angioedema during treatment with sacubitril and valsartan tablets.
People who are Black and take sacubitril and valsartan tablets may have a higher risk of having angioedema than people who are not Black and take sacubitril and valsartan tablets.
People who have had angioedema before taking sacubitril and valsartan tablets may have a higher risk of having angioedema than people who have not had angioedema before taking sacubitril and valsartan tablets. See
Prepared sacubitril and valsartan oral suspension also contains Ora-Sweet SF® and Ora-Plus®.
The brands listed are trademarks of their respective owners
Medication Guide available at https://www.xlcarepharma.com/medicationguides.
Manufactured for:
Manufactured by:
Revised: 05/25
For more information, call 1-866-495-1995.
10PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
Sacubitril and Valsartan Tablets 24/26 mg
