Sacubitril and valsartan 49 mg; 51 mg Tablet, Film Coated, 180-count — NDC 31722-674-18 (Billing 31722-0674-18)
This is a package of 180 tablets of Sacubitril and valsartan 49 mg; 51 mg Tablet, Film Coated from Camber Pharmaceuticals, Inc., marketed since Jul 2025 and currently FDA-listed; retail pharmacies pay about $0.5334 per tablet (NADAC).
Identity & classification
Regulatory identifiers FDA, NLM and CMS codes for this package
Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification
- GSN (GCN sequence number): 074409
- GCN: 39047
- GPI-14 (Medi-Span): 40992002600330
- HICL (First Databank): 042256
- AHFS class code: 24:32.12.00
- RxCUI (RxNorm): 1656340
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
- RxNorm (NLM RxNav) · catalog refreshed Oct 1, 2026
- Medi-Span GPI (licensed)
- First Databank (licensed) · refreshed Oct 1, 2026
RxNorm drug class
This medicine belongs to the Angiotensin II receptor blockers (ARBs), other combinations class.
Where does this data come from?
- RxClass (NLM) · catalog refreshed Oct 1, 2026
Clinical
- Sacubitril and valsartan works on two fronts at once. One part (sacubitril) helps your body's own protective heart hormones stick around longer, which helps your kidneys get rid of...
- What exactly is this medication supposed to do for my heart failure?
- That's a really important question. A few combinations need to be avoided or watched carefully. You should never take this with an ACE inhibitor like lisinopril or enalapril at the...
- Can I take it with my other medications? I'm also on ibuprofen sometimes for pain.
Patient education
Supplement & herbal interactions
Where does this data come from?
- MedlinePlus (NLM) · refreshed Oct 1, 2026
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Ask a licensed pharmacist directly — free, answered by our team.
Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.533 | $96.01 / 180 tablets |
| Medicaid paysCMS SDUD · 12 mo | $1.09 | $196.54 / 180 tablets |
| Medicare drug plans payPart D · Q2 2026 | $1.45 | $261.41 / 180 tablets |
Where does this data come from?
- CMS NADAC weekly file · file of Sep 30, 2026
- CMS ASP pricing files · refreshed Sep 20, 2026
- CMS Medicaid State Drug Utilization Data · through Q1 2026
- CMS Part D plan pricing files · refreshed Sep 24, 2026
- VA National Acquisition Center price file
Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Marketing end | Status |
|---|---|---|---|---|---|---|
| 31722-0674-18 You're viewing this | 180 TABLET, FILM COATED in 1 BOTTLE | $0.5334 / ea | $96.01 | 2025-07-23 | — | Active |
| 31722-0674-60 31722-674-60 Main listing | 60 TABLET, FILM COATED in 1 BOTTLE | $0.5334 / ea | $32.00 | 2025-07-23 | — | Active |
You're viewing the largest of 2 pack sizes for this product.
This pack has the lowest per-ea cost of the 2 priced pack sizes ($0.5334 NADAC).
This pack accounts for about 2.4% of this product's recent Medicaid fills; most go to the 60 tablets pack. See all packs ↓
Pack size FAQ
What quantity is in this package?
How does this package differ from NDC 31722-0674-60?
What NDC number is used to bill for this package of Sacubitril and valsartan 49 mg; 51 mg Tablet, Film Coated?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Sacubitril and Valsartan 49 mg/1; 51 mg 00904-7582-04 | Major | 1 tablet | $0.533 | AB | Availability likely | — |
| Sacubitril and valsartan 49 mg/1; 51 mgthis 31722-0674-18 | Camber | 180 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 33342-0571-09 | Macleods | 60 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan Sacubitril and Valsartan 49 mg/1; 51 mg 43598-0644-18 | Dr. | 180 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 50268-0607-15 | AvPAK | 1 tablet | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 60687-0966-57 | American | 1 tablet | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 69238-2732-01 | Amneal | 60 tablets | $0.533 | AB | Availability likely | — |
| sacubitril and valsartan 49 mg/1; 51 mg 70748-0196-07 | Lupin | 60 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 70954-0976-20 | ANI | 60 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 72205-0281-18 | Novadoz | 180 tablets | $0.533 | AB | Availability likely | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 82293-0028-10 | Novugen | 60 tablets | $0.533 | AB | Availability likely | — |
| Entresto 49 mg/1; 51 mg 00078-0777-20 | Novartis | 60 tablets | $11.561 | AB | Availability likely | +2067% |
| Entresto 49 mg/1; 51 mg 00078-9777-50 | Novartis | 28 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 13668-0635-05 | Torrent | 500 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 13668-0746-05 | Torrent | 500 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 42385-0931-18 | Laurus | 180 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 46708-0557-10 | Alembic | 10 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 51407-0936-10 | Golden | 1000 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 62332-0557-10 | Alembic | 10 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 67877-0708-51 | Ascend | 180 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 67877-0949-33 | Ascend | 10 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 70069-0854-60 | Somerset | 60 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 70377-0032-11 | Biocon | 30 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 70710-1273-04 | Zydus | 100 tablets | — | AB | FDA listed | — |
| sacubitril and valsartan 49 mg/1; 51 mg 70771-1922-04 | Zydus | 100 tablets | — | AB | FDA listed | — |
| Entresto 49 mg/1; 51 mg 71610-0806-32 | Aphena | 780 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 71610-0939-32 | Aphena | 780 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 71610-0982-89 | Aphena | 720 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 72865-0311-10 | XLCare | 1000 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 73190-0006-10 | AvKARE | 1000 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 51 mg/1; 49 mg 73190-0018-18 | AvKARE | 180 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 72603-0881-01 | NorthStar | 60 tablets | — | AB | FDA listed | — |
| Sacubitril and Valsartan 49 mg/1; 51 mg 60290-0086-01 | Umedica | 60 tablets | — | AB | FDA listed | — |
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- FDA Orange Book · refreshed Sep 3, 2026
- CMS NADAC weekly file · file of Sep 30, 2026
Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
- FDA Orange Book · refreshed Sep 3, 2026
What it looks like
Where does this data come from?
- FDA label on DailyMed · label index refreshed Oct 1, 2026
Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.- FDA label on DailyMed · label index refreshed Oct 1, 2026
- FDA openFDA NDC Directory · synced Oct 1, 2026
Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
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Manufacturer & labeler
Where does this data come from?
- FDA openFDA NDC Directory · synced Oct 1, 2026
- Drugs@FDA
Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue sacubitril and valsartan tablets as soon as possible (5.1) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. • When pregnancy is detected, discontinue sacubitril and valsartan tablets as soon as possible. (5.1) • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
(5.1)
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Sacubitril and valsartan tablets are a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and is indicated: • to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. ( 1.1 ). • for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. Sacubitril and valsartan tablets reduces NT-proBNP and is expected to improve cardiovascular outcomes.
( 1.2 )
1.1Adult Heart Failure Sacubitril and valsartan tablets are indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure and reduced ejection fraction. Left ventricular ejection fraction (LVEF) is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)] .
1.2Pediatric Heart Failure Sacubitril and valsartan tablets are indicated for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older. Sacubitril and valsartan tablets reduces NT-proBNP and is expected to improve cardiovascular outcomes.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION • The recommended starting dosage for adults is 49 mg/51 mg orally twice daily. The target maintenance dose is 97 mg/103mg orally twice daily. ( 2.2 ) • Adjust adult doses every 2 to 4 weeks to the target maintenance dose, as tolerated by the patient.
( 2.2 ) • For pediatric patients, see the Full Prescribing Information for recommended dosage, titrations, preparation and administration instructions. ( 2.3 , 2.4 ) • Reduce starting dose to half the usually recommended starting dosage for: o patients with severe renal impairment. ( 2.7 ) o patients with moderate hepatic impairment.
( 2.8 )
2.1General Considerations Sacubitril and valsartan tablets are contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. If switching from an ACE inhibitor to sacubitril and valsartan tablets allow a washout period of 36 hours between administration of the two drugs [see Contraindications ( 4 ) and Drug Interactions ( 7.1 )] .
2.2Adult Heart Failure The recommended starting dose of sacubitril and valsartan tablets is 49/51 mg orally twice-daily. Double the dose of sacubitril and valsartan tablets after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.
2.3Pediatric Heart Failure For the recommended dosage for pediatric patients aged 1 year and older, refer to Table 1 if using the tablets. Take the recommended dose orally twice daily. Adjust pediatric patient doses every 2 weeks, as tolerated by the patient.
Table 1: Recommended Dose and Titration for Pediatric Patients Using Tablets Weight (kg) Titration Step Dose (twice daily) Starting Second Final Less than 40 kg † 1.6 mg/kg 2.3 mg/kg 3.1 mg/kg At least 40 kg, less than 50 kg 24 mg/26 mg 49 mg/51 mg 72 mg/78 mg ‡ At least 50 kg 49 mg/51 mg 72 mg/78 mg ‡ 97 mg/103 mg † Use of the oral suspension recommended in these patients. Recommended mg/kg doses are of the combined amount of both sacubitril and valsartan [see Dosage and Administration (2.4)] . ‡ Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets [see Dosage Forms and Strengths (3)] .
2.4Preparation of Oral Suspension Using Tablets Sacubitril and valsartan oral suspension can be substituted at the recommended tablet dosage in patients unable to swallow tablets. Sacubitril and valsartan 800 mg/200 mL oral suspension can be prepared in a concentration of 4 mg/mL (sacubitril/valsartan 1.96/2.04 mg/mL). Use sacubitril and valsartan 49/51 mg tablets in the preparation of the suspension.
To make an 800 mg/200 mL (4 mg/mL) oral suspension, transfer eight tablets of sacubitril and valsartan 49/51 mg film-coated tablets into a mortar. Crush the tablets into a fine powder using a pestle. Add 60 mL of Ora-Plus ® into the mortar and triturate gently with pestle for 10 minutes, to form a uniform suspension.
Add 140 mL of Ora-Sweet ® SF into mortar and triturate with pestle for another 10 minutes, to form a uniform suspension. Transfer the entire contents from the mortar into a clean 200 mL amber colored PET or glass bottle. Place a press-in bottle adapter and close the bottle with a child resistant cap.
The oral suspension can be stored for up to 15 days. Do not store above 25°C (77°F) and do not refrigerate. Shake before each use. * Ora-Sweet SF ® and Ora-Plus ® are registered trademarks of Paddock Laboratories, Inc.
2.7Dose Adjustment for Severe Renal Impairment In adults and pediatric patients with severe renal impairment estimated glomerular filtration rate (eGFR less than 30 mL/min/1.73 m 2 ), start sacubitril and valsartan tablets at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter [see Dosage and Administration ( 2.2 , 2.3 )]. Note: Initiate pediatric patients weighing 40 to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension [see Dosage and Administration ( 2.3 , 2.4 )] .
No starting dose adjustment is n… [Excerpted — this section continues on DailyMed.]
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Sacubitril and Valsartan Tablets are supplied in the following strengths: Sacubitril and Valsartan Tablets 24 mg/26 mg are white colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S24’ on the other side. Sacubitril and Valsartan Tablets 49 mg/51 mg are blue colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S25’ on the other side. Sacubitril and Valsartan Tablets 97 mg/103 mg are brown colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S26’ on the other side. • Film-coated tablets: 24/26 mg; 49/51 mg; 97/103 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Sacubitril and valsartan tablets are contraindicated: • in patients with hypersensitivity to any component • in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warnings and Precautions ( 5.2 )] • with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions (7.1)] • with concomitant use of aliskiren in patients with diabetes [see Drug Interactions (7.1 )] • Hypersensitivity to any component.
( 4 ) • History of angioedema related to previous ACEi or ARB therapy. ( 4 ) • Concomitant use with ACE inhibitors. ( 4 , 7.1 ) • Concomitant use with aliskiren in patients with diabetes.
( 4 , 7.1 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS • Observe for signs and symptoms of angioedema and hypotension. ( 5.2 , 5.3 ) • Monitor renal function and potassium in susceptible patients. ( 5.4 , 5.5 )
5.1Fetal Toxicity Sacubitril and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alternative drug treatment and discontinue sacubitril and valsartan.
However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus [see Use in Specific Populations (8.1 )].
5.2Angioedema Sacubitril and valsartan may cause angioedema [see Adverse Reactions ( 6.1 )] . If angioedema occurs, discontinue sacubitril and valsartan immediately, provide appropriate therapy, and monitor for airway compromise. Sacubitril and valsartan must not be re-administered.
In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway.
Sacubitril and valsartan has been associated with a higher rate of angioedema in Black than in non-Black patients. Patients with a prior history of angioedema may be at increased risk of angioedema with sacubitril and valsartan [see Adverse Reactions ( 6.1 )] . Sacubitril and valsartan must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy [see Contraindications ( 4 )] .
Sacubitril and valsartan should not be used in patients with hereditary angioedema.
5.3Hypotension Sacubitril and valsartan lowers blood pressure and may cause symptomatic hypotension [see Adverse Reactions ( 6.1 )] . Patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. Correct volume or salt depletion prior to administration of sacubitril and valsartan or start at a lower dose.
If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue sacubitril and valsartan. Permanent discontinuation of therapy is usually not required.
5.4Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with sacubitril and valsartan [see Adverse Reactions ( 6.1 )] . In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, progressive azotemia and, rarely, acute renal failure and death.
Closely monitor serum creatinine, and down-titrate or interrupt sacubitril and valsartan in patients who develop a clinically significant decrease in renal function [see Use in Specific Populations ( 8.7 ) and Clinical Pharmacology ( 12.3 )] . As with all drugs that affect the RAAS, sacubitril and valsartan may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenos… [Excerpted — this section continues on DailyMed.]
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: • Angioedema [see Warnings and Precautions ( 5.2)] • Hypotension [see Warnings and Precautions (5.3)] • Impaired Renal Function [see Warnings and Precautions (5.4 )] • Hyperkalemia [see Warnings and Precautions (5.5 )] Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hetero Labs Limited at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
6.1Clinical 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. Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and sacubitril and valsartan run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing sacubitril and valsartan and enalapril.
During the enalapril run-in period, 1,102 patients (10.5%) were permanently discontinued from the study, 5.6% because of an adverse event, most commonly renal dysfunction (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). During the sacubitril and valsartan run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%). Because of this run-in design, the adverse reaction rates described below are lower than expected in practice.
In the double-blind period, safety was evaluated in 4,203 patients treated with sacubitril and valsartan and 4,229 treated with enalapril. In PARADIGM-HF, patients randomized to sacubitril and valsartan received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year. Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of sacubitril and valsartan treated patients and 516 (12.2%) of patients receiving enalapril.
Adverse reactions occurring at an incidence of greater than or equal to 5% in patients who were treated with sacubitril and valsartan in the double-blind period of PARADIGM-HF are shown in Table 3. In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and sacubitril and valsartan run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril and valsartan than enalapril (0.5% and 0.2%, respectively).
The incidence of angioedema in Black patients was 2.4% with sacubitril and valsartan and 0.5% with enalapril [see Warnings and Precautions ( 5.2 )] . Orthostasis was reported in 2.1% of patients treated with sacubitril and valsartan compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF. Falls were reported in 1.9% of patients treated with sacubitril and valsartan compared to 1.3% of patients treated with enalapril.
Table 3: Adverse Reactions Reported in greater than or equal to 5% of Patients Treated with Sacubitril and Valsartan in the Double-Blind Period of PARADIGM-HF Sacubitril and Valsartan (n = 4,203) % Enalapril (n = 4,229) % Hypotension 18 12 Hyperkalemia 12 14 Cough 9 13 Dizziness 6 5 Renal failure/acute renal failure 5 5 Pediatric Heart Failure The adverse reactions observed in pediatric patients 1 year to less than 18 years old who received treatment with sacubitril and valsartan were consistent with those observed in adult patients.
Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 5% of both sacubitril and valsartan- and enalapril-treated patients in the double… [Excerpted — this section continues on DailyMed.]
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS • Avoid concomitant use with aliskiren in patients with estimated glomerular filtration rate (eGFR) less than 60. ( 7.1 ) • Potassium-sparing diuretics: May lead to increased serum potassium. ( 7.2 ) • Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): May lead to increased risk of renal impairment. ( 7.3 ) • Lithium: Increased risk of lithium toxicity. ( 7.4 )
7.1Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of sacubitril and valsartan with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see Contraindications ( 4 )]. Avoid use of sacubitril and valsartan with an ARB, because sacubitril and valsartan contains the angiotensin II receptor blocker valsartan. The concomitant use of sacubitril and valsartan with aliskiren is contraindicated in patients with diabetes [see Contraindications ( 4 )].
Avoid use with aliskiren in patients with renal impairment (eGFR less than 60 mL/min/1.73 m 2 ).
7.2Potassium-Sparing Diuretics As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium [see Warnings and Precautions ( 5.5 )].
7.3Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with sacubitril and valsartan may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.
7.4Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with sacubitril and valsartan.
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding not recommended. ( 8.2 ) • Severe Hepatic Impairment: Use not recommended. ( 2.8 , 8.6 )
8.1Pregnancy Risk Summary Sacubitril and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.
In animal reproduction studies, sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits ( see Data ). When pregnancy is detected, consider alternative drug treatment and discontinue sacubitril and valsartan. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.
Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to sacubitril and valsartan for hypotension, oliguria, and hyperkalemia.
In neonates with a history of in utero exposure to sacubitril and valsartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).
Sacubitril and valsartan is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an sacubitril and valsartan dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of sacubitril and valsartan are attributed to the angiotensin receptor antagonist activity. Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with sacubitril and… [Excerpted — this section continues on DailyMed.]
🤰 Pregnancy ▾
8.1Pregnancy Risk Summary Sacubitril and valsartan can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death ( see Clinical Considerations ). Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.
In animal reproduction studies, sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits ( see Data ). When pregnancy is detected, consider alternative drug treatment and discontinue sacubitril and valsartan. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation.
Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to sacubitril and valsartan for hypotension, oliguria, and hyperkalemia.
In neonates with a history of in utero exposure to sacubitril and valsartan, if oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replacing renal function. Data Animal Data Sacubitril and valsartan treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses greater than or equal to 49 mg sacubitril/51 mg valsartan/kg/day (less than or equal to 0.06 [LBQ657, the active metabolite] and 0.72 [valsartan]-fold the maximum recommended human dose [MRHD] of 97/103 mg twice-daily on the basis of the area under the plasma drug concentration-time curve [AUC]) and rabbits at doses greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and LBQ657 AUC, respectively).
Sacubitril and valsartan is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an sacubitril and valsartan dose of greater than or equal to 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of sacubitril and valsartan are attributed to the angiotensin receptor antagonist activity. Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (2.2-fold the MRHD on the basis of LBQ657 AUC) and valsartan at doses up to 600 mg/kg/day (0.86-fold the MRHD on the basis of AUC) indicate that treatment with sacubitril and valsartan during organogenesis, gestation and lactation may affect pup development and survival.
🧒 Pediatric Use ▾
8.4Pediatric Use The safety and effectiveness of sacubitril and valsartan have been established for the treatment of heart failure in pediatric patients 1 year to less than 18 years. Use of sacubitril and valsartan was evaluated in a multinational, randomized, double-blind trial comparing sacubitril and valsartan and enalapril in 375 patients aged 1 month to less than 18 years (sacubitril and valsartan n = 187; Enalapril n = 188) (PANORAMA-HF) [see Clinical Studies ( 14.2 )] . The safety profile in pediatric patients (1 year to less than 18 years) receiving sacubitril and valsartan was similar to that seen in adult patients.
Limited safety and efficacy data in patients aged 1 month to less than 1 year were inadequate to support conclusions on safety and efficacy in this age group. Juvenile Animal Toxicity Data Sacubitril given orally to juvenile rats from postnatal day (PND) 7 to PND 35 or PND 70 (an age approximately equivalent to neonatal through pre-pubertal development or adulthood in humans) at doses greater than or equal to 400 mg/kg/day (approximately 2-fold the AUC exposure to the active metabolite of sacubitril, LBQ657, at an sacubitril and valsartan pediatric clinical dose of 3.1 mg/kg twice daily) resulted in decreases in body weight, bone length, and bone mass.
The decrease in body weight was transient from PND 10 to PND 20 and the effects for most bone parameters were reversible after treatment stopped. Exposure at the No-Observed-Adverse-Effect-Level (NOAEL) of 100 mg/kg/day was approximately 0.5-fold the AUC exposure to LBQ657 at the 3.1 mg/kg twice daily dose of sacubitril and valsartan. The mechanism underlying bone effects in rats and the translatability to pediatric patients are unknown.
Valsartan given orally to juvenile rats from PND 7 to PND 70 (an age approximately equivalent to neonatal through adulthood in humans) produced persistent, irreversible kidney damage at all dose levels. Exposure at the lowest tested dose of 1 mg/kg/day was approximately 0.2-fold the exposure at 3.1 mg/kg twice daily dose of sacubitril and valsartan based on AUC. These kidney effects in neonatal rats represent expected exaggerated pharmacological effects that are observed if rats are treated during the first 13 days of life.
This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans. In humans, nephrogenesis is thought to be complete around birth; however, maturation of other aspects of kidney function (such as glomerular filtration and tubular function) may continue until approximately 2 years of age. It is unknown whether post-natal use of valsartan before maturation of renal function is complete has long-term deleterious effects on the kidney.
🧓 Geriatric Use ▾
8.5Geriatric Use There were 4,143 heart failure patients 65 years of age and older in PARADIGM-HF [see Clinical Studies ( 14 )] . Of the total number of sacubitril and valsartan-treated patients, 2,087 (49.6%) were 65 years of age and older, while 786 (18.7%) were 75 years of age and older in PARADIGM-HF. No overall differences in safety or effectiveness of sacubitril and valsartan have been observed between patients 65 years of age and older and younger adult patients.
No relevant pharmacokinetic differences have been observed in elderly (≥ 65 years) or very elderly (≥ 75 years) patients compared to the overall population [see Clinical Pharmacology ( 12.3 )].
🆘 Overdosage ▾
10 OVERDOSAGE Limited data are available with regard to overdosage in human subjects with sacubitril and valsartan. In healthy volunteers, a single dose of sacubitril and valsartan 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. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of sacubitril and valsartan.
Symptomatic treatment should be provided. Sacubitril and valsartan is unlikely to be removed by hemodialysis because of high protein binding.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.
Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
12.2Pharmacodynamics The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.
In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. Sacubitril and valsartan also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril and valsartan decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.
In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for sacubitril and valsartan (40% and 50%) compared to baseline. The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for sacubitril and valsartan at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.
Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology ( 13 )].
Blood Pressure: Addition of a 50 mg single dose of sildenafil to sacubitril and valsartan at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of sacubitril and valsartan alone. Co-administration of sacubitril and valsartan did not significantly alter the BP effect of intravenous nitroglycerin.
12.3Pharmacokinetics Absorption Following oral administration, sacubitril and valsartan dissociates into sacubitril and valsartan. Sacubitril is further metabolized to LBQ657. The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively.
The oral absolute bioavailability of sacubitril is estimated to be greater than or equal to 60%. The valsartan in sacubitril and valsartan tablets is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril a… [Excerpted — this section continues on DailyMed.]
🧬 Mechanism of Action ▾
12.1Mechanism of Action Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.
Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Sacubitril and Valsartan Tablets 24 mg/26 mg are white colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S24’ on the other side. Bottle of 60 NDC 31722-673-60 Bottle of 180 NDC 31722-673-18 Sacubitril and Valsartan Tablets 49 mg/51 mg are blue colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S25’ on the other side. Bottle of 60 NDC 31722-674-60 Bottle of 180 NDC 31722-674-18 Sacubitril and Valsartan Tablets 97 mg/103 mg are brown colored, oval shaped, film-coated tablets debossed with ‘H’ on one side and ‘S26’ on the other side.
Bottle of 60 NDC 31722-675-60 Bottle of 180 NDC 31722-675-18 Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Protect from moisture.
📋 Description ▾
11 DESCRIPTION Sacubitril and Valsartan Tablets are a combination of a neprilysin inhibitor and an angiotensin II receptor blocker. Sacubitril and valsartan contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations in the molar ratio of 1:1:3 respectively. Following oral administration, the complex dissociates into sacubitril (which is further metabolized to LBQ657) and valsartan.
The complex is chemically described as Trisodium [3-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-1-butylcarbamoyl) propionate-(S)-3’-methyl-2’-(pentanoyl {2”-(tetrazol-5-ylate) biphenyl-4’-ylmethyl} amino) butyrate]. Its molecular formula is C 48 H 57 N 6 O 8 .3Na. Its molecular mass is 912.97 g/mol and its schematic structural formula is: Sacubitril and valsartan is 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 colloidal silicon dioxide, crospovidone, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, povidone, silicon dioxide. The film-coat inactive ingredients are hypromellose, di-acetylated monoglycerides, titanium dioxide. The film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet contains FD&C Blue No.
2. The film-coat for the 97 mg of sacubitril and 103 mg of valsartan tablet contains iron oxide red. sacubitrilandvalsartantabletsstructure
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling (Patient Information). Pregnancy: Advise female patients of childbearing age about the consequences of exposure to sacubitril and valsartan tablets during pregnancy. Discuss treatment options with women planning to become pregnant.
Ask patients to report pregnancies to their physicians as soon as possible [see Warnings and Precautions ( 5.1 ) and Use in Specific Populations (8.1 )]. Lactation: Advise patients that breastfeeding is not recommended during treatment with sacubitril and valsartan tablets [see Use in Specific Populations ( 8.2 )]. Angioedema: Advise patients to discontinue use of their previous ACE inhibitor or ARB.
Advise patients to allow a 36-hour wash-out period if switching from or to an ACE inhibitor [see Contraindications (4) and Warnings and Precautions ( 5.2 )]. Manufactured for: Camber Pharmaceuticals, Inc. Piscataway, NJ 08854.
By: HETERO TM Hetero Labs Limited Jeedimetla, Hyderabad - 500 055, India. Revised: 07/2025 camber1.
PATIENT INFORMATION Sacubitril and Valsartan (sak UE bi tril and val SAR tan) Tablets, for oral use 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 are sacubitril and valsartan tablets? Sacubitril and valsartan tablets are 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 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 tablets are 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 tablets if 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) • li… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacokinetics ▾
12.3Pharmacokinetics Absorption Following oral administration, sacubitril and valsartan dissociates into sacubitril and valsartan. Sacubitril is further metabolized to LBQ657. The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively.
The oral absolute bioavailability of sacubitril is estimated to be greater than or equal to 60%. The valsartan in sacubitril and valsartan tablets is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril and valsartan is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively. Following twice-daily dosing of sacubitril and valsartan, steady-state levels of sacubitril, LBQ657, and valsartan are reached in 3 days.
At steady state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold. Sacubitril and valsartan administration with food has no clinically significant effect on the systemic exposures of sacubitril, LBQ657, or valsartan. Although there is a decrease in exposure to valsartan when sacubitril and valsartan is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect.
Sacubitril and valsartan can therefore be administered with or without food. Distribution Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94% to 97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%).
The average apparent volumes of distribution of valsartan and sacubitril are 75 and 103 L, respectively. Metabolism Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent. Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites.
A hydroxyl metabolite has been identified in plasma at low concentrations (less than 10%). Elimination Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and approximately 13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces. Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T 1/2 ) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.
Linearity/Nonlinearity The pharmacokinetics of sacubitril, LBQ657, and valsartan were linear over an sacubitril and valsartan dose range of 24 mg sacubitril/26 mg valsartan to 194 mg sacubitril/206 mg valsartan. Drug Interactions: Effect of Co-administered Drugs on Sacubitril and Valsartan: Because CYP450 enzyme-mediated metabolism of sacubitril and valsartan is minimal, coadministration with drugs that impact CYP450 enzymes is not expected to affect the pharmacokinetics of sacubitril and valsartan. Dedicated drug interaction studies demonstrated that coadministration of furosemide, warfarin, digoxin, carvedilol, a combination of levonorgestrel/ethinyl estradiol, amlodipine, omeprazole, hydrochlorothiazide (HCTZ), metformin, atorvastatin, and sildenafil, did not alter the systemic exposure to sacubitril, LBQ657 or valsartan.
Effect of Sacubitril and Valsartan on Co-administered Drugs: In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. The effects of sacubitril and valsartan on the pharmacokinetics of coadministered drugs are summarized in Figure 1. Figure 1: Effect of Sacubitril and Valsartan on Pharmacokinetics of Coadministered Drugs Specific Populations Effect of specific populations on the pharmacokinetics of LBQ657 and valsartan are shown in Figure 2.
Figure 2: Pharmacokinetics of Sacubitril and Valsartan in Specific Populations Note: Child-Pugh Classification was used for hepatic impairment. Pediatric Patients: The pharmacokinetics of sacubitril and valsart… [Excerpted — this section continues on DailyMed.]
🧬 Pharmacodynamics ▾
12.2Pharmacodynamics The pharmacodynamic effects of sacubitril and valsartan were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.
In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. Sacubitril and valsartan also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril and valsartan decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.
In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for sacubitril and valsartan (40% and 50%) compared to baseline. The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for sacubitril and valsartan at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.
Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology ( 13 )].
Blood Pressure: Addition of a 50 mg single dose of sildenafil to sacubitril and valsartan at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of sacubitril and valsartan alone. Co-administration of sacubitril and valsartan did not significantly alter the BP effect of intravenous nitroglycerin.
🔬 Clinical Studies ▾
14 CLINICAL 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.
14.1Adult Heart Failure PARADIGM-HF PARADIGM-HF was a multinational, randomized, double-blind trial comparing sacubitril and valsartan 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, 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 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 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/1.73m 2 , 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, 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 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. Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF Sacubitril and Valsartan N=4,187 n (%) Enalapril N=4,212 n (%) Hazard Ratio (95% CI) p -value Primary composite endpoint of cardiovascular death or heart failure hospitalization Cardiovascular death as first event Heart failure hospitalization as first event 914 (21.8) 377 (9.0) 537 (12.8) 1,117 (26.5) 459 (10.9) 658 (15.6) 0.80 (0.73, 0.87) < 0.0001 Number of patients with events: * Cardiovascular death** Heart failure hospitalizations 558 (13.3) 537 (12.8) 693 (16.5) 658 (15.6) 0.80 (0.71, 0.89) 0.79 (0.71, 0.89) All-cause mortality 711 (17.0) 835 (19.8) 0.84 (0.76… [Excerpted — this section continues on DailyMed.]
🧪 Nonclinical Toxicology ▾
13 NONCLINICAL TOXICOLOGY
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for sacubitril and valsartan. The LBQ657 C max at the high dose (HD) of 1200 mg/kg/day in male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657 C max in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the MRHD.
The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m 2 basis. Mutagenicity and clastogenicity studies conducted with sacubitril and valsartan, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level. Impairment of Fertility Sacubitril and valsartan did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg valsartan/kg/day (≤ 1.0-fold and ≤ 0.18-fold the MRHD on the basis of the AUCs of valsartan and LBQ657, respectively).
13.2Animal Toxicology and/or Pharmacology The effects of sacubitril and valsartan on amyloid-β concentrations in CSF and brain tissue were assessed in young (2 to 4 years old) cynomolgus monkeys treated with sacubitril and valsartan (24 mg sacubitril/26 mg valsartan/kg/day) for 2 weeks. In this study, sacubitril and valsartan affected CSF Aβ clearance, increasing CSF Aβ 1 to 40, 1 to 42, and 1 to 38 levels in CSF; there was no corresponding increase in Aβ levels in the brain. In addition, in a toxicology study in cynomolgus monkeys treated with sacubitril and valsartan at 146 mg sacubitril/154 mg valsartan/kg/day for 39-weeks, there was no amyloid-β accumulation in the brain.
📄 Carcinogenesis, Mutagenesis, Impairment of Fertility ▾
13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for sacubitril and valsartan. The LBQ657 C max at the high dose (HD) of 1200 mg/kg/day in male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657 C max in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the MRHD.
The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m 2 basis. Mutagenicity and clastogenicity studies conducted with sacubitril and valsartan, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level. Impairment of Fertility Sacubitril and valsartan did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg valsartan/kg/day (≤ 1.0-fold and ≤ 0.18-fold the MRHD on the basis of the AUCs of valsartan and LBQ657, respectively).
📄 Package Label / Principal Display Panel ▾
PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Sacubitril and Valsartan Tablets, 24 mg/26 mg (60’s count) -Container Label Sacubitril and Valsartan Tablets, 49 mg/51 mg (60’s count) -Container Label Sacubitril and Valsartan Tablets, 97 mg/103 mg (60’s count) -Container Label sacubitrilandvalsartantablets24mg26mg60s sacubitrilandvalsartantablets49mg51mg60s sacubitrilandvalsartantablets97mg103mg60s