Sacubitril And Valsartan
FDA Drug Information • Also known as: Entresto, Sacubitril And Valsartan, Sacubitril And Valsartan Sacubitril And Valsartan
- Brand Names
- Entresto, Sacubitril And Valsartan, Sacubitril And Valsartan Sacubitril And Valsartan
- Drug Class
- Angiotensin 2 Receptor Blocker [EPC]
- Route
- ORAL
- Dosage Form
- TABLET
- Product Type
- HUMAN PRESCRIPTION DRUG
⚠ Boxed Warning (Black Box)
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)Description
11 DESCRIPTION Sacubitril and valsartan tablets is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker. Sacubitril and valsartan contains a complex comprised of anionic forms of Sacubitril, Valsartan and sodium cations in the 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 (4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4oxobutanoate) (N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate). Its empirical formula is C 48 H 55 N 6 O 8 .Na 3 . Its molecular mass is 913 g/mol and its schematic structural formula is: 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. 565
What Is Sacubitril And Valsartan Used For?
1 INDICATIONS AND USAGE Sacubitril and valsartan tablets are a combination of sacubitril, a neprilisin inhibitor, and valsartan, an angiotensin II receptor blocker, and 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. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. ( 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 reduces NT-proBNP and is expected to improve cardiovascular outcomes. ( 1.2 ) 1.1 Adult 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. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal. LVEF is a variable measure, so use clinical judgment in deciding whom to treat [ see Clinical Studies ( 14.1 )] . 1.2 Pediatric 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/103 mg 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 not currently taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) or previously taking a low dose of these agents. ( 2.6 ) o patients with severe renal impairment. ( 2.7 ) o patients with moderate hepatic impairment. ( 2.8 ) 2.1 General 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 )]. 2.2 Adult Heart Failure The recommended starting dose of sacubitril and valsartan tablets are 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. 2.3 Pediatric 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 is 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 )]. 2.4 Preparation 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...Side Effects (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 XLCare Pharmaceuticals, Inc. at 1-866-495-1995 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. A total of 6,622 heart failure patients were treated with sacubitril and valsartan in the PARADIGM-HF (vs. enalapril) and PARAGON-HF (vs. valsartan) clinical trials. Of these, 5,085 were exposed for at least 1 year. Adult Heart Failure In PARADIGM-HF, patients were required to complete sequential enalapril and sacubitril and valsartan tablets run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing sacubitril and valsartan tablets 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 tablets 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 tablets and 4,229 treated with enalapril. In PARADIGM-HF, patients randomized to sacubitril and valsartan tablets 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 tablets-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 tablets 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 tablets run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with sacubitril and valsartan tablets than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with sacubitril and valsartan tablets 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 tablets 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 tablets in the Double-Blind Period of PARADIGM-HF Sacubitril and valsartan tablets (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 In PARAGON-HF, no new adverse reactions were identified. Pediatric Heart Failure The adverse reactions...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 ) 7.1 Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of sacubitril and valsartan tablets with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see Contraindications ( 4 )] . Avoid use of sacubitril and valsartan tablets with an ARB, because sacubitril and valsartan tablets contains the angiotensin II receptor blocker valsartan. The concomitant use of sacubitril and valsartan tablets 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 m²). 7.2 Potassium-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 )]. 7.3 Nonsteroidal 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 tablets may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically. 7.4 Lithium 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 tablets.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 )Pregnancy and Breastfeeding
8.1 Pregnancy Risk Summary Sacubitril and valsartan tablets 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 tablets 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 tablets. 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...
Overdosage
10 OVERDOSAGE 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. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of sacubitril and valsartan tablets. Symptomatic treatment should be provided. Sacubitril and valsartan tablets is unlikely to be removed by hemodialysis because of high protein binding.
How Supplied
16 HOW 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. Tablet Color Debossment NDC # 72865-XXX-XX Sacubitril/Valsartan Bottle of 60 Bottle of 180 24 mg/26 mg White to off-white J13 310-60 310-18 49 mg/51 mg Light pink J14 311-60 311-18 97 mg/103 mg White to off-white J15 312-60 312-18 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.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.