Sacubitril and Valsartan

RECENT MAJOR CHANGES SECTION Dosage and Administration. ( 2.3 ) 4/2024

1 INDICATIONS AND USAGE Sacubitril and valsartan tablets are a combination of sacubitril, a neprilysin 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. 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 tablets 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.

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 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 is 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 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. 2.3 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 tablets 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 tablets 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. 2.6 Dose Adjustment for Patients Not Taking an ACE inhibitor or ARB or Previously Taking Low Doses of These Agents In patients not currently taking an ACE inhibitor or an angiotensin II receptor blocker (ARB) and for patients previously taking low doses of these agents, start sacubitril and valsartan tablets at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults an …

3 DOSAGE FORMS AND STRENGTHS Sacubitril and valsartan tablets are supplied as unscored, oval shaped, film-coated tablets in the following strengths: Sacubitril and valsartan tablets 24/26 mg, (sacubitril 24 mg and valsartan 26 mg) are purple colored, oval shaped, biconvex, film coated tablets one side debossed with 'M' and other side debossed with 'S1' and free from physical defects. Sacubitril and valsartan tablets 49/51 mg, (sacubitril 49 mg and valsartan 51 mg) are light yellow colored, oval shaped, biconvex, film coated tablets one side debossed with 'M' and other side debossed with 'S2' and free from physical defects. Sacubitril and valsartan tablets 97/103 mg, (sacubitril 97 mg and valsartan 103 mg) are light pink to pink colored, oval shaped, biconvex, film coated tablets one side debossed with 'M' and other side debossed with 'S3', free from physical defects. • Film-coated tablets: 24/26 mg; 49/51 mg; 97/103 mg ( 3 )

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 )

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 Amneal Pharmaceuticals LLC at 1-877-835-5472 or FDA at 1-800-FDA-1088 o r 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 tablets 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 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 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 observed in pediatric patients 1 year to less …

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.

8 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding not recommended. ( 8.2 ) • Severe Hepatic Impairment: Use not recommended. ( 2.8 , 8.6 ) 8.1 Pregnancy 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 a 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 val …

12.1 Mechanism of Action Sacubitril and valsartan tablets contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan tablets 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 tablets 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.

11 DESCRIPTION Sacubitril and valsartan tablets are a combination of sacubitril sodium, a neprilysin inhibitor and valsartan disodium, an angiotensin II receptor blocker. Sacubitril sodium is a white to almost white powder and freely soluble in methanol and water, and practically insoluble in acetone. The chemical name of sacubitril sodium is 4-(((2S,4R)-1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid sodium. The molecular formula is C 24 H 28 NO 5 ·Na and its molecular weight is 433.48. Its structural formula is: Valsartan disodium is a white to almost white powder and freely soluble in water and anhydrous ethanol, and almost insoluble in dichloromethane. The chemical name of valsartan disodium is L-Valine, N-(1-oxopentyl)-N-[[2′-(2H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-, sodium salt trihydrate (1:2:3). The molecular formula is C 24 H 33 N 5 Na 2 O 6 and its molecular weight is 533.54. Its structural formula is: Sacubitril and valsartan tablets are available as film-coated tablets for oral administration, containing 24 mg of sacubitril equivalent to 25.6 mg of sacubitril sodium and 26 mg of valsartan equivalent to 28.3 mg of valsartan disodium; 49 mg of sacubitril equivalent to 51.2 mg of sacubitril sodium and 51 mg of valsartan equivalent to 56.6 mg of valsartan disodium; and 97 mg of sacubitril equivalent to 102.4 mg of sacubitril sodium and 103 mg of valsartan equivalent to 113.2 mg of valsartan disodium. The tablet inactive ingredients are colloidal silicon dioxide, crospovidone, low-substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, and talc. The film-coat inactive ingredients are glycerol esters of fatty acids, polyvinyl alcohol-part hydrolysed, sodium lauryl sulfate, talc, and titanium dioxide. The film-coat for the 49 mg of sacubitril and 51 mg of valsartan tablet also contains iron oxide yellow. The film-coat for the 97 mg of sacubitril and 103 mg of valsartan tablet also contains iron oxide black, iron oxide red, and iron oxide yellow. sacubitril sodium valsartan disodium

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 are unlikely to be removed by hemodialysis because of high protein binding.

16 HOW SUPPLIED/STORAGE AND HANDLING Sacubitril and valsartan tablets are available as described below: Sacubitril and valsartan tablets 24/26 mg, (sacubitril 24 mg and valsartan 26 mg) are violet white color, oval shaped, biconvex film-coated tablets debossed with “S5” on one side and plain on the other side. Bottles of 30 NDC 42385-930-30 Bottles of 60 NDC 42385-930-60 Bottles of 180 NDC 42385-930-18 Carton with 100 (10 x 10) Unit-Dose Tablets containing cold form with desiccant blisters NDC 42385-930-68 Carton with 100 (10 x 10) Unit-Dose Tablets containing PVC/ACLAR blisters NDC 42385-930-72 Sacubitril and valsartan tablets 49/51 mg, (sacubitril 49 mg and valsartan 51 mg) are pale yellow color, oval shaped, biconvex film-coated tablets debossed with “S1” on one side and plain on the other side. Bottles of 30 NDC 42385-931-30 Bottles of 60 NDC 42385-931-60 Bottles of 180 NDC 42385-931-18 Carton with 100 (10 x 10) Unit-Dose Tablets containing cold form with desiccant blisters NDC 42385-931-68 Carton with 100 (10 x 10) Unit-Dose Tablets containing PVC/ACLAR blisters NDC 42385-931-72 Sacubitril and valsartan tablets 97/103 mg, (sacubitril 97 mg and valsartan 103 mg) are light pink color, oval shaped, biconvex film-coated tablets debossed with “S2” on one side and plain on the other side. Bottles of 30 NDC 42385-932-30 Bottles of 60 NDC 42385-932-60 Bottles of 180 NDC 42385-932-18 Carton with 100 (10 x 10) Unit-Dose Tablets containing cold form with desiccant blisters NDC 42385-932-68 Carton with 100 (10 x 10) Unit-Dose Tablets containing PVC/ACLAR blisters NDC 42385-932-72 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from moisture.