SACUBITRIL AND VALSARTAN

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. str

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.

• 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 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 and every 2 weeks in pediatric patients 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 )]. 2.7 Dose 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 needed for mild or moderate renal impairment. 2.8 Dose Adjustment for Hepatic Impairment In adults and pediatric patients with moderate hepatic impairment (Child-Pugh B classification), 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 needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

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 )

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 Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384 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 observed in pediatric patients 1 year to less than 18 years old who received treatment with sacubitril and valsartan tablets 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 tablets-and enalapril-treated patients in the double-blind period in PARADIGM-HF. Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 7% of sacubitril and valsartan tablets-treated patients and 9% of valsartan-treated patients in the double-blind period in PARAGON-HF. Serum Creatinine During the double-blind period in PARADIGM-HF, approximately 16% of both sacubitril and valsartan tablets- and enalapril-treated patients had increases in serum creatinine of greater than 50%. During the double-blind period in PARAGON-HF, approximately 17% of sacubitril and valsartan tablets -treated patients and 21% of valsartan-treated patients had increases in serum creatinine of greater than 50%. Serum Potassium During the double-blind period of PARADIGM-HF, approximately 16% of both sacubitril and valsartan tablets- and enalapril-treated patients had potassium concentrations greater than 5.5 mEq/L. During the double-blind period of PARAGON-HF, approximately 18% of sacubitril and valsartan tablets -treated patients and 20% of valsartan-treated patients had potassium concentrations greater than 5.5 mEq/L. 6.2 Postmarketing Experience The following additional adverse reactions have been reported in postmarketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity including rash, pruritus, and anaphylactic reaction

• 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.