Sacubitril and Valsartan 24 mg; 26 mg Tablet, Film Coated, 180-count — NDC 60290-085-02 (Billing 60290-0085-02)

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 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. 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 [see Use in Specific Populations (8.1) ] .

5.2Angioedema Sacubitril and valsartan tablets may cause angioedema [see Adverse Reactions (6.1) ] . If angioedema occurs, discontinue sacubitril and valsartan tablets immediately, provide appropriate therapy, and monitor for airway compromise. Sacubitril and valsartan tablets 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 tablets 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 tablets [see Adverse Reactions (6.1) ] . Sacubitril and valsartan tablets 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 tablets should not be used in patients with hereditary angioedema.

5.3Hypotension Sacubitril and valsartan tablets 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 tablets 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 tablets. 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 tablets [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 tablets 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 tablets may increase blood urea and serum creatinin… [Excerpted — this section continues on DailyMed.]

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 Umedica Laboratories USA Inc. at 1-855-288-5777 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. 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 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 tablets 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 reactio… [Excerpted — this section continues on DailyMed.]

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 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 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 tablets 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 tablets.