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)
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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 ) 5.1 Fetal 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)]. 5.2 Angioedema 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. 5.3 Hypotension 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. 5.4 Impaired 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 stenosis, monitor renal function. 5.5 Hyperkalemia Through its actions on the RAAS, hyperkalemia may occur with sacubitril and valsartan [see Adverse Reactions (6.1)] . Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of sacubitril and valsartan may be required [see Dosage and Administration (2.7)].
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 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 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 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 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-blind period in PARADIGM-HF. Decreases in hemoglobin/hematocrit of greater than 20% were observed in approximately 7% of sacubitril and valsartan-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 -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-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-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-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