Sacubitril and valsartan

Sacubitril and valsartan tablets are a combination of sacubitril, a neprilisin 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. 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 reduce NT-proBNP and is expected to improve cardiovascular outcomes.

1.1Adult 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 .

1.2Pediatric 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 reduce 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. Adjust adult doses every 2 weeks to 4 weeks to the target maintenance dose, as tolerated by the patient. 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: 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. patients with severe renal impairment. patients with moderate hepatic impairment.

2.1General 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 . 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 Doses of 72 mg/78 mg can be achieved using three 24 mg/26 mg tablets . At least 50 kg 49 mg/51 mg 72 mg/78 mg 97 mg/103 mg

2.4Preparation 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 mg/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 mg/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.

2.6Dose 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 weeks to 4 weeks in adults and every 2 weeks in pediatric patients to follow the recommended dose escalation thereafter . Note: Initiate pediatric patients weighing 40 kg to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension .

2.7Dose 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 . Note: Initiate pediatric patients weighing 40 kg to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension . No starting dose adjustment is needed for mild or moderate renal impairment.

2.8Dose 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 . Note: Initiate pediatric patients weighing 40 kg to 50 kg who meet this criterion at 0.8 mg/kg twice daily using the oral suspension . No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

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 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 .

5.2Angioedema Sacubitril and

valsartan may cause angioedema . 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 1:1,000 (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 tablets . Sacubitril and valsartan tablets must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy . Sacubitril and valsartan tablets should not be used in patients with hereditary angioedema.

5.3Hypotension Sacubitril and

valsartan tablets lower blood pressure and may cause symptomatic hypotension . 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 . 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 . As with all drugs that affect the RAAS, sacubitril and valsartan tablets 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.

5.5Hyperkalemia Through

its actions on the RAAS, hyperkalemia may occur with sacubitril and valsartan tablets . 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 tablets may be required .

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 with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor with concomitant use of aliskiren in patients with diabetes Hypersensitivity to any component. History of angioedema related to previous ACEi or ARB therapy.

Concomitant use with ACE inhibitors. (4 , 7.1) Concomitant use with aliskiren in patients with diabetes. (4 , 7.1)

8.1Pregnancy 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 . 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 . 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 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 tablets for hypotension, oliguria, and hyperkalemia.

In neonates with a history of in utero exposure to sacubitril and valsartan tablets, 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 mg/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 tablets 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 valsartan during organogenesis, gestation and lactation may affect pup development and survival.

Clinically significant adverse reactions that appear in other sections of the labeling include: Angioedema Hypotension Impaired Renal Function Hyperkalemia Adverse reactions occurring greater than or equal to 5% are hypotension, hyperkalemia, cough, dizziness, and renal failure. To report SUSPECTED ADVERSE REACTIONS, contact Novugen Pharma (USA) LLC at 1-888-966-8843 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 days 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 . 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 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.

6.2Postmarketing 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