Adult Heart Failure

DUVALSA 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.

LVEF is a variable measure, so use clinical judgment in deciding whom to treat [see Clinical Studies (14.1)].

General Considerations

DUVALSA is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor.If switching from an ACE inhibitor to DUVALSA allow a washout period of 36 hours between administration of the two drugs [see Contraindications (4) and Drug Interactions (7.1)].

Adult Heart Failure

The recommended starting dose of DUVALSA is 49/51 mg orally twice-daily.

Double the dose of DUVALSA after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily,as tolerated by the patient.

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 DUVALSA at half the usually recommended starting dose. After initiation, increase the dose every 2 to 4 weeks in adults to follow the recommended dose escalation thereafter [see 4.2 Posology and method of administration].

Dose Adjustment for Severe Renal Impairment

In adults with severe renal impairment (eGFR < 30 mL/min/1.73 m²), start DUVALSA at half the usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter [see 4.2 Posology and method of administration].

No starting dose adjustment is needed for mild or moderate renal impairment.

Dose Adjustment for Hepatic Impairment

In adults patients with moderate hepatic impairment (Child-Pugh B classification), start DUVALSA at halfthe usually recommended starting dose. After initiation, increase the dose to follow the recommended dose escalation thereafter [see 4.2 Posology and method of administration].

No starting dose adjustment is needed for mild hepatic impairment. Use in patients with severe hepatic impairment is not recommended.

4.4.  Fetal Toxicity

DUVALSA 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 DUVALSA. However, if there is no appropriate alternative to therapy withdrugs 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 4.6 Fertility, Pregnancy and lactation].

Angioedema

DUVALSA may cause angioedema [see 4.8 Undesirable effects]. If angioedema occurs, discontinue DUVALSA immediately, provide appropriate therapy, and monitor for airway compromise. DUVALSA mustnot 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 usefulin 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.

DUVALSA 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 DUVALSA [see

4.8 Undesirable effects]. DUVALSA must not be used in patients with a known history of angioedema

related to previous ACE inhibitor or ARB therapy [see 4.3 Contraindications]. DUVALSA should not beused in patients with hereditary angioedema.

Hypotension

DUVALSA lowers blood pressure and may cause symptomatic hypotension [see 4.8 Undesirable effects]. 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 priorto administration of DUVALSA or start at a lower dose. If hypotension occurs, consider dose adjustment ofdiuretics, 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 DUVALSA. Permanent discontinuation of therapy is usually not required.

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 DUVALSA [see 4.8 Undesirable effects]. 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 DUVALSA in patients

who develop a clinically significant decrease in renal function [see 5.2 Pharmacokinetic properties and

5.1 Pharmacodynamic properties].

As with all drugs that affect the RAAS, DUVALSA may increase blood urea and serum creatinine levels inpatients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function.

Hyperkalemia

Through its actions on the RAAS, hyperkalemia may occur with DUVALSA [see 4.8 Undesirable effects].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 DUVALSA may be required [see 4.2 Posology and method ofadministration].

Dual Blockade of the Renin-Angiotensin-Aldosterone System

Concomitant use of DUVALSA with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see 4.3 Contraindications].

Avoid use of DUVALSA with an ARB, because DUVALSA contains the angiotensin II receptor blocker valsartan.

The concomitant use of DUVALSA with aliskiren is contraindicated in patients with diabetes [see 4.3 Contraindications]. Avoid use with aliskiren in patients with renal impairment (eGFR < 60 mL/min/1.73 m²).

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 4.4 Special warnings and precautions for use].

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 DUVALSA may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically.

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 DUVALSA.

Pregnancy

Risk Summary

DUVALSA 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, DUVALSA 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 DUVALSA. 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 estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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 DUVALSA for hypotension, oliguria, and hyperkalemia. In neonates with a history of inutero exposure to DUVALSA, 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

DUVALSA treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥ 49mg sacubitril/51 mg valsartan/kg/day (≤ 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 ≥ 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). DUVALSA is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at an DUVALSA dose of ≥ 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of DUVALSA 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 DUVALSA during organogenesis, gestation and lactationmay affect pup development and survival.

Lactation

Risk Summary

There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with DUVALSA.

Data

Following an oral dose (15 mg sacubitril/15 mg valsartan/kg) of [¹⁴C] DUVALSA to lactating rats, transferof LBQ657 into milk was observed. After a single oral administration of 3 mg/kg [¹⁴C] valsartan to lactating rats, transfer of valsartan into milk was observed.

Duvalsa has a minor influence on the ability to drive and use machines. When driving vehicles or operatingmachines it should be taken into account that occasionally dizziness may occur.

Clinically significant adverse reactions that appear in other sections of the labeling include:

•  Angioedema [see 4.4 Special warnings and precautions for use]

•  Hypotension [see 4.4 Special warnings and precautions for use]

•  Impaired Renal Function [see 4.4 Special warnings and precautions for use]

•  Hyperkalemia [see 4.4 Special warnings and precautions for use]

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 DUVALSA 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 DUVALSA run-in periodsof (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparingDUVALSA 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 DUVALSA 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 DUVALSA and 4,229 treatedwith enalapril. In PARADIGM-HF, patients randomized to DUVALSA 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 DUVALSA treated patients and 516 (12.2%) of patients receiving enalapril.

Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with DUVALSA in the double-blind period of PARADIGM-HF are shown in Table 1.

In PARADIGM-HF, the incidence of angioedema was 0.1% in both the enalapril and DUVALSA run- in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with DUVALSA than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patientswas 2.4% with DUVALSA and 0.5% with enalapril [see 4.4 Special warnings and precautions for use].

Orthostasis was reported in 2.1% of patients treated with DUVALSA compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF. Falls were reported in 1.9% of patientstreated with DUVALSA compared to 1.3% of patients treated with enalapril.

Table 1 Adverse Reactions Reported in ≥ 5% of Patients Treated with DUVALSA in the Double-Blind Period of PARADIGM-HF

In PARAGON-HF, no new adverse reactions were identified.

Laboratory Abnormalities

Hemoglobin and Hematocrit

Decreases in hemoglobin/hematocrit of > 20% were observed in approximately 5% of both DUVALSA-and enalapril-treated patients in the double-blind period in PARADIGM-HF. Decreases in hemoglobin/hematocrit of >20% were observed in approximately 7% of DUVALSA-treated patients and9% 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 DUVALSA- and enalapril-treated patients had increases in serum creatinine of > 50%. During the double-blind period in PARAGON-HF, approximately 17% of DUVALSA-treated patients and 21% of valsartan-treated patients had increases in serum creatinine of > 50%.

Serum Potassium

During the double-blind period of PARADIGM-HF, approximately 16% of both DUVALSA- and enalapril-treated patients had potassium concentrations > 5.5 mEq/L. During the double-blind period of PARAGON-HF, approximately 18% of DUVALSA-treated patients and 20% of valsartan-treated patientshad potassium concentrations > 5.5 mEq/L.

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

To report any side effect (s):

Saudi Arabia:

-The national pharmacovigilance center (NPC):

-SFDA call center: 19999

-E-mail: npc.drug@sfda.gov.sa

-Website: http://ade.sfda.gov.sa

Other GCC states and other countries:

-Please contact the relevant competent authority

Limited data are available with regard to overdosage in human subjects with DUVALSA. In healthy volunteers, a single dose of DUVALSA 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mgsacubitril/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 DUVALSA. Symptomatic treatment should be provided.

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

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II antagonists, other combinations, ATC code: C09DX04

Mechanism of action

DUVALSA contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. DUVALSA inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of DUVALSA in heart failure patients are attributed to the increased levels of peptides thatare 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 AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

Pharmacodynamic effects

The pharmacodynamic effects of DUVALSA were evaluated after single and multiple dose administrationsin healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade.

In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of DUVALSA resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.

In a 21-day study in HFrEF patients, DUVALSA significantly increased urine ANP and cGMP and plasmacGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. DUVALSA also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, DUVALSA decreased plasma NT-proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

In PARAMOUNT, a randomized, double-blind, 36-week study in patients with heart failure with LVEF ≥ 45% comparing 97/103 mg of DUVALSA (n=149) to 160 mg of valsartan (n =152) twice-daily, DUVALSA decreased NT-proBNP by 17% while valsartan increased NT-proBNP by 8% at Week 12 (p

= 0.005).

In PARAGON-HF, DUVALSA decreased NT-proBNP by 24% (Week 16) and 19% (Week 48) comparedto 6% and 3% reductions on valsartan, respectively.

QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of DUVALSA194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.

Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of DUVALSA 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ1-38 compared to placebo; there were no changes in concentrations of CSF Aβ1-40 or CSF Aβ1-42. The clinical relevance of this finding is unknown [see 5.3 Preclinical safety data].

Blood Pressure: Addition of a 50 mg single dose of sildenafil to DUVALSA at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (~ 5/4 mmHg, systolic/diastolic BP) compared to administration of DUVALSA alone.

Co-administration of DUVALSA did not significantly alter the BP effect of intravenous nitroglycerin.

Clinical efficacy and safety

Dosing in clinical trials was based on the total amount of both components of DUVALSA, i.e., 24/26 mg,49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.

Adult Heart Failure

PARADIGM-HF

PARADIGM-HF was a multinational, randomized, double-blind trial comparing DUVALSA and enalaprilin 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients had to have been on an ACE inhibitor or ARB for at least four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of < 100 mmHg at screening were excluded.

The primary objective of PARADIGM-HF was to determine whether DUVALSA, a combination of sacubitril and a RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF).

After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by Duvalsa 49 mg/51 mgtwice-daily, increasing to 200 mg twice-daily. Patients who successfully completed the sequential

run-inperiods were randomized to receive either Duvalsa 97 mg/103 mg (N = 4,209) twice-daily or enalapril 10 mg (N = 4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to

4.3 years.

The population was 66% Caucasian, 18% Asian, and 5% Black; the mean age was 64 years and 78% were male. At randomization, 70% of patients were NYHA Class II, 24% were NYHA Class III, and 0.7% were NYHA Class IV. The mean left ventricular ejection fraction was 29%. The underlying cause of heart

failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR < 60 mL/min/1.73m2, and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy- defibrillator (CRT-D) (15%).

PARADIGM-HF demonstrated that DUVALSA, a combination of sacubitril and a RAS inhibitor (valsartan), was superior to a RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, p < 0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization; see Table 2 and Figure 1. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%.

DUVALSA also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 2). Thisfinding was driven entirely by a lower incidence of cardiovascular mortality on DUVALSA.

Table 2      Treatment Effect for the Primary Composite Endpoint, its Components, and All-cause Mortality in PARADIGM-HF

A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the primary composite endpoint were consistent across the subgroups examined (Figure 2).

Figure 2: Primary Composite Endpoint (CV Death or HF Hospitalization) - Subgroup Analysis (PARADIGM-HF)

Note: The figure above presents effects in various subgroups, all of which are baseline characteristics.
The 95% confidence limits that are shown do not take into account the number of comparisons made, and
may not reflect the effect of a particular factor after adjustment for all other factors. Apparent
homogeneity or heterogeneity among groups should not be over-interpreted.
PARAGON-HF
PARAGON-HF, was a multicenter, randomized, double-blind trial comparing DUVALSA and valsartan
in4,796 adult patients with symptomatic heart failure with left ventricular ejection fraction ≥ 45%, and
structural heart disease [either left atrial enlargement (LAE) or left ventricular hypertrophy (LVH)].
Patients with a systolic blood pressure of < 110 mmHg and patients with any prior echocardiographic
LVEF < 40% at screening were excluded.
The primary objective of PARAGON-HF was to determine whether DUVALSA reduced the rate of
the composite endpoint of total (first and recurrent) heart failure (HF) hospitalizations and
cardiovascular(CV) death.
After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind
run-in periods during which they received valsartan 80 mg twice-daily, followed by Duvalsa 49 mg/51
mgtwice-daily. Patients on prior low doses of an ACEi or ARB began the run-in period receiving
valsartan 40 mg twice-daily for 1-2 weeks. Patients who successfully completed the sequential run-in
periods wererandomized to receive either Duvalsa 97 mg/103 mg (N = 2,419) twice-daily or valsartan
160 mg (N = 2,403) twice-daily. The median follow-up duration was 35 months and patients were
treated for up to 4.7years.
The population was 81% Caucasian, 13% Asian, and 2% Black; the mean age was 73 years and 52% were
female. At randomization, 77% of patients were NYHA Class II, 19% were NYHA Class III, and 0.4%
were NYHA Class IV. The median left ventricular ejection fraction was 57%. The underlying cause of
heart failure was of ischemic etiology in 36% of patients. Furthermore, 96% had a history of
hypertension, 23% had a history of myocardial infarction, 46% had an eGFR < 60 mL/min/1.73 m2, and
43% had diabetes mellitus. Most patients were taking beta-blockers (80%) and diuretics (95%).
PARAGON-HF demonstrated that DUVALSA had a numerical reduction in the rate of the composite
endpoint of total (first and recurrent) HF hospitalizations and CV death, based on an analysis using a
proportional rates model (rate ratio [RR] 0.87; 95% CI [0.75, 1.01], p = 0.06); see Table 3. The treatment
effect was primarily driven by the reduction in total HF hospitalizations in patients randomized to
DUVALSA (RR 0.85; 95% CI [0.72, 1.00]).
Table 3: Treatment Effect for the Primary Composite Endpoint and its Components in
PARAGON-HF

TITRATION
TITRATION was a 12-week safety and tolerability study in 538 patients with chronic heart failure
(NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤35%) naïve to ACE
inhibitor or ARB therapy or on varying doses of ACE inhibitors or ARBs prior to study entry. Patients
received a starting dose of Duvalsa of 50 mg twice daily and were up-titrated to 100 mg twice daily, then
tothe target dose of 200 mg twice daily, with either a 3-week or a 6-week regimen.
More patients who were naïve to previous ACE inhibitor or ARB therapy or on low-dose therapy
(equivalent to <10 mg enalapril/day) were able to achieve and maintain Duvalsa 97 mg/103 mg
whenup-titrated over 6 weeks (84.8%) versus 3 weeks (73.6%). Overall, 76% of patients achieved
and maintained the target dose of Duvalsa 97 mg/103 mg twice daily without any dose interruption
or down-titration over 12 weeks.
 

The valsartan contained within sacubitril/valsartan is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril/valsartan is equivalent to 40 mg, 80 mg and 160 mg of valsartan in other marketed tablet formulations, respectively.

Adult population

Absorption

Following oral administration, sacubitril/valsartan dissociates into valsartan and the prodrug sacubitril. Sacubitril is further metabolised to the active metabolite LBQ657. These reach peak plasma concentrations in 2 hours, 1 hour, and 2 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be more than 60% and 23%, respectively.

Following twice daily dosing of sacubitril/valsartan, steady-state levels of sacubitril, LBQ657 and valsartan are reached in three days. At steady state, sacubitril and valsartan do not accumulate significantly, while LBQ657 accumulates 1.6-fold. Administration with food has no clinically significant impact on the systemic exposures of sacubitril, LBQ657 and valsartan. Sacubitril/valsartan can be administered with or without food.

Distribution

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94-97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%). The average apparent volume of distribution of valsartan and sacubitril were 75 litres to 103 litres, respectively.

Biotransformation

Sacubitril is readily converted to LBQ657 by carboxylesterases 1b and 1c; LBQ657 is not further metabolised to a significant extent. Valsartan is minimally metabolised, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite of valsartan has been identified in plasma at low concentrations (<10%).

Since CYP450-enzyme-mediated metabolism of sacubitril and valsartan is minimal, co-administration with medicinal products that impact CYP450 enzymes is not expected to impact the pharmacokinetics.

In vitro metabolism studies indicate that potential for CYP450-based drug interactions is low since there is limited metabolism of sacubitril/valsartan via CYP450 enzymes. Sacubitril/valsartan does not induce or inhibit CYP450 enzymes.

Elimination

Following oral administration, 52-68% of sacubitril (primarily as LBQ657) and ~13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as LBQ657) and 86% of valsartan and its metabolites are excreted in faeces.

Sacubitril, LBQ657 and valsartan are eliminated from plasma with a mean elimination half-life (T_½ ) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.

Linearity/non-linearity

The pharmacokinetics of sacubitril, LBQ657 and valsartan were approximately linear over a sacubitril/valsartan dose range of 24 mg sacubitril/26 mg valsartan to 97 mg sacubitril/103 mg valsartan.

Special populations

Elderly

LBQ657 and valsartan exposure are increased in subjects over 65 years of age by 42% and 30%, respectively, compared to younger subjects.

Renal impairment

A correlation was observed between renal function and systemic exposure to LBQ657 in patients with mild to severe renal impairment. The exposure of LBQ657 in patients with moderate (30 ml/min/1.73 m² ≤ eGFR <60 ml/min/1.73 m²) and severe renal impairment (15 ml/min/1.73 m² ≤ eGFR <30 ml/min/1.73 m²) was 1.4-fold and 2.2-fold higher compared to patients with mild renal impairment (60 ml/min/1.73 m² ≤ eGFR <90 ml/min/1.73 m²), the largest group of patients enrolled in PARADIGM-HF. The exposure of valsartan was similar in patients with moderate and severe renal impairment compared to patients with mild renal impairment. No studies have been performed in patients undergoing dialysis. However, LBQ657 and valsartan are highly bound to plasma protein and therefore unlikely to be effectively removed by dialysis.

Hepatic impairment

In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 3.4- fold, LBQ657 increased by 1.5- and 1.9-fold, and valsartan increased by 1.2-fold and 2.1-fold, respectively, compared to matching healthy subjects. However, in patients with mild to moderate hepatic impairment, the exposures of free concentrations of LBQ657 increased by 1.47- and 3.08-fold, respectively, and the exposures of free concentrations of valsartan increased by 1.09-fold and 2.20-fold, respectively, compared to matching healthy subjects. Sacubitril/valsartan has not been studied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see sections 4.3 and 4.4).

Effect of gender

The pharmacokinetics of sacubitril/valsartan (sacubitril, LBQ657 and valsartan) are similar between male and female subjects.

Paediatric population

The pharmacokinetics of sacubitril/valsartan were evaluated in paediatric heart failure patients aged 1 month to <1 year and 1 year to <18 years and indicated that the pharmacokinetic profile of sacubitril/valsartan in paediatric and adult patients is similar.

5.3 Preclinical Safety Data
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis and Mutagenesis
Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any
carcinogenic potential for DUVALSA. The LBQ657 Cmax at the high dose (HD) of 1200 mg/kg/day in
male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657
Cmax in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the
MRHD. The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats,
respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m2 basis.
Mutagenicity and clastogenicity studies conducted with DUVALSA, sacubitril, and valsartan did not
revealany effects at either the gene or chromosome level.
Impairment of Fertility
DUVALSA did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg
valsartan/kg/day (≤ 1.0-fold and ≤ 0.18-fold the MRHD on the basis of the AUCs of valsartan and
LBQ657, respectively).
Animal Toxicology and/or Pharmacology
The effects of DUVALSA on amyloid-β concentrations in CSF and brain tissue were assessed in young (2
to 4 years old) cynomolgus monkeys treated with DUVALSA (24 mg sacubitril/26 mg valsartan/kg/day)
for2 weeks. In this study, DUVALSA affected CSF Aβ clearance, increasing CSF Aβ 1-40, 1-42, and 1-
38 levels in CSF; there was no corresponding increase in Aβ levels in the brain. In addition, in a
toxicology study in cynomolgus monkeys treated with DUVALSA at 146 mg sacubitril/154 mg
valsartan/kg/day for
39-weeks, there was no amyloid-β accumulation in the brain.
 

Tablet core
Microcrystalline cellulose.
Low-substituted hydroxypropylcellulose.
Crospovidone.
Magnesium stearate.
Talc.
Colloidal Silicon dioxide.
Film coating (Duvalsa 24 mg/26 mg film-coated tablets):
Opadry II 85F18422 white; that contains:
Titanium dioxide (E171).
Macrogol 4000.
Talc.
Poly(vinyl alcohol) –partially hydrolyzed.
Film coating (Duvalsa 49 mg/51 mg film-coated tablets and Duvalsa 97 mg/103 mg film-coated
tablets):Opadry II 85F240088 pink; that contains:
Titanium dioxide (E171).
Macrogol 4000.
Talc.
Iron oxide red (E172).
Iron oxide yellow (E172)
 

Not applicable.
 

Store below 30° C
Store in the original package in order to protect from moisture.
 

The tablets are supplied in oPA/Al/PVC/Al blister packs.
Duvalsa 24 mg/26 mg film-coated
tabletsPack size: 30 film-coated tablets.
Duvalsa 49 mg/51 mg film-coated
tabletsPack size: 30 film-coated tablets.
Duvalsa 97 mg/103 mg film-coated
tabletsPack sizes: 60 film-coated tablets.
 

Do not throw away any medicines via wastewater. Ask your pharmacist how to throw away medicines
you no longer use. These measures will help protect the environment.