VYSAC
50/ 100 /200 mg
(Sacubitril /Valsartan) Film-Coated Tablets
PRESENTATION
Each Film – Coated Tablet Contains: Sacubitril and Valsartan 24/26, 49/51, 97 mg/103 mg
Pack Size: 2*14
Packing: Blister
CLINICAL PARTICULARS
Therapeutic Indications
Vysac is indicated in adult patients for the treatment of chronic heart failure (NYHA Class II-IV) with reduced ejection fraction.
Dose and Method of Administration
Vysac is administered in place of an ACE inhibitor or other ARB. Vysac should be initiated, and up-titration conducted, by a physician experienced with the treatment of heart failure.
Dosage
The recommended starting dose of Vysac is one tablet of 49 mg/51 mg twice daily, except in the situations described below.
The dose of Vysac should be doubled after 2 to 4 weeks to the target maintenance dose of one tablet of 97 mg/103 mg twice daily, as tolerated by the patient.
If patients experience tolerability issues (systolic blood pressure ≤95mmHg, symptomatic hypotension, hyperkalemia, renal dysfunction), consideration should be given to adjustment of concomitant medications, or to temporary down–titration or discontinuation of Vysac.
Starting Dose of Vysac of 24 Mg/26 Mg for Some Populations
A starting dose of Vysac of one tablet of 24 mg/26 mg taken twice daily is recommended for patients not currently taking an ACE inhibitor or an ARB, or patients previously taking low doses of these agents (see Pharmacodynamics properties; Clinical Trials and Dose and method of administration; other important considerations for dosing).
A starting dose of Vysac of one tablet of 24 mg/26 mg taken twice daily should be considered for patients who have risk factors for hypotension, including patient’s ≥ 75 years old and patients with low systolic blood pressure (SBP ≥100 to 110 mmHg) (see Special warnings and precautions for use; Hypotension).
The dose of Vysac should be doubled every 2-4 weeks to the target dose of one tablet of Vysac 97 mg/103 mg twice daily, as tolerated by the patient. See Special Populations section below for further starting dose recommendations in Renal insufficiency, Hepatic insufficiency and Geriatric patients.
Other Important Considerations for Dosing
Vysac is contraindicated with concomitant use of an angiotensin-converting enzyme (ACE) inhibitor. Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, Vysac must not be administered until 36 hours after the last dose of ACE inhibitor therapy and similarly, at least 36 hours must elapse after the last dose of Vysac before ACE inhibitor therapy is initiated (see Contraindications).
Vysac should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Vysac (see Special warnings and precautions for use and Interactions with Other Medicines and Other Forms on Interactions).
Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see Special warnings and precautions for use).
The valsartan contained within Vysac is more bioavailable than the valsartan in other marketed tablet formulations;
SPECIAL POPULATIONS
Renal Insufficiency
No dose adjustment is required in patients with mild (eGFR 60-90 mL/min/1.73 m2) to moderate (eGFR 30-60 mL/min/1.73 m2) renal impairment.
A starting dose of Vysac 24 mg/26 mg twice daily is recommended in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2). Caution is recommended when using
Vysac in these patients as there are no adequate data (see Pharmacokinetic properties; Special populations).
There is no experience in patients with end-stage renal disease and use of Vysac is not recommended.
Hepatic Insufficiency
No dose adjustment is required when administering Vysac to patients with mild hepatic impairment (Child-Pugh A classification).
A starting dose of Vysac 24 mg/26 mg twice daily is recommended for patients with moderate hepatic impairment (Child-Pugh B classification).
Patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child Pugh C classification) should not take Vysac (see Contraindications and Pharmacokinetic properties; Special populations).
Method of Administration
For oral use. Vysac may be administered with or without food (see Pharmacokinetic properties; Absorption).
CONTRAINDICATIONS
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS).Vysac must not be administered with an ACE inhibitor due to the risk of angioedema. Vysac must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with Vysac is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of Vysac (see Contraindications, Dose and method of administration, and Interactions with Other Medicines and Other Forms of Interactions).
Caution is required while co-administering Vysac with direct renin inhibitors such as aliskiren (see Contraindications and Interactions with Other Medicines and Other Forms of Interactions). Vysac must not be administered with aliskiren in patients with Type 2 diabetes (see Contraindications).
Vysac should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Vysac (see Dose and method of administration, and Interactions with Other Medicines and Other Forms of Interactions).
Hypotension
Vysac lowers blood pressure and may cause symptomatic hypotension, especially in patients ≥75 years old, patients with renal disease and patients with low systolic blood pressure (<112 mmHg) (see Adverse effects (undesirable effects)). Patients with systolic blood pressure <100 mmHg at the time of initiation of Vysac have not been studied; use of Vysac in these patients is not recommended. In the double-blind period of PARADIGM-HF, 18% of patients treated with Vysac and 12% of patients treated with enalapril reported hypotension as an adverse event, with hypotension reported as a serious adverse event in approximately 1.5% of patients in both treatment arms.
When initiating therapy or during dose titration with Vysac, blood pressure should be monitored routinely. 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.
If hypotension occurs, dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g. hypovolemia) should be considered. If hypotension persists despite such measures, the dosage of Vysac should be reduced or the product should be temporarily discontinued (see Dose and method of administration). Permanent discontinuation of therapy is usually not required. Symptomatic hypotension is more likely to occur if the patient has been volume-depleted, e.g., by diuretic therapy, dietary salt restriction, diarrhea or vomiting. Sodium and/or volume depletion should be corrected before starting treatment with Vysac.
Hyperkalemia
Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. Through its action on the renin‐angiotensin‐aldosterone system, hyperkalemia may occur with Vysac.
In the double-blind period of PARADIGM-HF, 12% of patients treated with Vysac and 14% of patients treated with enalapril reported hyperkalemia as an adverse event (see adverse effects (undesirable effects)). The incidence of clinically relevant hyperkalemia was low, resulting in treatment discontinuation in 0.26% of Vysac treated patients compared to 0.35% of enalapril treated patients. 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 Vysac may be required (see Dose and method of administration). Medications known to raise potassium levels (e.g. potassium sparing diuretics, potassium supplements) should be used with caution when co-administered with Vysac. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. In addition, if serum potassium level is >5.4 mmol/l, discontinuation of Vysac should be considered.
Angioedema
Angioedema has been reported in 0.5% of patients treated with Vysac and 0.2% of patients treated with enalapril in PARADIGM-HF. If angioedema occurs, Vysac should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. Vysac 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, appropriate therapy, e.g. subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly administered.
Patients with a prior history of angioedema were not studied. As they may be at higher risk for angioedema, caution is recommended if Vysac is used in these patients. Vysac must not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy or with hereditary or idiopathic angioedema (see Contraindications).
Black patients may have increased susceptibility to develop angioedema.
Patients with Renal Artery Stenosis
Similar to other drugs that affect the renin-angiotensin-aldosterone system, Vysac may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. Caution is required in patients with renal artery stenosis and monitoring of renal function is recommended.
Use in Hepatic Impairment
There is limited clinical experience in patients with moderate hepatic impairment (Child-Pugh B classification) or with AST/ALT values more than twice the upper limit of the normal range. In these patients, exposure may be increased and safety is not established.
Caution is therefore recommended when using it in these patients (see Dose and method of administration; and Pharmacokinetic properties). Vysac is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see Contraindications).
Use in Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, the use of Vysac may be associated with decreased renal function. In the double-blind period of PARADIGMHF, 5% of patients in both the Vysac and enalapril groups reported renal failure as an adverse event (see adverse effects (undesirable effects)). The incidence of clinically relevant renal impairment was low and associated treatment discontinuation was observed less frequently in patients receiving Vysac (0.65%) compared to enalapril (1.28%). 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.
Use of Vysac should include appropriate assessment of renal function, before initiation of therapy, and then during treatment, as appropriate. Closely monitor serum creatinine, and down-titrate or interrupt Vysac in patients who develop a clinically significant decrease in renal function (see Pharmacokinetic properties; Special populations). As with all drugs that affect the RAAS, Vysac 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.
Patients with mild and moderate renal impairment are more at risk of developing hypotension. There is very limited clinical experience in patients with severe renal impairment (estimated GFR <30 ml/min/1.73m2) and these patients may be at greatest risk of hypotension. Caution should be exercised when administering Vysac in patients with severe renal impairment. There is no experience in patients with end-stage renal disease and use of Vysac is not recommended (see Dose and method of administration, and Pharmacokinetic properties; Special populations).
Use in the Elderly
No dose adjustment is required in patients over 65 years. However, Vysac has been studied in a limited number of patients over 80 years. In patient’s ≥ 75 years old, a starting dose of one tablet of Vysac 24 mg/26 mg taken twice daily should be considered.
Pediatric Use
The safety and efficacy of Vysac in pediatric patients aged below 18 years have not been established.
Effects on Laboratory Tests
No data available.
INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF
INTERACTIONS
Anticipated Interactions Resulting in a Contraindication:
ACE Inhibitors: The concomitant use of Vysac with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE inhibitor therapy may increase the risk of angioedema. Vysac must not be started until 36 hours after taking the last dose of ACE inhibitor therapy. ACE inhibitor therapy must not be started until 36 hours after the last dose of Vysac (see Contraindications and Dose and method of administration).
Aliskiren: The concomitant use of Vysac with aliskiren is contraindicated in patients with Type 2 diabetes (see Contraindications). Combination of Vysac with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure).
Anticipated Interactions Resulting In Concomitant Use Not Being Recommended: Vysac should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of Vysac (see Special warnings and precautions for use). Concomitant use with aliskiren should be avoided in patients with renal impairment (eGFR < 60 mL/min/1.73 m2) (see Special warnings and precautions for use).
Observed Interactions To Be Considered:
Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters.
Vysac may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of Vysac increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Therefore, caution should be exercised upon co-administration of Vysac with statins.
Sildenafil: Addition of a single dose of sildenafil to Vysac at steady state in patients with hypertension was associated with greater BP reduction compared to administration of Vysac alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with Vysac.
Anticipated Interactions To Be Considered:
Potassium: Concomitant use of potassium-sparing diuretics (e.g. triamterene, amiloride), mineralocorticoid antagonists (e.g. spironolactone, eplerenone), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium, and to increases in serum creatinine. Monitoring of serum potassium is recommended if Vysac is co-administered with these agents (see Special warnings and precautions for use).
Non-Steroidal Anti-Inflammatory Agents (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 Inhibitors): In elderly patients, volume-depleted patients (including those on diuretic therapy), or patients with compromised renal function, concomitant use of Vysac and NSAIDs may lead to an increased risk of worsening of renal function.
Therefore, monitoring of renal function is recommended when initiating or modifying the treatment in patients on Vysac who are taking NSAIDs concomitantly.
Lithium: The potential for a drug interaction between Vysac and lithium has not been investigated. Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors or angiotensin II receptor antagonists. Therefore, careful monitoring of serum lithium levels is recommended during concomitant use with Vysac. If a diuretic is also used, the risk of lithium toxicity may be increased further.
Frusemide: Co-administration of Vysac and frusemide had no effect on the pharmacokinetics of Vysac but reduced Cmax and AUC of frusemide by 50% and 28%, respectively. While there was no relevant change in urine volume, the urinary excretion of sodium was reduced within 4 hours and 24 hours after co-administration. The average daily dose of frusemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with Vysac.
Transporters: The active metabolite of sacubitril (sacubitrilat) and valsartan are OATP1B1, OATP1B3 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of Vysac with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporine) or MRP2 (e.g. ritonavir) may increase the systemic exposure to sacubitrilat or valsartan, respectively. Exercise appropriate care when initiating or ending concomitant treatment with such drugs.
Metformin: Co-administration of Vysac with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with Vysac in patients receiving metformin, the clinical status of the patient should be evaluated.
No Significant Interactions: No clinically meaningful drug-drug interaction was observed upon co-administration of Vysac and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol, intravenous nitroglycerin or a combination of levonorgestrel/ethinyloestradiol. No interaction is expected with atenolol, indomethacin, glyburide, or cimetidine. CYP 450 Interactions: In vitro metabolism studies indicate that the potential for CYP 450 - based drug interactions is low since there is limited metabolism of Vysac via the CYP450 enzymes. Vysac does not induce or inhibit CYP450 enzymes.
FERTILITY, PREGNANCY AND LACTATION
Effects on Fertility
There are no available data on the effect of Vysac on human fertility. Vysac did not show any effects on fertility or early embryonic development in male and female rats up to a dose of 73 mg sacubitril/77 mg valsartan /kg/day (≤1.0 fold and ≤0.13 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively).
Use in Pregnancy – Pregnancy Category D
Drugs that act on the renin-angiotensin-aldosterone system (RAAS) can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors (a specific class of drugs acting on the RAAS).
As for other drugs that also act directly on the RAAS, Vysac must not be used during pregnancy (see Contraindications) or in women planning to become pregnant. Valsartan exerts its effects via angiotensin II antagonism. There have been reports of injury to the developing fetus (e.g. spontaneous abortion, oligohydramnios and newborn renal dysfunction), when pregnant women have taken valsartan. Physicians prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy. Patients should be advised to discontinue Vysac as soon as pregnancies occur and to inform their physicians.
The use of drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function. Oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation and hypo plastic lung development. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia.
In animal studies, Vysac treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥ 49 mg sacubitril/51 mg valsartan/kg/day (≤ 0.06 [sacubitrilat, the active metabolite] and 0.7 [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 ≥ 5 mg sacubitril/5 mg valsartan/kg/day (2-fold and 0.03-fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively). Vysac is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a Vysac dose of ≥ 5 mg sacubitril/5 mg valsartan/kg/day. The adverse embryo-fetal effects of Vysac are attributed to the angiotensin receptor antagonist activity.
Sacubitril
There are no data from the use of sacubitril in pregnant women. Studies in animals have shown reproductive toxicity.
There are no data from the use of Vysac in pregnant women. Animal studies with Vysac have shown reproductive toxicity.
Use in Lactation
It is not known whether Vysac is excreted in human milk. The components of Vysac, sacubitril and valsartan, were excreted in the milk of lactating rats.
Pre- and postnatal development studies in rats at sacubitril doses up to 750 mg/kg/day (1.1- fold the MRHD on the basis of sacubitrilat AUC) and valsartan at doses up to 600 mg/kg/day (0.9-fold the MRHD on the basis of AUC) indicate that treatment with Vysac during organogenesis, gestation and lactation may affect pup development and survival.
Because of the potential risk for adverse drug reactions in breastfed newborns/infants, Vysac is not recommended during breastfeeding. A decision should be made whether to abstain from breast-feeding or to discontinue Vysac while breast-feeding, taking into account the importance of Vysac to the mother.
Females of Child-Bearing Potential
Female patients of child-bearing potential should be advised about the consequences of exposure to Vysac during pregnancy and to use contraception during treatment with
Vysac and for 1 week after their last dose.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.
ADVERSE EFFECTS (UNDESIRABLE EFFECTS)
Very common (≥1/10);
Common (≥1/100to <1/10);
Uncommon (≥1/1,000 to <1/100);
Rare (≥1/10,000 to <1/1,000);
Very rare (<1/10,000).
Blood and Lymphatic System Disorders
Gastrointestinal Disorders
General Disorders and Administration Site Conditions
Infections and Infestations
Metabolism and Nutrition Disorders
Musculoskeletal and Connective Tissue Disorders
Nervous System Disorders
Psychiatric Disorders
Renal and Urinary Disorders
Respiratory, Thoracic and Mediastinal Disorders
Vascular Disorders
Blood and Lymphatic System Disorders
Immune System Disorders
Metabolism and Nutrition Disorders
Nervous System Disorders
Ear and Labyrinth Disorders
Vascular Disorders
Respiratory, Thoracic and Mediastinal Disorders
Gastrointestinal Disorders
Skin and Subcutaneous Tissue Disorders
Renal and Urinary Disorders
General Disorders and Administration Site Conditions
OVERDOSE
Hypotension is the most likely symptom of over dosage due to the blood pressure lowering effects of Vysac. Symptomatic treatment should be provided. Vysac is unlikely to be removed by hemodialysis due to high protein binding.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamics Properties
Mechanism of Action
Vysac exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor
(ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657 (sacubitrilat), the active metabolite of the prodrug sacubitril, and by blocking the angiotensin
II type-1 (AT1) receptor via valsartan. The complementary cardiovascular benefits and renal effects of Vysac in heart failure patients are attributed to the enhancement of peptides that are degraded by neprilysin, such as natriuretic peptides (NP), by sacubitrilat and the simultaneous inhibition of the deleterious effects of angiotensin II by valsartan. NPs exert their effects by activating membrane-bound guanylyl cyclase-coupled receptors, resulting in increased concentrations of the second messenger cyclic guanosine monophosphate (cGMP), thereby promoting vasodilation, natriuresis and diuresis, increased glomerular filtration rate and renal blood flow, inhibition of renin and aldosterone release, reduction of sympathetic activity, and anti-hypertrophic and anti-fibrotic effects. Sustained activation of the renin angiotensin-aldosterone system results in vasoconstriction, renal sodium and fluid retention, activation of cellular growth and proliferation, and subsequent maladaptive cardiovascular remodeling. Valsartan inhibits detrimental cardiovascular and renal effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
PHARMACOKINETIC PROPERTIES
Absorption
Following oral administration, Vysac dissociates into sacubitril, which is further metabolized to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 3 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively.
Following twice daily dosing of Vysac, steady state levels of sacubitril, sacubitrilat, and valsartan are reached in 3 days. At steady state, sacubitril and valsartan do not accumulate significantly, while sacubitrilat accumulates by 1.6-fold. Vysac administration with food has no clinically significant impact on the systemic exposures of sacubitril, sacubitrilat and valsartan. Although there is a decrease in exposure to valsartan when Vysac is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. Vysac can therefore be administered with or without food.
Distribution
Vysac is highly bound to plasma proteins (94% - 97%). Based on the comparison of plasma and CSF exposures, sacubitrilat does cross the blood brain barrier to a limited extent (0.28%).
Vysac has an apparent volume of distribution ranging from 75 L to 103 L.
Metabolism
Sacubitril is readily converted to sacubitrilat by esterases; sacubitrilat is not further metabolized to a significant extent. Valsartan is minimally metabolized, as only about 20% of the dose is recovered as metabolites. A hydroxyl metabolite has been identified in plasma at low concentrations (<10%). Since CYP450 enzyme mediated metabolism of sacubitril and valsartan is minimal, co-administration with drugs that impact CYP450 enzymes is not expected to impact the pharmacokinetics.
Excretion
Following oral administration, 52 – 68% of sacubitril (primarily as sacubitrilat) and ~13% of valsartan and its metabolites are excreted in urine; 37-48% of sacubitril (primarily as sacubitrilat), and 86% of valsartan and its metabolites are excreted in faces.
Sacubitril, sacubitrilat, and valsartan are eliminated from plasma with a mean elimination half-life (T1/2) of approximately 1.43 hours, 11.48 hours, and 9.90 hours, respectively.
Linearity/non-linearity
The pharmacokinetics of sacubitril, sacubitrilat, and valsartan are linear in the dose range tested
(24 mg sacubitril/26 mg valsartan - 194 mg sacubitril/206 mg valsartan).
SPECIAL POPULATIONS
Elderly Patients (Aged Over 65 Years)
The exposures of sacubitrilat and valsartan are increased in elderly subjects by 42% and 30%, respectively, compared to younger subjects. However, this is not associated with clinically relevant effects and therefore no dosage adjustment is necessary in patients over 65 years. In patient’s ≥ 75 years old, a lower starting dose of Vysac 24 mg/26 mg should be considered
(See Special warnings and precautions for use; Use in the elderly).
Pediatric Patients (Aged below 18 Years)
Vysac has not been studied in pediatric patients.
Impaired Renal Function
A correlation was observed between renal function and systemic exposure to sacubitrilat, but not to valsartan. In patients with mild (60 mL/min/1.73 m2 ≤eGFR<90 mL/min/1.73 m2) to moderate (30 mL/min/1.73 m2 ≤ eGFR< 60 mL/min/1.73 m2) renal impairment, the AUC for sacubitrilat was up to 2-fold higher. No dosage adjustment is required in patients with mild or moderate renal impairment. A 2.7-fold higher AUC for sacubitrilat was observed in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2). A starting dose of Vysac 24 mg/26 mg twice daily is recommended in patients with severe renal impairment. Caution is recommended when administering Vysac to these patients due to limited data.
No studies have been performed in patients undergoing dialysis. However, sacubitrilat and valsartan are highly bound to plasma protein and, therefore, unlikely to be effectively removed by dialysis.
Impaired Hepatic Function
In patients with mild to moderate hepatic impairment, the exposures of sacubitril increased by 1.5- and 3.4- fold, sacubitrilat 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. No dosage adjustment is recommended when administering Vysac to patients with mild hepatic impairment (Child Pugh A classification) including patients with biliary obstructive disorders. A starting dose of
Vysac 24 mg/26 mg twice daily is recommended in patients with moderate hepatic impairment (Child-Pugh B classification). Vysac has not been studied in patients with severe hepatic impairment. Therefore, its use is not recommended in patients with severe hepatic impairment.
Ethnic Group
The pharmacokinetics of Vysac (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Gender
The pharmacokinetics of Vysac (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
SPECIAL PRECAUTIONS FOR STORAGE
Store below 30 ^0 C. Protect from moisture. Store in the original package. Keep out of the reach and sight of children.