Uperio

Uperio

sacubitril + valsartan

Manufacturer:

Novartis Indonesia
The information highlighted (if any) are the most recent updates for this brand.
Full Prescribing Info
Contents
Sacubitril, valsartan.
Description
UPERIO 50 mg film-coated tablets: Each film-coated tablet contains 24.3 mg sacubitril and 25.7 mg valsartan (as Sacubitril valsartan sodium hydrate).
UPERIO 100 mg film-coated tablets: Each film-coated tablet contains 48.6 mg sacubitril and 51.4 mg valsartan (as Sacubitril valsartan sodium hydrate).
UPERIO 200 mg film-coated tablets: Each film-coated tablet contains 97.2 mg sacubitril and 102.8 mg valsartan (as Sacubitril valsartan sodium hydrate).
Sacubitril valsartan sodium hydrate. UPERIO contains a salt complex of the anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5 respectively. Following oral administration, UPERIO dissociates into sacubitril (which is further metabolized to LBQ657 [sacubitrilat]) and valsartan.
Excipients/Inactive Ingredients: Microcrystalline cellulose, low-substituted hydroxypropylcellulose, crospovidone, magnesium stearate (vegetable origin), talc and colloidal silicon dioxide.
Excipients of film coating: hypromellose, titanium dioxide (E 171), Macrogol 4000, talc, iron oxide red (E 172).
For 50 and 200 mg: iron oxide black (E 172). For 100 mg: iron oxide yellow (E 172).
Action
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system; angiotensin II antagonists, other combinations. ATC code: C09DX04.
Pharmacology: Mechanism of action (MOA): UPERIO exhibits the novel mechanism of action of an angiotensin receptor neprilysin inhibitor (ARNI) by simultaneously inhibiting neprilysin (neutral endopeptidase; NEP) via 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 UPERIO 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.
Pharmacodynamics (PD): The pharmacodynamic effects of UPERIO were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and RAAS blockade. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of UPERIO resulted in an initial 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, UPERIO significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1 compared to baseline. UPERIO also blocked the AT1-receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, UPERIO decreased plasma NT-proBNP and increased plasma BNP and urine cGMP compared with enalapril. While BNP is a neprilysin substrate, NT-proBNP is not. Therefore, NT-proBNP (but not BNP) is a suitable biomarker for monitoring of heart failure patients treated with UPERIO.
In a thorough QTc clinical study in healthy male subjects, single doses of 400 mg and 1200 mg UPERIO had no effect on cardiac repolarization.
Neprilysin is one of multiple enzymes involved in the clearance of amyloid-beta (A-beta) from the brain and cerebrospinal fluid (CSF). Administration of UPERIO 400 mg once daily for 2 weeks to healthy subjects was associated with an increase in CSF A-beta 1-38 compared to placebo; there were no changes in concentrations of CSF A-beta 1-40 and 1-42. The clinical relevance of this finding is unknown (see Nonclinical studies as follows).
Clinical studies: Dosing in clinical trials was based on the total amount of both components of Uperio, i.e., 24/26 mg, 49/51 mg and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.
PARADIGM-HF: PARADIGM-HF was a multinational, randomized, double-blind study of 8,442 patients comparing UPERIO to enalapril, both given to adult patients with chronic heart failure, NYHA class II-IV, and systolic dysfunction (left ventricular ejection fraction ≤ 40%), in addition to other heart failure therapy. The primary endpoint was the composite of cardiovascular (CV) death or hospitalization for heart failure (HF).
Prior to study participation, patients were well treated with standard of care therapy which included ACE inhibitors/ARBs (>99%), beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (83%). The median follow- up duration was 27 months and patients were treated for up to 4.3 years.
Patients were required to discontinue their existing ACE inhibitor or ARB therapy and entered a sequential single-blind run-in period during which patients received treatment with enalapril 10 mg twice daily, followed by treatment with UPERIO 100 mg twice daily, increasing to 200 mg twice daily. Patients were then randomized to the double-blind period of the study to receive either UPERIO 200 mg or enalapril 10 mg twice daily [UPERIO (n= 4209); enalapril (n= 4233)].
The mean age of the population studied was 64 years of age and 19% were 75 years or older. At randomization, 70% of patients were NYHA Class II and 25% were Class III/IV.
In the UPERIO group, 76% of patients remained on the target dose of 200 mg twice daily at the end of the study (mean daily dose of 375 mg). In the enalapril group, 75% of patients remained on the target dose of 10 mg twice daily at the end of the study (mean daily dose of 18.9 mg).
UPERIO demonstrated clinically relevant and statistically significant superiority to enalapril, reducing the risk of cardiovascular death or heart failure hospitalizations by 20% (hazard ratio (HR): 0.80, 95% CI [0.73; 0.87], 1-sided p =0.0000002) versus enalapril. This effect was observed early and was sustained throughout the duration of the trial. The absolute risk reduction was 4.69%. A statistically significant reduction for CV death and first HF hospitalization was observed (CV death, RRR 20%, HR 0.80; 95% CI [0.71, 0.89], 1-sided p= 0.00004; and hospitalization for heart failure RRR 21%; HR 0.79; 95% CI 0.71, 0.89], 1-sided p= 0.00004); see Table1 and Figure 1. Sudden death accounted for 45% of cardiovascular deaths and was reduced by 20% in UPERIO treated patients compared to enalapril treated patients (HR 0.80, p= 0.0082).
Pump failure accounted for 26% of cardiovascular deaths and was reduced by 21% in UPERIO treated patients compared to enalapril treated patients (HR 0.79, p = 0.0338).
This risk reduction was consistently observed across subgroups including: age, gender, race, geography, NYHA class, ejection fraction, renal function, history of diabetes or hypertension, prior heart failure therapy, and atrial fibrillation.
UPERIO also significantly reduced all-cause mortality by 16% compared with enalapril (RRR 16%, HR 0.84; 95% CI [0.76 to 0.93], 1-sided p=0.0005) (Table 1). The absolute risk reduction was 2.84%. (See Table 1.)


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The Kaplan-Meier presented in the figure as follows (left) shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalization. UPERIO treatment effect was evident early and sustained for the duration of the study. The Kaplan-Meier figure presented as follows (right) shows the time to CV death endpoint. (See Figure).


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Overall, there were fewer all cause hospital admissions in patients treated with UPERIO compared to enalapril, including a 12% relative risk reduction for the first hospitalization (HR 0.88 [95% CI: 0.82, 0.94], P<0.001), and a 16% relative rate reduction for total number of hospitalizations (RR 0.84 [95% CI: 0.78, 0.91], P<0.001).
UPERIO demonstrated a significantly better clinical summary score for the domains related to HF symptoms and physical limitations as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ), a self- administered questionnaire. More patients had improved NYHA functional class from baseline to Month 8 on UPERIO (16%) compared to enalapril (14%), and fewer patients had worsened NYHA functional class (10% vs 13%, respectively).
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 initiated UPERIO 50 mg twice daily, were uptitrated to 100 mg twice daily and then to the target dose of 200 mg twice daily with either a 3-week or 6-week regimen.
Overall, 76% of patients achieved and maintained the target dose of UPERIO 200 mg twice daily without any dose interruption or down-titration over 12-weeks. More patients who were naïve to previous ACE inhibitor or ARB therapy or on low dose therapy (equivalent to < 10 mg of enalapril/day) were able to achieve and maintain UPERIO 200 mg when uptitrated over 6 weeks versus 3 weeks.
Pharmacokinetics (PK): Absorption: Following oral administration, UPERIO dissociates into sacubitril, which is further metabolized to sacubitrilat, and valsartan, which reach peak plasma concentrations in 0.5 hours, 2 hours, and 1.5 hours, respectively. The oral absolute bioavailability of sacubitril and valsartan is estimated to be ≥ 60% and 23%, respectively. The valsartan in Uperio is more bioavailable than the valsartan in other marketed tablet formulations.
Following twice daily dosing of UPERIO, 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. UPERIO 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 UPERIO is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect. UPERIO can therefore be administered with or without food.
Distribution: UPERIO 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%). UPERIO has an apparent volume of distribution ranging from 75 L to 103 L.
Biotransformation/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.
Elimination: 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 feces.
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 (50-400 mg of UPERIO).
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.
Pediatric patients (aged below 18 years): UPERIO has not been studied in pediatric patients.
Impaired renal function: A correlation was observed between renal function and systemic exposure to sacubitrilat in patients with mild (60 ml/min/1.73 m2 ≤ eGFR <90 ml/min/1.73 m2) to severe renal impairment. The exposure of sacubitrilat 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, 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. However, in patients with mild to moderate hepatic impairment, the exposures of free concentrations of sacubitrilat 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. UPERIO should be used with caution 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 and the recommended starting dose is 50 mg twice daily. UPERIO has not been studied in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (see Contraindications and Precautions).
Ethnic groups: The pharmacokinetics of UPERIO (sacubitril, sacubitrilat and valsartan) are comparable across different race and ethnic groups (Caucasians, Blacks, Asians, Japanese and others).
Effect of gender: The pharmacokinetics of UPERIO (sacubitril, sacubitrilat and valsartan) are similar between male and female subjects.
Toxicology: Non-clinical safety data: Non-clinical safety studies conducted with UPERIO included assessment of safety pharmacology, repeated dose toxicity genotoxicity carcinogenicity and reproductive and development toxicity UPERIO had no adverse effects on vital organ systems. Most findings seen in repeated toxicity studies were reversible and attributable to the pharmacology of AT1 receptor blockade. Carcinogenicity, mutagenesis and genetic toxicity: Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for UPERIO. The doses of sacubitril studied (high dose of 1200 and 400 mg/kg/day in mice and rats, respectively) were about 29 and 19 times, respectively, the maximum recommended human dose (MRHD) on a mg/m2 basis. 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 maximum recommended human dose on a mg/m2 basis.
Mutagenicity and clastogenicity studies conducted with UPERIO, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level.
Fertility, reproduction and development: UPERIO did not show any effects on fertility or early embryonic development in rats up to a dose of 150 mg/kg/day (≤1.0 fold and ≤0.18 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively).
UPERIO treatment during organogenesis resulted in increased embryo-fetal lethality in rats at doses ≥100 mg/kg/day [≤0.72 fold the MRHD on the basis of AUC] and rabbits at doses ≥10 mg/kg/day [2 fold and 0.03 fold the MRHD on the basis of valsartan and sacubitrilat AUC, respectively]. UPERIO is teratogenic based on a low incidence of fetal hydrocephaly, associated with maternally toxic doses, which was observed in rabbits at a UPERIO dose of ≥10 mg/kg/day. The adverse embryo-fetal effects of UPERIO are attributed to the angiotensin receptor antagonist activity (see Use in Pregnancy & Lactation).
Pre- and postnatal development studies in rats conducted with sacubitril at doses up to 750 mg/kg/day [2.2 fold the MRHD on the basis of 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 UPERIO during organogenesis, gestation and lactation may affect pup development and survival.
Other preclinical findings: UPERIO: The effects of UPERIO on amyloid-beta concentrations in CSF and brain tissue were assessed in young (2 to 4 years old) cynomolgus monkeys treated with UPERIO (50 mg/kg/day) for two weeks. In this study CSF A-beta clearance in cynomolgus monkeys was reduced, increasing CSF A-beta 1-40, 1-42, and 1-38 levels; there was no corresponding increase in A-beta levels in the brain. Increases in CSF A-beta 1-40 and 1-42 were not observed in a two-week healthy volunteer study in humans. Additionally, in a toxicology study in cynomolgus monkeys treated with UPERIO at 300 mg/kg/day for 39-weeks, there was no evidence for the presence of amyloid plaques in the brain. Amyloid content was not, however, measured quantitatively in this study.
Sacubitril: In juvenile rats treated with sacubitril (postnatal days 7 to 70), there was a reduction in age-related bone mass development and bone elongation. A study in adult rats showed only a minimal transient inhibitory effect on bone mineral density but not on any other parameters relevant for bone growth, suggesting no relevant effect of sacubitril on bone in adult patient populations under normal conditions. However, a mild transient interference of sacubitril with the early phase of fracture healing in adults cannot be excluded.
Valsartan: In juvenile rats treated with valsartan (postnatal days 7 to 70), doses as low as 1 mg/kg/day produced persistent irreversible kidney changes consisting of tubular nephropathy (sometimes accompanied by tubular epithelial necrosis) and pelvic dilatation. These kidney changes represent an expected exaggerated pharmacological effect of angiotensin converting enzyme inhibitors and angiotensin II type 1 blockers; such effects are observed if rats are treated during the first 13 days of life. This period coincides with 36 weeks of gestation in humans, which could occasionally extend up to 44 weeks after conception in humans.
Indications/Uses
UPERIO is indicated for the treatment of heart failure (NYHA class II-IV) in patients with reduced ejection fraction (LVEF ≤40%).
Dosage/Direction for Use
The target dose of UPERIO is 200 mg twice daily.
The recommended starting dose of UPERIO is 100 mg twice daily. A starting dose of 50 mg twice daily is recommended for patients not currently taking an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB), and should be considered for patients previously taking low doses of these agents (see Pharmacology: Pharmacodynamics: Clinical studies under Actions).
The dose of UPERIO should be doubled every 2-4 weeks to the target dose of 200 mg twice daily, as tolerated by the patient.
Due to the potential risk of angioedema when used concomitantly with an ACE inhibitor, UPERIO must not be started until 36 hours after discontinuing ACE inhibitor therapy (see Contraindications).
Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see Precautions). A starting dose of 50 mg twice daily should be considered for patients with SBP ≥100 to 110 mmHg.
UPERIO should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of UPERIO (see Precautions and Interactions).
If patients experience tolerability issues (symptomatic hypotension, hyperkalemia, renal dysfunction), consideration should be given to adjustment of concomitant medications, or to temporary down-titration of UPERIO.
Special populations: Renal impairment: A starting dose of 50 mg twice daily should be considered in patients with moderate renal impairment (eGFR 30-60 mL/min/1.73 m2). As there is very limited clinical experience in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m2) (see Pharmacology: Pharmacodynamics (PD) under Actions) UPERIO should be used with caution and a starting dose of 50 mg twice daily is recommended. There is no experience in patients with end-stage renal disease and use of UPERIO is not recommended.
No dose adjustment is required in patients with mild (Estimated Glomerular Filtration Rate [eGFR] 60-90 mL/min/1.73 m2) renal impairment.
Hepatic impairment: No dose adjustment is required when administering UPERIO to patients with mild hepatic impairment (Child-Pugh A classification). 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. UPERIO should be used with caution in these patients and the recommended starting dose is 50 mg twice daily (see Precautions and Pharmacology: Pharmacokinetics (PK) under Actions). UPERIO is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see Contraindications).
Pediatric patients: The safety and efficacy of UPERIO in pediatric patients aged below 18 years has not been established.
Geriatric patients (older than 65 years): No dosage adjustment is required in patients over 65 years.
Method of administration: For oral use. UPERIO may be administered with or without food (see Pharmacology under Actions). The tablets must be swallowed with a glass of water.
Overdosage
Limited data are available with regards to overdosage in human subjects with UPERIO. In healthy volunteers, a single dose of UPERIO 1200 mg, and 900 mg multiple doses (14 days) have been studied and were well tolerated.
Hypotension is the most likely symptom of overdosage due to the blood pressure lowering effects of UPERIO. Symptomatic treatment should be provided.
UPERIO is unlikely to be removed by hemodialysis due to high protein binding.
Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Concomitant use with ACE inhibitors (see Precautions, Dosage & Administration, and Interactions). UPERIO must not be administered until 36 hours after discontinuing ACE inhibitor therapy.
Known history of angioedema related to previous ACE inhibitor or ARB therapy.
Hereditary or idiopathic angiodema (see Precautions).
Concomitant use with aliskiren in patients with Type 2 diabetes or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see Precautions, and Interactions).
Severe hepatic impairment, biliary cirrhosis and cholestasis.
Pregnancy. (see Use in Pregnancy & Lactation).
Special Precautions
Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS): UPERIO is contraindicated with an ACE inhibitor due to the risk of angioedema. UPERIO must not be initiated until 36 hours after taking the last dose of ACE inhibitor therapy. If treatment with UPERIO is stopped, ACE inhibitor therapy must not be initiated until 36 hours after the last dose of UPERIO (see Contraindications, Dosage & Administration, and Interactions).
The combination of UPERIO with direct renin inhibitors such as aliskiren is not recommended (see Interactions). The combination of UPERIO with aliskiren-containing products is contraindicated in patients with diabetes mellitus or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see Contraindications and Interactions).
UPERIO should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of UPERIO (see Dosage & Administration, and Interactions).
Hypotension: Treatment should not be initiated unless SBP is ≥100 mmHg. Patients with SBP <100 mmHg were not studied (see Pharmacology: Pharmacodynamics (PD) under Actions). Cases of symptomatic hypotension have been reported in patients treated with UPERIO during clinical studies (see Adverse Reactions), especially in patients ≥65 years old, patients with renal disease and patients with low SBP (<112 mmHg). When initiating therapy or during dose titration with UPERIO, blood pressure should be monitored routinely. If hypotension occurs, temporary down-titration or discontinuation of UPERIO is recommended (see Dosage & Administration). Dose adjustment of diuretics, concomitant antihypertensives and treatment of other causes of hypotension (e.g. hypovolaemia) should be considered.
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 UPERIO, however, such corrective action must be carefully weighed against the risk of volume overload.
Impaired renal function: Evaluation of patients with heart failure should always include assessment of renal function. Patients with mild and moderate renal impairment are more at risk of developing hypotension (see Dosage & Administration).
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 (see Dosage & Administration). There is no experience in patients with end-stage renal disease and use of UPERIO is not recommended.
Worsening renal function: Use of UPERIO may be associated with decreased renal function. The risk may be further increased by dehydration or concomitant use of non-steroidal anti-inflammatory agents (NSAIDs) (see Interactions).
Down-titration should be considered in patients who develop a clinically significant decrease in renal function.
Hyperkalemia: Treatment should not be initiated if the serum potassium level is >5.4 mmol/l. As for any drug that acts on the renin-angiotensin-aldosterone system, use of UPERIO may be associated with an increased risk of hyperkalemia, although hypokalaemia may also occur (see Adverse Reactions). In PARADIGM-HF, the incidence of clinically relevant hyperkalemia was low, resulting in treatment discontinuation in 0.26% of UPERIO treated patients compared to 0.35% of enalapril treated patients. Medications known to raise potassium levels (e.g. potassium-sparing diuretics, potassium supplements) should be used with caution when co-administered with UPERIO. If clinically significant hyperkalemia occurs, measures such as reducing dietary potassium, or adjusting the dose of concomitant medications should be considered. Monitoring of serum potassium is recommended especially in patients with risk factors such as severe renal impairment, diabetes mellitus, hypoaldosteronism or receiving a high potassium diet or on mineralocorticoid antagonists (see Dosage & Administration). If patients experience clinically significant hyperkalaemia adjustment of concomitant medicinal products, or temporary down-titration or discontinuation is recommended. If serum potassium level is >5.4 mmol/l discontinuation should be considered.
Angioedema: Angioedema has been reported in patients treated with UPERIO. If angioedema occurs, UPERIO should be immediately discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. UPERIO 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 UPERIO is used in these patients. UPERIO is contraindicated 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, UPERIO 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.
Patients with NYHA functional classification IV: Caution should be exercised when initiating UPERIO in patients with NYHA functional classification IV due to limited clinical experience in this population.
B-type natriuretic peptide (BNP): BNP is not a suitable biomarker of heart failure in patients treated with UPERIO because it is a neprilysin substrate (see Pharmacology: Pharmacodynamics (PD) under Actions).
Patients with 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 Dosage & Administration and Pharmacology: Pharmacokinetics (PK) under Actions). UPERIO is contraindicated in patients with severe hepatic impairment, biliary cirrhosis or cholestasis (Child-Pugh C classification) (see Contraindications).
Effects on ability to drive and use machines: UPERIO has a minor influence on the 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.
Use In Pregnancy & Lactation
Females of child-bearing potential (and contraceptive measures if applicable): Female patients of child-bearing potential should be advised about the consequences of exposure to UPERIO during pregnancy and to use contraception during treatment with UPERIO and for 1 week after their last dose. Pregnancy: As for other drugs that also act directly on the RAAS, UPERIO must not be used during pregnancy (see Contraindications). UPERIO exerts its effects via angiotensin II antagonism. As a result, a risk to the fetus cannot be excluded. 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. Patients should be advised to discontinue UPERIO as soon as pregnancies occur and to inform their physicians.
Breast-feeding: It is not known whether UPERIO is excreted in human milk. The components of UPERIO, sacubitril and valsartan, were excreted in the milk of lactating rats (see Pharmacology: Toxicology: Non-clinical safety data under Actions). Because of the potential risk for adverse drug reactions in breastfed newborns/infants, UPERIO is not recommended during breastfeeding. A decision should be made whether to abstain from breast-feeding or to discontinue UPERIO while breast-feeding, taking into account the importance of UPERIO to the mother.
Fertility: There are no available data on the effect of UPERIO on human fertility. No impairment of fertility was demonstrated in studies with UPERIO in male and female rats (see Pharmacology: Toxicology: Non-clinical safety data under Actions).
Adverse Reactions
Summary of the safety profile: The most commonly reported adverse reactions during treatment with UPERIO were hypotension, hyperkalaemia and renal impairment (see Precautions). Angioedema was reported in patients treated with UPERIO (see description of selected adverse reactions as follows).
The safety of UPERIO in patients with chronic heart failure was evaluated in the pivotal phase 3 study PARADIGM-HF, which compared patients treated twice daily with UPERIO 200 mg (n=4203) or enalapril 10 mg (n= 4229). Patients randomized to UPERIO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3271 patients were treated for more than one year.
Discontinuation of therapy due to an AE in the double-blind period of the PARADIGM-HF trial occurred in 450 (10.71%) of UPERIO treated patients and 516 (12.20%) of patients receiving enalapril. The events most commonly associated with dosage adjustment or treatment interruption were hypotension, hyperkalemia and renal impairment.
The overall incidence of adverse drug reactions (ADRs) of UPERIO in heart failure patients was comparable to enalapril. The pattern of the ADRs is consistent with the pharmacology of UPERIO and the patients underlying conditions.
The overall frequency of adverse reactions was not related to gender, age, or race.
Adverse drug reactions are ranked by System Organ Class and then by frequency with the most frequent first, using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are ranked in order of decreasing seriousness. (See Table 2.)


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Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with UPERIO via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency, which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. (See Table 3.)


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Description of selected adverse reactions: Angioedema: Angioedema has been reported in patients treated with UPERIO. In PARADIGM-HF, angioedema was reported in 0.5% of patients treated with UPERIO, compared with 0.2% of patients treated with enalapril. A higher incidence of angioedema was observed in Black patients treated with UPERIO (2.4%) and enalapril (0.5%).
Hyperkalaemia and serum potassium: In PARADIGM-HF, hyperkalaemia and serum potassium concentrations >5.4 mmol/l were reported in 11.6% and 19.7% of Uperio-treated patients and 14.0% and 21.1% of enalapril-treated patients, respectively.
Blood pressure: In PARADIGM-HF, hypotension and clinically relevant low systolic blood pressure (<90 mmHg and decrease from baseline of >20 mmHg) were reported in 17.6% and 4.76% of Uperio-treated patients compared with 11.9% and 2.67% of enalapril-treated patients, respectively.
Renal impairment: In PARADIGM-HF, renal impairment was reported in 10.1% of UPERIO-treated patients and 11.5% of enalapril-treated patients.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Drug Interactions
Anticipated interactions resulting in a contraindication: ACE inhibitors: The concomitant use of UPERIO with ACE inhibitors is contraindicated, as the concomitant inhibition of neprilysin (NEP) and ACE inhibitor therapy may increase the risk of angioedema. UPERIO 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 UPERIO (see Contraindications, and Dosage & Administration).
Aliskiren: The concomitant use of UPERIO with aliskiren is contraindicated in patients with Type 2 diabetes or in patients with renal impairment (eGFR <60 ml/min/1.73 m2) (see Contraindications).
The combination of UPERIO with direct renin inhibitors such as aliskiren is not recommended (see Precautions). Combination of UPERIO with aliskiren is potentially associated with a higher frequency of adverse events such as hypotension hyperkalaemia and decreased renal function (including acute renal failure) (see Contraindications and Precautions).
Anticipated interactions resulting in concomitant use not being recommended: UPERIO should not be co-administered with an ARB due to the angiotensin II receptor blocking activity of UPERIO (see Precautions).
Observed interactions to be considered: Statins: In vitro data indicates that sacubitril inhibits OATP1B1 and OATP1B3 transporters. UPERIO may therefore increase the systemic exposure of OATP1B1 and OATP1B3 substrates such as statins. Co-administration of UPERIO increased the Cmax of atorvastatin and its metabolites by up to 2-fold and AUC by up to 1.3-fold. Caution should be exercised upon co-administration of UPERIO with statins. No clinically relevant drug-drug interaction was observed when simvastatin and Uperio were co-administered.
Sildenafil: Addition of a single dose of sildenafil to UPERIO at steady state in patients with hypertension was associated with greater BP reduction compared to administration of UPERIO alone. Therefore, caution should be exercised when sildenafil or another PDE-5 inhibitor is initiated in patients treated with UPERIO.
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 UPERIO is co-administered with these agents (see Precautions).
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 UPERIO 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 UPERIO who are taking NSAIDs concomitantly.
Lithium: The potential for a drug interaction between UPERIO 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, this combination is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended during concomitant use with UPERIO. If a diuretic is also used, the risk of lithium toxicity may be increased further.
Furosemide: Co-administration of UPERIO and furosemide had no effect on the pharmacokinetics of UPERIO but reduced Cmax and AUC of furosemide 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 furosemide was unchanged from baseline until the end of the PARADIGM-HF study in patients treated with UPERIO.
Nitrates, e.g. nitroglycerine: There was no drug-drug interaction between UPERIO and intravenously administered nitroglycerin with regard to blood pressure reduction. Coadministration of nitroglycerin and UPERIO was associated with a treatment difference of 5 bpm in heart rate compared to the administration of nitroglycerine alone. A similar effect on the heart rate may occur when UPERIO is co-administered with sublingual, oral or transdermal nitrates. In general no dose adjustment is required.
OATP and MRP2 Transporters: The active metabolite of sacubitril (sacubitrilat) and valsartan are OATP1B1, OATP1B3, OAT1 and OAT3 substrates; valsartan is also a MRP2 substrate. Therefore, co-administration of UPERIO with inhibitors of OATP1B1, OATP1B3, OAT3 (e.g. rifampin, cyclosporine), OAT1 (e.g. tenofovir, cidofovir) 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 UPERIO with metformin reduced both Cmax and AUC of metformin by 23%. The clinical relevance of these findings is unknown. Therefore, when initiating therapy with UPERIO 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 UPERIO and digoxin, warfarin, hydrochlorothiazide, amlodipine, omeprazole, carvedilol or a combination of levonorgestrel/ethinyl estradiol. 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 UPERIO via the CYP450 enzymes. UPERIO does not induce or inhibit CYP450 enzymes.
Caution For Usage
Incompatibilities: Not applicable.
Instructions for use and handling: Not applicable.
Special precautions for disposal: Not applicable.
Storage
Do not store above 30°C. Store in the original package to protect from moisture.
MIMS Class
Angiotensin II Antagonists
ATC Classification
C09DX04 - valsartan and sacubitril ; Belongs to the class of angiotensin II receptor blockers (ARBs), other combinations. Used in the treatment of cardiovascular disease.
Presentation/Packing
FC tab 50 mg (violet white ovaloid biconvex with beveled edges, unscored, debossed with "NVR" on one side and "LZ" on the other side) x 2 x 14's. 100 mg (pale yellow ovaloid biconvex with beveled edges, unscored, debossed with "NVR" on one side and "L1" on the other side) x 2 x 14's. 200 mg (light pink ovaloid biconvex with beveled edges, unscored, debossed with "NVR" on one side and "L11" on the other side) x 4 x 7's.
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