Sibrava solution for injection 284 mg pre-filled syringe 1.5 ml No. 1

Instructions for use: Sibrava solution for injection 284 mg pre-filled syringe 1.5 ml No. 1

Composition

active ingredient: Sodium inclisiran;

1 pre-filled syringe contains 1.5 ml of solution containing Inclisiran Sodium equivalent to 284 mg Inclisiran.

1 ml contains Inclisiran sodium, equivalent to 189 mg Inclisiran;

Excipients: Water for injections, sodium hydroxide (for pH adjustment), phosphoric acid (for pH adjustment), nitrogen (free volume gas).

Dosage form

Solution for injection in a pre-filled syringe.

Main physicochemical properties: Transparent solution, colorless or pale yellow, practically free of particles.

Pharmacotherapeutic group

Lipid-modifying agents, other lipid-modifying agents.

ATX code: C10AX16.

Pharmacological properties

Mechanism of action

Inclisiran is a double-stranded cholesterol-lowering small interfering ribonucleic acid (siRNA) conjugated on the coding strand to triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes an RNA interference mechanism and directs the catalytic degradation of mRNA to the proprotein convertase subtilisin-kexin type 9. This increases the recycling and expression of LDL-C receptors on the surface of hepatocyte cells, which increases LDL-C uptake and reduces its levels in the bloodstream.

Pharmacodynamics.

Following a single subcutaneous dose of 284 mg inclisiran, LDL-C reductions were evident within 14 days. A mean LDL-C reduction of 48-51% was observed 30-60 days after dosing. At day 180, LDL-C levels were still reduced by approximately 53%.

Clinical efficacy and safety

In clinical trials and some publications, a dose of 284 mg inclisiran is equivalent and is referred to as 300 mg inclisiran sodium salt.

The efficacy of inclisiran was evaluated in three phase III studies in patients with atherosclerotic cardiovascular disease (ACSD) (ischaemic heart disease, cerebrovascular disease or peripheral arterial disease), at risk equivalents for ACSD (type 2 diabetes, familial hypercholesterolaemia or 10-year risk of cardiovascular events of 20% or greater, as assessed by the Framingham Risk Score or equivalent) and/or familial hypercholesterolaemia (FH). Patients were receiving the maximum tolerated dose of a statin, with or without other lipid-modifying therapy, and required additional LDL-C lowering (patients in whom treatment goals were not achieved). Approximately 17% of patients were statin intolerant. Patients received subcutaneous injections of 284 mg inclisiran or placebo on days 1, 90, 270, and 450. Patients were followed up to day 540.

The effect of inclisiran on cardiovascular morbidity and mortality has not been determined.

In a pooled analysis of phase III studies, subcutaneous inclisiran reduced LDL-C by 50–55% as early as day 90 (Fig. 1), and this reduction was maintained during long-term therapy. The maximum reduction in LDL-C was achieved at day 150 after the second dose. Small but statistically significant increases in LDL-C of up to 65% were associated with lower baseline LDL-C levels (approximately <2 mmol/L (77 mg/dL)), higher baseline PCSK9 levels, and higher statin doses and intensity.

Fig. 1 Mean percent change from baseline in LDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia treated with inclisiran compared with placebo (pooled analysis)

ACC and ACC risk equivalents

Two studies were conducted in patients with CAD and equivalent CAD risk (ORION-10 and ORION-11). Patients were receiving the maximally tolerated dose of a statin, with or without other lipid-modifying therapy (e.g., ezetimibe), and required additional LDL-C lowering. Because LDL-C reduction should improve cardiovascular outcomes, the co-primary endpoints in each study were the percent change from baseline in LDL-C to Day 510 compared with placebo and the time-adjusted percent change from baseline in LDL-C after Day 90 and to Day 540 to assess the overall effect on LDL-C over time.

ORION-10 is a multicenter, double-blind, randomized, placebo-controlled 18-month study in 1,561 patients with CAD9.

The mean age at baseline was 66 years (range: 35 to 90 years), 60% of patients were ≥65 years of age, 31% were female, 86% were Caucasian, 13% were black, 1% were Asian, and 14% were Hispanic or Latino. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). 69% of patients were receiving high-dose statins, 19% were receiving medium-dose statins, 1% were receiving low-dose statins, and 11% were not using statins. The most commonly used statins were atorvastatin and rosuvastatin.

Inclisiran significantly reduced the mean percent change from baseline in LDL-C at Day 510 compared with placebo by 52% (95% CI: -56%, -49%; p < 0.0001) (Table 2).

Inclisiran also significantly reduced the time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 by 54% compared with placebo (95% CI: -56%, -51%; p < 0.0001). See Table 2 for additional results.

Table 2 Mean percent change from baseline and difference from placebo in lipid parameters at day 510 in the ORION-10 study

At day 510, the target LDL-C <1.8 mmol/L (70 mg/dL) was achieved in 84% of patients with CAD in the inclisiran group compared with 18% of patients in the placebo group.
Consistent and statistically significant (p < 0.0001) reductions in percent change from baseline in LDL-C to Day 510 and in time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 were observed in all subgroups, regardless of baseline demographics, baseline disease characteristics (including sex, age, body mass index, race, and statin use), comorbidities, and geographic region.

ORION-11 is an international, multicenter, double-blind, randomized, placebo-controlled, 18-month study in 1617 patients with CVD or equivalent CVD risk. More than 75% of patients received background high-dose statin therapy, 87% of patients had CVD and 13% had equivalent CVD risk.

The mean age at baseline was 65 years (range: 20 to 88 years), 55% of patients were ≥65 years of age, 28% were female, 98% were Caucasian, 1% were black, 1% were Asian, and 1% were Hispanic or Latino. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). 78% of patients were receiving high-dose statins, 16% were receiving medium-dose statins, 0.4% were receiving low-dose statins, and 5% were not using statins. The most commonly used statins were atorvastatin and rosuvastatin.

Inclisiran significantly reduced the mean percent change in LDL-C from baseline to day 510 compared with placebo by 50% (95% CI: -53%, -47%; p<0.0001) (Table 3).

Inclisiran also significantly reduced the time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 by 49% compared with placebo (95% CI: -52%, -48%; p<0.0001). See Table 3 for additional results.

Table 3 Mean percent change from baseline and difference from placebo in lipid parameters at day 510 in the ORION-11 study

At day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved in 82% of patients with CAD in the inclisiran group compared with 16% of patients in the placebo group. In patients with equivalent CVD risk, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved in 78% of patients in the inclisiran group compared with 31% of patients in the placebo group. Consistent and statistically significant (p<0.05) reductions in percent change from baseline in LDL-C to Day 510 and in time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 were observed in all subgroups, regardless of baseline demographics, baseline disease characteristics (including sex, age, body mass index, race, and statin use), comorbidities, and geographic region.

Heterozygous familial hypercholesterolemia

ORION-9 was an international, multicenter, double-blind, randomized, placebo-controlled, 18-month study in 482 patients with heterozygous familial hypercholesterolemia (FH). All patients were receiving their maximally tolerated dose of a statin, with or without other lipid-modifying therapy (e.g., ezetimibe), and required additional LDL-C lowering. The diagnosis of FH was based on genotyping or clinical criteria (“confirmed FH,” using either the Simon Broome or BOO3/Dutch Lipid Network criteria).

The mean age at baseline was 55 years (range: 21 to 80 years), 22% of patients were ≥65 years, 53% were female, 94% were Caucasian, 3% were black, 3% were Asian, and 3% were Hispanic or Latino. The mean baseline LDL-C was 4.0 mmol/L (153 mg/dL). 74% of patients were receiving high-dose statins, 15% were receiving medium-dose statins, and 10% were not using statins. 52% of patients were receiving ezetimibe. The most commonly used statins were atorvastatin and rosuvastatin.

Inclisiran significantly reduced the mean percent change in LDL-C from baseline to day 510 compared with placebo by 48% (95% CI: -54%, -42%; p<0.0001) (Table 4).

Inclisiran also significantly reduced the time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 by 44% compared with placebo (95% CI: -48%, -40%; p<0.0001). See Table 4 for additional results.

Table 4 Mean percent change from baseline and difference from placebo in lipid parameters at day 510 in the ORION-9 study

At day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved in 52.5% of patients with CAD in the inclisiran group compared with 1.4% of patients with CAD in the placebo group, while in the population with equivalent CVD risk, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved in 66.9% of patients in the inclisiran group compared with 8.9% of patients in the placebo group.

Consistent and statistically significant (p<0.05) reductions in percent change from baseline in LDL-C to Day 510 and in time-adjusted percent change from baseline in LDL-C after Day 90 and through Day 540 were observed in all subgroups, regardless of baseline demographics, baseline disease characteristics (including sex, age, body mass index, race, and statin use), comorbidities, and geographic region.

Children

The European Medicines Agency has waived the obligation to submit the results of studies with inclisiran in one or more subsets of the paediatric population in the treatment of elevated cholesterol levels (see section 4.2 for information on paediatric use).

Pharmacokinetics

Absorption

Following a single subcutaneous dose, systemic exposure to inclisiran increased approximately dose-proportionally over the range of 24 mg to 756 mg. At the recommended dose regimen of 284 mg, plasma concentrations peaked approximately 4 hours after administration, with a mean Cmax of 509 ng/mL. Concentrations were below the threshold of detection within 48 hours of administration. The mean area under the plasma concentration/time curve, extrapolated to infinity, was 7980 ng*h/mL. The pharmacokinetic results following multiple subcutaneous doses of inclisiran were similar to those after a single dose.

Distribution

Inclisiran is 87% protein bound in vitro at clinically relevant plasma concentrations. Following a single subcutaneous dose of 284 mg inclisiran to healthy adults, the apparent volume of distribution is approximately 500 L. Nonclinical data indicate that inclisiran is well absorbed and highly selective for the liver, the target organ for cholesterol lowering.

Biotransformation

Inclisiran is primarily metabolized by nucleases to shorter inactive nucleotides of varying lengths. Inclisiran is not a substrate for conventional drug transporters and, although in vitro studies have not been performed, it is not expected to be a substrate for cytochrome P450.

Breeding

The terminal half-life of inclisiran is approximately 9 hours; accumulation does not occur with multiple dosing. 16% of inclisiran is excreted in the urine.

Linearity/nonlinearity

In a phase I clinical study, an approximately dose-proportional increase in exposure to inclisiran was observed after subcutaneous administration of doses ranging from 24 mg to 756 mg. No accumulation or time-dependent effects were observed after repeated subcutaneous administration of inclisiran.

Pharmacokinetic/pharmacodynamic relationship

In a phase I clinical trial, no relationship was observed between the pharmacokinetic parameters of inclisiran and the pharmacodynamic effect on LDL-C. Selective delivery of inclisiran to hepatocytes, where it is part of the RNA-induced silencing complex (RISC), results in a prolonged effect that exceeds that expected based on the plasma half-life of 9 hours. The maximum effect on LDL-C reduction was observed at a dose of 284 mg, with higher doses not providing a greater effect.

Indication

in combination with a statin or a statin and other lipid-lowering agents in patients in whom the target LDL-C level cannot be achieved with the maximally tolerated dose of a statin, or

alone or in combination with other lipid-lowering agents in patients with intolerance or contraindications to statins.

Contraindication

Hypersensitivity to the active substance or any of the excipients.

Interaction with other medicinal products and other types of interactions

Inclisiran is not a substrate for common drug transporters and, although in vitro studies have not been performed, it is not expected to be a substrate for cytochrome P450. Inclisiran is not an inhibitor or inducer of cytochrome P450 enzymes or common drug transporters. Therefore, no clinically significant interactions of inclisiran with other medicinal products are expected. Based on limited data, no clinically significant interactions with atorvastatin, rosuvastatin or other statins are expected.

Application features

Kidney failure

In a pharmacokinetic analysis of data from a dedicated renal impairment study, increases in inclusiran Cmax by approximately 2.3, 2.0 and 3.3 fold and increases in inclusiran AUC by approximately 1.6, 1.8 and 2.3 fold were reported in patients with mild (creatinine clearance [CrCL] 60 mL/min to 89 mL/min), moderate (CrCL 30 mL/min to 59 mL/min) and severe (CrCL 15 mL/min to 29 mL/min) renal impairment, respectively, compared to patients with normal renal function. Despite the higher transient plasma exposure over 48 hours, LDL-C reduction was similar across renal function groups. Based on population pharmacodynamic modeling, no dose adjustment is recommended in patients with end-stage renal disease. Based on pharmacokinetic and pharmacodynamic properties and safety evaluation, no dose adjustment is necessary in patients with mild, moderate, or severe renal impairment. The effect of hemodialysis on the pharmacokinetics of inclisiran has not been studied. Given that inclisiran is excreted by the kidneys, hemodialysis should not be performed for at least 72 hours after inclisiran administration.

Liver failure

In a pharmacokinetic analysis of data from a dedicated study in hepatic impairment, an increase in inclusiran Cmax of approximately 1.1 and 2.1 fold, and an increase in inclusiran AUC of approximately 1.3 and 2.0 fold, respectively, was reported in patients with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment compared to patients with normal hepatic function. Despite higher transient plasma exposure over 48 hours, LDL-C reductions were similar between the groups of patients with normal liver function and mild hepatic impairment receiving inclisiran. In patients with moderate hepatic impairment, baseline PCSK9 levels were significantly lower and LDL-C reductions were smaller than in patients with normal liver function.
with normal liver function. Dose adjustment for patients with mild to moderate
hepatic impairment (Child-Pugh class A and B) is not required. Inclisiran has not been studied in patients with severe hepatic impairment (Child-Pugh class C).

Other special categories

A population pharmacodynamic analysis was performed on 4328 patients. Age, body weight, gender, race, and creatinine clearance did not significantly affect the pharmacodynamics of inclisiran. No dose adjustment is recommended for patients based on these demographics.

Hemodialysis

The effect of hemodialysis on the pharmacokinetics of inclisiran has not been studied. Given that inclisiran is excreted by the kidneys, hemodialysis should not be performed for at least 72 hours.
after inclisiran administration.

Sodium content

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Use during pregnancy or breastfeeding

I am rich.

There are no or limited amount of data from the use of inclisiran in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of inclisiran during pregnancy.

Lactation

It is unknown whether inclisiran is excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of inclisiran in milk. A risk to the newborn/infants cannot be excluded.

A decision on whether to discontinue breast-feeding or to discontinue/abstain from inclisiran therapy should be made taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Reproductive function

There are no data on the effects of inclisiran on human reproductive function. Animal studies have not shown any effect on fertility.

Ability to influence reaction speed when driving or operating other mechanisms

Inclisiran has no or negligible influence on the reaction rate when driving vehicles or operating other mechanisms.

Method of administration and doses

Dosage

The recommended dose is 284 mg inclisiran, administered as a single subcutaneous injection at the start of treatment, then after 3 months, and then every 6 months.

Missed dose

If a scheduled dose is missed by more than 3 months, a new treatment schedule should be started - inclisiran should be administered initially, then 3 months later, and then every 6 months.

Switching from PCSK9 monoclonal antibody inhibitor treatment

Inclisiran can be administered immediately after the last dose of a PCSK9 monoclonal antibody inhibitor. To maintain LDL-C reduction, it is recommended that Inclisiran be administered for 2 weeks after the last dose of a PCSK9 monoclonal antibody inhibitor.

Special categories of patients

Elderly patients (≥ 65 years)

No dose adjustment is necessary in elderly patients.

Liver failure

No dose adjustment is necessary for patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment. No data are available for patients with severe hepatic impairment (Child-Pugh Class C). Inclisiran should be used with caution in patients with severe hepatic impairment.

Kidney failure

No dose adjustment is required for patients with mild, moderate, severe renal impairment and end-stage renal disease. Experience with inclisiran in patients with severe renal impairment is limited. In these patients, inclisiran should be used with caution. For precautions in case of haemodialysis, see section 4.4.

Children

The safety and effectiveness of inclisiran in children under 18 years of age have not been established.

Data is missing.

Method of application

The drug is intended for subcutaneous use.

Inclisiran is intended for subcutaneous administration in the abdomen; alternative injection sites are the shoulder or thigh. Injections should not be given into areas of skin disease or injury, such as sunburn, rashes, inflammation, or skin infections.

Each 284 mg dose is administered using one pre-filled syringe. Each pre-filled syringe is for single use only. Inclisiran should be administered by a healthcare professional.

Overdose

No clinically significant adverse reactions were observed in healthy volunteers receiving inclisiran in doses exceeding the therapeutic dose. There is no specific antidote for inclisiran overdose. In case of overdose, the patient should be treated symptomatically and supportive measures should be taken as necessary.

Side effects

Summary of the safety profile

The only adverse reactions associated with inclisiran were injection site reactions (8.2%).

List of adverse reactions

Adverse reactions are listed according to the main system organ classes (Table 1). The frequency is defined as follows: very common (≥1/10); common (≥1/100 - <1/10); uncommon (≥1/1000 - <1/100); rare (≥1/10000 - <1/1000); very rare (<1/10000); not known (cannot be estimated from the available data).

Table 1 Adverse reactions occurring in patients receiving inclisiran

Description of some adverse reactions

Adverse reactions at the injection site

In the pivotal studies, injection site reactions occurred in 8.2% and 1.8% of patients in the inclisiran and placebo groups, respectively. The proportion of patients in each group who discontinued treatment due to injection site reactions was 0.2% and 0.0%, respectively. All of these adverse reactions were mild to moderate in severity, transient, and resolved without sequelae. The most common injection site adverse reactions in patients receiving inclisiran were injection site reactions (3.1%), injection site pain (2.2%), injection site erythema (1.6%), and injection site rash (0.7%).

Special categories of patients

Elderly patients

Of the 1833 patients who received inclisiran in pivotal studies, 981 (54%) were 65 years of age and older, and 239 (13%) were 75 years of age and older. There were no overall differences in safety between these
patients and younger patients were not observed.

Immunogenicity

During the studies, 1,830 patients were tested for antibodies to the drug. Confirmed positivity was detected in 1.8% (33/1,830) of patients before dosing and in 4.9% (90/1,830) of patients during 18 months of inclisiran treatment. No clinically relevant differences in the clinical efficacy, safety, or pharmacodynamic profiles of inclisiran were observed in patients who tested positive for antibodies to inclisiran.

Laboratory indicators

In phase III clinical trials, elevations in serum hepatic transaminases from > 1 x upper limit of normal (ULN) to ≤ 3 x ULN were observed more frequently in patients treated with inclisiran (ALT: 19.7%; AST: 17.2%) compared to placebo (ALT: 13.6%; AST: 11.1%). These elevations did not exceed the clinically significant threshold of 3 x ULN, were asymptomatic, and were not associated with adverse reactions or other signs of hepatic dysfunction.

Reporting of suspected adverse events

Reporting suspected adverse events after the marketing authorisation of a medicinal product is important as it allows for further monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse events via the national reporting system listed in Annex V.

Expiration date

3 years.

Storage conditions

Does not require special storage conditions. Do not freeze.

Packaging

1.5 ml of solution in a pre-filled syringe, 1 pre-filled syringe in a cardboard box.

Vacation category

According to the recipe.

Producer

Novartis Pharma GmbH, Germany

Or

Sandoz GmbH, Austria

Location of the manufacturer and its place of business address.

Runstrasse 25 and Ober Turnstrasse 8 - 10, Nuremberg, Bavaria, 90429, Germany.

Or

Biochemiststrasse 10, Langkampfen, 6336, Austria