inclisiran: prescribing information – dosing, contraindications, interactions, side effects

Leqvio is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non- familial) or mixed dyslipidaemia, as an adjunct to diet, and in paediatric patients aged 12 years and older with heterozygous familial hypercholesterolaemia (HeFH):
- in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or
- alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

Posology

The recommended dose for adults and paediatric patients aged 12 years and older is 284 mg inclisiran administered as a single subcutaneous injection: initially, again at 3 months, followed by every 6 months.

Missed doses
If a planned dose is missed by less than 3 months, inclisiran should be administered and dosing continued according to the patient’s original schedule.

If a planned dose is missed by more than 3 months, a new dosing schedule should be started – inclisiran should be administered initially, again at 3 months, followed by every 6 months.

Treatment transition from monoclonal antibody proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors Inclisiran can be administered immediately after the last dose of a monoclonal antibody PCSK9 inhibitor. To maintain low-density lipoprotein cholesterol (LDL-C) lowering it is recommended that inclisiran is administered within 2 weeks after the last dose of a monoclonal antibody PCSK9 inhibitor.

Special populations
Elderly
No dose adjustments are necessary in elderly patients (see section 5.2).

Hepatic impairment
No dose adjustments are necessary for patients with mild (Child-Pugh class A) or moderate (Child- Pugh class B) hepatic impairment. No data are available in patients with severe hepatic impairment (Child-Pugh class C) (see section 5.2). Inclisiran should be used with caution in patients with severe hepatic impairment.

Renal impairment
No dose adjustments are necessary for patients with mild, moderate or severe renal impairment or patients with end-stage renal disease (see section 5.2). There is limited experience with inclisiran in patients with severe renal impairment. Inclisiran should be used with caution in these patients. See section 4.4 for precautions to take in case of haemodialysis.

Paediatric population
The safety and efficacy of inclisiran in children aged less than 12 years have not yet been established.
No data are available.

Method of administration

Subcutaneous use.

Inclisiran is for subcutaneous injection into the abdomen; alternative injection sites include the upper arm or thigh. Injections should not be given into areas of active skin disease or injury such as sunburns, skin rashes, inflammation or skin infections.

Each 284 mg dose is administered using a single pre-filled syringe. Each pre-filled syringe is for single use only.

Inclisiran is intended for administration by a healthcare professional.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Summary of the safety profile

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

Tabulated list of adverse reactions

Adverse reactions are presented by system organ class (Table 1). Frequency categories are defined as:
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) and not known (cannot be estimated from the available data).

Table 1
Adverse reactions reported in patients treated with inclisiran

System organ class
Adverse reaction
Frequency category
Immune system disorders
Hypersensitivity including anaphylactic reaction, angioedema, rash, urticaria, pruritus Not known General disorders and administration site conditions Adverse reactions at the injection site1 Common 1 See section “Description of selected adverse reactions”

Description of selected adverse reactions

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

Special populations

Paediatric population
The safety and efficacy of inclisiran were assessed in two phase III studies in paediatric patients. The first study was a 24-month, two-part study of 141 patients aged 12 to less than 18 years with HeFH, consisting of a 12-month double-blind, placebo-controlled part followed by a 12-month open-label part. The second study was a 24-month, two-part study of 13 patients aged 12 to less than 18 years with homozygous familial hypercholesterolaemia (HoFH), consisting of a 12-month double-blind, placebo-controlled part followed by a 12-month open-label part. The safety profile of inclisiran reported in these studies was consistent with the safety profile reported in adult patients and no new safety findings were observed during the studies.

Elderly
Of the 1 833 patients treated with inclisiran in the pivotal studies, 981 (54%) were 65 years of age or older, while 239 (13%) were 75 years of age or older. No overall differences in safety were observed between these patients and younger patients.

Immunogenicity

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

Laboratory values

In the phase III clinical studies, there were more frequent elevations of serum hepatic transaminases between >1x the upper limit of normal (ULN) and ≤3x ULN in patients on inclisiran (ALT: 19.7% and AST: 17.2%) than in patients on placebo (ALT: 13.6% and AST: 11.1%). These elevations did not progress to exceed the clinically relevant threshold of 3x ULN, were asymptomatic and were not associated with adverse reactions or other evidence of liver dysfunction.

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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Haemodialysis

The effect of haemodialysis on inclisiran pharmacokinetics has not been studied. Considering that inclisiran is eliminated renally, haemodialysis should not be performed for at least 72 hours after inclisiran dosing.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium-free”.

Inclisiran is not a substrate for common drug transporters and, although in vitro studies were not conducted, it is not anticipated to be a substrate for cytochrome P450. Inclisiran is not an inhibitor or inducer of cytochrome P450 enzymes or common drug transporters. Therefore, inclisiran is not expected to have clinically significant interactions with other medicinal products. Based on the limited data available, clinically meaningful interactions with atorvastatin, rosuvastatin or other statins are not expected.

Pregnancy

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 (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of inclisiran during pregnancy.

Breast-feeding

It is unknown whether inclisiran/metabolites are excreted in human milk. Available pharmacodynamic/toxicological data in animals have shown excretion of inclisiran in milk (see section 5.3). A risk to the newborns/infants cannot be excluded.

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

Fertility

No data on the effect of inclisiran on human fertility are available. Animal studies did not show any effects on fertility (see section 5.3).

Leqvio has no or negligible influence on the ability to drive and use machines.

No clinically relevant adverse reactions were observed in healthy volunteers who received inclisiran at doses up to three times the therapeutic dose. No specific treatment for inclisiran overdose is available.
In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: lipid modifying agents, other lipid modifying agents, ATC code:
C10AX16

Mechanism of action

Inclisiran is a cholesterol-lowering, double-stranded, small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilises the RNA interference mechanism and directs catalytic breakdown of mRNA for proprotein convertase subtilisin kexin type 9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.

Pharmacodynamic effects

Following a single subcutaneous administration of 284 mg inclisiran, LDL-C reduction was apparent within 14 days post-dose. Mean reductions of 49-51% for LDL-C were observed 30 to 60 days post- dose. At day 180, LDL-C levels were still reduced by approximately 53%.

Clinical efficacy and safety

In clinical studies and some publications, the 284 mg inclisiran dose is equivalent and referred to as 300 mg inclisiran sodium salt.

The efficacy of inclisiran was evaluated in three phase III studies in adult patients with atherosclerotic cardiovascular disease (ASCVD) (coronary heart disease, cerebrovascular disease or peripheral artery disease), ASCVD risk equivalents (type 2 diabetes mellitus, familial hypercholesterolaemia, or 10- year risk of 20% or greater of having a cardiovascular event assessed by Framingham Risk Score or equivalent) and/or familial hypercholesterolaemia (FH). Patients were taking a maximally tolerated dose of statin with or without other lipid-modifying therapy and required additional LDL-C reduction (patients unable to reach their treatment goals). Approximately 17% of patients were statin intolerant.
Patients were administered subcutaneous injections of 284 mg inclisiran or placebo on day 1, day 90, day 270 and day 450. Patients were followed until day 540.

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

In the phase III pooled analysis, subcutaneously administered inclisiran lowered LDL-C between 50% and 55% as early as day 90 (Figure 1), which was maintained during long-term therapy. Maximal LDL-C reduction was achieved at day 150 following a second administration. Small but statistically significant increased LDL-C reductions 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 statin intensity.

Figure 1
Mean percentage change from baseline LDL-C in patients with primary hypercholesterolaemia and mixed dyslipidaemia treated with inclisiran compared to placebo (pooled analysis)

ASCVD and ASCVD risk equivalents

Absorption

Following single subcutaneous administration, systemic exposure to inclisiran increased approximately dose-proportionally over a range from 24 mg to 756 mg. At the recommended dosing regimen of 284 mg plasma concentrations reached peak in approximately 4 hours post dose, with a mean Cmax of 509 ng/ml. Concentrations reached undetectable levels within 48 hours post dosing. The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7 980 ng*h/ml. Pharmacokinetic findings following multiple subcutaneous administrations of inclisiran were similar to single-dose administration.

Distribution

Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of inclisiran to healthy adults, the apparent volume of distribution is approximately 500 litres. Based on non-clinical data inclisiran has been shown to have high uptake into and selectivity for the liver, the target organ for cholesterol lowering. Body weight was a significant covariate on volume of distribution in the combined adult and adolescent population pharmacokinetic model.

Biotransformation

Inclisiran is primarily metabolised by nucleases to shorter inactive nucleotides of varying length.
Inclisiran is not a substrate for common drug transporters and, although in vitro studies were not conducted, it is not anticipated to be a substrate for cytochrome P450.

Elimination

The terminal elimination half-life of inclisiran is approximately 9 hours and no accumulation occurs with multiple dosing. Sixteen percent (16%) of inclisiran is cleared through the kidney. Body weight was a significant covariate on clearance in the combined adult and adolescent population pharmacokinetic model.

Linearity/non-linearity