Inclisiran

There is limited experience with inclisiran in patients with severe renal impairment. Inclisiran should be used with caution in these patients.

No data are available in patients with severe hepatic impairment (Child-Pugh class C). Inclisiran should be used with caution in patients with severe hepatic impairment.

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.

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.

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 newborns/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from inclisiran 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.

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

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:

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

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.