Sybrava Injection 284 mg Solution for Injection

Primary Hyperlipidaemia (including Heterozygous Familial Hypercholesterolaemia) Sybrava is indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with primary Hyperlipidaemia (including Heterozygous Familial Hypercholesterolaemia (HeFH)) to reduce low-density lipoprotein cholesterol (LDL-C).

Posology
The recommended dosage of Sybrava is 284 mg administered as a single subcutaneous injection: initially, again at 3 months and then every 6 months.
Missed doses
u2022 If a planned dose of Sybrava is missed by less than 3 months, Sybrava should be administered and dosing maintained according to the patientu2019s original schedule.
u2022 If a planned dose of Sybrava is missed by more than 3 months, a new dosing schedule should be started u2013 Sybrava should be administered initially, again at 3 months, followed by every 6 months.
Treatment Transition from PCSK9 Inhibitor Monoclonal Antibody
Sybrava can be administered immediately after the last dose of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibody. To maintain LDL-C lowering, it is recommended that Sybrava is administered within 2 weeks after the last dose of a PCSK9 inhibitor monoclonal antibody.
Special populations
Elderly patients (age u2265 65 years)
No dose adjustment is necessary in elderly patients.
Hepatic Impairment
No dose adjustment is necessary for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Renal Impairment
No dose adjustment is necessary for patients with renal impairment (mild, moderate or severe) or end-stage renal disease. If administering Sybrava to patients on haemodialysis, haemodialysis should not be performed for at least 72 hours after Sybrava dosing.
Paediatric population
The safety and efficacy of Sybrava in children aged less than 18 years has not yet been established. Sybrava should not be used in children under 18 years of age.
Method of administration
Sybrava is intended for administration by a healthcare professional. Sybrava is for subcutaneous injection into the abdomen. Injections should not be given into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections. Sybrava should be inspected visually for particulate matter prior to administration. If the solution contains visible particulate matter, the solution should not be used. Do not remove the needle cap until you are ready to inject, early removal of the needle cap prior to injection can lead to drying of the drug product within the needle, which can result in needle clogging.
If following insertion of the needle you cannot depress the plunger, use a new prefilled syringe. Each 284 mg dose is administered using a single pre-filled syringe. Each pre-filled syringe is for single use only.

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

Renal 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 Sybrava dosing.
Hepatic impairment
Patients with severe hepatic impairment (Child-Pugh class C) have not been studied (see section 5.2). Sybrava should be used with caution in patients with severe hepatic impairment.

Inclisiran is not a substrate, inhibitor or inducer of cytochrome P450 (CYP450) enzymes or common drug transporters, and therefore Sybrava is not expected to have clinically significant interactions with other medications. Drug-drug interaction assessments demonstrated a lack of clinically meaningful interactions with either atorvastatin or rosuvastatin or other statins.

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). Sybrava should not be used during pregnancy.
Breastfeeding
It is not known if inclisiran is transferred into human milk after administration of Sybrava. There are no data on the effects of inclisiran on the breastfed child or on milk production. Inclisiran was present in rat milk following once-daily subcutaneous injection. However, there is no evidence of systemic absorption in suckling rat neonates. Women on Sybrava should not breast feed their babies.
Fertility
There are no data on the effect of Sybrava on human fertility.

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

Summary of the safety profile
The safety of Sybrava was evaluated in 3 Phase III placebo-controlled trials that included 3,655 patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or familial hypercholesterolaemia, treated with maximally tolerated statins and Sybrava or placebo, including 1,833 patients exposed to inclisiran for up to 18 months (mean treatment duration of 526 days). Safety data from the 3 Phase III placebo-controlled pivotal trials showed that treatment-emergent adverse events (TEAEs) occurred at a similar incidence in the Sybrava-treated and placebo-treated patients. The majority of the TEAEs were mild and unrelated to Sybrava or placebo. The only adverse reactions associated with Sybrava in pivotal trials were adverse events at the injection site.
Tabulated summary of adverse drug reactions from clinical trials
Adverse drug reactions from clinical trials (Table 7-1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (u22651/10); common (u22651/100 to <1/10); uncommon (u22651/1,000 to <1/100); rare (u22651/10,000 to <1/1,000); very rare (<1/10,000).
Table 1: Adverse drug reactions reported in patients treated with inclisiran
Adverse drug reactions
Placebo (N=1822) %
Sybrava (N=1833) %
Frequency category
General disorders and administration site conditions
Adverse events at the injection site 1
1,8
8,2
Common
1 Most frequently occurring adverse events are: injection site reaction, injection site pain, injection site erythema, and injection site rash.
Description of selected adverse reactions
Adverse events at the injection site
Adverse events at the injection site occurred in 8,2 % and 1,8 % of Sybrava-treated and placebo-treated patients, respectively in the pivotal trials. The proportions of patients who discontinued treatment due to adverse events at the injection site in Sybrava-treated patients and placebo-treated patients were 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 events 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 %).
Immunogenicity
In the pivotal trials, 1,830 patients were tested for anti-drug antibodies. Confirmed positivity was detected in 1,8 % (33/1830) of patients prior to dosing and in 4,9 % (90/1830) of patients during the 18 months of treatment with Sybrava. No clinically significant differences in the clinical efficacy, safety or pharmacodynamic profiles of Sybrava were observed in the patients who tested positive for anti-inclisiran antibodies.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Health care providers are requested to report any suspected adverse drug reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

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