Inclisiran Sodium

Registered South African indications:

• Primary hyperlipidaemia (including heterozygous familial hypercholesterolaemia)
  - 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)

Contraindications

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient of any of its excipients

Cautions

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Haemodialysis
• Severe hepatic impairment (Child Pugh class C)

Use in renal impairment

• Inclisiran is eliminated renally; the effect of haemodialysis on its pharmacokinetics has not been studied
• Haemodialysis should not be performed for at least 72 hours after Sybrava administration

Use in hepatic impairment

• Inclisiran should be used with caution in patients with severe hepatic impairment (Child-Pugh class C), as these patients have not been studied

Effects on ability to drive and use machines

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

Recommendations in other jurisdictions

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Severe renal impairment
• End-stage renal disease
• Haemodialysis
• Severe hepatic impairment (Child Pugh class C)

Haemodialysis

• The effect of haemodialysis on inclisiran pharmacokinetics has not been studied
• As 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 and is therefore considered essentially sodium-free

Effects on ability to drive and use machines

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

Forms avail. in SA and covered in this monograph: pfs

South African registered indications and dosages

Primary hyperlipidaemia (including heterozygous familial hypercholesterolaemia)
- 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)

• SC: Initial: 284mg, admin. as a single dose; Followed by: 284mg, admin. at 3 months; Then 284mg, admin. every 6 months

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

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Treatment transition from PCSK9 inhibitor monoclonal antibody
Inclisiran 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 inclisiran is administered within 2 weeks after the last dose of a PCSK9 inhibitor monoclonal antibody

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Method of administration
Inclisiran is intended for administration by a healthcare professional
Inclisiran 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
Inclisiran should be inspected visually for particulate matter prior to administration. If the solution contains visible particulate matter, the solution should not be used
Each 284mg dose is administered using a single pre-filled syringe. Each pre-filled syringe is for single use only

Not established for use in children below 18 years

Pregnancy

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• 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

Breastfeeding

South African recommendations

• Caution; not recommended
• It is not known if inclisiran is transferred into human milk after administration of inclisiran. 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 inclisiran should not breastfeed their babies

Recommendations in other jurisdictions

• Caution; not recommended
• 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 breastfeeding or to discontinue/abstain from inclisiran therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman

Fertility

South African recommendations

• There are no data on the effect of inclisiran on human fertility

Recommendations in other jurisdictions

• No data on the effect of inclisiran on human fertility are available. Animal studies did not show any effects on fertility

South African recommendations

• Mild, moderate, severe or end-stage renal disease: No dose adjustment recommended
• Haemodialysis: Caution
  If administering inclisiran to patients on haemodialysis, haemodialysis should not be performed for at least 72 hours after inclisiran dosing

Recommendations in other jurisdictions

• Mild to moderate: No dose adjustment recommended
• Severe or patients with end-stage renal disease: Caution; no dose adjustment recommended
  There is limited experience with inclisiran in patients with severe renal impairment. Inclisiran should be used with caution in these patients
• Haemodialysis: Caution
  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

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate (Child-Pugh class A or B): No dose adjustment recommended
• Severe (Child Pugh class C): Caution; no information available
  Patients with severe hepatic impairment have not been studied

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended
  Age ≥ 65 years

General Disorders and Administration Site Conditions

Common

• Injection site reaction
• Injection site pain
• Injection site erythema
• Injection site rash

• None known

• Lipid profile
  • Fasting or non-fasting prior to initiation
  • Fasting lipid profile at 4 to 12 weeks after initiation and repeated every 3 to 12 months thereafter
• Low-density lipoprotein-cholesterol (LDL-C)
  • May be checked from 30 days after initiation, at any time, regardless of dose timing

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 utilizes 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.