inclisiran
Brand: Leqvio
Prototype Drug
Drug Class: small interfering RNA (siRNA) — PCSK9 inhibitor
Drug Family: antilipemic
Subclass: RNA interference lipid-lowering agent
Organ Systems: cardiovascular
Mechanism of Action
Double-stranded siRNA conjugated to N-acetylgalactosamine (GalNAc) for hepatocyte-targeted delivery; silences PCSK9 mRNA via RNA interference, reducing intracellular PCSK9 synthesis and thereby upregulating LDL receptors on hepatocyte surfaces to enhance LDL-C clearance.
PCSK9 mRNA (hepatic)
Indications
- heterozygous familial hypercholesterolemia
- atherosclerotic cardiovascular disease with elevated LDL-C inadequately controlled by maximally tolerated statin therapy
Contraindications
- hypersensitivity to inclisiran or excipients
Adverse Effects
Common
- injection site reactions (erythema, pain, swelling)
- nasopharyngitis
- urinary tract infection
Serious
- serious hypersensitivity reactions (rare)
Pharmacokinetics (ADME)
| Absorption | subcutaneous administration; Cmax within 4 hours of injection |
| Distribution | primarily distributed to the liver via GalNAc targeting; Vd approximately 500 L |
| Metabolism | metabolized by nucleases to shorter oligonucleotides; not a CYP450 substrate |
| Excretion | renal (minor — metabolite fragments); not dialyzable |
| Half-life | approximately 9 hours (plasma); intracellular RISC complex confers durable effect lasting approximately 6 months |
| Onset | LDL-C reduction begins within weeks; maximal effect at approximately 3 months |
| Peak | 4 hours (plasma Cmax) |
| Duration | approximately 6 months per dose |
| Protein Binding | approximately 87% |
| Vd | approximately 500 L |
Drug Interactions
| Drug / Agent | Mechanism | Severity |
|---|---|---|
| no clinically significant CYP450-mediated interactions identified | not a CYP substrate or inhibitor; interaction potential low | minor |
Nursing Considerations
- Administer as a subcutaneous injection (284 mg in 1.5 mL) in the abdomen, upper arm, or thigh; rotate injection sites and avoid areas of skin inflammation or active skin conditions.
- The dosing schedule is distinctive — initial dose, repeat at 3 months, then every 6 months; confirm the patient understands this schedule to prevent missed doses or unintended re-dosing.
- Monitor LDL-C at 3 months after initiation and periodically thereafter to confirm therapeutic response; expect approximately 50% LDL-C reduction.
- Inclisiran is not self-administered — it must be given by a healthcare professional in a clinical setting; document administration dates meticulously in the medical record.
Clinical Pearls
- Inclisiran achieves durable LDL-C lowering with only two doses per year after the initial loading doses, addressing adherence challenges associated with daily or monthly dosing regimens.
- Unlike PCSK9 monoclonal antibodies (evolocumab, alirocumab) which inhibit circulating PCSK9 protein, inclisiran prevents PCSK9 synthesis at the mRNA level — effectively reducing PCSK9 for months per injection.
Safety Profile
Pregnancy avoid
Lactation insufficient-data
Renal Adjustment Required
Hepatic Adjustment Not required
TDM Not required
Guideline Update pending
Concordance Terms
Cross-referenced clinical concepts — click any term to see all content where it appears.