Leqvio (Inclisiran)
inclisiran sodium
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypercholesterolemia (LDL-C reduction) | Adults | Monotherapy (with diet/exercise) or adjunctive to statin ± other LLT | FDA Approved |
| Heterozygous familial hypercholesterolemia (HeFH) | Adults | Adjunctive to diet ± statin therapy | FDA Approved |
| HeFH & HoFH (EMA only) | Adolescents ≥12 years | Adjunctive to diet and other LDL-C-lowering therapies | EMA Approved |
Inclisiran is a first-in-class small interfering RNA (siRNA) that reduces hepatic production of PCSK9, thereby lowering LDL-C levels. Initially approved in December 2021 for use alongside maximally tolerated statin therapy in ASCVD and HeFH patients, the label was broadened in July 2023 to include adults with primary hyperlipidemia at increased ASCVD risk. In July 2025, the FDA approved a further label update enabling inclisiran as monotherapy with diet and exercise, removing the requirement for concomitant statin use. Across pivotal trials, inclisiran reduced LDL-C by 48–52% versus placebo at day 510 (FDA PI).
Homozygous familial hypercholesterolemia (HoFH): The ORION-5 trial evaluated inclisiran in HoFH patients receiving maximal background therapy. Moderate LDL-C reductions were observed, though less than in HeFH. Evidence quality: Moderate.
Cardiovascular outcomes reduction: Exploratory pooled analysis of ORION-9, -10, and -11 suggested a 26% lower rate of MACE with inclisiran versus placebo, but these trials were not powered for cardiovascular endpoints. Dedicated CV outcomes trials (ORION-4, VICTORION-2 Prevent) are ongoing with results expected from 2026. Evidence quality: Low (hypothesis-generating).
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| ASCVD with LDL-C above goal despite maximally tolerated statin | 284 mg SC on Day 1 | 284 mg SC every 6 months Second dose at 3 months | 284 mg every 6 months | HCP-administered only. Single fixed dose; no titration required LDL-C may be assessed as early as 30 days post-dose |
| HeFH with residual LDL-C elevation on background LLT | 284 mg SC on Day 1 | 284 mg SC every 6 months Second dose at 3 months | 284 mg every 6 months | Often combined with high-intensity statin + ezetimibe; placebo-corrected LDL-C reduction of 48% at Day 510 (ORION-9; observed change −40% vs +8% placebo) |
| Hypercholesterolemia — monotherapy (statin-intolerant or first-line) | 284 mg SC on Day 1 | 284 mg SC every 6 months Second dose at 3 months | 284 mg every 6 months | July 2025 label allows use as monotherapy with diet/exercise. V-MONO trial: inclisiran reduced LDL-C by 46.5% from baseline (vs 1.4% with placebo) |
| Elevated ASCVD risk without prior CV event — adjunctive to statin | 284 mg SC on Day 1 | 284 mg SC every 6 months Second dose at 3 months | 284 mg every 6 months | July 2023 label expansion. For patients at increased ASCVD risk not achieving LDL-C targets on statin alone |
Missed Dose Management
| Scenario | Action | Subsequent Schedule | Maximum Dose | Notes |
|---|---|---|---|---|
| Dose missed by <3 months | Administer 284 mg SC | Continue original dosing schedule | 284 mg q6m | No need to restart the loading sequence |
| Dose missed by >3 months | Administer 284 mg SC (new Day 1) | Restart: Day 1 → 3 months → every 6 months | 284 mg q6m | Full re-initiation protocol required |
Special Populations
| Population | Dose Adjustment | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Renal impairment (mild, moderate, or severe) | None required | 284 mg q6m | 284 mg q6m | Higher plasma exposure occurs but LDL-C reduction is comparable (ORION-7). Not studied in ESRD. EMA advises avoiding hemodialysis within 72 hours of dosing. |
| Hepatic impairment (mild to moderate) | None required | 284 mg q6m | 284 mg q6m | LDL-C lowering may be less pronounced in moderate impairment due to lower baseline PCSK9 levels. Not studied in severe (Child-Pugh C). |
| Elderly (≥65 years) | None required | 284 mg q6m | 284 mg q6m | 54% of pivotal trial participants were ≥65 years. No differences in safety or efficacy observed (FDA PI). |
Inclisiran uses a single fixed dose of 284 mg for all patients regardless of body weight, age, renal function, or hepatic status (mild-moderate). This distinguishes it from PCSK9 monoclonal antibodies, which may require dose adjustments. The twice-yearly dosing schedule after the initial loading period offers a practical advantage for adherence, particularly in patients with complex medication regimens.
Pharmacology
Mechanism of Action
Inclisiran is a synthetic double-stranded siRNA conjugated to a triantennary N-acetylgalactosamine (GalNAc) ligand on its sense strand. The GalNAc moiety enables highly selective hepatocyte uptake via the asialoglycoprotein receptor, which is predominantly expressed on liver cells. Once internalized, inclisiran is loaded into the RNA-induced silencing complex (RISC) within the hepatocyte, where it directs catalytic degradation of PCSK9 messenger RNA. By silencing PCSK9 translation, inclisiran promotes increased recycling and surface expression of LDL receptors, enhancing clearance of circulating LDL-C. A single intracellular RISC complex can catalyze the cleavage of multiple PCSK9 mRNA transcripts, contributing to the prolonged duration of pharmacodynamic effect that persists well beyond the drug’s short plasma half-life. Following a single 284 mg dose, LDL-C reductions of 38–51% are observed between days 30 and 180. With the recommended two-dose loading regimen (Day 1 and Day 90), mean PCSK9 levels are reduced by approximately 75% at Day 120 and 69% at Day 180 (FDA PI).
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | SC administration; Tmax ~4 h; Cmax 509 ng/mL; linear dose-proportional PK (25–800 mg range) | Rapid absorption after injection; plasma levels undetectable by 24–48 hours, but pharmacodynamic effect persists for months due to intracellular RISC activity |
| Distribution | Vd ~500 L; 87% protein bound; high hepatic uptake via GalNAc-ASGPR pathway | Large Vd reflects liver-selective tissue distribution rather than systemic dispersal; targeted delivery minimizes off-target exposure |
| Metabolism | Degraded by nucleases to shorter inactive nucleotides; not a CYP450 substrate, inducer, or inhibitor; no transporter involvement | Absence of CYP involvement eliminates traditional drug-drug interaction risk; no dose adjustments needed with co-administered statins |
| Elimination | Terminal t½ ~9 h; ~16% renally excreted; no accumulation with repeat dosing | Short plasma half-life does not reflect duration of action. No need for renal dose adjustment despite some renal excretion. Clinically, the effect lasts 6 months between maintenance doses. |
Side Effects
No adverse effects with ≥10% incidence were identified in the pooled pivotal trials (ORION-9, -10, -11; N=1,833). Inclisiran demonstrated an adverse event profile broadly similar to placebo (73.5–82.7% any AE with inclisiran vs 74.8–81.5% placebo).
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Injection site reaction | 8% (vs 2% placebo) | Includes pain, erythema, and rash at injection site; predominantly mild; no severe cases reported in pivotal trials. Long-term ORION-8 data: 5.9% over up to 6.8 years (all mild/moderate) |
| Arthralgia | 5% (vs 4% placebo) | Generally mild; minimal 1% excess over placebo suggests limited clinical significance |
| Bronchitis | 4% (vs 3% placebo) | Small 1% difference from placebo; no clear causal mechanism identified |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nasopharyngitis | 7.6% | Reported in pooled phase 3 analysis of ~3,600 patients over 18 months; similar to background rates in placebo group. Not dose-limiting. |
| Upper respiratory tract infection | ~4–6% | Identified as a commonly reported AE in the pooled 7-trial safety analysis (Wright et al., JACC 2023); rates comparable to placebo |
| Headache | ~7% (21/284 in ORION-3 over 4 years) | Cumulative 4-year incidence; generally transient and mild. Also observed in FAERS real-world reports. |
| Hypertension | ~3–5% | Reported in ORION long-term data; no consistent dose-response relationship. Rates similar to placebo in controlled trials. |
| Anti-drug antibodies (treatment-emergent) | 5% (persistent in 2%) | No clinically significant impact on efficacy or safety observed over 18 months (FDA PI, section 12.6). Long-term consequences of continuing treatment with ADA present remain unknown. |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Anaphylaxis / Angioedema | Rare | Minutes to hours post-injection | Emergency treatment; permanent discontinuation of inclisiran. Added to prescribing information as a warning. |
| Hepatic enzyme elevation (>3× ULN) | ~1–3% | Variable; observed during ORION-3 extension | Monitor LFTs; evaluate for other causes. In ORION-3, 3% of switching arm had elevations felt related to study drug. No cases of drug-induced liver injury in pivotal trials. |
| Severe injection site reaction | Very rare | Hours to days post-injection | Assess for cellulitis or abscess; consider discontinuation if recurrent or severe |
| Reason for Discontinuation | Incidence (Pivotal Trials) | Context |
|---|---|---|
| Injection site reactions | 0.2% | Most injection site reactions were mild and self-limited; very few led to treatment cessation |
| All-cause AE-related discontinuation | 2.5% | Comparable to placebo (1.9%); no single adverse event was consistently responsible beyond injection site reactions |
Injection site reactions are the most clinically meaningful adverse effect distinguishing inclisiran from placebo. They typically present as localized pain, erythema, or rash and resolve spontaneously within days. Rotating injection sites (abdomen, upper arm, thigh) may reduce recurrence. No cases of injection site necrosis or persistent skin changes have been reported. The reaction rate appears stable or decreasing with long-term use (5.9% in ORION-8 over up to 6.8 years).
Drug Interactions
Inclisiran has a uniquely favorable drug interaction profile. As an siRNA molecule metabolized by nucleases, it is not a substrate, inhibitor, or inducer of any CYP450 enzyme or drug transporter. No formal clinical drug interaction studies have been required. Population pharmacokinetic analysis confirmed no clinically significant impact on atorvastatin or rosuvastatin concentrations when co-administered with inclisiran (FDA PI). This makes inclisiran particularly suitable for patients on complex polypharmacy regimens where CYP-mediated interactions may limit statin optimization.
Monitoring
-
LDL-C Level
As early as 30 days post-dose; per clinical need
Routine LDL-C can be measured at any time without regard to dose timing (FDA PI). Nadir occurs around Day 150. Assess at each scheduled visit to confirm target attainment. Consider measuring at baseline, 90 days, and 6 months initially. -
Lipid Panel (Full)
Baseline, then 6–12 monthly
Routine Total cholesterol, non-HDL-C, ApoB, and triglycerides to assess comprehensive lipid response. Inclisiran reduces total cholesterol by ~30–33%, non-HDL-C by ~42–47%, and ApoB by ~36–43%. -
Hepatic Function
Baseline; if clinically indicated
Trigger-based Not routinely required by the FDA label, but recommended at baseline to document hepatic status. Monitor if symptoms of hepatotoxicity emerge. Use caution in patients with moderate hepatic impairment (less LDL-C lowering may occur). -
Renal Function
Baseline
Routine Assess creatinine/eGFR before initiation to document baseline. No dose adjustment needed in mild, moderate, or severe renal impairment. Note: inclisiran has not been studied in ESRD. -
Injection Site Assessment
At each administration visit
Routine Inspect for erythema, pain, rash, or induration. Rotate injection sites between abdomen, upper arm, and thigh. Document and manage local reactions symptomatically. -
Pregnancy Status
Before each dose in women of childbearing potential
Trigger-based Inclisiran should be discontinued when pregnancy is recognized. Cholesterol and its metabolites are important for fetal development, and mechanism-based fetal harm is theoretically possible. -
Hypersensitivity Signs
During and immediately after each injection
Trigger-based Observe for signs of anaphylaxis or angioedema following administration. Have appropriate medical treatment available. Patients should be advised on recognizing hypersensitivity symptoms.
Contraindications & Cautions
Absolute Contraindications
- Prior serious hypersensitivity reaction to inclisiran or any excipient in Leqvio — serious hypersensitivity reactions have included anaphylaxis and angioedema. This contraindication was added in the 2025 label update; prior versions (2021 and 2023) listed no contraindications.
Relative Contraindications (Specialist Input Recommended)
- Severe hepatic impairment (Child-Pugh C): Inclisiran has not been studied in this population. Baseline PCSK9 production is lower in advanced liver disease, potentially limiting efficacy. Use only if benefits clearly outweigh risks.
- End-stage renal disease (ESRD) / Dialysis patients: Not studied. Approximately 16% of inclisiran is renally excreted, and the EMA recommends avoiding hemodialysis within 72 hours of dosing.
- Pregnancy: Should be discontinued upon recognition of pregnancy. Inclisiran crosses the placenta in animal models and may reduce cholesterol availability to the developing fetus based on mechanism of action.
Use with Caution
- Moderate hepatic impairment: Reduced LDL-C lowering may occur due to lower baseline PCSK9. No dose adjustment required, but clinical response should be monitored.
- Severe renal impairment: Limited clinical data. No dose adjustment per FDA PI, but use with caution. Higher plasma exposure has been observed without apparent safety concern.
- Breastfeeding: Inclisiran was present in milk of lactating rats. Likely present in human milk, though poor oral bioavailability of oligonucleotides makes systemic infant absorption unlikely. Consider risk-benefit on a case-by-case basis.
- Pediatric patients: Safety and efficacy not established in the US label. The EMA has approved use in adolescents ≥12 years with HeFH or HoFH based on ORION-13 and ORION-16 data.
Hypersensitivity reactions including anaphylaxis and angioedema have been reported in patients treated with inclisiran. Clinicians should advise patients on the signs and symptoms of hypersensitivity reactions and instruct them to seek immediate medical attention. Inclisiran is contraindicated in patients who have experienced a prior serious hypersensitivity reaction to the drug or its excipients.
Inclisiran has not yet been proven to reduce cardiovascular morbidity or mortality. While PCSK9 inhibition with monoclonal antibodies (evolocumab, alirocumab) has demonstrated MACE reduction in large RCTs, inclisiran-specific cardiovascular outcomes data await completion of ORION-4, VICTORION-1 Prevent, and VICTORION-2 Prevent trials. Current approval is based on the established surrogate endpoint of LDL-C reduction.
Patient Counselling
Purpose of Therapy
Inclisiran is a twice-yearly injection given by a healthcare professional to lower LDL cholesterol, commonly referred to as “bad cholesterol.” Elevated LDL-C is a key driver of atherosclerotic plaque buildup in arteries, increasing the risk of heart attack and stroke. This medication works by blocking the liver’s production of a protein called PCSK9, which allows the liver to clear more cholesterol from the bloodstream. The effect of each injection lasts approximately six months.
How Treatment Works
The injection is given under the skin by a healthcare provider at a clinic or office. Patients receive the first injection, a second at three months, and then one injection every six months. Patients cannot self-administer this medication. Each visit is an opportunity to check cholesterol levels and discuss overall cardiovascular health. Keeping scheduled appointments is essential for maintaining consistent cholesterol control.
Sources
- Novartis Pharmaceuticals Corporation. Leqvio (inclisiran) injection, for subcutaneous use. Full Prescribing Information. East Hanover, NJ: Novartis; revised July 2025. FDA Label (2025) Primary source for all dosing, adverse reactions, PK data, and contraindications in this monograph.
- Novartis Pharmaceuticals Corporation. Leqvio (inclisiran) injection, for subcutaneous use. Full Prescribing Information. East Hanover, NJ: Novartis; revised July 2023. FDA Label (2023) Contains the detailed adverse reaction tables from pivotal trials (ORION-9, -10, -11) and complete PK data.
- European Medicines Agency. Leqvio (inclisiran) — Summary of Product Characteristics. EMA SmPC Provides EMA-specific guidance including adolescent indication, hemodialysis timing, and severe renal impairment cautions.
- Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507–1519. doi:10.1056/NEJMoa1912387 ORION-10 and ORION-11 pivotal trials demonstrating 50–52% placebo-corrected LDL-C reduction in ASCVD patients.
- Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520–1530. doi:10.1056/NEJMoa1913805 ORION-9 trial showing 48% LDL-C reduction in HeFH patients on maximally tolerated statin therapy.
- Ray KK, Troquay RPT, Visseren FLJ, et al. Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated LDL cholesterol (ORION-3). Lancet Diabetes Endocrinol. 2023;11(2):109–119. doi:10.1016/S2213-8587(22)00353-9 Four-year open-label extension demonstrating sustained 44% LDL-C reduction and acceptable long-term safety profile.
- Ray KK, Raal FJ, Kallend DG, et al. Inclisiran administration potently and durably lowers LDL-C over an extended-term follow-up: the ORION-8 trial. Eur Heart J. 2024;45(44):4653–4662. doi:10.1093/eurheartj/ehae496 Longest follow-up data (up to 6.8 years); confirmed sustained LDL-C lowering of ~49% with no new safety signals.
- Wright RS, Koenig W, Engelbrecht Lozano D, et al. Safety and tolerability of inclisiran for treatment of hypercholesterolemia in 7 clinical trials. J Am Coll Cardiol. 2023;82(24):2251–2261. doi:10.1016/j.jacc.2023.10.007 Pooled safety analysis of 3,576 patients across 7 ORION trials with up to 6 years of exposure; no new safety signals identified.
- Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur Heart J. 2023;44(2):129–138. doi:10.1093/eurheartj/ehac594 Exploratory pooled CV endpoint analysis suggesting 26% lower MACE rate with inclisiran; hypothesis-generating pending ORION-4 results.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1082–e1143. doi:10.1161/CIR.0000000000000625 Foundation guideline establishing LDL-C targets and criteria for adding non-statin LDL-lowering therapies in high-risk patients.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111–188. doi:10.1093/eurheartj/ehz455 European guidelines recommending PCSK9 inhibition for patients at very high risk who do not reach LDL-C goals on maximally tolerated statin + ezetimibe.
- Lamb YN. Inclisiran: first approval. Drugs. 2021;81(3):389–395. doi:10.1007/s40265-021-01473-6 Comprehensive review of inclisiran’s mechanism, GalNAc-conjugation technology, and RISC-mediated mRNA silencing in the context of first regulatory approval.
- German CK, Guedeney P, Bhatt DL. Harnessing RNA interference for cholesterol lowering: the bench-to-bedside story of inclisiran. J Am Heart Assoc. 2024;13(6):e032031. doi:10.1161/JAHA.123.032031 Detailed bench-to-bedside review covering siRNA mechanism, hepatocyte targeting, and practical considerations for inclisiran use in clinical practice.
- FDA Center for Drug Evaluation and Research. Clinical Pharmacology Review: Application 214012Orig1s000 (Inclisiran). FDA Clinical Pharmacology Review FDA pharmacology review confirming absence of CYP450 involvement, lack of drug-drug interaction potential, and PK data across renal and hepatic impairment.
- Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182–1193. doi:10.1016/j.jacc.2020.12.058 Pooled patient-level analysis confirming consistent efficacy across demographic and clinical subgroups, including elderly and diabetic patients.