Inclisiran (Monograph)

Brand name: Leqvio
Drug class: Antilipemic Agents, Miscellaneous

Medically reviewed by Drugs.com on Sep 26, 2023. Written by ASHP.

Introduction

Antilipemic agent; small interfering RNA (siRNA) directed to proprotein convertase subtilisin kexin type 9 PCSK9 mRNA.

Uses for Inclisiran

Primary Hyperlipidemia

Used as an adjunct to diet and statin therapy for the treatment of adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C).

AHA/ACC cholesterol management guideline states that lifestyle modification is the foundation of atherosclerotic cardiovascular disease (ASCVD) risk reduction.

If pharmacologic therapy is needed, statins are the first-line drugs of choice.

Certain patient groups may benefit from the addition of a nonstatin drug such as inclisiran if maximally tolerated statin therapy is insufficient to achieve goal reductions in LDL cholesterol concentrations.

Guidelines support the use of inclisiran in patients receiving maximal statin therapy who require additional LDL-lowering therapy despite treatment with ezetimibe and/or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.

Inclisiran Dosage and Administration

General

Patient Monitoring

• Monitor LDL-C) when clinically indicated during treatment; the LDL-lowering effect of inclisiran may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose.

Administration

Sub-Q Administration

Administer by sub-Q injection.

Available as single-dose prefilled syringes containing 284 mg/1.5 mL (189 mg/mL).

Administer by a healthcare professional. Administer sub-Q injections into the abdomen, upper arm, or thigh; do not inject in areas of active skin disease or injury (e.g., sunburns, skin rashes, inflammation, skin infections).

Dosage

Available as inclisiran sodium; dosage expressed in terms of inclisiran. Each 1.5-mL syringe contains the equivalent of 284 mg inclisiran.

Adults

Primary Hyperlipidemia

Sub-Q

284 mg as a single injection, again at 3 months, and then every 6 months; used in combination with statin therapy.

If a planned dose is missed by <3 months, administer inclisiran and maintain dosing according to the patient’s original schedule.

If a planned dose is missed by >3 months, restart with a new dosing schedule by administering inclisiran initially, again at 3 months, and then every 6 months.

Special Populations

Hepatic Impairment

No dose adjustments necessary in mild or moderate hepatic impairment. Not evaluated in patients with severe hepatic impairment.

Renal Impairment

No dose adjustments necessary in mild, moderate, or severe renal impairment. Not evaluated in patients with end stage renal disease.

Geriatric Use

No specific dosage recommendations at this time.

Related/similar drugs

Repatha, atorvastatin, rosuvastatin, simvastatin, ezetimibe, Lipitor, Crestor

Cautions for Inclisiran

Contraindications

None.

Warnings/Precautions

Immunogenicity

Potential for immunogenicity with all oligonucleotides, including inclisiran. In clinical studies, anti-inclisiran antibodies detected. No evidence that presence of anti-drug binding antibodies impacted efficacy, safety, or pharmacodynamics; however, long-term consequences of continued inclisiran treatment in presence of anti-drug binding antibodies unknown.

Specific Populations

Pregnancy

No available data on use in pregnant women to assess for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Based on mechanism of action, may cause fetal harm when administered during pregnancy. Discontinue inclisiran when pregnancy is recognized or, alternatively, consider ongoing therapeutic needs of the individual patient. Treatment of hyperlipidemia is not generally necessary during pregnancy.

Lactation

Not known whether inclisiran is distributed into human milk; effects of the drug on breast-fed infants or on milk production also unknown. Inclisiran was detected in milk of lactating rats; therefore, likely that the drug will be present in human milk. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for inclisiran and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

In clinical studies, no overall differences in safety or efficacy observed between patients ≥65 years of age and younger patients; however, greater sensitivity to adverse reactions in some older individuals cannot be ruled out.

Hepatic Impairment

No dose adjustment necessary for patients with mild to moderate hepatic impairment. Not studied in patients with severe hepatic impairment.

Renal Impairment

No dose adjustment necessary for patients with mild, moderate, or severe renal impairment. Not studied in patients with end stage renal disease.

Common Adverse Effects

Common adverse reactions (≥3%): injection site reaction, arthralgia, bronchitis.

Drug Interactions

No formal drug interaction studies. Not a substrate, inhibitor, or inducer of CYP450 enzymes. Not expected to cause drug-drug interactions.

Specific Drugs

Inclisiran Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations achieved in approximately 4 hours after single, sub-Q administration of inclisiran 284 mg.

Pharmacokinetics following multiple sub-Q doses similar to single-dose administration.

Onset

Reduction in LDL-C apparent within 14 days following a single, sub-Q administration of inclisiran 284 mg. Mean reductions of 38–51% for LDL-C observed 30–180 days post dose, with LDL-C levels reduced by approximately 53% at day 180.

Duration

Inclisiran concentrations undetectable 24–48 hours after single dose.

Distribution

High, selective uptake into the liver; 87% bound to plasma protein in vitro.

Elimination

Metabolism

Metabolized primarily by nucleases to shorter nucleotides of varying lengths.

Excretion

16% cleared through the kidney.

Half-life

Approximately 9 hours; no accumulation occurs with multiple dosing.

Special Populations

Pharmacokinetics not significantly influenced by patient age, body weight, gender, or race.

Stability

Storage

Parenteral

Injection, for subcutaneous use

Store at controlled room temperature between 20–25°C (excursions permitted between 15–30°C).

Actions

• Inclisiran is a double-stranded small interfering RNA (siRNA), conjugated on the sense strand with triantennary N-acetylgalactosamine to facilitate delivery to hepatocytes with high affinity.

• In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9, the protein that promotes the degradation of LDL receptors. This results in increased LDL receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers its levels in the circulation.

• Mechanism is unique in comparison with the monoclonal antibodies (alirocumab, evolocumab) that target PCSK9.

Advice to Patients

• Inform patients that injection site reactions may occur following administration of inclisiran.

• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Advise pregnant women and females of reproductive potential of the potential risk to the fetus. Inform patients that the clinician may discontinue inclisiran in case of known or suspected pregnancy.

• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.

• Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Inclisiran may be obtained through specialty pharmacies for in-office administration. Consult the inclisiran website for specific information regarding distribution of the drug at: [Web].

Reload page with references included

Frequently asked questions

• What is the difference between Leqvio and Repatha?
• Can Leqvio be taken without a statin?
• Does Leqvio cause weight gain?
• How is Leqvio injection administered?
• What is the mechanism of action for Leqvio (inclisiran)?
• Is Leqvio FDA approved as a high cholesterol treatment?
• Who is the actor in the Leqvio commercial?
• Where can I find the Leqvio FDA package insert?
• How does Leqvio work in treating high cholesterol?

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