inclisiran

Action and Spectrum

Actions and spectrum: 

inclisiran is a small interfering RNA (siRNA) therapeutic agent used for the treatment of hypercholesterolemia. It targets PCSK9 mRNA and inhibits its translation into PCSK9 protein, which in turn leads to a reduction in LDL cholesterol levels in the blood.

inclisiran is administered as a subcutaneous injection and has a long half-life, allowing for less frequent dosing. Its spectrum of action is limited to reducing LDL cholesterol levels and has no effect on other lipid parameters. 

Drug Interaction

Adverse Reaction

Frequency defined 

1-10% 

Dyspnea (3.2%) 

Diarrhea (3.9%) 

UTI (4.4%) 

Reaction at Injection site (8.2%) 

Pain in the extremities (3.3%) 

Bronchitis (4.3%) 

Arthralgia (5%) 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

inclisiran is contraindicated in individuals with a history of hypersensitivity to inclisiran or any of its components. It is contraindicated in patients having liver impairment or active liver disease. It should not be used while pregnancy & lactation until the benefits outweigh the risks.  

Caution: 

• Hypersensitivity reactions: inclisiran can cause hypersensitivity reactions, including anaphylaxis, which can be life-threatening. 
• Liver function: inclisiran can cause liver function abnormalities, so liver function tests should be performed before starting treatment and periodically thereafter. 
• Bleeding: inclisiran can increase the risk of bleeding, particularly in patients who are also taking anticoagulant medications. 
• Pregnancy and breastfeeding: The safety of inclisiran during pregnancy and breastfeeding is unknown, and it is not recommended for use in these populations. 
• Pediatric use: The safety and efficacy of inclisiran in children have not been established. 
• Renal impairment: inclisiran has not been studied in patients with severe renal impairment, and caution should be exercised when prescribing it in this population.

Comorbidities: 

There are no specific comorbidities associated with the use of inclisiran. However, like any medication, caution should be exercised in patients with hypersensitivity reactions or allergies to the drug or its components. 

Pregnancy / Lactation

Pregnancy consideration: N/A 

Lactation: N/A  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

inclisiran is a small interfering RNA (siRNA) that acts on proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger RNA (mRNA) in the liver, which is responsible for regulating low-density lipoprotein cholesterol (LDL-C) levels. By inhibiting PCSK9, inclisiran leads to increased hepatic uptake of LDL-C and reduced plasma LDL-C levels. inclisiran is metabolized in the liver by endonucleases and exonucleases, and the metabolites are excreted in the feces.  

Pharmacodynamics: 

PCSK9 is responsible for reducing the number of LDL receptors, which results in higher levels of LDL cholesterol in the blood. By reducing PCSK9, inclisiran increases the number of LDL receptors on liver cells, leading to increased removal of LDL cholesterol from the bloodstream. This results in decrease in the LDL cholesterol levels in the blood. The exact pharmacodynamics of inclisiran are still being studied.  

Pharmacokinetics: 

Absorption 

inclisiran is administered via subcutaneous injection and is rapidly absorbed into the systemic circulation. 

Distribution 

After intravenous administration, inclisiran is distributed to the liver due to the specific uptake of the siRNA molecule by the hepatocytes. 

Metabolism 

It is metabolized in the liver by nucleases, which cleave the phosphodiester backbone of the siRNA, producing smaller oligonucleotides and nucleotides. 

Elimination and excretion 

inclisiran is eliminated primarily by hepatic metabolism, followed by biliary excretion of the metabolites. Clinical studies have shown that about 70% of the administered dose of inclisiran is eliminated in the feces, with only a small amount being eliminated in the urine. It has a mean elimination half-life of approximately 90 days. 

Adminstartion

Administration: 

inclisiran is administered as a subcutaneous injection. It is given once every six months as two separate 284 mg injections. The injection is usually given by a healthcare professional in a clinical setting, but some patients may be trained to self-administer the medication at home. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: inclisiran 

Pronounced: (in-KLYE-si-ran)  

Why do we use inclisiran? 

inclisiran is a medication used for the treatment of hypercholesterolemia in adults. It is used for the treatment of hyperlipidemia in adults who have not achieved adequate LDL-C reduction with maximally tolerated statin therapy or for whom a statin is contraindicated.