Usage
Inclisiran is prescribed for adults with primary hypercholesterolemia (including heterozygous familial and non-familial) or mixed dyslipidemia, as an add-on to diet and maximally tolerated statin therapy (or other lipid-lowering therapies for statin-intolerant patients), to lower low-density lipoprotein cholesterol (LDL-C) when LDL-C goals are not met. It belongs to the pharmacological class of lipid-lowering agents, specifically small interfering RNA (siRNA) therapeutics. Inclisiran works by targeting and degrading the mRNA that codes for proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that increases LDL-C levels. By reducing PCSK9, inclisiran increases the number of LDL receptors in the liver, leading to increased LDL-C removal from the bloodstream.
Alternate Names
Inclisiran is also known by the brand name Leqvio®.
How It Works
Pharmacodynamics: Inclisiran lowers LDL-C levels by inhibiting the synthesis of PCSK9 in the liver. This leads to an increase in LDL receptors on the surface of liver cells, facilitating greater uptake and clearance of LDL-C from the circulation. The effect on LDL-C levels is sustained due to the long duration of action of inclisiran.
Pharmacokinetics: Inclisiran is administered subcutaneously and is rapidly absorbed. It is distributed primarily to the liver, its site of action. Inclisiran is not metabolized by cytochrome P450 enzymes and is primarily eliminated through renal excretion. It has a long half-life, allowing for infrequent dosing (every 6 months after initial doses).
Mode of Action: Inclisiran binds to and degrades PCSK9 mRNA in hepatocytes. This RNA interference mechanism reduces PCSK9 protein production, resulting in increased LDL receptor availability and enhanced LDL-C clearance.
Elimination Pathways: Inclisiran is eliminated predominantly through renal excretion.
Dosage
Standard Dosage
Adults:
The standard dosage is 284 mg administered subcutaneously by a healthcare professional, initially, again at 3 months, and then every 6 months.
Children:
The safety and efficacy of inclisiran in children under 18 years of age have not been established. No data are available.
Special Cases:
- Elderly Patients: No dose adjustment is necessary.
- Patients with Renal Impairment: No dose adjustment is necessary.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild or moderate impairment. Use with caution in severe hepatic impairment.
- Patients with Comorbid Conditions: No specific dosage adjustments are mentioned for other comorbid conditions; however, consider overall patient health and potential drug interactions.
Clinical Use Cases
Inclisiran’s indicated use is for chronic LDL-C lowering in the settings of primary hypercholesterolemia or mixed dyslipidemia as an adjunct to diet and maximally tolerated statin therapy (or other lipid-lowering therapies for statin-intolerant patients). It is not specifically indicated for acute clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
No dose adjustments are necessary based on renal or hepatic dysfunction (except severe hepatic impairment), age, or other common metabolic or genetic factors.
Side Effects
Common Side Effects:
Injection site reactions (pain, redness, rash), joint pain, bronchitis, diarrhea, urinary tract infections, pain in extremities, dyspnea.
Rare but Serious Side Effects:
Allergic reactions (including angioedema), elevated liver enzymes.
Long-Term Effects:
Long-term effects are still being studied.
Adverse Drug Reactions (ADR):
Serious hypersensitivity reactions, including angioedema, have been reported.
Contraindications
- Hypersensitivity to inclisiran or any of its components.
Drug Interactions
No clinically significant drug interactions have been observed. Inclisiran is not metabolized by cytochrome P450 enzymes and is not expected to interact with drugs that are substrates, inhibitors, or inducers of these enzymes. Statins are generally used concurrently.
Pregnancy and Breastfeeding
- Pregnancy: Use is generally avoided during pregnancy as safety data are limited. Based on its mechanism of action, inclisiran may cause fetal harm.
- Breastfeeding: It is unknown if inclisiran is excreted in human milk. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breastfeeding or discontinue inclisiran therapy, considering the benefits and risks for both mother and child.
Drug Profile Summary
- Mechanism of Action: siRNA targeting PCSK9 mRNA, leading to reduced PCSK9 protein, increased LDL receptors, and lower LDL-C.
- Side Effects: Injection site reactions, joint pain, bronchitis, diarrhea, urinary tract infection. Rarely, allergic reactions.
- Contraindications: Hypersensitivity to inclisiran.
- Drug Interactions: No clinically significant interactions noted.
- Pregnancy & Breastfeeding: Avoid during pregnancy. Use with caution during breastfeeding.
- Dosage: 284 mg subcutaneously initially, again at 3 months, then every 6 months.
- Monitoring Parameters: LDL-C levels should be monitored periodically.
Popular Combinations
Inclisiran is often used in combination with statins (or other lipid-lowering therapies for statin-intolerant patients), especially when maximum tolerated statin doses are insufficient to reach LDL-C goals.
Precautions
- General Precautions: Screen for hypersensitivity before administration. Monitor injection site.
- Specific Populations: Avoid use during pregnancy. Caution advised during breastfeeding. No data for use in children.
- Lifestyle Considerations: Advise patients to maintain a healthy diet and exercise regimen in conjunction with inclisiran therapy.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Inclisiran?
A: 284 mg subcutaneously initially, at 3 months, then every 6 months.
Q2: How does Inclisiran work?
A: Inclisiran is an siRNA that lowers LDL-C by blocking PCSK9 synthesis, which leads to increased LDL receptor expression and enhanced LDL-C clearance from the blood.
Q3: What are the common side effects of Inclisiran?
A: Injection site reactions (pain, redness, rash), joint pain, bronchitis, diarrhea, urinary tract infections.
Q4: Is Inclisiran safe for use during pregnancy?
A: Inclisiran is generally avoided during pregnancy due to limited safety data. It may cause fetal harm based on its mechanism of action.
Q5: Can Inclisiran be used with statins?
A: Yes, inclisiran is often used in combination with statins or other lipid-lowering therapies if statins are not tolerated, especially in patients who do not achieve LDL-C goals on maximally tolerated statin doses.
Q6: How often does Inclisiran need to be administered?
A: After the initial dose and a second dose at 3 months, inclisiran is administered every 6 months.
Q7: Are there any contraindications for Inclisiran?
A: Yes, a known hypersensitivity to inclisiran or any of its components is a contraindication.
Q8: How is Inclisiran administered?
A: Inclisiran is administered subcutaneously by a healthcare professional.
Q9: What should be monitored in patients receiving Inclisiran?
A: LDL-C levels should be monitored periodically. Monitor the injection site for reactions.
Q10: Is Inclisiran safe for patients with renal or hepatic impairment?
A: No dose adjustment is necessary for patients with mild, moderate, or severe renal impairment. No dose adjustment is needed for mild or moderate hepatic impairment, but caution is advised in patients with severe hepatic impairment.
