Inclisiran

Inclisiran is a small interfering RNA that switches off production of PCSK9 in the liver. A health professional gives it as a subcutaneous injection on day 0, at 3 months, and then every 6 months. It lowers LDL cholesterol by about 50% on top of a statin.

It is used in familial hypercholesterolaemia and in high risk patients who do not reach the LDL target on the maximum tolerated statin and ezetimibe. It needs no cold chain, which helps in East Africa, but cost and supply limit its use.

Classification. PCSK9 synthesis inhibitor; small interfering RNA (siRNA), liver targeted.

Mechanism. The RNA is taken up by liver cells through a sugar attached to the molecule, and breaks down the messenger RNA that codes for PCSK9. Less PCSK9 means more LDL receptors on the liver surface and more LDL cleared from blood.

Pharmacodynamics. LDL cholesterol falls within 2 weeks, with the full effect at about 3 months. The effect lasts for months because the RNA stays in liver cells; LDL returns toward baseline slowly after the last dose.

Pharmacokinetics. Subcutaneous absorption is rapid, with a peak at about 4 hours. Plasma half life about 9 hours, but the liver effect lasts much longer. Not metabolised by CYP enzymes. About 16% excreted in urine within 24 hours. Protein binding 87%.

Primary hypercholesterolaemia (including heterozygous familial) and established cardiovascular disease, adult.

• 284 mg SC on day 0.

• Second dose of 284 mg at 3 months.

• Then 284 mg every 6 months.

• Give with the maximum tolerated statin, with or without ezetimibe.

Missed doses. A planned dose missed by under 3 months: give it and continue the 6 monthly schedule from that date. A dose missed by more than 3 months: restart with day 0, 3 months, then every 6 months. A second dose missed by more than 3 months: restart the initial schedule.

Children. Not established; limited approval for adolescents with heterozygous familial hypercholesterolaemia in some regions (specialist).

Kidney impairment. No adjustment, including severe impairment and dialysis (limited data).

Liver impairment. Mild to moderate: no adjustment; severe: not studied.

Contraindications. Hypersensitivity to inclisiran or its ingredients.

Warnings. Injection site reactions (pain, redness, rash); joint pain; arthralgia; antibody formation (rare); limited long term safety data; low LDL levels are safe.

Adverse effects. Injection site reaction, arthralgia, urinary tract infection, diarrhoea, bronchitis, pain in the limbs, shortness of breath.

Interactions. No clinically important interactions; it is not metabolised by CYP enzymes and does not change statin levels.

Special groups.

• Pregnancy: avoid unless essential; limited data.

• Breastfeeding: avoid unless essential; no data.

• Patients of African ancestry: no dose change.

• Older adults: no adjustment.

• Kidney impairment: no adjustment.

• Liver impairment: mild to moderate: no adjustment.

Formulations. Prefilled syringe 284 mg/1.5 mL.

Administration. SC injection into the abdomen, upper arm or thigh by a health professional, avoiding areas of active skin disease. Store at room temperature up to 25 degrees C, with no refrigeration. Do not shake.

Baseline. Lipid profile, alanine aminotransferase, pregnancy status, a full list of other lipid lowering drugs.

Monitoring. Lipid profile at 3 months (before the second dose), then 6 to 12 monthly. Injection sites and allergic symptoms. Adherence to the dosing calendar.

Stopping. Stop for serious hypersensitivity. LDL returns to baseline over months.

Common prescribing errors. Giving it without a statin or ezetimibe when these could be used; missing the 3 month second dose; counting from the wrong date after a late dose; treating it as a patient administered drug; giving it to a pregnant woman.