inclisiran (Rx)

1-10%

Injection site reaction (8.2%)

Arthralgia (5%)

Urinary tract infection (4.4%)

Bronchitis (4.3%)

Diarrhea (3.9%)

Pain in extremity (3.3%)

Dyspnea (3.2%)

Contraindications

None

Pregnancy

No data are available on use in pregnant females for drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes

Discontinue therapy when pregnancy is recognized

Based on mechanism of action, therapy may cause fetal harm when administered to pregnant females

Animal data

• No evidence of embryo-fetal toxicity or teratogenicity was observed in rats with SC administration during organogenesis at doses up to 5-10x the maximum recommended human dose (MRHD)
• No effects on the development of the F1 generation (eg, survival, growth, physical and reflexological development, behavior, and reproductive performance) were observed at doses up to 5x the MRHD, based on body surface area comparison/dose

Lactation

There is no information on drug presence in human milk, effects on breastfed infants, or effects on milk production

Inclisiran was present in the milk of lactating rats in all dosing groups

When a drug is present in animal milk, it is likely that the drug will be present in human milk

Oligonucleotide-based products usually have poor bioavailability; consider it unlikely that low levels of inclisiran present in milk will adversely impact an infant’s development during lactation

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Small interfering ribonucleic acid (siRNA) directed to proprotein convertase subtilisin kexin type 9 (PCSK9); inclisiran is conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes

LDL-C is cleared from the circulation preferentially through the LDL receptor (LDLR) pathway

PCSK9 is a serine protease that destroys LDLR in the liver, resulting in decreased LDL-C clearance and increased plasma LDL-C

In hepatocytes, inclisiran utilizes RNA interference mechanism and directs catalytic breakdown of mRNA for PCSK9; this increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake, thereby lowering LDL-C levels in the circulation

Absorption

Peak plasma time: 4 hr

Peak plasma concentration: 509 ng/mL

AUC: 7980 ng⋅hr/mL

Distribution

Protein bound: 87%

Vd: 500 L (healthy adults)

Metabolism

Primarily metabolized by nucleases to shorter nucleotides of varying length

Not a substrate for CYP450 or transporters

Elimination

Half-life: 9 hr

Renally cleared: ~16% of drug

SC Administration

Injection should be administered by healthcare provider

Administer SC into abdomen, upper arm, or thigh; do NOT inject in areas of active skin disease or injury (eg, sunburns, skin rashes, inflammation, or skin infections)

Visually inspect before use; solution appears clear and colorless to pale yellow; discard if particulate matter or discoloration is seen

Missed dose

• <3 months: administer inclisiran and maintain dosing according to original schedule
• >3 months: Restart with new dosing schedule; administer inclisiran initially, again at 3 months, and then q6months

Storage

Store at 20-25ºC (68-77ºF); excursions allowed to 15-30ºC (59-86ºF)