Dosing & Uses
Dosage Forms & Strengths
injectable SC solution
- 284mg/1.5mL (prefilled syringe)
Hypercholesterolemia
Indicated as an adjunct to diet and statin therapy for adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH), to reduce low-density lipoprotein cholesterol (LDL-C)
284 mg SC x 1 dose initially
Repeat in 3 months and then every 6 months thereafter
Dosage Modifications
Renal impairment
- Mild, moderate, or severe: No dosage adjustment necessary
Hepatic impairment
- Mild or moderate: No dosage adjustment necessary
- Severe: Not studied
Dosing Considerations
Monitor parameters: Assess LDL-C when clinically indicated; may be measured as early as 30 days after initiation
Limitation of use: Effect on cardiovascular morbidity and mortality has not been determined
Safety and efficacy not established
Adverse Effects
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%)
Warnings
Contraindications
None
Pregnancy & Lactation
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
Treatment of hyperlipidemia is not generally necessary during pregnancy; atherosclerosis is a chronic process and the discontinuation of lipid-lowering drugs during pregnancy should have little impact on outcome of long-term therapy of primary hyperlipidemia for most patients
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.Pharmacology
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
Administration
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)
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Formulary
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