Inclisiran is a parenteral small interfering RNA (siRNA) directed to PCSK9 (proprotein convertase subtilisin/kexin type 9) mRNA indicated for use as an adjunct to diet and statin therapy in the treatment of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C). In clinical trials of adults with HeFH or clinical ASCVD with elevated LDL-C while receiving maximally tolerated statin therapy, inclisiran resulted in sustained LDL-C reduction of 48% to 52% compared to placebo. Inclisiran may be associated with development of anti-drug antibodies; however, there has been no clinically significant effect of anti-inclisiran antibodies on pharmacodynamics, safety, or effectiveness of inclisiran over the treatment duration of 18 months.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Inclisiran is a clear and colorless to pale yellow solution. Do not use if particulate matter or discoloration is present.
-Missed dose: If a planned dose is missed by less than 3 months, administer inclisiran and maintain the patient's original dosing schedule. If a planned dose is missed by more than 3 months, start with a new dosing schedule. Administer inclisiran initially, again at 3 months, then every 6 months.
Subcutaneous Administration
-Inclisiran should be administered by a health care professional.
-Inject subcutaneously into the abdomen, upper arm, or thigh. Do not inject in areas of active skin disease or injury (e.g., sunburns, skin rashes, inflammation, skin infections).
-Use caution during injection to avoid accidental needlestick injuries. The syringe needles do not have safety guards, and the needles are not removable.
Injection site reaction, including injection site pain, erythema, and rash, was reported in 8% of patients receiving inclisiran during clinical trials.
Arthralgia (5%) and bronchitis (4%) were reported in patients receiving inclisiran during clinical trials.
Antibody formation may occur with inclisiran use. During clinical trials (n = 1,830), confirmed positivity for anti-drug antibodies was detected in 33 (2%) patients prior to dosing and in 90 (5%) patients during 18 months of treatment. Approximately 31 (2%) inclisiran-treated patients with a negative sample at baseline had a persistent anti-drug antibody response, defined as 2 confirmed positive samples separated by at least 16 weeks or a single confirmed final sample. There was no clinically significant evidence that the presence of anti-drug binding antibodies affected the pharmacodynamic profile, clinical response, or safety of inclisiran over the treatment duration of 18 months. However, the long-term consequences of continuing inclisiran treatment in the presence of anti-drug antibodies are unknown.
Discontinue inclisiran when pregnancy is recognized. Temporary discontinuation of lipid-lowering drugs during pregnancy should have little impact on the outcome of long-term therapy of primary hyperlipidemia for most patients. Alternatively, consider the ongoing therapeutic needs of the patient. Inclisiran may cause fetal harm when administered during pregnancy based on its mechanism of action; inclisiran increases LDL-C uptake and lowers LDL-C concentrations in the circulation, therefore decreasing cholesterol and potentially other biologically active substances derived from cholesterol. There are no available data on the use of inclisiran in pregnant patients to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were seen when inclisiran was administered at doses up to 5 to 10 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison during organogenesis through lactation.
There is no information on the presence of inclisiran in human milk, the effects on the breast-fed infant, or the effects on milk production. Inclisiran was present in the milk of lactating rats. Oligonucleotide-based products typically have poor bioavailability; therefore, it is unlikely that low concentrations of inclisiran present in milk will adversely affect infant development during breast-feeding. Consider the developmental and health benefits of breast-feeding, along with the mother's clinical need for inclisiran and any potential adverse effects on the breast-fed infant from inclisiran or the underlying maternal condition.
General dosing information:
-Assess LDL-C when clinically indicated. The LDL-lowering effect of inclisiran may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose.
For the treatment of primary hypercholesterolemia (including heterozygous familial hypercholesterolemia) to reduce low-density lipoprotein cholesterol (LDL-C) as an adjunct to diet and statin therapy:
Subcutaneous dosage:
Adults: 284 mg subcutaneously every 3 months for 2 doses, then 284 mg subcutaneously every 6 months.
Maximum Dosage Limits:
-Adults
284 mg/dose subcutaneously.
-Geriatric
284 mg/dose subcutaneously.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. Inclisiran has not been studied in patients with severe hepatic impairment.
Patients with Renal Impairment Dosing
No dosage adjustment is necessary in patients with mild, moderate, or severe renal impairment. Inclisiran has not been studied in patients with end-stage renal disease.
*non-FDA-approved indication
There are no drug interactions associated with Inclisiran products.
Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA) that prevents proprotein convertase subtilisin/kexin type 9 (PCSK9) translation in the liver. This increases LDL-C receptor recycling and expression on the hepatocyte cell, which increases LDL-C uptake and reduces LDL-C concentrations in the circulation.
Inclisiran is administered subcutaneously. It is 87% protein bound in vitro. Apparent Vd is approximately 500 L. Inclisiran has a high uptake into and selectively for the liver, the target organ for cholesterol lowering. Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. The terminal elimination half-life of inclisiran is approximately 9 hours, with no accumulation after multiple dosing. Approximately 16% of inclisiran is cleared renally.
After a single dose, LDL-C reduction was apparent within 14 days. Mean LDL-C reductions of 38% to 51% were observed 30 to 180 days post dose. At day 180, LDL-C concentrations were still reduced approximately 53%.
Affected CYP450 isoenzymes and drug transporters: none
Inclisiran is not a substrate, inhibitor, or inducer of CYP450 isoenzymes or drug transporters.
-Route-Specific Pharmacokinetics
Subcutaneous Route
A mean Cmax of 509 ng/mL was attained in approximately 4 hours post dose at the recommended dosing regimen. Concentrations were undetectable after 24 to 48 hours post dose. Mean AUC from dosing extrapolated to infinity was 7,980 ng/mL x hour. The pharmacokinetics of inclisiran were similar after single- and multiple-dosing. Systemic exposure to inclisiran increased in a linear and dose-proportional manner over a dosage range of 25 to 800 mg.
-Special Populations
Hepatic Impairment
Cmax and AUC increased approximately 1.1- to 2.1-fold and 1.3- to 2-fold, respectively, in patients with mild and moderate hepatic impairment compared to patients with normal hepatic function. Despite increased inclisiran exposure, reductions in LDL-C were similar between patients with normal hepatic function and mild hepatic impairment. In patients with moderate hepatic impairment, baseline PCSK9 concentrations were lower and reductions in LDL-C were less that those seen in patients with normal hepatic function. Inclisiran has not been studied in patients with severe hepatic impairment.
Renal Impairment
Cmax and AUC increased approximately 2.3- to 3.3-fold and 1.6- to 2.3-fold, respectively, in patients with mild, moderate, or severe renal impairment compared to patients with normal renal function. Despite higher inclisiran exposures, LDL-C reduction was similar across all groups based on renal function.
Geriatric
Age was not found to significantly influence inclisiran pharmacokinetics in a population analysis.
Gender Differences
Gender was not found to significantly influence inclisiran pharmacokinetics in a population analysis.
Ethnic Differences
Race was not found to significantly influence inclisiran pharmacokinetics in a population analysis.
Obesity
Body weight was not found to significantly influence inclisiran pharmacokinetics in a population analysis.