BRIEF SUMMARY

INCLISSIRAN-(Dec 2021)

Indn-    to treat Heterozygous Familial    Hypercholesterolemia or clinical Atheroscleric                 Cardiovascular Diseases as an add on therapy  

Comp-   ­ Injection: 284 mg/1.5 mL (189 mg/mL) in a single-dose prefilled syringe. The recommended dosage  in combination with maximally tolerated statin therapy, is 284 mg administered as a single subcutaneous

ADR-   Common adverse reactions in clinical trials (= 3%): injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea

CI- None.

Pat Inform-

Pregnancy-                                                                                                                             Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus. Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if it  should be discontinued 

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U.S. FDA APPROVED DRUGS SURING 2021                                        

Serial No 50

Name of the Drug-    LEGVIO

Active Ingredient -   Inclisiran

Pharmacological Classification- To treat Heterozygous Familial                                                                                         Hypercholesterolemia or clinical Atheroscleric                                                             Cardiovascular Diseases as an add on therapy                                                                                                                           

 Date of Approval-          12/22//21 

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use                                  LEQVIO safely and effectively.                                                                                             See full prescribing information for LEQVIO. LEQVIO® (inclisiran) injection, for subcutaneous use

Initial U.S. Approval: 2021

INDICATIONS AND USAGE-

­ LEQVIO is a small interfering RNA (siRNA) directed to PCSK9 (proprotein convertase subtilisin kexin type 9) mRNA indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (ASCVD), who require additional lowering of lowdensity lipoprotein cholesterol (LDL-C). 

Limitations of Use: The effect of LEQVIO on cardiovascular morbidity and mortality has not been determined.

ADVERSE REACTIONS

 Common adverse reactions in clinical trials (= 3%): injection site reaction, arthralgia, urinary tract infection, diarrhea, bronchitis, pain in extremity, and dyspnea. 

CONTRAINDICATIONS-

­ None.

DOSAGE AND ADMINISTRATION-

 • The recommended dosage of LEQVIO, in combination with maximally tolerated statin therapy, is 284 mg administered as a single subcutaneous

LEQVIO should be administered by a healthcare professional.                                               • Inject LEQVIO subcutaneously into the abdomen, upper arm, or thigh.

DOSAGE FORMS AND STRENGTHS-

­ Injection: 284 mg/1.5 mL (189 mg/mL) in a single-dose prefilled syringe.

PATIENT COUNSELING INFORMATION

Pregnancy-                                                                                                                             Advise pregnant patients and patients who can become pregnant of the potential risk to a fetus.

Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if LEQVIO should be discontinued 

Injection Site Reactions Advise patients that injection site reactions can occur with LEQVIO.

Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 For more information, visit www.leqvio.com or call 1-833-LEQVIO2 (1-833-537-8462). © Novartis

CLINICAL PHARMACOLOGY

1. Mechanism of Action-                                                                                         Inclisiran is a double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-Acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes.

2. Pharmacodynamics-                                                                                                      Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post dose. Mean reductions of 38% to 51% for LDL-C were observed 30 to 180 days post dose.

3. Pharmacokinetics-                                                                                               Absorption-                                                                                                                 Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose proportional manner over a range from 25 mg to 800 mg of inclisiran sodium.

At the recommended dosing regimen of 284 mg of LEQVIO, plasma concentrations reached peak in approximately 4 hours post dose with a mean Cmax of 509 ng/mL. Concentrations reached undetectable levels after 24 to 48 hours post dosing.

The mean area under the plasma concentration-time curve from dosing extrapolated to infinity was 7980 ng*h/mL. Pharmacokinetic findings following multiple subcutaneous administrations of LEQVIO were similar to singledose administration.

Distribution-                                                                                                                 Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of LEQVIO to healthy adults, the apparent volume of distribution is approximately 500 L.

Inclisiran has been shown to have high uptake into, and selectively for the liver, the target organ for cholesterol lowering.

Elimination-                                                                                                                   The terminal elimination half-life of LEQVIO is approximately 9 hours, and no accumulation occurs with multiple dosing. Approximately 16% of LEQVIO is cleared through the kidney.

Metabolism-                                                                                                               Inclisiran is primarily metabolized by nucleases to shorter nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters.

Specific Populations-                                                                                                       A population pharmacodynamic analysis was conducted on data from 4328 patients. Age, body weight, gender, race, and creatinine clearance were found not to significantly influence inclisiran pharmacokinetics. 

Renal Impairment-                                                                                              Pharmacokinetic analysis of data from a dedicated renal impairment study reported increases in inclisiran Cmax and AUC of approximately 2.3 to 3.3-fold and 1.6 to 2.3-fold, respectively, in patients with mild, moderate or severe renal impairment, relative to patients with normal renal function.

Despite the higher plasma exposures, reductions in LDL-C were similar across all groups based on renal function.

Hepatic Impairment-                                                                                         Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported increases in inclisiran Cmax and AUC of approximately 1.1- to 2.1-fold and 1.3- to 2.0-fold, respectively, in patients with mild and moderate hepatic impairment, relative to patients with normal hepatic function.

Despite the higher plasma inclisiran exposures, reductions in LDL-C were similar between the groups of patients administered inclisiran with normal hepatic function and mild hepatic impairment.

In patients with moderate hepatic impairment, baseline PCSK9 levels were lower and reductions in LDL-C were less than those observed in patients with normal hepatic function. LEQVIO has not been studied in patients with severe hepatic impairment.

Drug Interaction Studies-                                                                                              No formal clinical drug interaction studies have been performed.

The components of LEQVIO are not substrates, inhibitors or inducers of cytochrome P450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran did not have a clinically significant impact on atorvastatin or rosuvastatin concentrations.

LEQVIO is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of cytochrome P450 enzymes or transporters.

USE IN SPECIFIC POPULATIONS

1. Pregnancy Risk Summary-

 Discontinue LEQVIO when pregnancy is recognized. Alternatively, consider the ongoing therapeutic needs of the individual patient. Inclisiran increases LDL-C uptake and lowers LDL-C levels in the circulation, thus decreasing cholesterol and possibly other biologically active substances derived from cholesterol; therefore, LEQVIO may cause fetal harm when administered to pregnant patients based on the mechanism of action

 In addition, 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 the outcome of long-term therapy of primary hyperlipidemia for most patients.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

2. Lactation Risk Summary-                                                                                           There is no information on the presence of inclisiran in human milk, the effects on the breastfed infant, or the effects on milk production. Inclisiran was present in the milk of lactating rats in all dose groups.

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

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for LEQVIO and any potential adverse effects on the breastfed infant from LEQVIO or from the underlying maternal condition.

3.Pediatric Use-                                                                                                            The safety and effectiveness of LEQVIO have not been established in pediatric patients.

4.Geriatric Use-                                                                                                                    Of the 1833 patients treated with LEQVIO in clinical studies, 981 (54%) patients were 65 years of age and older, while 239 (13%) patients were 75 years of age and older.

No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity to adverse reactions of some older individuals cannot be ruled out.

5.Renal Impairment-                                                                                                            No dose adjustments are necessary for patients with mild, moderate, or severe renal impairment

. LEQVIO has not been studied in patients with end stage renal disease

6.Hepatic Impairment-                                                                                                      No dose adjustment is necessary in patients with mild to moderate hepatic impai-   rment. LEQVIO has not been studied in patients with severe hepatic impairment