Leqvio Drug Information
Generic name: INCLISIRAN
Uses of Leqvio
LEQVIO ® is indicated as an adjunct to diet and exercise to reduce low-density lipoprotein cholesterol (LDL-C) in: adults with hypercholesterolemia. adults and pediatric patients aged 12 years and older with heterozygous familial hypercholesterolemia (HeFH). pediatric patients aged 12 years and older with homozygous familial hypercholesterolemia (HoFH). Cardiovascular outcomes trials have demonstrated that reducing LDL-C lowers the risk for major adverse cardiovascular events (MACE) in adults at increased risk when treated with statins or monoclonal antibody proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors as an add-on to statin therapy.
Dosage & Administration of Leqvio
Recommended Dosage
The recommended dosage of LEQVIO for adults and pediatric patients aged 12 years and older is 284 mg administered as a single subcutaneous injection initially, again at 3 months, and then every 6 months. If a planned dose is missed by less than 3 months, administer LEQVIO and maintain dosing according to the patient’s original schedule. If a planned dose is missed by more than 3 months, restart with a new dosing schedule - administer LEQVIO initially, again at 3 months, and then every 6 months.
Assess LDL-C when clinically indicated. The LDL-lowering effect of LEQVIO may be measured as early as 30 days after initiation and anytime thereafter without regard to timing of the dose.
Important Administration Instructions LEQVIO should be administered by a healthcare professional. Inject LEQVIO subcutaneously into the abdomen, upper arm, or thigh. Do not inject in areas of active skin disease or injury, such as sunburns, skin rashes, inflammation, or skin infections.
Inspect LEQVIO visually before use. It should appear clear and colorless to pale yellow. Do not use if particulate matter or discoloration is seen.
For more detailed instruction on administration of the prefilled syringe, see Instructions for Use.
Side Effects of Leqvio
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. At baseline, 12% of patients had a diagnosis of HeFH and 85% had clinical atherosclerotic cardiovascular disease (ASCVD). Adverse reactions reported in at least 3% of LEQVIO-treated patients, and more frequently than in placebo-treated patients, are shown in Table 1.
Table 1: Adverse Reactions Occurring in Greater Than or Equal to 3% of LEQVIO-treated Adults with Hypercholesterolemia and More Frequently than with Placebo Trials Adverse reactions led to discontinuation of treatment in 2.5% of patients treated with LEQVIO and 1.9% of patients treated with placebo. The most common adverse reactions leading to treatment discontinuation in patients treated with LEQVIO were injection site reactions (0.2% versus 0% for LEQVIO and placebo, respectively). The safety profile reported in pediatric patients with HeFH was consistent with the description above for adult patients with hypercholesterolemia, with the exception of headache.
In pediatric patients with HeFH, the incidence of headache was 6% among patients who received placebo versus 13% of LEQVIO-treated patients during the double-blind study period.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of LEQVIO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity: anaphylaxis, angioedema, rash, pruritus, and urticaria.
| Adverse Reactions | Placebo (N = 1,822) % | LEQVIO (N = 1,833) % |
|---|---|---|
| a includes related terms such as: injection site pain, erythema and rash | ||
| Injection site reaction a | 2 | 8 |
| Arthralgia | 4 | 5 |
| Bronchitis | 3 | 4 |
Warnings & Cautions for Leqvio
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis and angioedema, have been reported in patients treated with LEQVIO. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to seek medical attention promptly. LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO.
Pregnancy Safety for Leqvio
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 hypercholesterolemia 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 hypercholesterolemia for most patients. There are no available data on the use of LEQVIO 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 observed in rats and rabbits with subcutaneous administration of inclisiran during organogenesis at doses up to 5 to 10 times the maximum recommended human dose (MRHD) based on body surface area (BSA) comparison ( see Data ). No adverse developmental outcomes were observed in offspring of rats administered inclisiran from organogenesis through lactation at 5 times the MRHD based on BSA comparison ( see Data ). 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. There is a pregnancy safety study for LEQVIO. Report pregnancies by contacting Novartis at 1-888-669-6682 or [email protected].
There was no evidence of embryo-fetal toxicity or teratogenicity at doses up to 5 and 10 times, respectively, the MRHD based on BSA comparison/dose. Inclisiran crosses the placenta and was detected in rat fetal plasma at concentrations that were 65 to 154 times lower than maternal levels. Inclisiran was well-tolerated in maternal rats, with no evidence of maternal toxicity and no effects on maternal performance.
There were no effects on the development of the F1 generation, including survival, growth, physical and reflexological development, behavior, and reproductive performance at doses up to 5 times the MRHD, based on BSA comparison/dose.
Pediatric Use of Leqvio
Pediatric Use The safety and effectiveness of LEQVIO as an adjunct to diet and other LDL-C-lowering therapies for the treatment of HeFH have been established in pediatric patients aged 12 years and older. Use of LEQVIO for this indication is based on data from a 12-month, randomized, placebo-controlled, double-blind study in 141 pediatric patients with HeFH. This indication is also supported by evidence from an adequate and well-controlled study in adults with HeFH.
The safety profile reported in pediatric patients aged 12 years and older with HeFH was consistent with adult patients with hypercholesterolemia, with the exception of headache. The safety and effectiveness of LEQVIO have not been established in pediatric patients with HeFH or HoFH younger than 12 years of age. The safety and effectiveness of LEQVIO have not been established in pediatric patients with other types of hypercholesterolemia.
Contraindications for Leqvio
LEQVIO is contraindicated in patients with a prior serious hypersensitivity reaction to inclisiran or any of the excipients in LEQVIO. Serious hypersensitivity reactions have included anaphylaxis and angioedema.
Clinical Studies of Leqvio
Adults with Primary Hypercholesterolemia or HeFH The efficacy of LEQVIO was investigated in three randomized, double-blind, placebo-controlled trials that enrolled 3,660 adults with HeFH, clinical ASCVD, or increased risk for ASCVD, who were taking maximally tolerated statin therapy and who required additional LDL-C lowering. Demographics and baseline disease characteristics were balanced between the treatment arms in all trials. Patients were taking a maximally tolerated dose of statin with or without other lipid modifying therapy and required additional LDL-C reduction.
Patients were stratified by current use of statins or other lipid-modifying therapies. Patients taking PCSK9 inhibitors were excluded from the trial. Forty-five percent (45%) of patients had diabetes at baseline.
The mean baseline LDL-C was 105 mg/dL. At the time of randomization, 89% of patients were receiving statin therapy and 69% were receiving high-intensity statin therapy. The primary efficacy outcome measure in Trial 1 was the percent change from baseline to Day 510 in LDL-C.
The difference between the LEQVIO and placebo groups in mean percentage change in LDL-C from baseline to Day p < 0.0001. For additional results, see Table 2 and Figure 1. Thirty-five percent (35%) of patients had diabetes at baseline.
At the time of randomization, 95% of patients were receiving statin therapy and 78% were receiving high-intensity statin therapy. For additional results, see Table 3 and Figure 2. Table 3: Changes in Lipid Parameters in Adults with Hypercholesterolemia and ASCVD or Increased Risk for ASCVD on Maximally Tolerated Statin Therapy (Mean % Change from Baseline to Day 510 in Trial 2) Figure 2: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with Hypercholesterolemia and ASCVD or Increased Risk for ASCVD on Maximally Tolerated Statin Therapy (Trial 2) In a pooled analysis of Trial 1 and Trial 2, the observed treatment effect was similar across predefined subgroups, such as sex, age, race, disease characteristics, geographic regions, presence of diabetes, body mass index, baseline LDL-C levels, and intensity of statin treatment.
The diagnosis of HeFH was made either by genotyping or clinical criteria using either the Simon Broome or WHO/Dutch Lipid Network criteria. Ten percent (10%) of patients had diabetes at baseline. The mean baseline LDL-C was 153 mg/dL.
At the time of randomization, 90% of patients were receiving statin therapy and 74% were receiving high-intensity statin therapy. Fifty-two percent (52%) of patients were treated with ezetimibe. The most commonly administered statins were atorvastatin and rosuvastatin.
For additional results, see Table 4 and Figure 3. Table 4: Changes in Lipid Parameters in Adults with HeFH on Maximally Tolerated Statin Therapy (Mean % Change from Baseline to Day 510 in Trial 3) Figure 3: Mean Percent Change from Baseline in LDL-C Over 18 Months in Adults with HeFH on Maximally Tolerated Statin Therapy (Trial 3) Pediatric Patients with HeFH Trial 4 (ORION-16, NCT04652726) was a 12-month randomized, double-blind, placebo-controlled trial in 141 pediatric patients aged 12 years and older with HeFH and elevated LDL-C. Patients were receiving maximally tolerated statin therapy with or without additional LDL-C-lowering therapies.
The diagnosis of HeFH was made either by genetic testing or clinical criteria. The mean LDL-C at baseline was 183 mg/dL; 93% of patients were taking statins and 23% were on ezetimibe. The primary efficacy outcome measure in Trial 4 was the percent change from baseline to Day 330 in LDL-C.
For additional results, see Table 5 and Figure 4. All patients were taking LDL-C-lowering therapies. Patients with a null (negative) variant in both low-density lipoprotein receptor (LDLR) alleles, who were considered unlikely to benefit from a reduction in PCSK9, were excluded.
The diagnosis of HoFH was made by genetic testing. The mean LDL-C at baseline was 272 mg/dL; all patients were taking statins and 85% were on ezetimibe. The difference between the LEQVIO and placebo groups in mean percentage change in LDL-C from baseline to Day For additional results, see Table 6 and Figure 5.
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol a 11.5% of subjects on LEQVIO and 14.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using a mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. | ||||
| Day 510 (mean percentage change from baseline) a | ||||
| Placebo (n = 780) | 1 | 0 | 0 | -2 |
| LEQVIO (n = 781) | -51 | -34 | -47 | -45 |
| Difference from placebo (LS Mean) (95% CI) | -52 (-56, -49) | -33 (-35, -31) | -47 (-50, -44) | -43 (-46, -41) |
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol a 10.6% of subjects on LEQVIO and 8.4% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using a mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value. Missing data were imputed using a control-based pattern-mixture model approach. | ||||
| Day 510 (mean percentage change from baseline) a | ||||
| Placebo (n = 807) | 4 | 2 | 2 | 1 |
| LEQVIO (n = 810) | -46 | -28 | -41 | -38 |
| Difference from placebo (LS Mean) (95% CI) | -50 (-53, -47) | -30 (-32, -28) | -43 (-46, -41) | -39 (-41, -37) |
| Treatment Group | LDL-C | Total Cholesterol | Non-HDL-C | ApoB |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol a 4.5% of subjects on LEQVIO and 4.6% of subjects on placebo had missing LDL-C data at primary endpoint (Day 510). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effect for treatment group and baseline LDL-C as a covariate. Other endpoints were analyzed using mixed-effect model for repeated measure (MMRM) with fixed effects for treatment group, visit, interaction between treatment and visit, and baseline value as a covariate. Missing data were imputed using a control-based pattern-mixture model approach. | ||||
| Day 510 (mean percentage change from baseline) a | ||||
| Placebo (n = 240) | 8 | 7 | 7 | 3 |
| LEQVIO (n = 242) | -40 | -25 | -35 | -33 |
| Difference from placebo (LS Mean) (95% CI) | -48 (-54, -42) | -32 (-36, -28) | -42 (-47, -37) | -36 (-40, -32) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol a 3.2% of subjects on LEQVIO and 0% of subjects on placebo had missing LDL-C data at primary endpoint (Day 330). Missing data were imputed using a modified control-based multiple imputation to account for treatment adherence. Percent change from baseline in LDL-C was analyzed using analysis of covariance (ANCOVA) with fixed effects for treatment group and baseline age group, and baseline LDL-C as a covariate. Other endpoints were analyzed using same approach. | ||||
| Day 330 (mean percentage change from baseline) a | ||||
| Placebo (n = 48) | 1 | 4 | 2 | 0 |
| LEQVIO (n = 93) | -27 | -21 | -25 | -19 |
| Difference from placebo (LS Mean) (95% CI) | -29 (-36, -21) | -26 (-32, -20) | -27 (-34, -20) | -19 (-25, -14) |
| Treatment Group | LDL-C | ApoB | Non-HDL-C | Total Cholesterol |
|---|---|---|---|---|
| ApoB = apolipoprotein B; CI = confidence interval; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol The trial was designed as a descriptive trial and was not powered to test any hypothesis. a No subject in either LEQVIO or placebo had missing LDL-C data at primary endpoint (Day 330). No statistical model was performed. The mean and 95% CI of the difference from placebo were calculated based on a t-distribution for the percent change from baseline in LDL-C and other endpoints. | ||||
| Day 330 (mean percentage change from baseline) a | ||||
| Placebo (n = 4) | 12 | 5 | 9 | 9 |
| LEQVIO (n = 9) | -22 | -19 | -23 | -19 |
| Difference from placebo (Mean) (95% CI) | -33 (-80, 13) | -23 (-50, 4) | -33 (-87, 22) | -28 (-75, 19) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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