Sybrava

Inclisiran (Sybrava) is supplied as a solution for injection. The solution is clear, colorless to pale yellow and essentially free of particulates.
Each mL contains inclisiran sodium equivalent to 189 mg of inclisiran.
Each pre-filled syringe contains 1.5 mL of solution containing 284 mg inclisiran (equivalent to 300 mg inclisiran sodium).
Excipients/Inactive Ingredients: Water for injection, sodium hydroxide (for pH adjustment), phosphoric acid (for pH adjustment).

Pharmacology: Mechanism of action: Inclisiran is a cholesterol-lowering double-stranded small interfering ribonucleic acid (siRNA), conjugated on the sense strand with triantennary N-acetylgalactosamine (GalNAc) to facilitate uptake by hepatocytes. In hepatocytes, inclisiran utilizes the RNA interference mechanism and directs catalytic breakdown of mRNA for proprotein convertase subtilisin/kexin type 9. This increases LDL-C receptor recycling and expression on the hepatocyte cell surface, which increases LDL-C uptake and lowers LDL-C levels in the circulation.
Pharmacodynamics: Following a single subcutaneous administration of 284 mg of inclisiran, LDL-C reduction was apparent within 14 days post-dose. Mean reductions of 49%-51% for LDL-C were observed 30 to 60 days post-dose. At Day 180, LDL-C levels were still reduced by approximately 53%.
In the Phase III studies, following four doses of inclisiran at Day 1, Day 90 (~3 months), Day 270 (~6 months) and Day 450 (~12 months), LDL-C, total cholesterol, apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a) (Lp(a)) were reduced.
Cardiac Electrophysiology: In a randomized, double-blind, placebo-controlled, active-comparator, 3-way crossover trial, 48 healthy subjects were administered an 852 mg subcutaneous dose of inclisiran (3 times the maximum recommended dose), moxifloxacin, and placebo. No increase in QTc or any other ECG parameter was observed with the supratherapeutic dose of inclisiran.
Clinical Studies: The safety and efficacy of Inclisiran (Sybrava) was evaluated in three 18-month, Phase III, randomized, double-blind, placebo-controlled trials in patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or heterozygous familial hypercholesterolemia (HeFH).
Patients were taking a maximally tolerated dose of statins with or without other lipid-modifying therapy (such as ezetimibe), and required additional LDL-C reduction. Approximately 17% of patients were statin-intolerant. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months). Patients were followed until Day 540 (~18 months).
Phase III Pooled Analysis: In the Phase III pooled analysis, inclisiran administered subcutaneously lowered LDL-C between 50% and 55% as early as Day 90 (Figure 1), which was maintained during long-term therapy. Maximal LDL-C reduction was achieved at Day 150 following a second administration. Small but statistically significant increased LDL-C reductions up to 65% were associated with lower baseline LDL-C levels (approximately <2 mmol/L [77 mg/dL]), higher baseline PCSK9 levels, and higher statin doses and statin intensity.
Reduction in LDL-C was observed across all subgroups, including age, race, gender, region, body mass index, National Cholesterol Education Program risk, current smoking status, baseline coronary heart disease (CHD) risk factors, family history of premature CHD, glucose tolerance status (i.e. diabetes mellitus type 2, metabolic syndrome, or neither), hypertension, and baseline triglycerides.
Inclisiran also reduced non-HDL-C, Apo B, total cholesterol, and Lp(a) in patients with primary hypercholesterolemia and mixed dyslipidemia. There were no clinically significant changes in high-density lipoprotein cholesterol (HDL-C) and triglycerides. (See Figure 1.)

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Two studies were conducted in patients with ASCVD and ASCVD Risk Equivalents (ORION-10 and ORION-11).
The co-primary endpoints in each study were the percentage change in LDL-C from baseline to Day 510 relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 to estimate the integrated effect on LDL-C over time.
Key secondary endpoints were the absolute change in LDL-C from baseline to Day 510, the time-adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540, and the percentage change from baseline to Day 510 in PCSK9, total cholesterol, Apo B, and non-HDL-C. Additional secondary endpoints included the individual responsiveness to inclisiran, and the proportion of patients attaining global lipid targets for their level of ASCVD risk.
ORION-10 was a multicenter, double-blind, randomized, placebo-controlled 18-month trial conducted in 1,561 patients with ASCVD. Patients were taking a maximally tolerated dose of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months).
The mean age at baseline was 66 years (range: 35 to 90 years), 60% were ≥65 years old, 31% were women, 86% were White, 13% were Black, 1% were Asian, and 14% identified as Hispanic or Latino ethnicity. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). Sixty-nine percent (69%) were taking high-intensity statins, 19% were taking medium-intensity statins, 1% were taking low-intensity statins, and 11% were not on a statin. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 52% compared to placebo (95% CI: -56%, -49%; p<0.0001) (Table 1 and Figure 2).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 54% compared to placebo (95% CI: -56%, -51%; p<0.0001). For additional results, see Table 1. (See Table 1 and Figure 2.)

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At Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 84% of inclisiran-treated patients with ASCVD compared to 18% of placebo-treated patients.
ORION-11 was an international, multicenter, double-blind, randomized, placebo-controlled 18-month trial which evaluated 1,617 patients with ASCVD or ASCVD risk equivalents (ASCVD risk equivalent was defined as those patients with type 2 diabetes mellitus, familial hypercholesterolemia, or 10-year risk of 20% or greater of having a cardiovascular event assessed by Framingham Risk Score or equivalent). More than 75% of patients were receiving a high-intensity statin background treatment, 87% of patients had ASCVD, and 13% were ASCVD risk equivalent. Patients were taking a maximally tolerated dose of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. Patients were administered subcutaneous injections of 284 mg of inclisiran or placebo on Day 1, Day 90 (~3 months), Day 270 (~9 months) and Day 450 (~15 months).
The mean age at baseline was 65 years (range: 20 to 88 years), 55% were ≥65 years old, 28% were women, 98% were White, 1% were Black, 1% were Asian, and 1% were Hispanic or Latino ethnicity. The mean baseline LDL-C was 2.7 mmol/L (105 mg/dL). Seventy-eight percent (78%) were taking high-intensity statins, 16% were taking medium-intensity statins, 0.4% were taking low-intensity statins, and 5% were not on a statin. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 50% compared to placebo (95% CI: -53%, -47%; p<0.0001) (Table 2 and Figure 3).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 49% compared to placebo (95% CI: -52%, -47%; p<0.0001). For additional results, see Table 2. (See Table 2 and Figure 3.)

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At Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 82% of Inclisiran (Sybrava)-treated patients with ASCVD compared to 16% of placebo-treated patients. In patients with an ASCVD risk equivalent, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved by 78% of Inclisiran (Sybrava)-treated patients compared to 31% of placebo-treated patients.
In a pooled analysis of the two ASCVD studies (ORION-10 and -11), consistent and statistically significant (p<0.05) percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 were observed. This was observed across all subgroups irrespective of baseline demographics, baseline disease characteristics (including gender, age, body mass index, race and baseline statin use), comorbidities, and geographic regions (Figure 4). (See Figure 4.)

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Heterozygous Familial Hypercholesterolemia (HeFH): ORION-9 was an international, multicenter, double-blind, randomized, placebo-controlled 18-month trial in 482 patients with heterozygous familial hypercholesterolemia (HeFH). All patients had HeFH, were taking maximally tolerated doses of statins with or without other lipid modifying therapy, such as ezetimibe, and required additional LDL-C reduction. The diagnosis of HeFH was made either by genotyping or clinical criteria ("definite FH" using either the Simon Broome or WHO/Dutch Lipid Network criteria).
The co-primary endpoints were the percentage change in LDL-C from baseline to Day 510 (~17 months) relative to placebo, and the time-adjusted percentage change in LDL-C from baseline after Day 90 (~3 months) and up to Day 540 (~18 months) to estimate the integrated effect on LDL-C over time. Key secondary endpoints were the absolute change in LDL-C from baseline to Day 510, the time-adjusted absolute change in LDL-C from baseline after Day 90 and up to Day 540, and the percentage change from baseline to Day 510 in PCSK9, total cholesterol, Apo B, and non-HDL-C. Additional secondary endpoints included the individual responsiveness to inclisiran, and the proportion of patients attaining global lipid targets for their level of ASCVD risk.
The mean age at baseline was 55 years (range: 21 to 80 years), 22% were ≥65 years old, 53% were women, 94% were White, 3% were Black, 3% were Asian, and 3% were Hispanic or Latino ethnicity. The mean baseline LDL-C was 4.0 mmol/L (153 mg/dL). Seventy-four percent (74%) were taking high-intensity statins, 15% were taking medium-intensity statins, and 10% were not on a statin. Fifty-two percent (52%) of patients were treated with ezetimibe. The most commonly administered statins were atorvastatin and rosuvastatin.
Inclisiran significantly reduced the mean percentage change in LDL-C from baseline to Day 510 by 48% compared to placebo (95% CI: -54%, -42%; p<0.0001) (Table 3 and Figure 5).
Inclisiran also significantly reduced the time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 by 44% compared to placebo (95% CI: -48%, -40%; p<0.0001). For additional results, see Table 3. (See Table 3 and Figure 5.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

At Day 510, the LDL-C target of <1.8 mmol/L (70 mg/dL) was achieved by 53% of inclisiran-treated patients with ASCVD compared to 1% of placebo-treated patients. In patients with an ASCVD risk equivalent, the LDL-C target of <2.6 mmol/L (100 mg/dL) was achieved by 67% of inclisiran-treated patients compared to 9% of placebo-treated patients.
Consistent and statistically significant (p<0.05) percentage change in LDL-C from baseline to Day 510 and time-adjusted percentage change in LDL-C from baseline after Day 90 and up to Day 540 were observed across all subgroups, irrespective of baseline demographics, baseline disease characteristics (including gender, age, body mass index, race and baseline statin use), comorbidities, and geographic regions.
Pharmacokinetics: Absorption: Following a single subcutaneous administration, systemic exposure to inclisiran increased in a linear and dose-proportional manner over a range from 24 mg to 756 mg. At the recommended dosing regimen of 284 mg of inclisiran, plasma concentrations reached peak in approximately 4 hours post-dose with a mean C_max 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. Minimal to no accumulation of inclisiran in plasma was observed after repeat dosing.
Distribution: Inclisiran is 87% protein bound in vitro at the relevant clinical plasma concentrations. Following a single subcutaneous 284 mg dose of inclisiran to healthy adults, the apparent volume of distribution is approximately 500 L. Inclisiran has been shown to have high uptake into, and selectivity for the liver, the target organ for cholesterol-lowering.
Biotransformation/metabolism: Inclisiran is primarily metabolized by nucleases to shorter inactive nucleotides of varying length. Inclisiran is not a substrate for CYP450 or transporters.
Elimination: The terminal elimination half-life of inclisiran is approximately 9 hours, and no accumulation occurs with multiple dosing. Sixteen percent (16%) of inclisiran is cleared through the kidney.
Linearity/non-linearity: In the Phase I clinical study, an approximately dose-proportional increase in inclisiran exposure was observed after administration of subcutaneous doses of inclisiran ranging from 24 mg to 756 mg. No accumulation and no time-dependent changes were observed after multiple subcutaneous doses of inclisiran.
In the Phase I clinical study, a dissociation was observed between inclisiran pharmacokinetic parameters and LDL-C pharmacodynamic effects. Selective delivery of inclisiran to hepatocytes, where it is incorporated into the RNA-induced silencing complex (RISC), results in a long duration of action, beyond that anticipated based on the plasma elimination half-life of 9 hours. The maximal effects of reducing LDL-C were observed with a 284 mg dose, with higher doses not producing greater effects.
In Vitro evaluation of drug interaction potential: No formal clinical drug interaction studies have been performed. Inclisiran is not a substrate, inhibitor or inducer of CYP450 enzymes or transporters and is not expected to cause drug-drug interactions or to be affected by inhibitors or inducers of CYP450 enzymes or transporters. In a population pharmacokinetic analysis, concomitant use of inclisiran had no meaningful impact on atorvastatin or rosuvastatin concentrations.
Special populations: A population pharmacodynamic analysis was conducted on data from 4,328 patients. Age, body weight and gender did not significantly influence inclisiran pharmacodynamics. No dose adjustments are recommended for these demographics.
Renal impairment: Pharmacokinetic analysis of data from a dedicated renal impairment study reported an increase in inclisiran C_max of approximately 2.3-, 2.0- and 3.3-fold, and an increase in inclisiran AUC of approximately 1.6-, 1.8- and 2.3-fold, in patients with mild, moderate and severe renal impairment relative to patients with normal renal function. Despite the higher transient plasma exposures over 24-48 hours, the reduction in LDL-C was similar across all groups of renal function. Based on population pharmacodynamic modeling, no dose adjustment is necessary in patients with end-stage renal disease. Based on PK, PD and safety assessments, no dose adjustment is recommended in patients with renal impairment (mild, moderate, or severe). The effect of hemodialysis on inclisiran pharmacokinetics has not been studied. Considering that inclisiran is eliminated renally, hemodialysis should not be performed for at least 72 hours after inclisiran dosing.
Hepatic impairment: Pharmacokinetic analysis of data from a dedicated hepatic impairment study reported an increase in inclisiran C_max of approximately 1.1- and 2.1-fold, and an increase in inclisiran AUC of approximately 1.3- and 2.0-fold, in patients with mild and moderate hepatic impairment relative to patients with normal hepatic function. Despite the higher transient inclisiran plasma exposures, the reduction in LDL-C was 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 markedly lower and the reduction in LDL-C was less than that observed in patients with normal hepatic function. No dose adjustment is necessary in patients with mild to moderate hepatic impairment (Child-Pugh class A and B). Inclisiran has not been studied in patients with severe hepatic impairment (Child-Pugh class C).
Toxicology: Non-Clinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, and carcinogenic potential.
Repeat dose toxicity: In repeat dose toxicology studies conducted in rats and monkeys, the no observed adverse effect levels (NOAEL) were identified as the highest doses of inclisiran administered subcutaneously (250 mg/kg and 300 mg/kg, respectively) and were associated with safety margins of 54.9-fold in rats and 112-fold in monkeys, based on AUC, compared to exposures observed at the MRHD.
Carcinogenicity and mutagenicity: The carcinogenic potential of inclisiran was evaluated in a 6-month study in TgRasH2 mice and a 2-year study in Sprague-Dawley rats. Male and female TgRasH2 mice were administered inclisiran by subcutaneous injection once every 28 days at 300, 600 and 1500 mg/kg. Male and female Sprague-Dawley rats were administered inclisiran by subcutaneous injection once every 28 days at 40, 95 and 250 mg/kg. Inclisiran was not carcinogenic up to the highest doses tested, corresponding to safety margins of 256-fold in mice and 60.7-fold in rats, based on AUC, compared to exposures observed at the MRHD.
No mutagenic or clastogenic potential of inclisiran was found in a battery of tests, including a bacterial mutagenicity assay, in vitro chromosomal aberration assay in human peripheral blood lymphocytes, and an in vivo rat bone marrow micronucleus assay.
Reproductive toxicity: In a male fertility study, inclisiran was administered to male Sprague-Dawley rats by subcutaneous injection at 10, 50 and 250 mg/kg once every two weeks prior to and through mating. Inclisiran was not associated with paternal toxicity or effects on spermatogenesis, fertility or early embryonic development. The highest dose tested was associated with a safety margin of 44.1-fold based on AUC, compared to exposures observed at the MRHD.
In a female fertility study, inclisiran was administered to female Sprague-Dawley rats by subcutaneous injection at 10, 50 and 250 mg/kg once every four days prior to and through mating, and then once daily during the gestation period up to Day 7 post coitum. The high dose administered prior to gestation, 250 mg/kg, was reduced to 150 mg/kg for daily administration during gestation. Inclisiran did not produce maternal toxicity or have adverse effects on female fertility or early embryonic development. The highest dose tested was associated with a safety margin of 20.4-fold based on AUC, compared to exposures observed at the MRHD.

Inclisiran (Sybrava) is indicated in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet: In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with a maximally tolerated dose of a statin or, alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

Dosage regimen: The recommended dose is 284 mg administered as a single subcutaneous injection: initially, again at 3 months, followed by every 6 months.
Missed dose: If a planned dose of Inclisiran (Sybrava) is missed by less than 3 months, inclisiran (Sybrava) should be administered and dosing maintained according to the patient's original schedule.
If a planned dose of Inclisiran (Sybrava) is missed by more than 3 months, a new dosing schedule should be started - Inclisiran (Sybrava) should be administered initially, again at 3 months, followed by every 6 months.
Treatment Transition from PCSK9 Inhibitor Monoclonal Antibody: Inclisiran (Sybrava) can be administered immediately after the last dose of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibody. To maintain LDL-C lowering, it is recommended that inclisiran (Sybrava) is administered within 2 weeks after the last dose of a PCSK9 inhibitor monoclonal antibody.
Special populations: Renal impairment: No dose adjustment is necessary for patients with renal impairment (mild, moderate or severe) or end-stage renal disease. If administering inclisiran (Sybrava) to patients on hemodialysis, hemodialysis should not be performed for at least 72 hours after inclisiran (Sybrava) dosing (see Pharmacology under Actions).
Hepatic impairment: No dose adjustment is necessary for patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh class C) have not been studied.
Pediatric patients (below 18 years): The safety and efficacy of inclisiran (Sybrava) in patients below 18 years of age have not been established.
Geriatric patients (65 years of age or above): No dose adjustment is necessary in patients 65 years of age or above.
Method of administration: Inclisiran (Sybrava) is intended for administration by a healthcare professional.
Inclisiran (Sybrava) is for subcutaneous injection into the abdomen. Injections should not be given into areas of active skin disease or injury such as sunburns, skin rashes, inflammation, or skin infections.
Inclisiran (Sybrava) should be inspected visually for particulate matter prior to administration. If the solution contains visible particulate matter, the solution should not be used.
Each 284 mg dose is administered using a single pre-filled syringe. Each pre-filled syringe is for single use only.

No clinically relevant adverse effects were observed in healthy volunteers who received inclisiran at doses up to three times the therapeutic dose. No specific treatment for inclisiran (Sybrava) overdose is available. In the event of an overdose, the patient should be treated symptomatically, and supportive measures instituted as required.

Hypersensitivity to the active substance or to any of the excipients.

None.

Pregnancy: Risk summary: There are no available data on the use of inclisiran (Sybrava) in pregnant women to inform a drug-associated risk. Animal reproduction studies in rats and rabbits have not shown risk of increased fetal abnormalities with subcutaneous administration of inclisiran during organogenesis at doses equivalent to 16- to 39-fold the maximum recommended human dose (MRHD) based on AUC (see Animal data as follows).
Animal data: In embryo-fetal development studies conducted in pregnant female Sprague-Dawley rats and New Zealand White rabbits, inclisiran was administered by subcutaneous injection at 50, 100 and 150 mg/kg once daily during the period of organogenesis (rats: Days 6 to 17 post coitum; rabbits: Days 7 to 19 post coitum). There was no evidence of embryo-fetal death, fetotoxicity or teratogenicity. The highest doses tested were associated with safety margins in rats and rabbits of 16.0-fold and 39.3-fold, respectively, based on AUC, compared to exposures observed at the MRHD.
In rats, inclisiran was detected in fetal plasma; the concentrations generally increased with increasing dose, but were markedly (65- to 154-fold) lower compared to maternal levels. There was no inclisiran detected in fetal livers in any dose group. In rabbits, inclisiran was below the lower limit of quantitation in fetal plasma as well as liver.
In the pre- and postnatal development study conducted in pregnant female Sprague-Dawley rats, inclisiran was administered once daily by subcutaneous injection at 50, 100 and 150 mg/kg from Day 6 post coitum to lactation Day 20. Inclisiran was well-tolerated with no evidence of maternal toxicity and no effects on maternal performance. There were no adverse effects on the offspring.
Lactation: Risk Summary: It is not known if inclisiran is transferred into human milk after administration of inclisiran. There are no data on the effects of inclisiran on the breastfed child or on milk production. Inclisiran was present in rat milk following once-daily subcutaneous injection. However, there is no evidence of systemic absorption in suckling rat neonates. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for inclisiran and any potential adverse effects on the breastfed child from inclisiran.
Females and males of reproductive potential: Infertility: There are no data on the effect of inclisiran on human fertility. No effects on fertility were observed in female and male rats at doses equivalent to 20.4-fold and 44.1-fold based on AUC, compared to exposures observed at the MRHD (see Pharmacology: Toxicology: Non-Clinical Safety Data under Actions).

Summary of the safety profile: The safety of inclisiran was evaluated in 3 Phase III placebo-controlled trials that included 3,655 patients with atherosclerotic cardiovascular disease (ASCVD), ASCVD risk equivalents, or familial hypercholesterolemia, treated with maximally tolerated statins and inclisiran or placebo, including 1,833 patients exposed to inclisiran for up to 18 months (mean treatment duration of 526 days).
Safety data from the 3 Phase III placebo-controlled pivotal trials showed that treatment-emergent adverse events (TEAEs) occurred at a similar incidence in the inclisiran-treated and placebo-treated patients. The majority of the TEAEs were mild and unrelated to inclisiran or placebo. The only adverse reactions associated with inclisiran in pivotal trials were adverse events at the injection site.
Tabulated summary of adverse drug reactions from clinical trials: Adverse drug reactions from clinical trials (Table 4) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 4.)

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Description of selected adverse drug reactions: Adverse events at the injection site: Adverse events at the injection site occurred in 8.2% and 1.8% of inclisiran-treated and placebo-treated patients, respectively, in the pivotal trials. The proportion of patients who discontinued treatment due to adverse events at the injection site in inclisiran-treated patients and placebo-treated patients were 0.2% and 0.0%, respectively. All of these adverse drug reactions were mild or moderate in severity, transient and resolved without sequelae. The most frequently occurring adverse events at the injection site in patients treated with inclisiran were injection site reaction (3.1%), injection site pain (2.2%), injection site erythema (1.6%), and injection site rash (0.7%).
Immunogenicity: In the pivotal trials, 1,830 patients were tested for anti-drug antibodies. Confirmed positivity was detected in 1.8% (33/1830) of patients prior to dosing and in 4.9% (90/1830) of patients during the 18 months of treatment with inclisiran. No clinically significant differences in the clinical efficacy, safety or pharmacodynamic profiles of inclisiran were observed in the patients who tested positive for anti-inclisiran antibodies.

Inclisiran (Sybrava) is not a substrate, inhibitor or inducer of cytochrome P450 (CYP450) enzymes or common drug transporters, and therefore inclisiran is not expected to have clinically significant interactions with other medications. Drug-drug interaction assessments demonstrated a lack of clinically meaningful interactions with either atorvastatin, rosuvastatin or other statins (see Pharmacology under Actions).

Incompatibilities: In the absence of compatibility studies, this product must not be mixed with other medicinal products.

Do not store above 30°C. Do not freeze.

Dyslipidaemic Agents

C10AX16 - inclisiran ; Belongs to the class of other lipid modifying agents.

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