Praluent - instructions for use, dose, side effects, contraindications

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Dosage form: & nbsphypodermic solution

Composition:

In one syringe / syringe pen with a dosage of 75 mg / ml contains:

active substance: alirocoumab 75.0 mg;

auxiliary substances: L-cystidine and L-histidine hydrochloride monohydrate - 1,241 * mg, sucrose - 100.0 mg, polysorbate-20 - 0.1 mg, water for injection - up to 1.0 ml.

In one syringe / syringe pen with a dosage of 150 mg / ml contains:

active substance: alirocoumab - 150.0 mg;

Excipients: L-cystidine and L-histidine hydrochloride monohydrate 0.931 * mg, sucrose 100.0 mg, polysorbate 20 0.1 mg, water for injection 1.0 ml.

* - total quantity L-histidine and L-histidine hydrochloride monohydrate in terms of L-histidine.

Description:

Transparent or slightly opalescent, colorless or yellowish liquid.

Pharmacotherapeutic group:A fully humanized monoclonal antibody (IgG1). Protein convertase inhibitor subtilisin-kexin type 9 (PCSK9)

Pharmacodynamics:

Alirocoumab is a fully humanized monoclonal antibody [isotype of immunoglobulins G1 (IgG1)], the target of which is the enzyme pro-proteinase subtilisin-keksin type 9 (PCSK9). Alirocoumab is produced using recombinant DNA technology using a suspension culture of Chinese hamster ovary cells.

Alirocoumab has a molecular weight of approximately 146 kDa.

Mechanism of action

PCSK9 binds to low-density lipoprotein (L-LDL) receptors on the surface of hepatocytes, promoting the degradation of R-LDL in the liver. R-LDL are the main receptors that release circulating LDL from the circulatory system, so reducing the amount of R-LDL when binding them to PCSK9 leads to an increase in the concentration of LDL cholesterol (LDL-C) in the blood. Inhibiting binding PCSK9 with R-LDL, alirocoumab increases the amount of R-LDL for elimination of LDL, thus reducing the concentration of LDL-C in the blood.

R-LDL also bind very low density lipoprotein (VLDL)-rich triglycerides (TG) and intermediate-density lipoproteins (LDL). Therefore, treatment with alirocoumab may reduce the concentrations of these lentoproteins, as evidenced by their decrease in apolipoprotein B (Apo B), lipoprotein cholesterol, which are not high-density lipoproteins (CS-LPNEV) and TG. Alirocoumab also reduces the concentrations of lipoproteins a (Rn (a)), which are a form of LDL, which are associated with apolipoprotein (a). However, it has been shown that P-LDL have a low affinity for Aβ (a), and therefore the exact mechanism by which alirocoumb reduces Aβ (a) is not completely established.

Genetic research

In genetic studies conducted in humans, varieties of the gene PCSK9 with loss or enhancement mutations. In patients with one allele PCSK9 with a loss of function mutation, lower concentrations of LDL-C were observed, which correlated with a significantly lower incidence of coronary heart disease. Some patients showed mutations in function loss in the two alleles, and they had very low concentrations of LDL-C in the blood with blood concentrations of HDL-C and HD in the normal range. Conversely, mutations in the function increase in the gene PCSK9 were detected in patients with elevated concentrations of LDL-C in the blood and a clinical diagnosis of familial hypercholesterolemia.

Observational analysis showed that without treatment of the concentration of LDL-C in blood in patients with mutations in the increase in function in the gene PCSK9 were in a range similar to that observed in patients with more frequent mutations causing a heterozygous form of familial hypercholesterolemia (such as mutations in the R-LDL gene), demonstrating the central role of the enzyme PCSK9 in the metabolism of LDL-C and its concentrations in the blood.In a multicenter, double-blind, placebo-controlled study of 14 weeks, 13 patients with a heterozygous form of familial hypercholesterolemia associated with a mutation in the increase in function in the gene PCSK9, were randomized into 2 groups: a group receiving alirocumab 150 mg once every 2 weeks, and a group receiving a placebo. The average concentration of LDL-C in the blood was 151.5 mg / dL. In the second week of treatment, the mean reduction in baseline LDL-C in the blood was 62.5% in the alicocrum-treated group compared with 8.8% in patients receiving placebo. At the 8th week of treatment, the average value of the decrease in LDL-C in the blood from the initial value in all patients receiving alirocoumus was 72.4%.

Pharmacodynamic properties

Alirocoumab is a fully humanized monoclonal an antibody that suppresses activity PCSK9 as in studies in vitro, and in systems of models in vivo. A large number of studies conducted in humans and animals have demonstrated the central role played by elevated concentrations of LDL-C in the blood at the onset and progression of atherosclerosis.Other lipoproteins containing Apo B-100, especially triglyceride-rich lentative lipoproteins (formed from VLDL and LLPP) and Lp (a), are also considered to promote the development of atherosclerosis. However, studies conducted to date have not revealed an independent effect of reducing the concentrations of these lipoproteins on cardiovascular morbidity and mortality.

In studies in vitro, alirocoumab did not induce antibody-dependent cell-mediated toxicity and complement-dependent cytotoxicity (Fc-mediated effector function), both in the presence and in the absence PCSK9. In alirocoumus associated with PCSK9, There was no formation of insoluble immune complexes capable of binding complement proteins.

Clinical efficacy / clinical studies

The efficacy of alirocoumab was studied in 10 phase III studies (5 placebo-controlled and 5 ezetimibe-controlled trials), including 5,296 randomized patients with hypercholesterolemia (non-familial and heterozygous family form) or mixed hypercholesterolemia, of which 3,188 patients were randomized to receive alirocoumab.Three of these 10 studies were performed exclusively in patients with a heterozygous form of familial hypercholesterolemia. Most patients in the Phase III clinical trials program received lipid-modifying therapy at the same time, consisting of the maximum tolerated doses of statins in combination

or without combination with other lipid-modifying therapies and had a high and very high cardiovascular risk. Two studies were conducted in patients who did not receive statins simultaneously, including one study in patients with documented statin intolerance.

Two studies (LONG TERM and HIGH FH), involving a total of 2416 patients, were conducted only with a dose of 150 mg once every 2 weeks. Eight studies were conducted at a dose of 75 mg once every 2 weeks, and a criterion for increasing the dose to 150 mg once in 2 weeks at week 12 was the failure of patients to achieve a target level of LDL-C in the blood, based on the degree of their cardiovascular risk at the 8th week of treatment.

The initial demographic characteristics were well balanced between the groups of alirocoumab and control.The age of patients in all studies was in the range of 18 to 89 years (mean age was 60 years); 38% of the patients were female, most of the patients were white, 5% were black, 2% were Asian; the mean BMI was 30 kg / m². In phase III clinical trials, 31% of patients had type 2 diabetes and 64% had a history of ischemic heart disease.

The main endpoint of efficacy in all Phase III clinical trials was the mean reduction in LDL-C in the blood at week 24 compared with placebo and ezetimibe. All the studies corresponded to their main endpoint.

In general, the use of alirocoumab also resulted in a statistically significantly greater percentage reduction in concentrations of OX, XC-LPnVP, Apo B and Lp (a) compared with placebo / ezetimibe, regardless of whether or not statin patients received it. Alirocoumab also reduced concentration of TG and increased concentrations of cholesterol-HDL and Apr A-1 in comparison with placebo.

Reducing the concentration of LDL-C in the blood was observed in all age groups, in people of both sexes, with different indexes of body mass index (BMI), in individuals of different races, and with different initial concentrations of LDL-C in the blood.The results for efficacy were uniform in patients with a heterozygous form of familial hypercholesterolemia, without heterozygous familial hypercholesterolemia, in patients with mixed dyslipidemia and patients with diabetes mellitus. Reducing the concentration of LDL-C in the blood was uniform, regardless of whether the patients were taking or not taking statins simultaneously, and from doses of the latter.

In the alirocoumab group, when compared with placebo or ezetimibe groups at the 12th and 24th week, the concentration of LDL-C in the blood, <70 mg / dl, was statistically significant in a higher percentage of patients.

In studies using dose titration schemes based on appropriate criteria, most patients achieved a target value of the LDL-C concentration in the blood (based on their degree of cardiovascular risk) at a dose of 75 mg once in 2 weeks, and most patients continued treatment in a dose of alirocoumab 75 mg once every 2 weeks. The lipid-lowering effect of alirocoumab was observed within 15 days after the application of the first dose, the maximum effect was observed at about 4 weeks.Efficacy was maintained throughout the duration of the study (up to 78 weeks in the study LONG TERM).

After the cessation of the administration of alirocoumab, there was no "withdrawal syndrome" and the concentration of LDL-C in the blood gradually returned to the baseline values.

Pharmacokinetics:

Absorption

After subcutaneous administration of Praluent in a dose of 50 mg to 300 mg, the mean time to reach the maximum concentration of alirocoum in serum was 3-7 days.

The pharmacokinetics of alirocoumab following a single subcutaneous injection at a dose of 75 mg into the abdominal, hip or shoulder region was similar.

According to the population analysis of pharmacokinetic parameters, the absolute bioavailability of alirocoumab after subcutaneous administration was 85%.

A slightly larger (2.1-2.7-fold) than a proportional dose, an increase in the concentrations of alirocoumab, was observed with a doubling of the dose from 75 mg to 150 mg once every 2 weeks.

The equilibrium state was achieved after the administration of 2-3 doses with a double accumulation coefficient.

Distribution

After intravenous administration, the volume of distribution of alirocoumab was 0.04-0.05 l / kg, indicating the distribution of alirocoumab, mainly in the circulatory system.

Metabolism

Special studies of metabolism have not been carried out, since alirocoumab is a protein. It is assumed that alirocoumab is split into small peptides and individual amino acids.

Excretion

In alirocoumab there were 2 phases of excretion. At low concentrations, elimination is primarily through saturable binding to the target (PCSK9), while at higher concentrations, the elimination of alirocoumab takes place predominantly through the unsaturation of the proteolytic pathway. According to the population analysis of pharmacokinetic parameters, the average half-life of alirocoumab was 17-20 days in patients who received alirocoumab in monotherapy subcutaneously at doses of 75 mg once every 2 weeks or 150 mg once every 2 of the week. With simultaneous use with statins, the average half-life of alirocoumab was 12 days.

Special patient groups

Floor

According to the population analysis of pharmacokinetic parameters, the sex of patients did not affect the pharmacokinetics of alirocoumab.

Elderly patients

According to the population analysis of pharmacokinetic parameters,age was associated with a slight difference in the systemic exposure of alirocoumab in an equilibrium state without affecting its efficacy and safety.

Body mass

According to the population analysis of pharmacokinetic parameters, body weight had little effect on the systemic exposure of alirocoumab without affecting its efficacy and safety.

Patients of childhood

The pharmacokinetic effects of alirocoumab in pediatric patients have not been studied to date.

Dysfunction of the liver

In the Phase I clinical study, with a single subcutaneous injection of alicrocumab at a dose of 75 mg, the pharmacokinetic indices of alirocoumab in patients with hepatic insufficiency of mild and moderate severity were similar to those in patients with normal liver function. Available data on the pharmacokinetics of alirocoumab in patients with severe hepatic insufficiency are absent.

Renal impairment

Since there is no evidence that monoclonal antibodies are excreted by the kidneys, it is not expected that the functional state of the kidneys will affect the pharmacokinetics of alirocoumab. Population analysis pharmacokinetic parameters demonstrated that renal function of mild and moderate severity did not have a significant effect on the pharmacokinetics of alirocoumab. Data on the pharmacokinetics of alirocoumab in patients with severe renal dysfunction are limited.

Race

According to the population analysis of pharmacokinetic parameters, race did not influence the pharmacokinetics of alirocoumab. After a single subcutaneous administration of alirocoumab in doses of 100-300 mg, there were no significant differences in systemic exposure in healthy volunteers who are Japanese and representatives of the white race.

Indications:

Pralulent is indicated for the long-term treatment of adult patients with primary hypercholesterolemia (non-familial and heterozygous form of familial hypercholesterolemia) or mixed dyslipidemia, including patients with type 2 diabetes, in addition to diet, to reduce the concentration of low-density lipoprotein cholesterol (LDL-C), total cholesterol (total-cholesterol), lipoprotein cholesterol, which are not high-density lipoproteins (cholesterol-LPNE), apolipoprotein B (Apo B),Triglycerides (TG) and lipoprotein a (LPa) and increasing concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo A-1).

The preparation Pruluent is shown:

- in combination with statins (HMG-CoA reductase inhibitors) in combination or without combination with other lipid-modifying therapy if it is not possible to achieve the target concentration of LDL-C in patients when taking the maximum allowable dose of statins;

- in monotherapy or as an addition to another statin-free lipid-modifying therapy, in patients with statin intolerance or in the presence of contraindications to their use.

Effect of Praluent on cardiovascular morbidity and mortality is currently not established.

Contraindications:

- Hypersensitivity to alirocoumab or to any auxiliary substance of the drug.

- Pregnancy (efficacy and safety not established).

- Breastfeeding period (efficacy and safety not established).

- Children under 18 years of age (efficacy and safety not established).

Carefully:

- Renal failure is severe.

- Hepatic insufficiency is severe.

Pregnancy and lactation:

Pregnancy

There are no data on the use of Praluent in pregnant women.

It is expected that alicocrum, as well as other antibodies of the class IgG, penetrates the placental barrier.

During pregnancy, the use of Pralulent is not recommended.

Breastfeeding period

It is not known whether alirocoumab penetrates human breast milk.

Due to the fact that many medications, including immunoglobulins, penetrate human milk in humans, the use of Praluent in women during breast-feeding is not recommended. If you need to use the drug Praluent in this period should stop breastfeeding.

Dosing and Administration:

The initial dose of Praluent is 75 mg, which is administered subcutaneously every 2 weeks. In patients who require a greater decrease in LDL cholesterol (> 60%), the initial dose of Praluent may be 150 mg, which is also administered subcutaneously every 2 weeks.

The dose of Pralulent should be selected individually based on parameters such as the baseline values of LDL cholesterol, the purpose of therapy, and the patient's response to treatment.Lipid concentrations in the blood can be assessed 4 weeks after the start of treatment or titration of the dose and appropriate dose adjustment.

If a dose is missed, the patient should receive an injection as soon as possible, and then continue treatment after 2 weeks from the date of the missed dose.

Special patient groups

Children

Safety and efficacy of Pralulent in children under the age of 18 years have not been established.

Elderly patients

In elderly patients, correction of the dose of Pralulent is not required (see section "Special instructions").

Liver failure

Patients with hepatic insufficiency of mild or moderate severity of correction of the dose of Pralulent is not required. Data on use of Praluent in patients with hepatic insufficiency of severe degree is absent.

Renal insufficiency

In patients with mild or moderate renal insufficiency, correction of the dose of Pralulent is not required. Data on the use of the drug in patients with severe renal insufficiency are limited.

Body mass

There is no need to correct the dosage regimen depending on the patient's body weight.

Rules of drug administration

The preparation Pruluent is used in the form of subcutaneous injections, performed in the area of the thigh, abdomen or shoulder, using a disposable pre-filled syringe pen or disposable pre-filled syringe.

It is recommended to change the injection site for each injection.

Pralulent should not be administered in the field of active skin diseases or lesions, such as sunburn, skin rash, skin inflammation or skin infections.

Do not administer the drug Pruluent to the same place in which other medications have been administered.

Side effects:

The following safety data reflects the use of alirocoumab in 3,340 patients, most of whom had a high or very high risk of developing cardiovascular disease and who received alicrocumab at a dose of 75 mg or 150 mg in the form of subcutaneous injections every 2 weeks with a duration of treatment up to 18 months (including 2408 patients treated with alirocoumab for 52 weeks and 639 patients treated with alirocoumab for at least 76 weeks). The safety data are based on the combined results of 9 placebo-controlled studies (4 phase II studies and 5 phase III studies (all studies in patients,concurrently taking statins), and 5 ezetimib-controlled Phase III studies (in 3 of which patients simultaneously took statins).

The most frequent adverse reactions (≥1% of patients treated with Praluent) were reactions at the injection site, subjective symptoms and objective signs from the upper respiratory tract and skin pruritus.

The most frequent adverse reactions leading to discontinuation of treatment in patients treated with Pralwent were reactions at the injection site.

There was no difference in the safety profile between the two doses (75 mg once every 2 weeks and 150 mg once every 2 weeks) used in the Phase III clinical research program.

In controlled trials, 1158 patients (34.7%) receiving Pralwent were ≥65 years of age, and 241 patients (7.2%) receiving Pralwent were aged ≥75 years. There were no significant differences in the safety and efficacy of the drug as the age of the patients increased.

Undesirable reactions reported by the use of Praluent in pooled controlled trials

Undesirable reactions are presented in accordance with the frequency, the classification of which is recommended by the World Organization Health: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1 000 to <1/100), rarely (from ≥ 1/10 000 to < 1/1 000), very rarely (<1/10000), the frequency is unknown (the frequency can not be determined by based on available data).

Immune system disorders

Rarely: hypersensitivity, allergic vasculitis.

Disturbances from the respiratory system, chest and mediastinal organs

Often: subjective symptoms and objective signs from the upper respiratory tract, including pain in the oropharynx, rhinorrhea, sneezing.

Disturbances from the skin and subcutaneous tissues

Often: itching.

Rarely: hives, coin-like eczema.

General disorders and disorders at the site of administration

Often: reactions at the injection site, including erythema / flushing, pruritus, edema, pain / pain sensitivity.

Description of individual adverse reactions

Reactions at the injection site

Reactions at the injection site, including erythema / flushing, pruritus, edema, pain / pain sensitivity, were noted in 6.1% of patients treated with alirocoumab compared with 4.1% in the control group.Most of the reactions at the site of injection were transient and mild. The frequency of cessation of treatment due to the development of reactions at the site of administration was comparable in both groups (0.2% in the alirocoumab group compared with 0.3% in the control group).

Generalized allergic reactions

Generalized allergic reactions were more frequent in the group of alirocoumab than in the control group, mainly with a difference in the incidence of skin pruritus. The itchy skin was usually mild and transitory. In addition, controlled clinical trials reported the development of rare and sometimes severe allergic reactions, such as hypersensitivity reactions, coin-like eczema, urticaria and allergic vasculitis.

Values of LDL-C <25 mg / dL

In the combined controlled trials, 796 patients from 3340 patients (23.8%) treated with Praluent received two successively obtained LDL-C values in blood <25 mg / dl, including 288 patients (8.6%) with two successively obtained values of the concentration of LDL-C <15 mg / dL.

These cases were mainly observed,when patients started and continued treatment with Praluent 150 mg once every 2 weeks, regardless of baseline LDL-C in the blood or response to treatment.

There were no undesirable reactions associated with these values of the concentration of LDL-C in the blood.

Cardiovascular complications

Cardiovascular outcomes are currently ongoing, in which the major endpoint is the large adverse cardiovascular complications (BNSSO) confirmed by the examination, such as coronary death, myocardial infarction, ischemic stroke and unstable angina that required hospitalization.

In the planned analysis of the combined Phase III studies, the following cardiovascular complications, confirmed by examination, were observed in 110 patients (3.5%) in the alirocoumab group and in 53 patients (3%) in the control group (placebo or active control) treatment: death associated with coronary artery disease heart, myocardial infarction, ischemic stroke, unstable angina, requiring hospitalization, hospitalization for chronic heart failure and revascularization. ConfirmedBNSSO was observed in 52 of 3182 patients (1.6%) in the alirocoumab group and in 33 of 1792 patients (1.8%) in the control group (placebo and active control).

With the planned final analysis of the clinical trial LONG TERM confirmed cardiovascular complications developed during treatment were observed in 72 of 1550 patients (4.6%) in the alirocoumab group and 43 of 788 patients (5.1%) in the placebo group; confirmed by the examination of BNSSO were observed in 27 of 1550 patients (1.7%) in the group of alirocoumab and in 26 of 788 patients (3.3%) in the placebo group. The risk ratio (RR) was calculated retrospectively; for all cardiovascular complications, the risk ratio = 0.91 (95% CI, 0.62-1.34); for BNSSO the risk ratio is 0.52 (95% CI, 0.31-0.90).

Mortality from all causes

In phase III clinical trials, all-cause mortality was 0.6% (20 of 3182 patients) in the alirocoumab group and 0.9% (17 of 1792 patients) in the control group. The main cause of death was cardiovascular complications.

Immunogenicity / antibodies to alirocoumab

Like all other proteins used for treatment, alirocoumb has potential immunogenicity. In Phase III studies, 4.8% patients receiving treatment with alirocoumab, education was noted antibodies to alirocoumab (AA), compared with 0.6% in the control group (placebo and ezetimibe). Most of these patients were observed transient AA reactions with low titres without neutralizing activity. Compared with patients who were AA-negative, patients with AA-positive status are not demonstrated differences in the systemic exposure of alirocoumab, efficiency or safety, except for a higher frequency development of reactions at the injection site. Only 1.2% of patients in the alirocoumab group had neutralizing antibodies. Most of these patients had only one positive test result for the presence of neutralizing antibodies; 10 patients (0.3%) had two or more positive results of the analysis for the presence of neutralizing antibodies. The data in these patients do not corroborate the correlation between the presence of neutralizing antibodies and the efficacy in reducing the level of LDL-C in the blood and in safety.

The immunogenicity data depend on the sensitivity and specificity of the method of their determination, as well as on other factors.In addition, the observed frequency of the AA-positive result of the test is influenced by several factors, including treatment of blood samples taken, blood sampling time, concomitant medications and underlying disease. For these reasons, the comparison of the incidence of AA with the frequency of antibodies to other drugs may not be correct.

Overdose:

In controlled clinical trials, no safety changes were observed with more frequent doses than the recommended dosing regimen once every 2 weeks.

Interaction:

Effect of alirocoumab on other drugs

Since alirocoumab is a biological substance, no pharmacokinetic effects of alirocoumab are expected on other drugs.

In clinical studies with the use of alirocoumab in combination with atorvastatin or rosuvastatin, no significant changes in statin concentrations in the blood were observed with repeated administrations alirocoumab, indicating that alirocoumab does not affect isoenzymes cytochrome P450 (mainly isoenzymes CYP3A4 and CYP2C9) and transport proteins such as P-glycoprotein (P-gp) and OATP (a protein transporter of organic anions).

The effect of other drugs on alirocoumb

Statins and other lipid-modifying therapy are known to increase synthesis PCSK9, protein, which is the target of alirocoumab. Increase in concentration PCSK9 may lead to a decrease in the systemic exposure of alirocoumab. However, this does not affect the duration of the drug when using alirocoumab once every 2 weeks.

Special instructions:

Allergic reactions

Clinical studies reported the development of generalized allergic reactions, including pruritus; There have also been reports of rare and sometimes serious cases of allergic reactions, such as hypersensitivity reactions, coin-like eczema, urticaria and allergic vasculitis. When symptoms and signs of serious allergic reactions appear, treatment with Praluent should be stopped and appropriate symptomatic therapy should be started.

Impact on fertility

Data on the adverse effects of alirocoumus on fertility are not available.

Elderly patients

Data on the use of alirocoumab in patients older than 75 years are limited.In controlled trials, 1158 patients (34.7%) who received Pruluent were ≥65 years of age, and 241 patients (7.2%) who received Pruluent were aged ≥ 75 years. Significant differences in the safety and efficacy of Praluent with no increase in age was observed.

Renal insufficiency

In clinical trials, the number of patients with severe renal insufficiency (creatinine clearance <30 mL / min / 1.73 m²) was limited. Pralulent should be used with caution in patients with severe renal insufficiency (see "With caution").

Liver failure

Studies of alirocoumab in patients with severe hepatic insufficiency (class C on the Child-Pugh scale) were not conducted. Pralulent should be used with caution in this category of patients (see "With caution").

Effect on the ability to drive transp. cf. and fur:

The preparation of Praluent does not influence or almost does not influence the ability to drive vehicles and work with mechanisms.

Form release / dosage:

A solution for subcutaneous administration is 75 mg / ml and 150 mg / ml.

Packaging:

1 ml per disposable syringe made of transparent glass (type I), equipped with a non-removable stainless steel needle protected by a soft polymer cap.

1 syringe per plastic blister coated.

1 blister or 2 connected blisters or 3 pairs of connected blisters with instructions for use in a cardboard box.

1 syringe into the syringe pen. For 1, 2 or 6 syringe pens with instructions for use in a cardboard box, equipped with a latch.

Storage conditions:

Store at temperatures between 2 ° C and 8 ° C. Do not freeze.

Keep out of the reach of children.