Praluent,extract 75 mg/ml 1 ml syringe-pen 2 pcs
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A fully humanized monoclonal antibody [immunoglobulin isotype G1 (IgG1)] targeting the enzyme proprotein convertase subtilisin-kexin type 9 (PCSK9). Alirocumab is produced by recombinant DNA technology using a suspension culture of Chinese hamster ovary cells.
Alirocumab has a molecular weight of approximately 146 kDa.
PCSK9 binds to LDL receptors (R-LDL) on the surface of hepatocytes, promoting the degradation of R-LDL in the liver. R-LDLs are the main receptors that remove circulating LDL from the systemic bloodstream, so a decrease in R-LDL when it binds to PCSK9 leads to an increase in the concentration of hs-LDL in the blood. By inhibiting PCSK9 binding to P-LDL, alirocumab increases the amount of P-LDL for LDL excretion, thus reducing the concentrations of hs-LDL in blood.
P-LDL also binds triglyceride-rich (TG) remnant LDL and LDL. Therefore, treatment with alirocumab may decrease concentrations of these remnant lipoproteins, as evidenced by their decrease in apolipoprotein B (Apo B), non-high-density lipoprotein cholesterol (hs-LDLNP) and TG.
Alirocumab also reduces concentrations of lipoprotein a (LP(a)), which is a form of LDL that is related to apolipoprotein (a). However, P-LDL has been shown to have low affinity for LDL(a), so the exact mechanism by which alirocumab reduces LDL(a) is not fully established.
Human genetic studies have identified variants of the PCSK9 gene with loss-of-function or gain-of-function mutations. Patients with one PCSK9 allele with a loss-of-function mutation had lower concentrations of Chs-LDL, which correlated with a significantly lower incidence of CHD.
Some patients had loss-of-function mutations in the two alleles and had very low blood concentrations of hs-LDL with blood concentrations of hs-LDL and TG in the normal range. In contrast, up-regulation mutations in the PCSK9 gene were found in patients with elevated blood concentrations of hs-LDL and a clinical diagnosis of familial hypercholesterolemia.
. An observational analysis showed that without treatment, blood concentrations of hs-LDL in patients with upregulation mutations in the PCSK9 gene were in a range similar to that observed in patients with more common mutations causing heterozygous familial hypercholesterolemia (such as mutations in the P-LDL gene), demonstrating the central role of the PCSK9 enzyme in hs-LDL metabolism and its blood concentrations.
In a multicenter, double-blind, placebo-controlled study lasting 14 weeks, 13 patients with a heterozygous form of familial hypercholesterolemia associated with an upregulation mutation in the PCSK9 gene were randomized into 2 groups: a group receiving alirocumab at a dose of 150 mg once every 2 weeks and a group receiving placebo.
The median blood Chs-LDL concentration was 151.5 mg/dL. At week 2 of treatment, the mean reduction in baseline blood CHDL concentration was 62.5% in the alirocumab-treated group compared with 8.8% in patients receiving placebo. At week 8 of treatment, the mean decrease in blood CHDL concentration from baseline in all patients receiving alirocumab was 72.4%.
A large number of studies in humans and animals have demonstrated the central role that elevated blood concentrations of Chs-LDL play in the onset and progression of atherosclerosis.
Other lipoproteins containing Apo B-100, especially triglyceride-rich remnant lipoproteins (formed from HDL-CLDL and LDL-CLDL) and LP(a), are also thought to contribute to the development of atherosclerosis. However, studies to date have found no independent effect of decreasing concentrations of these lipoproteins on cardiovascular morbidity and mortality.
In in vitro studies, alirocumab did not induce antibody-dependent cell-mediated toxicity and complement-dependent cytotoxicity (Fc-mediated effector function) in both the presence and absence of PCSK9. No formation of insoluble immune complexes capable of binding complement proteins was observed in alirocumab bound to PCSK9.
Pharmacokinetics
After p/k administration at a dose of 50-300 mg, the average time to reach Cmax of alirocumab in serum was 3-7 days. The pharmacokinetics of alirocumab were similar after a single p/c injection at a dose of 75 mg in the abdomen, thigh, or shoulder. According to a population-based pharmacokinetic analysis, the absolute bioavailability of alirocumab after p/c administration was 85%.
Significantly greater (2.1-2.7-fold) than dose-proportional increases in alirocumab concentrations were observed when the dose was increased twice from 75 mg to 150 mg once every 2 weeks.
The equilibrium state was reached after administering 2-3 doses with twice the accumulation rate.
After IV administration, the Vd of alirocumab was 0.04-0.05 L/kg, indicating distribution of alirocumab primarily in the circulatory system.
Alirocumab is thought to break down into small peptides and individual amino acids.
Alirocumab has had 2 phases of excretion. At low concentrations, elimination occurs predominantly through a saturable binding to the target (PCSK9), while at higher concentrations, elimination of alirocumab occurs predominantly through an unsaturated proteolytic pathway.
In a population-based pharmacokinetic analysis, the mean T1/2 of alirocumab was 17-20 days in patients receiving alirocumab in monotherapy subcutaneously at doses of 75 mg once every 2 weeks or 150 mg once every 2 weeks. When used concomitantly with statins, the mean T1/2 of alirocumab was 12 days.
Indications
The drug Praluent is indicated for long-term treatment of adult patients with primary hypercholesterolemia (non-family and heterozygous form of familial hypercholesterolemia) or mixed dyslipidemia, including patients with type 2 diabetes, in addition to diet, to reduce low-density lipoprotein cholesterol (LDL-C) total cholesterol (total-C), non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (Apo B), triglycerides (TG) and lipoprotein a (LPa) and increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-1 (Apo A-1). The drug Praluent is indicated for:
- in combination with statins (HMG-CoA reductase inhibitors) in combination or without combination with other lipid-modifying therapies when patients fail to achieve target LDL-C concentrations when taking the maximum tolerated dose of statins;
- in monotherapy or as an adjunct to other statin-free lipid-modifying therapy, in patients with statin intolerance or with contraindications to their use.
The effect of Praluent on cardiovascular morbidity and mortality is currently unknown.
Active ingredient
Alirocumab
Composition
One syringe/syringe pen with a dosage of 75 mg/ml contains:
active ingredient: alirocumab – 75.0 mg;
excipients: L-histidine 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.
How to take, the dosage
The starting dose of Praluent is 75 mg administered subcutaneously once every 2 weeks. In patients who require greater decrease of LDL-C concentration (> 60%), the initial dose of the drug Praluent may be 150 mg, which is also administered subcutaneously once every 2 weeks.
The dose of the drug Praluent should be selected individually based on such parameters as baseline values of LDL-C, goals of therapy and patient response to treatment. Blood lipid concentrations can be assessed 4 weeks after treatment initiation or dose titration and appropriate dose adjustments can be made.
In case of missed dose, the patient should receive an injection as soon as possible and then continue treatment 2 weeks from the date of missed dose.
Special patient groups
Children
The safety and efficacy of Praluent in children under the age of 18 years has not been established.
Elderly patients
In elderly patients dosage adjustment of the drug Praluent is not required (see section “Special Indications).
Hepatic impairment
In patients with hepatic impairment of mild to moderate severity dosage adjustment of the drug Praluent is not required. There is no data concerning Praluent drug administration in patients with severe hepatic insufficiency.
Renal insufficiency
In patients with renal insufficiency of mild or moderate severity dosage adjustment of Praluent is not required. The data concerning the drug administration in patients with severe renal insufficiency are limited.
Body weight
It is not required the dosage adjustment depending on the body weight of patients.
Rules of drug administration
The drug Praluent is used in the form of subcutaneous injections carried out in the thigh, abdomen or shoulder, using a single-use pre-filled syringe pen or single-use pre-filled syringe.
It is recommended to change injection sites with each injection.
Praluent should not be injected in areas of active skin conditions or lesions such as sunburns, skin rashes, skin inflammations or skin infections.
Praluent should not be injected in the same area where other medications have been injected.
Interaction
Effect of alirocumab on other drugs
Since alirocumab is a biological substance, no pharmacokinetic effects of alirocumab on other drugs are expected.
In clinical studies, when alirocumab was used in combination with atorvastatin or rosuvastatin, no significant changes in blood concentrations of statins were observed when alirocumab was repeatedly administered, which indicates that alirocumab does not affect cytochrome P450 isoenzymes (mainly CYP3A4 and CYP2C9 isoenzymes) and protein transporters such as P-glycoprotein (P-gp) and OATP (organic anion transporter protein).
Effects of other medications on alirocumab
Statins and other lipid-modifying therapies are known to increase the synthesis of PCSK9, a protein that is a target of alirocumab. Increased PCSK9 concentrations may result in decreased systemic exposure to alirocumab. However, this does not affect the duration of drug action when alirocumab is used once every 2 weeks.
Special Instructions
Allergic reactions
The development of generalized allergic reactions, including pruritus, has been reported in clinical trials; rare and sometimes severe cases of allergic reactions such as hypersensitivity reactions, montane eczema, urticaria and allergic vasculitis have also been reported.
In the event of symptoms and signs of serious allergic reactions, treatment with Praluent should be discontinued and appropriate symptomatic therapy should be initiated.
Influence on fertility
There are no data on adverse effects of alirocumab on fertility.
Elderly patients
There are limited data on the use of alirocumab in patients over 75 years of age. In controlled trials, 1,158 patients (34.7%) who received Praluent were aged >65 years, and 241 patients (7.2%) who received Praluent were aged >75 years. There were no significant differences in safety or efficacy of Praluent with increasing age.
Renal failure
In clinical trials, the number of patients with severe renal impairment (creatinine clearance <30 ml/min/1.73 m2) was limited. Praluent should be used with caution in patients with severe renal impairment (see section “Caution”).
Hepatic failure
There have been no studies of alirocumab in patients with severe hepatic impairment (Child-Pugh class C). Praluent should be used with caution in this category of patients (see section “Caution”).
Impact on driving and operating machinery
Praluent has little or no effect on the ability to drive vehicles and operate machinery.
Contraindications
- High sensitivity to alirocumab or any excipient of the drug.
- Pregnancy (efficacy and safety not established).
- Breast-feeding period (efficacy and safety not established).
- Children under 18 years of age (efficacy and safety not established).
With caution
- Severe renal failure.
- Severe hepatic failure.
.
Side effects
Immune system disorders: rare: – hypersensitivity, allergic vasculitis.
Respiratory system disorders: often – subjective symptoms and objective signs of the upper respiratory tract, including pain in the oropharynx, rhinorrhea, sneezing.
Skin and subcutaneous tissue: often – skin itching; rarely – urticaria, coin eczema.
Others: often – reactions at the site of administration of the drug, including erythema/hyperemia, skin itching, edema, pain/painful sensitivity.
Overdose
No changes in safety have been found in controlled clinical trials with more frequent doses than the recommended dosing regimen of once every 2 weeks.
Pregnancy use
Pregnancy
There are no data on the use of the drug Praluent in pregnant women.
Alirocumab, like other IgG antibodies, is expected to penetrate the placental barrier.
During pregnancy Praluent is not recommended.
Breastfeeding
It is unknown whether alirocumab penetrates into human breast milk.
Due to the fact that many drugs, including immunoglobulins, penetrate into human breast milk, the use of Praluent in women during breastfeeding is not recommended. If it is necessary to use the drug Praluent during this period, breastfeeding should be stopped.
Weight | 0.094 kg |
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Shelf life | 2 years. |
Conditions of storage | Store at the temperature from 2°C to 8°C. Do not freeze. Keep out of reach of children. |
Manufacturer | Sanofi Winthrop Industry, France |
Medication form | solution |
Brand | Sanofi Winthrop Industry |
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