Repata, 140 mg/ml 1 ml syringe pens

Name: Repata, 140 mg/ml 1 ml syringe pens
SKU: 279375
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EAN: 8715131010829 SKU: 279375 Categories: Cardiovascular, Medicine

Description

Mechanism of Action

Evolocumab is a fully human monoclonal immunoglobulin G2 (IgG2) that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Evolocumab selectively and with a high degree of affinity binds to PCSK9 and inhibits the binding of circulating PCSK9 to the low-density lipoprotein receptor (LDL) on the surface of liver cells, thus preventing PCSK9-mediated breakdown of LDL. As a result, increased expression of R-LDL in the liver leads to a decrease in the serum concentration of low-density lipoprotein cholesterol (LDL-C).

Pharmacodynamic properties

. In patients with primary hyperlipidemia and mixed dyslipidemia, involocumab has been shown to reduce concentrations of unbound PCSK9, LDL-C, total cholesterol (TC), apolipoprotein B (apoB), low-density lipoprotein cholesterol (non-LDL-C), very low density lipoprotein cholesterol (VLDL-C), triglycerides and lipoprotein(a) (Lp[a]), increases concentrations of high density lipoprotein cholesterol009(HDL-C) and apolipoprotein A1(apoA1), improving the ratio OS/CS-LDL, apoB/apolipoprotein A1 (apoA1).

A single subcutaneous injection of 140 or 420 mg of involocumab results in maximal suppression of cycling unbound PCSK9 after 4 hours, accompanied by a decrease in LDL-C reaching mean nadir by 14 and 21 days, respectively. Changes in unbound PCSK9 and serum lipoprotein concentrations are reversible after withdrawal of involocumab.

There was no compensatory increase in PCSK9 and LDL-C production during treatment, and no increase in unbound PCSK9 or LDL-C concentrations (no “ricochet syndrome”) was noted after evolocumab withdrawal. With the dosing regimen of 140 mg evolocumab every two weeks or 420 mg evolocumab once a month, maximum reductions in LDL-C achieved from -72% to -57% of initial values compared with placebo. The dosing regimens were equivalent with respect to the average decrease in LDL-C (mean at weeks 10 and 12).

A similar decrease in LDL-C was observed both when using involocumab in monotherapy and as part of combination therapy with other hypolipidemic drugs. The effect with regard to LDL-C decrease is stable, the maximum duration of therapy is currently 112 weeks.

External and internal factors such as demographic characteristics, concurrent therapy, variability of laboratory parameters and disease status have no effect on the response to therapy with everolocumab (see “Dosing regimen”.

Immunogenicity

As with any therapeutic protein, there is a potential risk of immunogenicity.Immunogenicity was determined by

immunochemiluminescence binding to detect antibodies to involocumab. If patients were found to have antibodies to involocumab during immunological screening, an additional biological assay was performed to assess whether these antibodies were neutralizing.

In clinical trials, 0.1% of patients (7 of 4,846 patients with primary hypercholesterolemia and mixed dyslipidemia and none of 80 patients with homozygous familial hypercholesterolemia [HFHH]) who received at least 1 dose of involocumab were found to have binding antibodies (4 patients had transient antibodies).

An additional neutralizing antibody assay was performed for these patients. Neutralizing antibodies were not detected in any of the patients. The detected binding antibodies did not alter the pharmacokinetic parameters of the drug and did not affect the therapeutic response or safety of the drug. Clinical efficacy and safety

The results of clinical studies of involocumab prove that inhibition of PCSK9 activity by involocumab provides a decrease in the concentration of LDL-C in serum and improve other parameters of lipid metabolism. These results demonstrate stable efficacy of involocumab in improving lipid metabolism parameters in patients with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia and GOSHCHS in all populations and with any study design.

The 140 mg bi-weekly (Q2W) and 420 mg (QM) evolocumab monthly dosing regimens are clinically equivalent in patients with primary hypercholesterolemia and mixed dyslipidemia with respect to decreases in LDL-C, total cholesterol, apoB, non-LDL-C, LDL-C, triglycerides and Lp(a); increase of concentration of HDL and ApoA1 and improvement of the ratio of total cholesterol/HDL, ApoB/ApoA1.

Evolocumab therapy resulted in a decrease in LDL-C concentrations of approximately 55-75%, which persisted throughout the duration of long-term therapy. Maximum response was generally achieved 12 weeks after administration of 140 mg times Q2W and 420 mg QM, respectively. In 80-85% of patients receiving devolocumab at any dosage, there was a reduction in LDL-C concentrations of more than 50% on average by 10 to 12 weeks of use.

. Evolocumab was superior to ezetimibe in reducing LDL-C concentrations, Evolocumab 140 mg Q2W and 420 mg QM was effective in all placebo and ezetimibe subgroups, with no significant differences between subgroups defined by patient characteristics such as age, race gender, region of origin, body mass index (BMI), National Cholesterol Education Program (NCEP) risk score, statin dose and intensity, smoking status, baseline risk of coronary heart disease (CHD), early CHD family history, glucose tolerance or intolerance (ie.е. type 2 diabetes mellitus, metabolic syndrome, or neither), arterial hypertension, baseline unbound PCSK9, baseline LDL-C concentration, and baseline triglyceride concentration, were not observed.

The results of the overall efficacy analysis in the GOSHCS trials suggest that everolocumab effectively reduced concentrations of CHD-LDL, total cholesterol, apoB, and non-HLDP in patients with GOSHCS.

Long-term treatment with involocumab at doses of 420 mg QM and 420 mg Q2W showed a prolonged therapeutic effect, which was confirmed by a decrease in LDL-C concentrations of approximately 20% to 30% in patients with GOSHCA who did not receive apheresis treatment and approximately 15% to 25% in patients with GOSHCA who received apheresis. Overall, no differences were observed with respect to the safety or efficacy of involocumab between groups aged 12 years and older and adult patients with GOSHCS.

The ratio of patients with adverse events was generally balanced between groups during all 3 periods of composite safety data collection, as well as between subgroups and treatment regimens.

There were no safety concerns regarding adverse events reported for other hypolipidemic therapies (i.e., episodes of diabetes mellitus and liver and muscle complications) and events that could theoretically be associated with PCSK9 inhibition/increased LDL receptor expression (i.e., hepatitis C episodes). There were no indications of any risk of neurocognitive complications with the use of everolucumab. Neurocognitive complications in studies with placebo or active controls were similar.

Types and number of adverse events in all studies were comparable, both when using involocumab as monotherapy and as part of combination therapy (with statins in combination with or without ezetimibe) or in patients with intolerance to statins.

No new drug safety signals were identified in a comparative study of adverse event data developed in studies of patients with GOSHS and adverse event data developed in studies of primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Pharmacokinetics

The pharmacokinetics of involocumab after subcutaneous administration demonstrate a nonlinear pattern.

absorption

The median maximum serum concentration was reached within 3 to 4 days with an estimated absolute bioavailability of 72% after a single subcutaneous injection of evolocumab 140 mg or 420 mg in healthy volunteers. The mean maximum concentration (Cmax mean (SD)) was 18.6 (7.3) mcg/ml after a 140 mg dose. The final area under the concentration-time curve (AUClast) was 188 (98.6) days “μg/ml. Similar Cmax and AUClast values were 59.0 (17.2) mcg/ml and 924 (346) 24 hours “mcg/ml, respectively, after administration of the 420 mg dose.

Distribution

The mean estimated equilibrium distribution volume was 3.3 (0.5) L after a single 420 mg dose of involocumab administered intravenously, suggesting limited tissue distribution of involocumab.

Metabolism

The calculated mean systemic clearance was 12 (2) mL/h after a single intravenous injection of 420 mg of involocumab. Repeated subcutaneous administration of involocumab for 12 weeks in clinical trials resulted in dose-proportional increases in exposure for dosing regimens of 140 mg or greater. Approximately two- and threefold cumulation was observed at a minimum serum concentration (Cmin [SD]) of 7.21 [6.6]) with dosing regimens of 140 mg every 2 weeks or 420 mg once a month (Cmin [SD] 11.2 [10.8]). The minimum serum concentration reached an equilibrium state by 12 weeks of dosing. The calculated effective elimination half-life of everolucumab was 11 to 17 days. There were no time-related changes in evolocumab serum concentrations over 124 weeks.

Evolocumab

Because evolocumab is a fully human IgG2 monoclonal antibody, evolocumab clearance is due to specific binding and complex formation with the target ligand, PCSK9, as are the standard IgG clearance pathways in the reticulo-endothelial system. Evolocumab is broken down to small peptides and amino acids via these catabolic pathways.

An increase in clearance of approximately 20% has been noted when combined with statins. This increase is due in part to the statin-induced increase in PCSK9 concentrations and does not adversely affect the pharmacodynamics of involocumab with respect to lipids. Population-based pharmacokinetic analysis showed no significant differences in the serum concentrations of involocumab in patients with hypercholesterolemia (familial and non-familial), while taking statins simultaneously.

Separate patient groups

According to the results of pharmacokinetic analysis in populations no dose adjustments based on age, race or sex are required. Body weight affects the pharmacokinetics of involocumab, but has no significant effect on the hypolipidemic effect of involocumab. Consequently, dosing regimen adjustment depending on body weight is not required.

Pharmacokinetic analysis in populations by pooled data from clinical trials revealed no differences in the pharmacokinetics of the drug in patients with mild to moderate renal dysfunction compared to patients with normal renal function.

The drug was administered as a single subcutaneous injection of 140 mg to 8 patients with mild renal dysfunction, 8 patients with moderate renal dysfunction and 8 healthy volunteers. Exposure to involocumab was reduced by 40% to 50% compared with healthy volunteers. Nevertheless, baseline PCSK9 concentrations as well as the degree and time of PCSK9 neutralization remained similar in all three groups. Thus, there was a similar effect on the reduction of LDL-C.

Indications
Indications
-Primary hyperlipidemia and mixed dyslipidemia
Repata is administered to adults with primary hyperlipidemia (heterozygous familial and non-familial) and with mixed dyslipidemia (types IIa, IIb, IV according to Fredrickson classification) as a dietary supplement to reduce LDL-C, total in combination with statin or in combination with statin and other hypolipidemic therapy (for example, ezetimibe), or
-In monotherapy or in combination with other hypolipidemic therapy in patients with statin intolerance, or
-In monotherapy or in combination with other hypolipidemic therapy in patients in whom statin use is not considered clinically appropriate.
-Homozygous familial hypercholesterolemia (HFH)
Repata is indicated for use in adult patients and adolescents aged 12 years and older with GOSHCHS (type IIa according to the Fredrickson classification) to reduce concentrations of LDL-C, OH, apoB, and non-LDL-C in combination with other hypolipidemic therapy (eg, statins, LDL apheresis).

Active ingredient
Active ingredient

Composition
Composition
Each pre-filled syringe (PFS) contains:
Active Substance:
140 mg of involocumab in 1.0 ml of solution.
Associates:
Proline – 25 mg;
Glacial acetic acid – 1.2 mg;
Polysorbate 80 – 0.1 mg;
Sodium hydroxide – in the amount necessary to bring the pH to 5.0;
Injection water – in the amount necessary to bring the volume to 1 ml.

How to take, the dosage
How to take, the dosage
Patients should switch to an appropriate hypocholesterolemic diet before initiating therapy and maintain this diet for the duration of therapy with Repata.
Primary hyperlipidemia and mixed dyslipidemia
Adults: The recommended dose of Repata is one subcutaneous injection of 140 mg every 2 weeks or 420 mg monthly. Both doses are clinically equivalent. One pre-filled syringe (PFS) or one pre-filled syringe pen (PSP) contains one 140-mg dose for a biweekly dosing regimen. Three NSPs or three PZSRs must be administered consecutively over 30 minutes to deliver a 420 mg dose for the once-monthly dosing regimen.
Homozygous familial hypercholesterolemia
Adults and children older than 12 years:The recommended dose of Repata is 420 mg bi-weekly or once a month subcutaneously. Patients receiving apheresis can start treatment with 420 mg every two weeks according to the apheresis schedule. Three NSPs or three NSPs must be administered consecutively for 30 minutes to deliver the 420 mg dose on bi-weekly or monthly dosing regimens.
Special patient groups
Patients with impaired renal function
No dosing adjustment is required (see Pharmacokinetics section).
Patients with hepatic impairment
No dosing adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh grades A and B i.e. 9 points or less on the Child-Pugh scale). Patients with severe hepatic impairment (Child-Pugh class C) were not included in clinical trials (see SPECIFICATIONS).
Elderly patients
There were no differences in efficacy and safety of the drug in elderly patients. No dosing regimen adjustment is required.
Children
The efficacy and safety of Repata have not been studied in children with primary hyperlipidemia and mixed dyslipidemia. Fourteen adolescents aged 12 years and older were included in Go-SHCS studies. No differences were noted in the efficacy and safety of the drug in these adolescents and adults.
Instructions for Use
The solution should be evaluated before administration for inclusions or color changes. The solution must not be used if it is cloudy or discolored, or if it contains cloudy or colored inclusions. Do not shake. To avoid discomfort at the injection site, warm the solution to room temperature (up to 25Â°C) before injection and then slowly inject the entire contents of a pre-filled syringe or pre-filled syringe pen. The NPS or NPSP with residual medication should be discarded. Any amounts of unused drug or unused materials must be disposed of in accordance with local requirements.

Interaction
Interaction
There have been no studies of drug interactions. Pharmacokinetic interaction between statins and involocumab has been evaluated in a program of clinical trials. There was approximately 20% increase in clearance of involocumab when concomitant use with statins. Increased clearance is due to statin-mediated increase in PCSK9 concentration, which, however, did not affect the pharmacodynamic effect of involocumab on lipids. There is no need to adjust doses of statins when concomitantly prescribed with the drug Repata.
PHARMACEUTICAL INHIBITIES
The drug should not be mixed with other medicinal products.

Special Instructions
Special Instructions
Possible secondary causes of hyperlipidemia or mixed dyslipidemia (e.g., diabetes mellitus, hypothyroidism, nephrotic syndrome) should be evaluated before starting therapy with Repata and measures should be taken to adequately control the associated conditions (see also “WARNING. also see “WITH CAUTION” section).
Hepatic Impairment
In patients with moderate hepatic impairment, decreased exposure to involocumab has been noted, potentially resulting in a reduced effect on LDL-C. Patients with severe hepatic impairment (class C according to Child-Pugh classification) were not included in clinical trials.
Elevation of creatine phosphokinase activity
Patients with creatine phosphokinase activity more than 3 times the upper limit of normal were not included in clinical trials. However, no safety signals in the form of muscle adverse events or increased creatine phosphokinase activity have been found in clinical trials.
Thyroid disorders
Patients with uncontrolled thyroid disorders (TTG > 1.5 above and below normal) were not included in clinical trials until adequate control of the disease was achieved. During clinical trials, adverse events of hypothyroidism or hyperthyroidism were reported at approximately the same rate of less than 0.3% of all treatment groups.
Unstable angina
Patients with unstable angina were not included in clinical trials. Long-term safety data for involocumab from open-label phase studies showed that the risks of major cardiovascular events and hospitalizations for unstable angina and heart failure did not increase (risk ratio 0.5 (95% CI 0.29, 0.86)).
Serious arrhythmias
Patients with severe cardiac rhythm disturbances were not included in clinical trials. A separate evaluation of adverse cardiac reactions showed that the incidence of new-onset electrocardiogram abnormalities was comparable between the involocumab and control groups in the studies and adverse cardiac events were rarely reported. Similar results were obtained in a separate analysis of adverse reactions potentially associated with increased repolarization. This analysis did not identify any effect of involocumab on the QT/QTc interval.
Arterial hypertension
Patients with uncontrolled arterial hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg at rest) were not included in clinical trials. Analysis of mean changes from baseline systolic and diastolic blood pressures showed no significant differences in the involocumab groups or control groups in the clinical trials.
Chronic Heart Failure
Patients with chronic heart failure (NYHA functional classes III and IV) were not included in clinical trials. During clinical trials, adverse events of heart failure or chronic heart failure were reported with approximately equal frequency from all treatment groups – less than 0.3%. Long-term safety data on involocumab from open phase studies showed that the risks of major cardiovascular events and hospitalizations for unstable angina and heart failure did not increase (hazard ratio 0.5 (95% CI 0.29, 0.86)).
Diabetes
Patients with type 1 diabetes or decompensated type 2 diabetes (HbA1c > 8.5%) were not included in clinical trials. Separate assessment of adverse reactions showed that changes in glycosylated hemoglobin and fasting glucose were comparable in all study groups. No clinically significant differences were found in the safety analysis in the subgroup of patients with type 2 diabetes mellitus.
Use as part of combination therapy
When concomitant administration of Repata with other hypolipidemic drugs (e.g., ezetimibe, statins), contraindications and special instructions given in the approved instructions for use of other drugs should be considered.
Impact on driving and operating machinery
No studies have been conducted on the effect on the ability to drive vehicles and operate mechanisms requiring increased concentration.
The needle cap for PZSH and PZTTTR consists of natural rubber derived from latex. Tell your doctor if you are allergic to latex.

Contraindications
Contraindications
-high sensitivity to any of the drug components;
-pregnancy and breastfeeding period;
Ages under 18 in primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia;
Ages under 12 years old in homozygous familial hypercholesterolemia.
WARNING
Available clinical data in patients with the following conditions are limited at this time. The decision to prescribe Repata to these patients should be based on an individual assessment of the potential benefits of the drug in these patients and the possible risks (see also “SPECIFICATIONS”). See also section “SPECIAL DIRECTIONS”):
-severe hepatic insufficiency (class C according to the Child-Pugh classification);
-increased creatine phosphokinase activity (more than 3 times the upper limit of normal);
-uncontrolled thyroid function abnormalities (thyroid hormone (TSH) elevation > 1.5 above normal and below normal);
-unstable angina;
-severe arrhythmias (such as paroxysmal ventricular tachycardia, atrial fibrillation with rapid ventricular response, supraventricular tachycardia, uncontrollable medically);
-uncontrolled arterial hypertension (systolic blood pressure > 180 mm Hg or diastolic blood pressure > 110 mm Hg at rest);
– Chronic heart failure (functional class III and IV according to NYHA classification or left ventricular ejection fraction less than 30%);
– Diabetes mellitus type 1.

Side effects
Side effects
Safety Profile Conclusion.
The data in the table describe adverse reactions reported in phase II and III clinical trials in patients with primary hypercholesterolemia and mixed dyslipidemia and homozygous familial hypercholesterolemia.
The following gradation was used to classify adverse reactions: Very common (> 1/10), common (> 1/100, < 1/10), infrequent (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), and very rare (< 1/10,000) based on the frequency of reports. In each frequency and organ system group, adverse events are listed in descending order of severity.
The safety profile in the Go-SHCS population is similar to that of patients with primary hyperlipidemia and mixed dyslipidemia.
Infections and invasions Influenza Frequently
Nasopharyngitis Frequently
Upper respiratory tract infections Frequently009009\0009
Digestive System Disorders Nausea Frequently

Overdose
Overdose
No cases of drug overdose have been reported and the effects of overdose are unknown. There is no specific antidote for overdose of the drug. In case of overdose – treatment-symptomatic, supportive therapy if necessary.

Additional information
Weight 0.074 kg
Manufacturer
Amgen Manufacturing Limited, Puerto Rico
Medication form
solution
Brand
Amgen Manufacturing Limited