Repata, 140 mg/ml 1 ml syringe pens

Indications

-Primary hyperlipidemia and mixed dyslipidemia

Repatha is indicated for adults with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia (Fredrickson types IIa, IIb, IV) as an adjunct to diet to lower LDL-C, total in combination with a statin or in combination with a statin and other lipid-lowering therapy (eg, ezetimibe), or

-In monotherapy or in combination with other lipid-lowering therapy in patients intolerant to statins, or

-In monotherapy or in combination with other lipid-lowering therapy in patients in whom the use of statins is considered inappropriate from a clinical point of view.

– Homozygous familial hypercholesterolemia (HoFH)

Repata is indicated for use in adult patients and adolescents aged 12 years and older with HoFH (Fredrickson type IIa) to reduce concentrations of LDL-C, TC, ApoB, and non-HDL-C in combination with other lipid-lowering therapy (eg, statins, LDL apheresis).

Pharmacological effect

Mechanism of action

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

Pharmacodynamic properties

In patients with primary hyperlipidemia and mixed dyslipidemia, evolocumab has been shown to reduce concentrations of unbound PCSK9, LDL-C, total cholesterol (TC), apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein cholesterol (VLDL-C), triglycerides, and lipoprotein(a). (Lp[a]), increases the concentrations of high-density lipoprotein cholesterol009 (HDL-C) and apolipoprotein A1 (ApoA1), improving the ratio of OC/HDL-C, ApoB/apolipoprotein A1 (ApoA1).

A single subcutaneous injection of 140 or 420 mg evolocumab resulted in maximal suppression of circulating unbound PCSK9 at 4 hours, accompanied by a reduction in LDL-C reaching a mid-nadir at days 14 and 21, respectively. Changes in unbound PCSK9 and serum lipoprotein concentrations are reversible after discontinuation of evolocumab.

There was no compensatory increase in the production of PCSK9 and LDL-C during treatment, nor was there an increase in the concentrations of unbound PCSK9 or LDL-C after withdrawal of evolocumab (no “rebound syndrome”). With a dosing regimen of 140 mg evolocumab every two weeks or 420 mg evolocumab once a month, the maximum reduction in LDL-C reached from -72% to -57% of baseline values ​​compared with placebo. Dosing regimens are equivalent in terms of mean reduction in LDL-C (average at weeks 10 and 12).

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

External and internal factors such as demographic characteristics, concomitant therapy, laboratory variability and disease status do not affect the response to evolocumab therapy (see Dosage Regimen).

Immunogenicity

As with any therapeutic proteins, there is a potential risk of developing immunogenicity. Immunogenicity was determined using

immunochemiluminescent binding to detect antibodies to evolocumab. If antibodies to evolocumab were detected in patients during immunological screening, an additional biological analysis was performed to assess whether these antibodies were neutralizing.

In clinical studies, 0.1% of patients (7 of 4846 patients with primary hypercholesterolemia and mixed dyslipidemia and none of 80 patients with homozygous familial hypercholesterolemia [HoFHH]) who received at least 1 dose of evolocumab had binding antibodies (4 patients had transient antibodies).

For these patients, additional testing for neutralizing antibodies was performed. Neutralizing antibodies were not detected in any of the patients. The detected binding antibodies did not lead to changes in the pharmacokinetic parameters of the drug and did not affect the therapeutic response or safety of the drug. Clinical efficacy and safety

Results from clinical studies of evolocumab demonstrate that inhibition of PCSK9 activity by evolocumab reduces serum LDL-C concentrations and improves other parameters of lipid metabolism. These results demonstrate the consistent effectiveness of evolocumab in improving lipid metabolism in patients with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia and HoFH in all populations and with any study design.

Dosing regimens of evolocumab 140 mg every two weeks (Q2W) and evolocumab 420 mg (QM) once monthly are clinically equivalent in patients with primary hypercholesterolemia and mixed dyslipidemia in reducing LDL-C, total cholesterol, ApoB, non-HDL-C, VLDL-C, triglycerides, and Lp(a); increasing the concentration of HDL-C and ApoA1 and improving the ratio of total cholesterol/HDL-C, ApoB/ApoA1.

As a result of therapy with evolocumab, a decrease in LDL-C concentrations of approximately 55-75% was achieved, which was maintained throughout the entire period of long-term therapy. Maximum response was typically achieved 12 weeks after administration of 140 mg Q2W and 420 mg QM, respectively. 80-85% of patients receiving evolocumab at any dosage experienced a decrease in LDL-C concentrations of more than 50% by an average of 10-12 weeks of use.

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

Results from the overall efficacy analysis in the HoFH trials suggest that evolocumab was effective in reducing LDL-C, total cholesterol, ApoB, and non-HDL-C concentrations in patients with HoFH.

With long-term treatment with evolocumab at doses of 420 mg QM and 420 mg Q2W, a prolonged therapeutic effect was observed, as evidenced by a decrease in LDL-C concentrations of approximately 20% to 30% in HoFH patients not treated with apheresis and in approximately 15% to 25% of HoFH patients treated with apheresis. Overall, no differences in the safety or efficacy of evolocumab were observed between groups aged 12 years or older and adult patients with HoFH.

The proportion of patients experiencing adverse events was generally balanced between groups across all 3 comprehensive safety data periods and between subgroups and treatment regimens.

There were no safety concerns regarding adverse events reported for other lipid-lowering therapies (i.e., episodes of diabetes mellitus and liver and muscle complications) or events that may theoretically be associated with PCSK9 inhibition/increased LDL receptor expression (i.e., episodes of hepatitis C). There were no signs indicating a risk of developing neurocognitive complications with evolocumab. Neurocognitive complications were similar between placebo and active control studies.

The types and numbers of adverse events were comparable across all studies, whether evolocumab was used as monotherapy or as part of combination therapy (with or without statins with or without ezetimibe) or in patients intolerant to statins.

No new safety signals were identified when comparing adverse event data from studies of HoFH patients with adverse event data from studies of primary hyperlipidemia (heterozygous familial and nonfamilial) and mixed dyslipidemia.

Pharmacokinetics

The pharmacokinetics of evolocumab after subcutaneous administration shows a non-linear pattern.

Suction

Median maximum serum concentrations were achieved 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 average maximum concentration (Cmax mean (SD)) was 18.6 (7.3) μg/ml after administration of a dose of 140 mg. 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) μg/ml and 924 (346) μg/ml day, respectively, after administration of a dose of 420 mg.

Distribution

The mean estimated volume of distribution at steady state was 3.3 (0.5) L after a single dose of 420 mg IV evolocumab, suggesting limited tissue distribution of evolocumab.

Metabolism

The calculated mean systemic clearance was 12 (2) ml/h after a single 420 mg intravenous dose of evolocumab. Repeated subcutaneous administration of evolocumab over 12 weeks in clinical studies resulted in a dose-proportional increase in exposure for dosing regimens of 140 mg or greater. Approximately two- to three-fold accumulation was observed at minimum serum concentrations (Cmin [SD]) of 7.21 [6.6]) with dosing regimens of 140 mg every 2 weeks or 420 mg once monthly (Cmin [SD] 11.2 [10.8]). Trough serum concentrations reached equilibrium by week 12 of dosing. The estimated effective half-life of evolocumab was 11 to 17 days. There were no time-related changes in evolocumab serum concentrations over 124 weeks.

Removal

Because evolocumab is a fully human IgG2 monoclonal antibody, clearance of evolocumab is due to specific binding and complexation with the target ligand, PCSK9, as well as standard IgG clearance pathways in the reticuloendothelial system. Evolocumab is broken down into small peptides and amino acids through these catabolic pathways.

An increase in clearance of approximately 20% was observed when combined with statins. This increase is due in part to a statin-induced increase in PCSK9 concentrations and does not adversely affect the lipid pharmacodynamics of evolocumab. Pharmacokinetic analysis in populations did not reveal significant differences in serum concentrations of evolocumab in patients with hypercholesterolemia (familial and non-familial) while taking statins.

Selected patient groups

Based on the results of pharmacokinetic analysis in populations, no dose adjustment is required depending on age, race or gender. Body weight affects the pharmacokinetics of evolocumab, but does not significantly affect the lipid-lowering effect of evolocumab. Therefore, adjustment of the dosage regimen depending on body weight is not required.

Pharmacokinetic analysis in populations based on pooled clinical trial data did not reveal differences in the pharmacokinetics of the drug in patients with mild to moderate renal impairment compared with patients with normal renal function.

The drug was administered as a single subcutaneous injection of 140 mg to 8 patients with mild liver dysfunction, 8 patients with moderate impairment, and 8 healthy volunteers. Exposure to evolocumab was reduced by 40% – 50% compared to healthy volunteers. However, baseline PCSK9 concentrations and the extent and timing of PCSK9 neutralization remained similar in all three groups. Thus, a similar effect on lowering LDL-C was observed.

Special instructions

Before initiating therapy with Repata, possible secondary causes of hyperlipidemia or mixed dyslipidemia (eg, diabetes mellitus, hypothyroidism, nephrotic syndrome) should be assessed and measures should be taken to adequately control associated diseases (see also section “CAUTIONS”).

Liver failure

In patients with moderate hepatic impairment, decreased exposure to evolocumab was observed, which could potentially lead to decreased effect on LDL-C. Patients with severe hepatic impairment (Child-Pugh class C) were not included in clinical studies.

Increased activity of creatine phosphokinase

Patients with creatine phosphokinase activity greater than 3 times the upper limit of normal were not included in clinical studies. However, clinical studies did not detect safety signals in the form of muscle adverse events or increased creatine phosphokinase activity.

Thyroid dysfunction

Patients with uncontrolled thyroid dysfunction (TSH > 1.5 above and below normal) were not included in clinical studies until adequate control of the disease was achieved. During clinical trials, adverse events of hypothyroidism or hyperthyroidism were reported at approximately the same frequency across all treatment groups, less than 0.3%.

Unstable angina

Patients with unstable angina were not included in clinical studies. Long-term safety data from open-label phase studies of evolocumab 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)).

Severe arrhythmias

Patients with severe cardiac arrhythmias were not included in clinical studies. A separate assessment of cardiac adverse events showed that the incidence of new electrocardiogram abnormalities was comparable between the evolocumab and control groups in the studies, and cardiac adverse events were rarely reported. Similar results were obtained when adverse reactions potentially associated with increased repolarization were analyzed separately. The analysis did not reveal any effect of evolocumab on the QT/QTc interval.

Arterial hypertension

Patients with uncontrolled hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at rest) were not included in clinical studies. Analysis of mean changes from baseline in systolic and diastolic blood pressure did not reveal any significant differences in the evolocumab or control groups in clinical trials.

Chronic heart failure

Patients with chronic heart failure (NYHA functional classes III and IV) were not included in clinical studies. During clinical trials, adverse events of heart failure or chronic heart failure were reported at approximately the same rate across all treatment groups, less than 0.3%. Long-term safety data from open-label phase studies of evolocumab 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 mellitus

Patients with type 1 diabetes mellitus or decompensated type 2 diabetes mellitus (HbA1c > 8.5%) were not included in clinical studies. A 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 prescribing Repata with other lipid-lowering drugs (for example, ezetimibe, statins), contraindications and special instructions given in the approved instructions for use of other drugs should be taken into account.

Influence on the ability to drive a car and work with machinery

There have been no studies of the effect on the ability to drive vehicles and operate mechanisms that require 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.

Active ingredient

Evolocumab

Composition

Each pre-filled syringe (PFS) contains:

Active substance:

140 mg evolocumab in 1.0 ml solution.

Excipients:

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;

Water for injection in the amount necessary to bring the volume to 1 ml.

Contraindications

– hypersensitivity to any of the components of the drug;

-pregnancy and breastfeeding period;

– age up to 18 years with primary hyperlipidemia (heterozygous familial and non-familial) and with mixed dyslipidemia;

– age up to 12 years with homozygous familial hypercholesterolemia.

WITH CAUTION

Available clinical data in patients with the diseases listed below are currently limited. The decision to prescribe Repata to such patients should be based on an individual assessment of the potential benefits of using the drug in such patients and the possible risks (see also section “SPECIAL INSTRUCTIONS”):

-severe liver failure (class C according to the Child-Pugh classification);

-increased creatine phosphokinase activity (more than 3 times compared to the upper limit of normal);

-uncontrolled dysfunction of the thyroid gland (increased thyroid-stimulating hormone (TSH) > 1.5 above normal and below normal);

-unstable angina;

– severe arrhythmias (for example, paroxysmal ventricular tachycardia, atrial fibrillation with rapid ventricular response, supraventricular tachycardia uncontrolled with medication);

– uncontrolled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg at rest);

– chronic heart failure (III and IV functional classes according to the NYHA classification or left ventricular ejection fraction less than 30%);

– type 1 diabetes mellitus.

Side Effects

Conclusion on the safety profile.

The data presented in the table describe the 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, 1/1,000, 1/10,000, < 1/1,000) and very rare (< 1/10,000), based on the frequency of reports. Within each frequency and organ system group, adverse events are listed in descending order of severity.The safety profile in the Ho-FH population is similar to that in patients with primary hyperlipidemia and mixed dyslipidemia.Infections and infestations Flu OftenNasopharyngitis OftenUpper respiratory tract infections Common009009009From the digestive system Nausea OftenSkin and subcutaneous tissue disorders Skin rash Common, Urticaria UncommonMusculoskeletal and connective tissue disorders Back pain Common, Arthralgia Common.General disorders and reactions at the injection site Reactions at the injection site Often (pain, redness, hematoma)009009

Interaction

No drug interaction studies have been conducted. The pharmacokinetic interaction between statins and evolocumab was assessed in a clinical research program. There was an approximately 20% increase in the clearance of evolocumab when used concomitantly with statins. The increased clearance was due to a statin-mediated increase in PCSK9 concentrations, which, however, did not affect the pharmacodynamic effect of evolocumab on lipids. No dose adjustment of statins is required when administered concomitantly with Repata.

PHARMACEUTICAL INCOMPATIBILITY

The drug should not be mixed with other drugs.

Overdose

There have been no cases of drug overdose reported; the effects of overdose are unknown. There is no specific antidote for an overdose of the drug. In case of overdose, treatment is symptomatic, supportive therapy if necessary.

Manufacturer

Amgen Manufacturing Limited, Puerto Rico