Repat - instructions for use, doses, side effects, contraindications

Active substanceEwolokumabEwolokumab

Similar drugsTo uncover

Repata

solution PC

Amgen Europe BV Netherlands

Dosage form: & nbspRAzvor for subcutaneous administration.

Composition:

Each pre-filled syringe (PESH) or a pre-filled syringe pen (BWR) contains:

Active substance: 140 mg e-volovacab 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 adjust the pH to 5.0, water for injection in the amount necessary to bring the volume to 1 ml .

Description:

Transparent or slightly opalescent liquid from colorless to yellowish color, free from mechanical inclusions.

Pharmacotherapeutic group:Other drugs that affect lipid metabolism. Monoclonal antibodies

ATX: & nbsp

C.10.A.X.13 Ewolokumab

Pharmacodynamics:

Mechanism of action

E-volokumab is a fully human monoclonal immunoglobulin G2 (IgG2), a pro-protein-converting subtilisin / kexin type 9 (PCSK9). Ewolokumab selectively and with a high degree of affinity binds to PCSK9 and inhibits the binding of circulating PCSK9 with a low-density lipoprotein (L-LDL) receptor on the surface of liver cells, thereby preventing PCSK9-mediated decay of R-LDL.As a result, an increase in the expression of R-LDL in the liver leads to a decrease in serum cholesterol concentration of low-density lipoprotein (LDL-C).

Pharmacodynamic properties

It was shown that in patients with primary hyperlipidemia and mixed dyslipidemia ehvolocumab reduces the concentration of unbound PCSK9, LDL cholesterol, total cholesterol (OX), apolipoprotein B (ApoB), low-density lipoprotein cholesterol (non-HDL cholesterol), very low-density lipoprotein cholesterol (CH-VLDL), triglycerides and lipoprotein (a) ]), increases the concentration of high-density lipoprotein cholesterol (Xc-HDL) and apolipoprotein A1 (APoA1), improving the ratio of OC / Xc-HDL, ApoB / apolipoprotein A1 (АпоА1).

A single subcutaneous administration of 140 or 420 mg of e-volovumab results in maximum suppression of the circulating unbound PCSK9 after 4 hours, which is accompanied by a decrease in LDL-C, reaching the mean nadir by 14 and 21 days, respectively. Changes in the concentration of unbound PCSK9 and serum lipoproteins are reversible after the abolition of ehvolocoumab. No compensatory increase in production PCSK9 and LDL-C during treatment, as well as after elimination of evolocoumab, there was no increase in concentrations of unbound PCSK9 or LDL cholesterol (there is no "bounce syndrome"). In the dosing regimen of 140 mg Ebotocoumab every two weeks or 420 mg E-Volunteer once a month, the maximum decrease in LDL-C was from -72% to -57% of the baseline values compared with placebo. Dosage regimens are equivalent to the average decrease in LDL-C (average at weeks 10 and 12).

A similar decrease in LDL cholesterol was observed both with the use of ewolocoumab in monotherapy, and in combination therapy with other lipid-lowering drugs. The effect of reducing LDL-C is stable, the maximum duration of therapy at the moment is 112 weeks.

External and internal factors such as demographic characteristics, concomitant therapy, variability in laboratory parameters and the status of the disease do not affect the response to e-volunteer therapy (see "Dosage regimen").

Immunogenicity

As with any other therapeutic protein, there is a potential risk of developing immunogenicity.Immunogenicity was determined by immunochemiluminescent binding for the purpose of detecting antibodies to ehvolocumab. In the case of detection in patients with immunological screening of antibodies to ewolocumab, biological analysis was additionally performed to assess whether these antibodies are neutralizing.

In clinical studies, binding antibodies were found in 7 patients (7 of the 4,846 patients with primary hypercholesterolemia and mixed dyslipidemia and none of the 80 patients with homozygous familial hypercholesterolemia [GosGHS]) who received at least 1 dose of eVoloucumab (in 4 patients - transient antibodies). For these patients, an additional assay for neutralizing antibodies was performed. Neutralizing antibodies were not found in any of the patients. The detected binding antibodies did not lead to a change in the pharmacokinetic parameters of the preparation, did not affect the therapeutic response or the safety of the preparation.

Clinical efficacy and safety

The results of clinical studies of ewolocoumab prove that inhibition of activity PCSK9 with e-volunteemate provides a reduction in the concentration of LDL-C in serum and an improvement in other parameters of lipid metabolism.These results demonstrate the stable efficacy of ewolocumab in improving the lipid metabolism in patients with primary hyperlipidemia (heterozygous familial and non-familial) and mixed dyslipidemia and GOSGHS in all populations and with any design studies.

Dosage regimens 140 mg evolocumab every two weeks (Q2W) and 420 mg (QM) evolocoumab once a month are clinically equivalent in patients with primary hypercholesterolemia and mixed dyslipidemia in terms of reduced LDL cholesterol, total cholesterol, apoB, cholesterol non-HDL cholesterol, cholesterol-VLDL, triglycerides and Lp (a); increase in the concentration of HDL-C and APoA1 and improvement of the ratio of total cholesterol / HDL-C, AHB / ApoA1.

As a result of ebotocoumab therapy, a reduction in the concentration of LDL-C was approximately 55-75%, which persisted throughout the period of long-term therapy. The maximum response was achieved, as a rule, 1-2 weeks after the administration of 140 mg once Q2W and 420 mg QM respectively. In 80-85% of patients who received ehvolocumab in any dosage, there was a decrease in the concentration of LDL-C in more than 50% on average to 10-12 weeks of use.

Ewolokumab was superior ezetimibe in terms of lowering the concentration of LDL-C, total cholesterol, ApoB, cholesterol-lowering cholesterol, cholesterol / HDL-C, AHB / AHAO and LP (a).

The use of evolocoumab 140 mg Q2W and 420 mg QM was effective in all the 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), degree of risk in the National Education Program on cholesterol (NCEP), the dose and intensity of statins, the status of smoking, the initial risk of developing coronary heart disease (CHD), the history of early history of IHD, the tolerability or intolerance of glucose (ie, type 2 diabetes, metabolic syndrome or neither) arterial hypertension, initial unrelated PCSK9, the initial concentration of LDL-C and the initial concentration of triglycerides were not observed.

The results of the general efficiency analysis in the studies of GOSGHS show that ehvolocumab effectively reduced the concentrations of LDL-C, total cholesterol, ApoV, and non-HDL cholesterol in patients with GOSGHS.

With long-term treatment with e-volovacamab in doses of 420 mg QM and 420 mg Q2W a prolonged therapeutic effect was observed, which is confirmed by a decrease in the concentration of LDL-C in approximately 20-30% in patients with HGHHS who were not treated with apheresis, and approximately 15-25% of patients with HGHHS receiving apheresis. In general, there were no differences in the safety or efficacy of e-Volokumab between the 12-year-olds and the older patients with GOSGHS.

The ratio of patients with adverse events was generally balanced between groups during all 3 collection periods of a comprehensive set of safety data, and between subgroups and treatment regimens. There were no safety-related problems with adverse events reported for other types of lipid-lowering therapy (ie, episodes of diabetes mellitus, as well as complications from the liver and muscle tissue), as well as phenomena that could theoretically be associated with inhibition of RSA / 9 / increased expression of LDL receptors (ie, episodes of hepatitis C development). There were no signs of a risk of developing neurocognitive complications with the use of e-volucumab.Neurocognitive complications in studies with placebo control or active controls were similar.

The types and amounts of adverse events in all studies were comparable, both with the use of ewolocoumab as monotherapy, and in combination therapy (with statins in combination with or with ezetimibe) or in patients with statin intolerance.

There were no new signals regarding the safety of the drug when comparing the data on adverse events that developed during the studies of patients with GOSGHS and data on adverse events that developed in studies of primary hyperlipidemia (heterozygous family and non-family) and mixed dyslipidemia.

Pharmacokinetics:

The pharmacokinetics of evolocoumab after subcutaneous administration demonstrates a nonlinear character.

Suction

The median maximum serum concentration was achieved within 3-4 days with an estimated absolute bioavailability of 72% after a single subcutaneous injection of ewolocoumab 140 mg or 420 mg in healthy volunteers. Mean maximum concentration (C_max mean (SD)) was 18.6 (7.3) μg / ml after the dose of 140 mg.The final area under the "concentration-time" curve (AUC_last) was 188 (98.6) days * μg / ml. Similar values FROM_m_Oh and AUC_last were 59.0 (17.2) μg / ml and 924 (346) days * μg / ml, respectively, after the administration of a dose of 420 mg.

Distribution

The average calculated volume of distribution in the equilibrium state was 3.3 (0.5) L after a single dose of 420 mg of eVolu- commab intravenously, which suggests a limited distribution of e-volokumab in the tissue.

Metabolism

The calculated average systemic clearance was 12 (2) ml / h after intravenous administration once 420 mg ehvolocumab. Subsequent subcutaneous administration of eVOL for 12 weeks in clinical studies resulted in a dose-proportional increase in exposure for dosing regimens 140 mg and more. Approximately two- and three-fold cumulation was observed with a minimum serum concentration (C_min [SD]) 7,21 [6,6]) at dosing regimes 140 mg every 2 weeks or 420 mg once a month (C_min [SD] 11,2 [10,8]). The minimum serum concentration reached the equilibrium state by the 12th week of dosing. The calculated effective half-life of evolocumab was from 11 before 17 days.

There were no changes in serum concentrations of evolocoumab for 124 weeks associated with time.

Excretion

Because the ehvolocumab is a fully human monoclonal antibody IgG2, the clearance of evolocoumab is due to specific binding and formation of the complex with the target ligand, PCSK9, as well as standard clearance routes IgG in the reticulo-endothelial system. Ewolokumab decomposes to small peptides and amino acids through these catabolism pathways.

An increase in clearance of approximately 20% was noted with combined use with statins. This increase is partly due to statin-induced increase in concentrations PCSK9 and does not have a negative effect on the pharmacodynamics of evolocoumab against lipids. Pharmacokinetic analysis in populations did not reveal significant differences in serum concentrations of e-volokumab in patients with hypercholesterolemia (familial and non-familial), while taking statins simultaneously.

Individual patient groups

According to the results of pharmacokinetic analysis, no dosage adjustment is required in populations depending on age, race or gender.

Body mass affects the pharmacokinetics of e-volucumab, but does not significantly affect the hypolipidemic effect of e-volucumab. Therefore, correction of the dosing regimen in relation to body weight is not required.

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

The drug was administered as a single subcutaneous injection of 140 mg to 8 patients with a weak degree of impaired liver function, 8 patients with a moderate degree of impairment, and 8 healthy volunteers. Exposure to evolocumab decreased by 40-50% compared to healthy volunteers. Nevertheless, the baseline concentrations PCSK9, as well as the degree and time of neutralization PCSK9, remained similar in all three groups. Thus, there was a similar effect on the decrease in LDL-C.

Indications:

- Primary hyperlipidemia and mixed dyslipidemia

Repata is assigned to adults with primary hyperlipidemia (heterozygous family and non-familial) and with mixed dyslipidemia (types IIa, IIb, IV on the classification of Fredrickson) as a supplement to the diet for reducing LDL-C, total cholesterol, ApoB, cholesterol-lowering cholesterol, cholesterol / HDL-C, ApoB / ApoA1, cholesterol-VLDL, triglycerides, Lp (a), and for increase in HDL-C and ApoAl:

- in combination with statin or in combination with statin and other lipid-lowering therapy (eg, ezetimibe), or

- in monotherapy or in combination with other lipid-lowering therapy in patients with statin intolerance, or

- in monotherapy or in combination with other lipid-lowering therapy in patients in whom the use of statins is considered clinically unreasonable.

- Homozygous familial hypercholesterolemia (GosGHS)

Repat is indicated for use in adult patients and adolescents aged 12 years and older with GOSGHS (type IIa according to Fredrickson classification) to reduce the concentrations of LDL-C, OX, ApoB, and cholesterol non-HDL in combination with other lipid-lowering therapy (eg, statins, LDL-apheresis).

Contraindications:

- Hypersensitivity to any of the components of the drug;

- pregnancy and the period of breastfeeding;

- age under 18 years with primary hyperlipidemia (heterozygous family and non-familial) and with mixed dyslipidemia;

- age up to 12 years with homozygous familial hypercholesterolemia.

Carefully:

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

- severe hepatic insufficiency (class C according to the Child-Pugh classification);

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

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

- unstable angina;

- severe arrhythmias (eg, paroxysmal ventricular tachycardia, atrial fibrillation with rapid ventricular response, supraventricular tachycardia, uncontrolled medication);

- uncontrolled arterial hypertension (systolic arterial pressure> 180 mm Hg or diastolic blood pressure> 110 mm Hg at rest);

- chronic heart failure (III and IV functional classes by classification NYHA or left ventricular ejection fraction less than 30%);

- type 1 diabetes mellitus.

Pregnancy and lactation:

Pregnancy

There were no controlled studies of evolocoumab that included pregnant women, therefore, the use of the drug Repata in pregnancy is not recommended. When diagnosing a pregnancy, the drug should be stopped. Pre-clinical studies in Javanese macaques showed no effect on embryo-fetal or postnatal development (up to the age of 6 months) with the introduction of e-Volokumab during pregnancy and exposure 12 times higher than that achieved in patients with 420 mg monthly.

It is not known whether a negative effect on the fetus is possible in humans, so the drug Repata can only be used if the potential benefit of treatment for a pregnant woman exceeds the possible risk to the fetus. In combination therapy with statins or other lipid-lowering agents (eg, ezetimibe) in women of childbearing age, the precautions outlined in the approved instructions of these drugs should be considered.

Breast-feeding

It is not known whether ehvolocumab with breast milk.The decision to discontinue the drug or stop breastfeeding should be made on the basis of an assessment of the potential benefit of continuing therapy for the mother or the potential risk of adverse effects on the newborn.

Dosing and Administration:

Before starting therapy, patients should go to the appropriate hypocholesterolemic diet and follow this diet during the entire period of therapy with the drug Repata.

Primary hyperlipidemia and mixed dyslipidemia

Adults: the recommended dose of the drug Repata is one subcutaneous injection of 140 mg every 2 weeks or 420 mg monthly. Both doses are clinically equivalent.

One pre-filled syringe (PZH) or one pre-filled syringe pen (MRL) contains a single dose of 140 mg for a bi-weekly dosing regimen. Three PZHs or three PNPHRs should be injected sequentially for 30 minutes to deliver a 420 mg dose at a dosage regimen once a month.

Homozygous familial hypercholesterolemia

Adults and children over 12 years of age: the recommended dose of the drug is 420 mg once every two weeks or once a month subcutaneously.

Patients receiving apheresis may begin treatment with 420 mg every two weeks in accordance with the apheresis schedule.

Three PZHs or three MNRs should be injected sequentially within 30 minutes to deliver a 420 mg dose at dosing regimes every two weeks or once a month.

Special patient groups

Patients with impaired renal function

No dosage adjustment is required (see "Pharmacokinetics").

Patients with hepatic impairment

There is no need for correction of the dosing regimen in patients with impaired liver function of mild to moderate degree (Child-Pugh classes A and B, ie, not more than 9 on the Child-Pugh scale). Patients with severe hepatic impairment (Child-Pugh class C) were not included in the clinical studies (see "SPECIAL INSTRUCTIONS").

Elderly patients

There were no differences in efficacy and safety of the drug in elderly patients. No dosage adjustment is required.

Children

The effectiveness and safety of the drug Repata has not been studied in children with primary hyperlipidemia and mixed dyslipidemia. Fourteen teenagers aged 12 years and over were included in the Go-SGHS study.There were no differences 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 discoloration. The solution can not be used in case of turbidity or discoloration, the content of turbid or colored inclusions.

Do not shake.

To avoid discomfort at the injection site, the solution should be warmed to room temperature (up to 25 ° C) before injection, and then slowly enter the entire contents of the pre-filled syringe or pre-filled syringe pen. PZHS or PNZHR with the remnants of the drug discarded.

Detailed recommendations for independent subcutaneous administration of the drug are included in this manual for medical use.

Any quantities of unused product or unused materials must be destroyed in accordance with local requirements.

Side effects:

Conclusion on the security profile

The data in the table describe the adverse reactions reported in Phase II and Phase III clinical trials in patients with primary hypercholesterolemia and mixed dyslipidemia and homozygous familial hypercholesterolemia.

The following gradation was used to classify unwanted reactions: very often (≥ 1/10), often (≥ 1/100, <1/10), infrequently (≥ 1 / 1,000, <1/100), rarely (≥ 1 / 10,000 , <1 / 1,000) and very rarely (<1 / 10,000), based on the message frequency. In each group of frequencies and organ systems, adverse events are listed in descending order of severity.

The safety profile in the Go-SGHS population is similar to that in patients with primary hyperlipidemia and mixed dyslipidemia.

Class of organ system	Unwanted reaction	Frequency messages
Infections and invasions	Flu	Often
	Nasopharyngitis	Often
	Upper respiratory tract infections	Often
From the side of the digestive system	Nausea	Often
From the skin and subcutaneous tissues	Skin rash	Often
From the skin and subcutaneous tissues	Hives	Infrequently
From the musculoskeletal system and connective tissue	Backache	Often
From the musculoskeletal system and connective tissue	Arthralgia	Often
General disorders and reactions at the injection site	Reactions at the site of administration (pain, redness, bruising)	Often

Overdose:

No cases of drug overdose have been reported, effects with overdose are unknown.

There is no specific antidote for an overdose of the drug.In case of an overdose, treatment is symptomatic, supportive therapy if necessary.

Interaction:

Studies of drug interactions have not been conducted.

Pharmacokinetic interaction between statins and evolocumab was evaluated in a clinical research program. Around 20% increase in ehvolocoumab clearance was noted with simultaneous use with statins. Increased clearance due to statin-mediated increase in concentration PCSK9, which nevertheless did not affect the pharmacodynamic effect of evolocoumab against lipids. It is not necessary to correct the dosages of statins with a simultaneous appointment with the drug Repata.

Pharmaceutical incompatibility

The drug should not be mixed with other drugs.

Special instructions:

Before starting therapy with Repat, the possible secondary causes of hyperlipidemia or mixed dyslipidemia (eg, diabetes mellitus, hypothyroidism, nephrotic syndrome) should be evaluated and measures taken to adequately control associated diseases (see also "With CAUTION").

Liver failure

Patients with a moderate degree of hepatic insufficiency had a decrease in exposure to evolocoumab, which could potentially lead to a decrease in the effect of LDL-C. Patients with severe hepatic insufficiency (class C according to the Child-Pugh classification) were not included in the clinical studies.

Increase in activity of creatine phosphokinase

Patients with the activity of creatine phosphokinase were more than 3 times higher than the upper limit of the norm, were not included in the clinical studies. However, in clinical studies, no safety signals in the form of undesirable phenomena from the side of muscles or increased activity of creatine phosphokinase.

Thyroid dysfunction

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

Unstable angina

Patients with unstable angina were not included in the clinical studies.Long-term safety data for the use of eVoloukamab from open-label studies have shown that the risks of major cardiovascular events and hospitalizations for unstable angina and heart failure have not increased (risk ratio 0.5 (95% CI 0.29, 0.86)).

Severe arrhythmias

Patients with severe heart rhythm disturbances were not included in the clinical studies. A separate evaluation of unwanted reactions from the heart showed that the frequency of newly emerging abnormalities on electrocardiograms was comparable between evolocoumab groups and control groups in studies and reports of adverse cardiac events were rare. Similar results were obtained by a separate analysis of undesirable reactions potentially associated with an increase in repolarization. The conducted analysis did not reveal any effect of ewolocoumab on the interval QT/QTc.

Arterial hypertension

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

Chronic heart failure

Patients with chronic heart failure (III and IV functional classes by classification NYHA) were not included in clinical studies. During clinical trials, adverse events of heart failure or chronic heart failure were reported with approximately the same frequency of all treatment groups - less than 0.3%. Long-term safety data for the use of eVoloukamab from open-label studies have shown that the risks of major cardiovascular events and hospitalizations for unstable angina and heart failure have not increased (risk ratio 0.5 (95% CI 0.29, 0.86)).

Diabetes

Patients with type 1 diabetes mellitus or decompensated type 2 diabetes mellitus (HbA1c > 8.5%) were not included in clinical trials. A separate assessment of adverse reactions showed that changes in glycosylated hemoglobin and fasting glucose were comparable in all study groups.There were no clinically significant differences in the safety analysis in a subgroup of patients with type 2 diabetes mellitus.

Application in combination therapy

With the simultaneous administration of the drug Repat with other lipid-lowering drugs (for example, ezetimibe, statins), contraindications and special instructions given in the approved instructions for the use of other drugs should be considered.

The cap for the PZH and PZSH needles consists of natural rubber, obtained from latex. Tell your doctor, if you are allergic to latex.

INSTRUCTION FOR INTRODUCTION

Repata pre-filled syringe-pen (SEM) of single use

Description - see Fig. 1.

Important. Carefully read the following important information before using the REPAIR MAP:

- xRinse the PHARM REPAIR in the original packaging to protect it from exposure to light;

- xRinse the PHARMATE of REPAIR in the refrigerator (2 ° C - 8FROM);

- Mr.Do not attempt to inject by yourself unless your doctor, nurse or pharmacist teaches you.

If you have any questions, consult your doctor, nurse.

- aboutThe capsule cap of the REMARK CAPTER is equipped with a protective cap for the needle (placed inside the orange cap), which consists of natural rubber, obtained from latex. Tell your doctor if you are allergic to latex.

- xRan PEZHR REPAIR in the place inaccessible to children.

DO NOT DO IT:

x to freeze PEHBR REPATHER or to use the preparation, which was subjected to freezing;

x shake the REPAIR MAP;

x remove the orange cap from the REMOTE SOLUTION while you are not prepared for the injection;

x Use the REMOTE SHRT if you drop it on a hard surface. Parts of the REPAIR MAXIMUM may be damaged, even if you do not see any damage. Use the new PHARMA RETURN and call your doctor.

x Use the REPAIR MAP after the expiration date.

Your doctor will answer any questions you may have. Contact your doctor.

Step 1: Preparation

A. Take out one of the REPAIR CLEAR from the packagingand.

1. Carefully remove one handle from the package.

2. Put the packaging with unused syringes back into the refrigerator.

3. Wait at least 30 minutes until the REPAIR MAXIMUM does not warm up to room temperature for safe injection.

DO NOT DO IT:

x Try to warm up the MESH REPAIR using any heat sources, such as hot water or microwave oven;

x Keep the REPAIR MAXIMUM in direct sunlight;

x shake the REPAIR MAP;

x remove the orange cap from the PHRRR REPAIR until You are not ready for an injection.

AT. Look at the REPAIR MAP (see Figure 2).

Make sure that the drug visible in the window is transparent, colorless to slightly yellow. Check expiration date.

Do not use REPAIR PRIMARY REPAIR, if:

x the solution is cloudy or discolored, or contains flakes or colored particles;

x any part of the device looks damaged or broken;

x if you dropped the device;

x the orange cap is missing or loosely closed;

x after the expiration date.

In the cases listed, use a new device and call your doctor.

FROM. Prepare everything you need for injection.

Wash your hands thoroughly with soap and water.

Place on a clean, well-lit surface:

- Mr.New REPARATOR;

- frompirate napkins;

- ata tampon or a gauze pad;

- Pthe shepherd;

- tocontainer for the disposal of stabbing objects.

D. Prepare and disinfect the injection site (withm. Fig.3).

The injection can be entered in:

- bedro;

- fIvot, except for the five-centimeter navel area;

- atExternal surface of upper arm (if someone helps you with injections).

Clean the injection site with an alcohol wipe. Allow to dry the skin.

DO NOT TOUCH place of injection.

Each time, inject the injection into different parts. If you inject into the same site, make sure that you inject the drug at another point.

DO NOT ENTER the drug in the areas of the skin with compaction, hematoma, inflammation or redness. Avoid injections into scars or stretch marks.

Step 2: Introduction

A. Remove the orange cap immediately before injection (see Figure 4).

The presence of a drop of solution at the tip of the needle or the yellow protective device is normal

DO NOT DO IT:

x twist, unscrew or bend the orange cap;

x place the orange cap in place;

x take a yellow protective device with your fingers.

DO NOT REMOVE the orange cap until you are ready to inject.

AT. Stretch or pinch the injection site to create a firm surface.

The stretching method - see Fig. 5. Stretch the skin with your fingers, creating an area 5 cm wide.

or Clamping method - see Fig.6. Pinch the skin with your fingers creating a hard surface area of 5 cm.

Step 3: Injection

It is important to keep the skin stretched or compressed during injection.

A. Keep skin stretched or compressed. Attach the REPAIR MIRROR with the removed
orange cap perpendicularly (at an angle of 90 degrees) to the skin - see Fig. 7th.

!Till DO NOT CLICK to the gray "Start" button.

AT. Tightly squeeze the PEARB of REPATH into the skin until the syringe stops moving.

!! You have to push the syringe heavily into the skin, but DO NOT PRESS the gray "start" button, until you are ready for injection (see Figure 8).

FROM. When you are ready to inject, press the gray "start" button. You will hear a click (see Figure 9).

D. Continue pressing the BZD into the skin. Then remove the BSR. Injection may take 15 seconds (see Figure 10).

NOTE: After you remove the BWR, the needle automatically closes.

Step 4: Completion

A. Discard the used BWR and the orange cap (see Figure 11).

Throw away the used BOPRR REPATHER and the orange cap into the container for sharp objects.

Ask your doctor how to dispose of PZHR.

Keep the MAP and the container for stabbing objects out of the reach of children.

DO NOT TRY:

x re-use the MULTIPLE REPAIR;

x put back the orange cap or fingers inside the yellow protective device;

x throw the MILLED REPAX into household garbage.

AT. Examine the injection site.

When blood appears, press a cotton swab or gauze to the injection site. DO NOT RINSE the injection site. If necessary, cover with adhesive tape.

ANNEX 1 - BRIEF INSTRUCTIONS

Repat syringe pen for single use

Party 1. Read all instructions on the card before insertion - see Fig. 12.

Side 2. Brief instruction on the introduction. First read on the reverse side - see Fig. 13.

Pre-filled single-use syringe (PES)

Instructions for introduction - see Fig. 14.

Important. Carefully read the following important information before using a single use PZS:

- xRinse the PZH REPATH in the original packaging to protect it from exposure to light;

- xRinse the PZH REPATH in the refrigerator (2 ° C-8 ° C);

- Mr.Do not attempt to inject by yourself unless your doctor does not teach you;

- fromThe first protective cap of the PZSH REPAIR needle consists of natural rubber, obtained from latex.Tell your doctor if you are allergic to latex;

- xRinse the PZH REPATER out of the reach of children.

DO NOT DO IT:

x Use PZH REPAIR if the package is damaged or open;

x to freeze PZH REPATH or to use the preparation which has undergone to a frost;

x Use the PZH REPAIR if you dropped it on a hard surface. PGM parts can be damaged even if you do not see any damage. Use the new CAP REPAIR;

x remove the gray protective cap of the needle from the PZH REPAIR, until you are ready for the injection.

Your doctor will answer any questions you may have. Contact your doctor.

Step 1: Preparation

A. Remove the PET packing from the refrigerator and wait 30 minutes.

Wait at least 30 minutes, until the PCR REPAIR warms up to room temperature for injection.

Check the name of the REPAIR indicated on the package.

DO NOT DO IT:

x Try to warm the PZH REPAX using any heat sources such as hot water or microwave oven;

x leave the CLEAR REPAIR in direct sunlight;

x shake the FIR REPA.

AT. Prepare everything you need for an injectiontion.

Wash your hands thoroughly with soap and water.

Place on a clean, well-lit surface:

- aboutthe bottom of the package is PZH REPA;

- frompirate napkins;

- ata tampon or a gauze pad;

- Pthe shepherd;

- tocontainer for the disposal of stabbing objects.

DO NOT DO IT Use the PET SHRAP after the expiration date indicated on the package.

FROM. Choose a place for injection.

The injection can be entered in:

- hip;

- The stomach, with the exception of the five-centimeter navel;

- the outer surface of the upper arm (if someone helps you with injections).

DO NOT ENTER the drug in the areas of the skin with compaction, hematoma, redness or inflammation. Avoid injections into scars or stretch marks.

!! Each time, inject the injection into different parts. If you inject into the same site, make sure that you inject the drug at another point.

D. Disinfect the injection site.

Disinfect the injection site using an alcohol wipe. Wait until the skin has dried.

DO NOT touch the injection site.

E. Removal of the PZS from the blister (see Fig. 15).

For removing:

- aboutopen the package and remove the blister;

- PPlace the blister in your hand;

- PTurn the blister and gently push the middle of the blister to remove the syringe from the blister;

- eIf the PZS did not work out of the blister, gently press the blister again.

DO NOT DO IT:

- remove the FSP from the package by the piston rod or gray protective cap. This can damage the syringe.

- remove the gray protective cap of the needle from the PZH REPAIR until you are ready for the injection.

Always hold the PZH for the syringe barrel.

F. Examine the drug and syringe (see Fig. 16).

Always hold the PZH for the piston cylinder.

Check:

- Mr.The name of the drug REPTA indicated on the label PZH;

- RThe solution in PZS is clear, colorless or slightly yellow in color.

DO NOT USE PZSH if:

x any of the parts of the PSP looks damaged or broken;

x gray protective cap missing or loosely closed;

x a color change solution or contains flakes or colored particles;

x after the expiry date indicated on the label PZH.

In the cases listed, use a new PTC and call your doctor.

Step 2: Introduction

A. Carefully remove the gray protective cap (see Fig. 17).

Presence of a drop of drug on the tip of the needle is normal.

Immediately place the cap in the container for sharp objects.

DO NOT DO IT:

x twist or bend the gray protective cap. This can damage the needle;

x Re-dress the protective cap on the PZS.

AT.Removal of air bubbles / airspace.

You may notice air bubbles / airspace in the CAP REPAIR.

If you notice air bubbles / airspace:

- thehold the PZS needle up;

- agently click on the cylinder of the syringe with your finger until air bubbles / airspace are at the top of the syringe;

- mSlowly and gently push the piston rod to release air from the PZH. Be very careful not to pour out the product (see Figure 18).

DO NOT touch the needle of the syringe.

FROM. Pinch the injection site to create a hard surface.

Pinch the skin with your fingers, creating a hard surface of about 5 cm. It is important to keep the skin compressed during the injection (see Figure 19).

Step 3: Injection

A. Keep skin tightly closed. Insert the needle into the skin at an angle of 45 to 90 degrees (see Figure 20).

DO NOT PRESS the piston rod while inserting the needle.

AT. Slowly and continuously push the piston rod until the syringe is empty.

FROM. When finished, remove the finger from the piston rod and gently remove the syringe from the skin.

Do not put a gray protective cap on the used syringe.

Step 4: Completion

A. Immediately place the used syringe in a container for sharp objects.

DO NOT TRY:

reuse the used syringe;

x use any remaining amount in the syringe.

Do NOT dispose of the syringe or sharps container in household garbage.

AT. Examine the injection site.

When blood appears, press a cotton swab or gauze pad to the injection site. If necessary, cover with adhesive tape.

DO NOT RINSE the injection site.

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

No studies influence on the ability to drive vehicles and working with machinery that require high concentration of attention.

Form release / dosage:Solution for subcutaneous administration, 140 mg / ml.

Packaging:

Pre-filled syringes with a solution for subcutaneous administration of 140 mg / ml

1 ml of solution in a pre-filled syringe made of glass of hydrolytic class I with a stainless steel needle, a closed cap and elastomeric bromobutyl elastomer stroke limiter syringe piston laminated fluoropolymer film on the side in contact with the product.The elastomeric cap for the needle is made of dry natural rubber, protects the cannula of the needle and can additionally be covered with a plastic hard cap. The plastic piston rod of the syringe is screwed onto the travel stop.

1 PZH with a label is placed in the contour mesh package. One contour pack of cells along with the instruction for use is placed in a cardboard pack. For each pack, a transparent protective label is affixed - control of the first autopsy. The control of the first opening is a transparent label with a longitudinal color stripe. One control label of the first opening is placed on each closing valve of the pack.

Pre-filled syringe pen with a solution for subcutaneous administration of 140 mg / ml

The pre-filled syringe pen is assembled from a pre-filled 1 ml syringe. The syringe inside the pen syringe is identical to that described above, except for the elastomeric needle cap and the hard plastic cap. One or two BWRs are placed in a pack of cardboard along with the instructions for use and instructions for the introduction. A pack of cardboard is equipped with a label for controlling the first opening.The control of the first opening is a transparent label with a longitudinal color stripe. One control label of the first opening is placed on each closing valve of the pack. Three packs, 2 FWRM in each, can be arranged in a package of 6 (3 x 2) FWR.

Storage conditions:

Store at 2-8 ° C. Do not freeze.

Keep in original packaging to protect from light.

Do not shake.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date indicated on the cardboard pack.

Terms of leave from pharmacies:On prescription

Registration number:LP-003574

Date of registration:19.04.2016

Expiration Date:19.04.2021