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

Active substanceRELESUUMABRELESUUMAB

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Sinqueiro

concentrate d / infusion

Teva Pharmaceutical Enterprises Co., Ltd. Israel

Dosage form: & nbspconcentrate for solution for infusion

Composition:

In 1 ml of the concentrate contains:

active substance: reslisumab 10.00 mg;

Excipients: sucrose 70.00 mg, sodium acetate trihydrate 2.45 mg, acetic acid ice 0.12 mg, water for injection up to 1 ml.

Description:

Transparent or slightly opalescent solution from colorless to light yellow or yellow *.

* The solution may contain protein particles, which are transparent or white formless inclusions, some of which can be fibrous.

Pharmacotherapeutic group:Interleukin Inhibitor

ATX: & nbsp

R.03.D.X.08 RELESUUMAB

Pharmacodynamics:

Reeswizumab specifically binds to interleukin-5 (IL-5) and interferes with the binding of IL-5 to its receptor on the cell surface. IL-5 is the main cytokine, which is responsible for the differentiation, maturation, survival and activation of human eosinophils. Consequently, IL-5 plays a key role in the pathogenesis of eosinophilic inflammation in the lungs in patients with bronchial asthma. Eosinophilic inflammation, which continues despite treatment with inhaled glucocorticosteroids (GCS), determines the phenotype of resistant eosinophilic asthma.

Studies of reslisumab in vitro showed its affinity binding ability (Kd) to human IL-5 equal to 81 pM, measured by the system BIAcore, ability to inhibit the binding of IL-5 to a cognate (related) receptor at IC₅₀ equal 0.5 nM, and block the proliferation of the IL-5 sensitive cell line at IC₅₀, equal to 45 nM.

The safety and efficacy of Sinkeiro was evaluated in four randomized, double-blind, placebo-controlled trials (Studies I-IV), lasting from 16 to 52 weeks, with the participation of 978 patients 12 years of age and older suffering from moderate to severe bronchial asthma that did not achieve adequate control with moderate to high doses of inhaled glucocorticosteroids (at least 440 μg fluticasone propionate once every day or equivalent doses of other inhaled glucocorticosteroids) with or without the use of other control agents. Previous stable allergen-specific immunotherapy was allowed. With the use of Sinkeiro, the frequency of exacerbations of bronchial asthma decreased, the severity of symptoms decreased, and lung function improved in patients with bronchial asthma with increased eosinophil content in peripheral blood.In addition, during the open expanded study (Study V), the safety of the Sinkeiro preparation was studied with prolonged use and the preservation of the therapeutic effect.

Pharmacokinetics:

The pharmacokinetics of reslizumab was studied with the participation of healthy adults (n= 130), adolescents and adults suffering from bronchial asthma (n= 438) and other groups of patients (n= 206). The pharmacokinetic parameters of reslisumab are similar in all groups. Interindividual variability in its use at maximum and medial doses is approximately 20-30%.

The maximum concentration in the blood plasma is usually observed at the end of the infusion. The concentration of reslisumab in the blood plasma as a whole decreases twofold after reaching the maximum. After repeated use of the Sinkeiro preparation, a large concentration of reslisumab accumulates in the blood plasma approximately 1.5-1.9 times. Circulating antibodies to reslisumab do not affect the systemic action of reslizumab.

Distribution

The volume distribution of reslizumab is approximately 5 liters, indicating a minimal distribution in the extravascular tissues.

Metabolism

By analogy with other monoclonal antibodies, it is considered that reslisumab is cleaved by enzymatic proteolysis into small peptides and amino acids. As reslisumab binds to soluble targets, linear non-target clearance is expected.

Excretion

The clearance of reslisumab is approximately 7 ml / hr. The elimination half-life is 24 days.

Indications:

Prevent exacerbations, alleviate symptoms and improve lung function in adult patients with asthma with an increased number of eosinophils in the peripheral blood and lack of adequate control as a result of therapy with inhaled glucocorticosteroids.

Contraindications:

- Hypersensitivity to the active substance or to one of the components of the drug

- Children under 18 years old

- Intolerance to fructose, glucose-galactose malabsorption or sugar-andsomatase insufficiency

- Pregnancy (see the section "Application during pregnancy and during breastfeeding").

Carefully:

Use in patients with high risk of helminthiosis, simultaneous administration of immunosuppressant therapy, vaccination and the use of live / attenuated vaccines, the elderly age is over 75 years.

Pregnancy and lactation:

Data on the use of reslisumab by women in pregnancy are absent or there are a limited number.

Studies in animals do not show an indirect or direct toxic effect on reproductive function. As a precaution, it is recommended not to use Sinkeiro during pregnancy.

There is no information on the withdrawal of reslisumab with breast milk. Pharmacodynamic / toxicological data obtained as a result of animal studies showed the occurrence of reslisumab in the milk of a nursing mouse. During breastfeeding it is necessary to assess the benefit / risk balance for newborns and young children.

Dosing and Administration:

Treatment with Sinkeiro should be carried out under the supervision of medical professionals who have experience in the diagnosis and treatment of uncontrolled bronchial asthma.

It is used at a high relative content of eosinophils in blood plasma, persistent asthmatic symptoms and / or frequent exacerbations of bronchial asthma, despite standard treatment.

The recommended dose is 3 mg / kg.is applied once every four weeks as a supplement to the standard therapy of bronchial asthma, which should include a minimum of an average dose of inhaled glucocorticosteroids (minimum 440 μg of inhalation fluticasone propionate or equivalent daily dose of other inhaled glucocorticosteroids).

The drug Sinkeiro is designed for long-term treatment.

Improvement of lung function and alleviation of symptoms were observed after the expiration of the 4th week and lasted up to 52 weeks. The decision to continue using Sinkeiro should be based on the results of clinical tests and control of bronchial asthma. If the infusion of Sinkeiro was missed on the scheduled day, it should be done in the near future with the same dose and regimen. The introduction of a double dose to fill the missed is unacceptable.

Elderly patients (over 65 years of age)

Data on the use of Sinkeiro in patients older than 65 years are limited. Given the similar effect of reslizumab. observed in patients older than 65 years and patients from 18 to 65 years, dose adjustment is not required.

Renal insufficiency

Patients with mild to moderate renal insufficiency do not need a dose selection. Studies of the effects of Sinkeiro on patients with severe renal insufficiency have not been conducted, there is no recommendation for dose selection.

Liver failure

Studies of the effect of Sinkeiro on patients with hepatic insufficiency have not been conducted, there is no recommendation for dose selection.

Children

The safety and effectiveness of the use of Sinkeiro for use in children from 6 to 18 years is not currently established. Available age data from 12 to 18 years are presented in the section "Special instructions", there are no recommendations for the selection of a dose in this age group of patients.

The drug Sinkeiro is contraindicated in children under 18 years of age.

Mode of application

The drug Sinkeiro is intended only for intravenous administration. The use of subcutaneous, oral and intramuscular methods is unacceptable.

The required volume of Sinkeiro preparation (10 mg / ml) should be placed in an infusion bottle containing 50 ml of 0.9% sodium chloride solution.

The Sinkeiro preparation is dissolved in the form of intravenous infusion infor 20-50 minutes through a sterile, non-pyrogenic, disposable, slightly protein-binding filter (0.2 μm). Do not use Sinkeiro's preparation bolus or undiluted.

Preparation of the infusion day solution:

1. Get the drug Sinkeiro from the refrigerator. Do not shake the bottle.

2. Perform a visual check for mechanical inclusions and discolouration before administration. The Sinkeiro solution should be clear / slightly cloudy, colorless or slightly yellowish / yellow. Since the Sinkeiro preparation is a protein drug, protein particles, which are transparent or white formless inclusions, some of which can be fibrous, may be present in the solution. These signs are not unusual for protein solutions. Do not use the solution when changing the color or when foreign substances are found in it.

3. The required volume (in ml) taken from the vial (s) is calculated as follows: 0.3 x patient's body weight (in kg). For example, a volume of 18 ml (180 mg) is required for a patient weighing 60 kg (0.3 * 60).

4. The drug Sinkeiro contains no preservatives.Unused un-diluted solution remaining in the vial should be disposed of.

5. Slowly insert the contents of the syringe into the infusion bottle with 50 ml of 0.9% sodium chloride solution for infusion. Carefully turn the vial to mix the solution. Do not mix or dissolve with other medications.

6. It is recommended to inject the solution immediately after preparation. If the prepared solution was not used immediately, it should be stored under aseptic conditions at a temperature of 2 to 8 ° C in a dark place for not more than 16 hours.

7. The drug Sinkeiro is compatible with infusion tanks made of polyvinyl chloride or polyolefin.

Instructions for administering the solution:

1. If the drug has been cooled, it is necessary to give the diluted solution time to reach room temperature.

2. A diluted solution of the Sinkeiro preparation should be administered intravenously for 20-50 minutes. The infusion time may vary depending on the total volume calculated on the patient's body weight. It is necessary to use an infusion system with a built-in sterile, pyrogen-free filter with a small protein binding function (cell size is 0.2 μm).

3. The introduction of Sinkeiro should be controlled by a medical professional who has the skills of arresting an anaphylactic reaction. Patients should be instructed to detect symptoms of severe allergic reactions.

4. The drug Sinkeiro should not be administered concomitantly with other medications. Studies of the physical and biochemical compatibility of the Sinkeiro preparation with other drugs have not been conducted with simultaneous administration.

5. It is necessary to observe the patient during and after the infusion.

6. At the end of the infusion, it is necessary to rinse the infusion system with a sterile 0.9% sodium chloride solution to ensure that the entire Sinkeiro preparation has been administered to the patient.

7. The Sinkeiro product is compatible with the built-in insignificantly protein-binding filters from polyethersulfone, polyvinylidene fluoride, nylon, cellulose acetate.

Unused solution and waste must be disposed of in accordance with local regulations.

Side effects:

The following adverse reactions were recorded in placebo-controlled trials at a dose of 3 mg / kg.

Undesirable effects are classified according to the frequency of their development: very often (≥ 1/10), often (≥ 1/100. <1/10), infrequently (≥ 1/1000. <1/100), rarely (≥ 1 / 10000. <1/1000), very rarely (<1/10000), unknown frequency - the available data are insufficient to estimate the frequency of the side effect.

Immune system disorders: infrequently anaphylactic reaction.

Disturbances from the musculoskeletal and connective tissue: infrequently - myalgia.

Anaphylactic reaction

In less than 1% (infrequently, 3/1611) of patients, a serious undesirable phenomenon was noted in the form of an anaphylactic reaction, which was considered to be associated with reception of reslisumab. This undesirable phenomenon was observed during or immediately after the completion of the second and eleventh infusions of reslizumab and was completely eliminated without consequences. There was a lesion of the skin and mucous membranes, dyspnoea, wheezing, symptoms from the gastrointestinal tract and chills. These cases led to the cancellation of treatment in less than 1% (infrequently, 3/1028). None of the patients had an immune response in the form of antibody formation on reslisumab. Patients should be monitored during the infusion of the drug Sinkeiro and after its completion.In the event of an anaphylactic reaction, the administration of Sinkeiro should be immediately discontinued, and appropriate medical attention should be provided. In such cases, treatment with Sinkeiro should be reversed.

Myalgia

Myalgia was noted in less than 1% (infrequently, 10/1028) of patients in the group who received reslisumab in a dose of 3 mg / kg, compared with less than 1% (infrequently, 4/730) of patients in the placebo group.

The following are other adverse events, regardless of the frequency of development in patients who received reslisumab at a dose of 3 mg / kg every 4 weeks during controlled and open safety studies.

Malignant formations

In placebo-controlled trials, less than 1% (infrequently, 6/1028) of patients receiving reslisumab in a dose of 3 mg / kg, a case of malignancy was registered and less than 1% (infrequently, 2/730) of patients in the placebo group. In a long-term open clinical trial, less than 1% (infrequently, 15/1051) patients who received reslisumab in a dose of 3 mg / kg. a case of malignant formation was registered.In general, the data do not indicate a relationship between the use of reslisumab and the risk of malignant tumors.

Immunogenicity

During the phase III placebo-controlled trials, lasting from 16 to 52 weeks, more than 5% (often, 53/983) of patients with bronchial asthma who received reslisumab in a dose of 3 mg / kg, there was a small amount of transient antibodies to reslisumab in the blood plasma. During the 111th phase of an open, prolonged study, the presence of a small number of transient antibodies to reslisumab in plasma was noted in more than 5% (often 49/1014) of patients with bronchial asthma who received reslisumab in a dose of 3 mg / kg not more than 36 months. Antibodies to reslisumab do not affect the systemic action of reslizumab. Effects of antibodies on pharmacodynamics, efficacy and safety of the use of reslisumab were not noted.

Data from specific analyzes reflect the percentage of patients with positive test results for antibodies to reslisumab. The observed frequency of positive results in the analysis depends on several factors, including the sensitivity of the analysis and the specificity of the method,methods of selection and treatment of samples, concomitant treatment and disease of patients, and therefore comparison of the incidence of antibodies to remesumab with the frequency of antibodies to other drugs may not be significant and may be erroneous.

Overdose:

The maximum dose of Sinkeiro in clinical trials was 3 mg / kg. The maximum tolerated dose of Sinkeiro was not determined. The maximum reported single dose administered intravenously was 12.1 mg / kg, no adverse events were observed. In case of an overdose, it is recommended that the patient be under the supervision of a physician in order to detect possible adverse events.

Treatment is symptomatic.

Interaction:

Given the pharmacological properties of remesumab, interaction with other drugs is unlikely. Data in vitro show that the effect of IL-5 and reslisumab on activity CYP1A2, 2B6 or 3A4 is unlikely. Clinical studies of the interaction of remesumab with other drugs have not been conducted. Pharmacokinetic analysis of groups of patients shows that simultaneous use of leukotriene antagonists or GCS does not affect the pharmacokinetics of remesumab.

In clinical trials involving patients with bronchial asthma with eosinophilia, the simultaneous use of reslizumab with other drugs, such as oral GCS, long-acting beta-agonists and leukotriene inhibitors. does not lead to an increase in the incidence of adverse events.

Studies with the simultaneous use of reslizumab in patients receiving immunosuppressant therapy in parallel have not been conducted, therefore, the safety and effectiveness profiles of reslisumab in this category of patients are unknown. Studies of the use of reslizumab by patients receiving live vaccines have not been conducted. Data on secondary transmission of infection from people receiving live vaccines to patients receiving reslisumab. or there is no response to new immunizations.

Special instructions:

Age

The age range of differences in the pharmacokinetics of reslisumab was not observed. The pharmacokinetics of reslisumab was similar in adults (18-65 years; n= 759) and elderly patients (over 65 years; n= 30).The range of systemic exposure in patients aged 12 to 18 years (n= 15) partially coincided with other groups, but the median value was slightly lower than in adults and elderly patients.

Liver failure

Studies of Sinkeiro in patients with hepatic insufficiency have not been performed. When carrying out pharmacokinetic analysis in most patients, the results of functional liver tests were normal (n= 766, approximately 95%) or slightly above the norm (total bilirubin above the upper limit of the norm is not more than 1.5 times, or aspartate aminotransferase (ACT) above the upper limit of the norm, and bilirubin is less than or equal to the upper limit of the norm; n= 35, about 4%). There were no significant differences in the pharmacokinetics of reslisumab between these groups.

Renal insufficiency

In most patients who participated in the pharmacokinetic analysis, renal function was normal (glomerular filtration rate (GFR) was greater than or equal to 90 ml / min / 1.73 m²; n= 294, approximately 37%), or there was a slight renal Insufficiency (GFR was 60-89 ml / min / 1.73 m²; n= 446.approximately 56%), or moderate renal failure (GFR was 30-59 ml / min / 1.73 m²; n= 63, about 8%). There were no significant differences in the pharmacokinetics of reslisumab between groups with different renal function.

Anaphylactic reaction

Anaphylactic reaction associated with the use of Sinkeiro. was observed in less than 1% of patients with bronchial asthma, during or immediately after infusion. In all cases, the anaphylactic reaction was stopped without consequences, treatment with Sinkeiro was canceled. Patients should be monitored during the infusion of the drug Sinkeiro and after its completion. In case of an anaphylactic reaction, the administration of Sinkeiro should be stopped immediately, after which appropriate medical attention should be given: the treatment with Sinkeiro should be reversed.

Infectious and parasitic diseases

Some helminthic infections may be accompanied by the involvement of eosinophils in the immune response. In clinical studies of the Sinkeiro drug, no cases of helminthic infection were reported.Sinkeiro should be used with caution in patients with a high risk of helminthiasis, particularly when traveling to places where helminth infections are widespread. In the event of a decrease in the effectiveness of anthelmintic treatment, consideration should be given to discontinuing the use of Sinkeiro.

Sodium

The preparation of Sinkeiro contains 0.20 mmol or 4.6 mg of sodium per 1 vial. This fact should be taken into account in the treatment of patients with a controlled sodium diet.

Sucrose

The drug Sinkeiro contains 2 bottles of 2.05 mmol or 700 mg of sucrose. Use in patients with rare hereditary diseases associated with intolerance to fructose, glucose-galactose malabsorption or sugar-isomaltase deficiency is not shown.

Data from clinical studies in healthy patients showed that reslisumab in a dose of 3 mg / kg does not affect the lengthening of the interval QT, the relationship between the concentration of reslisumab and the intervals QT absent.

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

The drug Sinkeiro does not affect the ability to drive vehicles and work with mechanisms. Care should be taken in case of side effects.

Form release / dosage:

Concentrate for solution for infusion, 10 mg / ml.

Packaging:

For 10 ml of the drug in a bottle of transparent colorless glass type I, sealed with a plug of butyl rubber and an aluminum cap, equipped with a protective cap made of colored polypropylene plastic. 1 bottle with instructions for use in a cardboard box.

Storage conditions:

Store at a temperature of 2 to 8 ° C in a dark place.

Do not freeze.

Shelf life:

3 years. Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004265

Date of registration:28.04.2017

Expiration Date:28.04.2022

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

BAXTER PHARMACEUTICAL SOLUTIONS, LLC USA

SICOR BIOTECH, UAB Republic of Lithuania

Representation: & nbspTeva Teva Israel

Information update date: & nbsp23.05.2017

Illustrated instructions

Instructions

Sinqueiro (Sinceiro)