Cinqaero (Concentrate) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

Manufactured By

Baxter Pharmaceutical Solutions, LLC (USA)

Contact Information

TEVA (Israel)

ATC Code

R03DX08 (Reslizumab)

Active Substance

Reslizumab (Rec.INN registered by WHO)

Dosage Form

Cinqaero

Concentrate for solution for infusion 10 mg/1 ml: 10 ml vial 1 pc.

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion in the form of a clear or slightly opalescent solution from colorless to light yellow or yellow (the solution may contain protein particles, which are clear or white amorphous inclusions, some of which may be fibrous).

Excipients: sucrose – 70 mg, sodium acetate trihydrate – 2.45 mg, glacial acetic acid – 0.12 mg, water for injection – up to 1 ml.

10 ml – vials of colorless glass (1) – cardboard packs.

Clinical-Pharmacological Group

Interleukin inhibitor. Drug for the treatment of bronchial asthma

Pharmacotherapeutic Group

Interleukin inhibitor

Pharmacological Action

Reslizumab specifically binds to interleukin-5 (IL-5) and prevents IL-5 from binding to its receptor on the surface of cells. IL-5 is a key cytokine 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 of patients with bronchial asthma. Persistent eosinophilic inflammation, despite treatment with inhaled corticosteroids, defines the phenotype of resistant eosinophilic asthma.

In vitro studies of reslizumab showed its affinity binding capacity (K_d) to human IL-5 equal to 81 pM, measured using the BIAcore system, the ability to inhibit IL-5 binding to its cognate receptor with an IC₅₀ of 0.5 nM, and to block the proliferation of IL-5-sensitive cell lines with an IC₅₀ of 45 nM.

The safety and efficacy of Cinqaero were evaluated in four randomized, double-blind, placebo-controlled studies (Studies I-IV), lasting from 16 to 52 weeks, involving 978 patients aged 12 years and older with moderate to severe asthma that was not adequately controlled with medium and high doses of inhaled corticosteroids (at least 440 mcg of fluticasone propionate once daily or equivalent doses of other inhaled corticosteroids) with/without the use of other controller medications. Prior stable allergen-specific immunotherapy was allowed. The use of Cinqaero reduced the frequency of asthma exacerbations, reduced symptom severity, and improved lung function in patients with asthma and elevated peripheral blood eosinophil counts. Furthermore, an open-label extension study (Study V) investigated the safety of Cinqaero with long-term use and the maintenance of therapeutic effect.

Pharmacokinetics

The pharmacokinetics of reslizumab were studied in healthy adults (n=130), adolescents and adults with asthma (n=438), and other patient groups (n=206). The pharmacokinetic parameters of reslizumab are similar across all groups. Interindividual variability at maximum and medium therapeutic doses is approximately 20-30%.

Distribution

C_max in plasma is typically observed at the end of the infusion. The plasma concentration of reslizumab generally decreases biphasically after reaching the peak. After multiple administrations of Cinqaero, the plasma concentration of reslizumab accumulates approximately 1.5-1.9 times greater. Circulating antibodies to reslizumab do not affect the systemic action of reslizumab.

The V_d of reslizumab is approximately 5 L, indicating minimal distribution to extravascular tissues.

Metabolism

By analogy with other monoclonal antibodies, Reslizumab is considered to be broken down by enzymatic proteolysis into small peptides and amino acids. Since Reslizumab binds to soluble targets, linear non-target clearance is expected.

Elimination

The clearance of reslizumab is approximately 7 ml/h. The T_1/2 is 24 days.

Indications

• Prevention of exacerbations, relief of symptoms, and improvement of lung function in adult patients with bronchial asthma with elevated peripheral blood eosinophil counts and inadequate control resulting from therapy with inhaled corticosteroids.

ICD codes

Dosage Regimen

Treatment with Cinqaero should be carried out under the supervision of healthcare professionals experienced in the diagnosis and treatment of uncontrolled bronchial asthma.

The drug is used in cases of high relative eosinophil count in peripheral blood, persistent asthmatic symptoms, and/or frequent asthma exacerbations despite standard treatment.

The recommended dose is 3 mg/kg administered once every 4 weeks as an add-on to standard asthma therapy, which must include at least a medium dose of inhaled corticosteroid (at least 440 mcg of inhaled fluticasone propionate or an equivalent daily dose of other inhaled corticosteroids).

Cinqaero is intended for long-term treatment.

Improvement in lung function and symptom relief were observed by the 4th week and persisted for up to 52 weeks. The decision to continue Cinqaero should be based on clinical test results and asthma control. If an infusion of Cinqaero is missed on the scheduled day, it should be administered as soon as possible at the same dose and regimen. Administering a double dose to make up for a missed dose is not permissible.

Data on the use of Cinqaero in elderly patients over 65 years of age are limited. Given the similar effect of reslizumab observed in patients over 65 years and patients from 18 to 65 years, dose adjustment is not required.

Patients with mild to moderate renal impairment do not require dose adjustment. Studies on the effect of Cinqaero on patients with severe renal impairment have not been conducted; no dosage recommendations are available.

Studies on the effect of Cinqaero on patients with hepatic impairment have not been conducted; no dosage recommendations are available.

The safety and efficacy of Cinqaero for use in children aged 6 to 18 years have not been established at this time. Available data for ages 12 to 18 are presented in the “Special Precautions” section; there are no dosage recommendations for this age group of patients. Cinqaero is contraindicated for use in children under 18 years of age.

Method of Administration

Cinqaero is for intravenous administration only. Subcutaneous, oral, and intramuscular administration are not permissible.

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

Cinqaero in dissolved form is administered by intravenous infusion over 20-50 minutes through a sterile, apyrogenic, single-use, low protein-binding filter (0.2 µm).

Do not administer Cinqaero as a bolus or undiluted.

Preparation of the Infusion Solution

1. Remove Cinqaero from the refrigerator. Do not shake the vial.
2. Before administration, visually inspect for particulate matter and discoloration. The Cinqaero solution should be clear/slightly opalescent, colorless or slightly yellowish/yellow. Since Cinqaero is a protein drug, the solution may contain protein particles, which are clear or white amorphous inclusions, some of which may be fibrous. These signs are not unusual for protein solutions. Do not use the solution if discolored or if foreign particles are found in it.
3. The required volume (in ml) to be withdrawn from the vial(s) is calculated as follows: 0.3 × patient’s body weight (in kg). For example, a volume of 18 ml (180 mg) would be required for a patient weighing 60 kg (0.3×60).
4. Cinqaero does not contain preservatives. Any unused, undiluted solution remaining in the vial must be discarded.
5. Slowly inject the contents of the syringe into the infusion bottle with 50 ml of 0.9% sodium chloride solution for infusion. Gently invert the bottle to mix the solution. Do not mix or dissolve with other drugs.
6. It is recommended to administer the solution immediately after preparation. If the prepared solution is not used immediately, it should be stored under aseptic conditions at a temperature of 2°C (35.6°F) to 8°C (46.4°F) protected from light for no more than 16 hours.
7. Cinqaero is compatible with polyvinyl chloride or polyolefin infusion containers.

Instructions for Solution Administration

1. If the drug has been refrigerated, allow the diluted solution to reach room temperature.
2. The diluted Cinqaero solution should be administered intravenously over 20-50 minutes. The infusion time may vary depending on the total volume calculated based on the patient’s body weight. An infusion set with an integrated sterile, apyrogenic, low protein-binding filter (pore size 0.2 µm) must be used.
3. Administration of Cinqaero should be supervised by a healthcare professional skilled in managing anaphylactic reactions. Patients should be instructed to recognize symptoms of severe allergic reactions.
4. Cinqaero should not be administered simultaneously with other drugs. Studies on the physical and biochemical compatibility of Cinqaero with other drugs during simultaneous administration have not been conducted.
5. The patient should be monitored during the infusion and after its completion.
6. At the end of the infusion, the infusion set should be flushed with sterile 0.9% sodium chloride solution to ensure that all of the Cinqaero has been administered to the patient.
7. Cinqaero is compatible with integrated low protein-binding filters made of polyethersulfone, polyvinylidene fluoride, nylon, and cellulose acetate.

Unused solution and waste should be disposed of in accordance with local requirements.

Adverse Reactions

Adverse reactions reported in placebo-controlled studies of Cinqaero at a dose of 3 mg/kg

Definition of frequency categories of adverse reactions: very common (≥1/10), common (≥1/100, < 1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), frequency not known (insufficient data to estimate the frequency of the side effect).

Immune system disorders: uncommon – anaphylactic reaction.

Musculoskeletal and connective tissue disorders: uncommon – myalgia.

Anaphylactic reaction

In less than 1% (uncommon, 3/1611) of patients, a serious adverse event of anaphylactic reaction was recorded, considered related to reslizumab administration. Anaphylactic reaction was observed during or immediately after the second and eleventh infusions of reslizumab and was completely resolved without consequences. Involvement of skin and mucous membranes, dyspnea, wheezing, gastrointestinal symptoms, and chills were observed. These cases led to treatment discontinuation in less than 1% (uncommon, 3/1028). None of the patients had an immune response in the form of antibody formation to Reslizumab. Patients should be monitored during the infusion of Cinqaero and after its completion. In case of an anaphylactic reaction, the administration of Cinqaero must be stopped immediately, and appropriate medical treatment should be provided thereafter; in such cases, treatment with Cinqaero should be permanently discontinued.

Myalgia

Myalgia was reported in less than 1% (uncommon, 10/1028) of patients in the group receiving Reslizumab 3 mg/kg, compared with less than 1% (uncommon, 4/730) of patients in the placebo group.

The following are other adverse events regardless of frequency in patients receiving Reslizumab 3 mg/kg every 4 weeks during controlled and open-label safety studies.

Malignancies

In placebo-controlled studies, less than 1% (uncommon, 6/1028) of patients receiving Reslizumab 3 mg/kg had a case of malignancy and less than 1% (uncommon, 2/730) of patients in the placebo group. In the long-term open-label clinical study, less than 1% (uncommon, 15/1051) of patients receiving Reslizumab 3 mg/kg had a case of malignancy. Overall, these data do not indicate a relationship between the use of reslizumab and the risk of malignancies.

Immunogenicity

In Phase III placebo-controlled studies, lasting from 16 to 52 weeks, more than 5% (common, 53/983) of asthma patients receiving Reslizumab 3 mg/kg had a low level of transient antibodies to reslizumab in plasma. In the Phase III open-label extension study, the presence of low levels of transient antibodies to reslizumab in plasma was noted in more than 5% (common, 49/1014) of asthma patients receiving Reslizumab 3 mg/kg for up to 36 months. Antibodies to reslizumab did not affect the systemic action of reslizumab. No effect of antibodies on the pharmacodynamics, efficacy, or safety of reslizumab was observed.

Data from specific assays reflect the percentage of patients with positive test results for antibodies to reslizumab. The observed incidence of positive results in an assay depends on several factors, including the sensitivity and specificity of the assay, sample selection and handling methods, concomitant medications and patient diseases, so comparing the incidence of antibodies to reslizumab with the incidence of antibodies to other drugs may not be meaningful and could be misleading.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients;
• Fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase deficiency;
• Pregnancy;
• Children under 18 years of age.

Use with caution in patients at high risk of helminth infections; when prescribing concomitant immunosuppressant therapy, vaccination and the use of live/attenuated vaccines; in elderly patients over 75 years of age.

Use in Pregnancy and Lactation

Data on the use of reslizumab in pregnant women are absent or limited.

Animal studies do not show indirect or direct toxic effects on reproductive function.

As a precaution, it is recommended not to use Cinqaero during pregnancy.

There are no data on the excretion of reslizumab in breast milk. Pharmacodynamic/toxicological data from animal studies showed penetration of reslizumab into the milk of lactating mice. During breastfeeding, the benefit-risk ratio for neonates and young children should be assessed.

Use in Renal Impairment

Patients with mild to moderate renal impairment do not require dose adjustment. Studies on the effect of Cinqaero on patients with severe renal impairment have not been conducted; no dosage recommendations are available.

Special Precautions

Age

No differences in the pharmacokinetics of reslizumab were observed across age ranges. The pharmacokinetics of reslizumab were 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 overlapped with other groups, but the median value was slightly lower than in adult and elderly patients.

Hepatic impairment

Studies of Cinqaero in patients with hepatic impairment have not been conducted. In a pharmacokinetic analysis, the majority of patients had normal liver function test results (n=766, approximately 95%) or slightly above normal (total bilirubin above ULN no more than 1.5 times: or AST above ULN, and bilirubin less than or equal to ULN (n=35, approximately 4%). No significant differences in the pharmacokinetics of reslizumab were observed between these groups.

Renal impairment

In the majority of patients included in the pharmacokinetic analysis, renal function was normal (GFR was greater than or equal to 90 ml/min/1.73 m²; n=294, approximately 37%), or had mild renal impairment (GFR was 60-89 ml/min/1.73 m²; n=446, approximately 56%), or moderate renal impairment (GFR was 30-59 ml/min/1.73 m²; n=63, approximately 8%). No significant differences in the pharmacokinetics of reslizumab were observed between groups with different renal function.

Anaphylactic reaction

An anaphylactic reaction associated with the use of Cinqaero was observed in less than 1% of asthma patients during or immediately after the infusion. In all cases, the anaphylactic reaction was managed without consequences, and treatment with Cinqaero was discontinued. Patients require monitoring during the infusion of Cinqaero and after its completion. In case of an anaphylactic reaction, the administration of Cinqaero should be stopped immediately, and appropriate medical assistance should be provided thereafter; treatment with Cinqaero should be permanently discontinued.

Infectious and parasitic diseases

Some helminthic infections may be accompanied by the involvement of eosinophils in the immune response. No cases of helminthic infection were reported in the clinical studies of Cinqaero. Cinqaero should be used with caution in patients at high risk of helminthiasis, in particular, when traveling to areas where helminthic infections are widespread. If the effectiveness of antihelminthic treatment decreases, discontinuation of Cinqaero should be considered.

Sodium

Cinqaero contains 0.20 mmol or 4.6 mg of sodium per vial. This should be taken into account when treating patients on a controlled sodium diet.

Sucrose

Cinqaero contains 2.05 mmol or 700 mg of sucrose per vial. Its use in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency is not recommended.

Data from clinical studies in healthy patients showed that Reslizumab at a dose of 3 mg/kg does not affect QT interval prolongation, and there is no relationship between reslizumab concentration and QT interval.

Effect on the ability to drive vehicles and machinery

Cinqaero does not affect the ability to drive vehicles and operate machinery. In case of adverse reactions, caution should be exercised.

Overdose

The maximum dose of Cinqaero in clinical studies was 3 mg/kg. The maximum tolerated dose of Cinqaero has not been determined. The maximum recorded single intravenous dose was 12.1 mg/kg, with no adverse events observed.

Treatment symptomatic therapy. In case of overdose, the patient requires medical supervision to identify possible adverse events.

Drug Interactions

Given the pharmacological properties of reslizumab, interaction with other drugs is unlikely. In vitro data indicate that the effect of IL-5 and reslizumab on CYP1A2, 2B6, or 3A4 activity is unlikely. Clinical studies of the interaction of reslizumab with other drugs have not been conducted. Pharmacokinetic analysis of patient groups shows that concomitant use of leukotriene antagonists or corticosteroids does not affect the pharmacokinetics of reslizumab.

In clinical studies involving patients with eosinophilic asthma, concomitant use of reslizumab with other drugs, such as oral corticosteroids, long-acting beta-adrenergic agonists and leukotriene inhibitors, did not lead to an increase in the frequency of adverse events.

Studies with concomitant use of reslizumab in patients receiving immunosuppressive therapy have not been conducted; therefore, the safety and efficacy profiles of reslizumab in this category of patients are unknown.

Studies on the use of reslizumab in patients receiving live vaccines have not been conducted. There are no data on the secondary transmission of infection from people receiving live vaccines to patients taking Reslizumab, or on the response to new immunization.

Storage Conditions

The drug should be stored in the original packaging at a temperature between 2°C (35.6°F) and 8°C (46.4°F). Do not freeze.

Shelf Life

Shelf life is 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.