Complareit^® (Concentrate) Instructions for Use

Marketing Authorization Holder

Generium, JSC (Russia)

ATC Code

L04AC07 (Tocilizumab)

Active Substance

Tocilizumab (Rec.INN registered by WHO)

Dosage Form

Complareit®

Concentrate for solution for infusion 20 mg/ml

Dosage Form, Packaging, and Composition

Concentrate for solution for infusion

10 ml – vials – cassettes – In-Bulk
10 ml – vials – cartons – In-Bulk
10 ml – vials – cardboard packs – Prescription only
4 ml – vials – cassettes – In-Bulk
4 ml – vials – cartons – In-Bulk
4 ml – vials – cardboard packs – Prescription only

Clinical-Pharmacological Group

Specific immunosuppressive drug. Interleukin-6 receptor antagonist

Pharmacotherapeutic Group

Immunosuppressants, interleukin inhibitors

Pharmacological Action

Immunosuppressant. Tocilizumab is a recombinant humanized monoclonal antibody to the human interleukin-6 (IL-6) receptor of the immunoglobulin IgG₁ subclass. It selectively binds to and inhibits both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). IL-6 is a multifunctional cytokine produced by various cell types and is involved in paracrine regulation, systemic physiological and pathological processes, such as stimulation of Ig secretion, T-cell activation, stimulation of acute-phase protein production in the liver, and stimulation of hematopoiesis. IL-6 is involved in the pathogenesis of various diseases, including inflammatory diseases, osteoporosis, and neoplasms.

The possibility of a negative impact of tocilizumab on the body’s antitumor and anti-infective defenses cannot be excluded. The role of IL-6 receptor inhibition in tumor development is not known.

In patients with COVID-19, after a single intravenous dose of tocilizumab 8 mg/kg, a decrease in C-reactive protein levels to normal values was observed as early as day 7.

Pharmacokinetics

In patients with rheumatoid arthritis receiving tocilizumab infusion every 4 weeks at a dose of 8 mg/kg, the following parameters are characteristic: steady-state AUC – 35,000±15,500 µg×h/ml, C_min and C_max – 9.74±10.5 µg/ml and 183±85.6 µg/ml, respectively. The accumulation coefficients for AUC and C_max are low – 1.22 and 1.06, respectively. AUC, C_min, and C_max values increase with increasing body weight.

In patients with systemic juvenile idiopathic arthritis (sJIA) receiving tocilizumab infusion every 2 weeks at a dose of 8 mg/kg for body weight ≥30 kg or 12 mg/kg for body weight <30 kg, the following parameters are characteristic: AUC_{2 wk}– 32,200±9960 µg×h/ml, C_max and C_min – 245±57.2 µg/ml and 57.2±23.3 µg/ml, respectively. The accumulation coefficient for C_min (12 wk/2 wk) – 3.2±1.3. Tocilizumab C_min stabilized after 12 weeks. The estimated mean tocilizumab exposure parameters did not differ between the patient group with body weight ≥30 kg and the patient group with body weight <30 kg.

In patients with rheumatoid arthritis, V_d in the central compartment is 3.5 L, in the peripheral compartment – 2.9 L, and V_d at steady state is 6.4 L.

In children with sJIA, V_d in the central compartment is 0.94 L, in the peripheral compartment – 1.6 L, and V_d at steady state is 2.54 L.

After IV infusion of tocilizumab, elimination from the systemic circulation is biphasic.

The total clearance of tocilizumab is concentration-dependent and represents the sum of linear and nonlinear clearance. Linear clearance is 12.5 ml/h in patients with rheumatoid arthritis and 7.1 ml/h in children with sJIA.

In rheumatoid arthritis at a dose of 8 mg/kg once every 4 weeks, T_1/2 is up to 13 days.

In sJIA at a tocilizumab dose of 8 mg/kg for children with body weight ≥30 kg and 12 mg/kg for children with body weight <30 kg, T_1/2 at week 12 is up to 23 days.

Indications

Rheumatoid arthritis with moderate or high activity in adults, both as monotherapy and in combination with methotrexate and/or other basic anti-inflammatory drugs, including to inhibit radiographically proven joint destruction.

Active polyarticular juvenile idiopathic arthritis and active systemic juvenile idiopathic arthritis in patients aged 2 years and older, both as monotherapy and in combination with methotrexate.

Active systemic juvenile idiopathic arthritis in patients aged 2 years and older, both as monotherapy and in combination with methotrexate.

Treatment of novel coronavirus infection (COVID-19) in hospitalized adult patients receiving systemic corticosteroids, requiring supplemental oxygen or mechanical ventilation.

Severe or life-threatening cytokine release syndrome induced by T-cell engaging therapies with chimeric antigen receptors in adult patients.

ICD codes

Dosage Regimen

Administered by intravenous drip infusion.

Adults – 8 mg/kg over at least 1 hour, once every 4 weeks. A dose increase of more than 800 mg per infusion is not recommended for patients weighing more than 100 kg.

Children over 2 years old – 8 mg/kg and, depending on the indication, administered once every 2-4 weeks in patients with body weight ≥ 30 kg or 10-12 mg/kg once every 2-4 weeks in patients with body weight < 30 kg.

The dose should be calculated based on the patient’s body weight at each administration. Dose adjustment should be based solely on an appropriate change in the patient’s body weight over time.

Adverse Reactions

Infections: very common – upper respiratory tract infections; common – cellulitis, infections caused by Herpes simplex type 1 and Herpes zoster; uncommon – diverticulitis.

Gastrointestinal system: common – abdominal pain, mouth ulcers, increased liver transaminase activity, gastritis; uncommon – stomatitis, gastric ulcer, increased total bilirubin.

Skin and subcutaneous tissue: common – rash, pruritus, urticaria.

Nervous system : common – headache, dizziness.

Cardiovascular system: common – increased blood pressure.

Hematopoietic system: common – leukopenia, neutropenia.

Metabolism : common – hypercholesterolemia, weight gain; uncommon – hypertriglyceridemia.

Respiratory system: common – cough, dyspnea.

Organ of vision: common – conjunctivitis.

Urinary system: uncommon – nephrolithiasis.

Endocrine system: uncommon – hypothyroidism.

General disorders: common – peripheral edema, hypersensitivity reactions.

Contraindications

Hypersensitivity to tocilizumab; active infectious diseases (including tuberculosis); combination with TNF-alpha inhibitors or use within 1 month after treatment with anti-TNF antibodies; increase in liver enzyme activity ≥10 times the upper limit of normal (ULN); absolute neutrophil count (ANC) < 1×10⁹/L; platelet count <50×10³ /µL (COVID-19); age under 18 years for patients with rheumatoid arthritis; children under 2 years of age for patients with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis; age under 18 years for patients with COVID-19; children under 18 years of age for patients with cytokine release syndrome.

With caution

History of recurrent or chronic infections, as well as concomitant diseases (e.g., diverticulitis, diabetes mellitus, and interstitial lung disease) that predispose to the development of infections. History of ulcerative gastrointestinal lesions or diverticulitis. Active liver disease or hepatic insufficiency. ALT or AST levels exceeding ULN by more than 1.5 times. Platelet count below 100×10³ /µL.

Use in Pregnancy and Lactation

Tocilizumab should not be used during pregnancy, except in cases of proven clinical necessity.

It is not known whether Tocilizumab is excreted in human breast milk. Although endogenous IgG is excreted in breast milk, systemic absorption of tocilizumab during breastfeeding is unlikely due to rapid proteolytic degradation of such proteins in the digestive system. When deciding to continue/discontinue breastfeeding or to continue/discontinue tocilizumab therapy, the benefit of breastfeeding for the child and the benefit of continued therapy for the mother should be taken into account.

Use in Hepatic Impairment

The safety and efficacy of tocilizumab in patients with hepatic impairment have not been studied.

Use in Renal Impairment

No dose adjustment is required in patients with mild renal impairment. The use of tocilizumab in patients with moderate and severe renal impairment has not been studied.

Pediatric Use

Contraindicated in children and adolescents under 18 years of age, except for patients aged 2 years and older with polyarticular juvenile idiopathic arthritis and systemic juvenile idiopathic arthritis.

Geriatric Use

No dose adjustment is required in elderly patients (≥ 65 years).

Special Precautions

Treatment with tocilizumab should not be initiated in patients with active infectious diseases. If a serious infection develops, tocilizumab therapy should be interrupted until the infection is resolved. Use with caution in patients with a history of recurrent infectious diseases, as well as in the presence of concomitant conditions that predispose to the development of infections (e.g., diverticulitis, diabetes mellitus).

Particular caution should be exercised for the early detection of serious infectious diseases in patients with moderate to high activity rheumatoid arthritis or in patients with sJIA receiving biological drugs, since signs or symptoms of acute inflammation may be masked due to suppression of the acute phase response.

Use with caution in patients with a history of ulcerative lesions of the gastrointestinal tract or diverticulitis. Patients with signs possibly indicating complicated diverticulitis (abdominal pain) should be examined immediately for early detection of gastrointestinal perforation.

Before starting treatment with tocilizumab, as with the prescription of other biological drugs for the treatment of rheumatoid arthritis or sJIA, patients should be screened for latent tuberculosis. If latent tuberculosis is detected, a standard course of antimycobacterial therapy should be administered before starting treatment with tocilizumab.

Immunization with live and live attenuated vaccines should not be carried out simultaneously with tocilizumab therapy, as the safety of such a combination has not been established. There are no data on the secondary transmission of infection from patients receiving live vaccines to patients receiving Tocilizumab.

During treatment, the number of neutrophils, platelets in peripheral blood, and liver transaminase activity should be regularly monitored and the dosage regimen should be adjusted accordingly.

Tocilizumab therapy is not recommended when ALT or AST values are 5 times above the ULN.

If lipid metabolism parameters (total cholesterol, LDL, triglycerides) increase, patient management should be guided by national recommendations for the treatment of hyperlipidemia.

Effect on ability to drive vehicles and operate machinery

Given the fact that dizziness has been frequently observed during tocilizumab therapy, patients experiencing this adverse reaction should be advised not to drive vehicles or operate machinery until the dizziness subsides.

Drug Interactions

Since the expression of hepatic CYP450 isoenzymes is suppressed under the influence of cytokines (e.g., IL-6, which stimulates chronic inflammation), during therapy with agents that inhibit the action of cytokines (e.g., Tocilizumab), the expression of CYP450 isoenzymes may be impaired.

In in vitro studies conducted on human hepatocyte culture, it was shown that IL-6 causes a decrease in the expression of CYP1A2, CYP2C9, CYP2C19, and CYP3A4 isoenzymes. The use of tocilizumab normalizes the expression of these isoenzymes.

The effect of tocilizumab on CYP isoenzymes (except CYP2C19 and CYP2D6) is clinically significant for drugs that are CYP450 substrates, have a narrow therapeutic index, and for which doses are individually selected.

In patients with rheumatoid arthritis, the concentration of simvastatin (a CYP3A4 substrate) decreased by 57% one week after a single administration of tocilizumab, i.e., it was slightly elevated or similar to that in healthy volunteers.

At the beginning or upon completion of a course of tocilizumab therapy, patients receiving drugs in individually selected doses that are metabolized via CYP450 3A4, 1A2, or 2C9 isoenzymes (e.g., atorvastatin, slow calcium channel blockers, theophylline, warfarin, phenytoin, cyclosporine, or benzodiazepines) should be closely monitored. To ensure the therapeutic effect of these drugs, it may be necessary to increase their dose. Given the long T_1/2 of tocilizumab, its effect on CYP450 isoenzyme activity may persist for several weeks after discontinuation of therapy.

Storage Conditions

Store at 2°C (36°F) to 8°C (46°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.