Limiris^® (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Generium, JSC (Russia)

ATC Code

L04AC08 (Canakinumab)

Active Substance

Canakinumab (Rec.INN registered by WHO)

Dosage Form

Limiris®

Lyophilisate for the preparation of a solution for subcutaneous administration 150 mg

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of a solution for subcutaneous administration

150 mg – vials – cardboard packs – By prescription

Pharmacotherapeutic Group

Immunosuppressants, interleukin inhibitors

Pharmacological Action

Immunosuppressant, monoclonal antibodies to interleukin-1β.

Canakinumab is a fully human monoclonal antibody of the IgG1/kappa isotype directed against interleukin-1β (IL-1β). Canakinumab binds with high affinity to human IL-1β, thereby preventing the interaction of IL-1β with its receptors, IL-1β-induced gene activation, and the production of inflammatory mediators such as IL-6 and COX-2.

In patients with gouty arthritis and various phenotypes of cryopyrin-associated periodic syndrome (CAPS), including Familial Cold Autoinflammatory Syndrome/Familial Cold Urticaria (FCAS/FCU), Muckle-Wells Syndrome (MWS), and Neonatal onset multisystemic inflammatory disease/Chronic infantile neurological cutaneous and articular syndrome (NOMID/CINCA), Canakinumab reduces the severity of local and systemic inflammatory reactions caused by excessive production of IL-1β. When used in patients with an acute attack of gouty arthritis, it reduces the concentration of laboratory markers of inflammation (C-reactive protein (CRP), serum amyloid A (SAA)), and signs of inflammation in the affected joint (pain, swelling, redness) resolve within a short time.

When canakinumab is used in patients with various CAPS phenotypes, a reduction in the following disease manifestations is observed as early as the first day: fever, increased fatigue, skin rash, arthralgia, myalgia, headache/migraine, conjunctivitis, weakness, as well as a reduction (within several days) in the production of inflammatory markers, including CRP and SAA, and leads to normalization of leukocyte and platelet counts (if they were elevated).

Pharmacokinetics

In adult patients with various CAPS phenotypes after a single s.c. administration of canakinumab at a dose of 150 mg, the T_max of canakinumab is about 7 days. With s.c. administration of canakinumab, the absolute bioavailability is 63% (population pharmacokinetic analysis).

C_max in plasma and AUC increase proportionally to the dose in the dose range from 0.30 to 10.0 mg/kg for intravenous infusion or from 150 mg to 300 mg for subcutaneous administration.

No significant difference in the pharmacokinetic properties of canakinumab was found in patients with gouty arthritis and various CAPS phenotypes.

The V_ss of canakinumab varies depending on body weight. For typical patients suffering from gouty arthritis, with a body weight of 93 kg, V_ss is 7.92 L. For patients with various CAPS phenotypes, V_ss is 6.01 L for a typical patient with a body weight of 70 kg.

When the drug is administered subcutaneously for 6 months (at a dose of 150 mg) every 8 weeks, the accumulation coefficient of canakinumab is 1.3; every 12 weeks – 1.1.

The mean terminal T_1/2 is 26 days. The clearance of canakinumab varies depending on body weight. For typical patients suffering from gouty arthritis, with a body weight of 93 kg, the clearance is 0.23 L/day. For patients with various CAPS phenotypes, the clearance is 0.17 L/day for a typical patient with a body weight of 70 kg.

Indications

Acute gouty arthritis: treatment of acute attacks of gouty arthritis and prevention of new attacks when NSAIDs and/or colchicine are ineffective, intolerable, or contraindicated, and when repeated courses of corticosteroid therapy are not possible.

Cryopyrin-associated periodic syndrome (CAPS) in adults and children aged 4 years and older with body weight >15 kg, including: Familial Cold Autoinflammatory Syndrome (FCAS)/Familial Cold Urticaria (FCU); Muckle-Wells Syndrome (MWS); Neonatal onset multisystemic inflammatory disease (NOMID)/Chronic infantile neurological cutaneous and articular syndrome (CINCA).

ICD codes

Dosage Regimen

Administer subcutaneously only.

Determine the dose individually based on indication, age, and body weight.

For acute gouty arthritis in adults, administer a single 150 mg dose.

For Cryopyrin-Associated Periodic Syndrome (CAPS) in adults and children (≥4 years and >15 kg body weight), administer 150 mg for patients with body weight >40 kg.

For pediatric patients (≥4 years) with body weight 15-40 kg, administer 2 mg/kg.

Administer subsequent doses at intervals of 8 weeks.

If an inadequate response occurs in CAPS patients, consider increasing the dose to 300 mg or 4 mg/kg for pediatric patients (15-40 kg).

Reconstitute the lyophilisate with 1.0 mL of Water for Injections to obtain a 150 mg/mL solution.

Gently swirl the vial for 1 minute without shaking to dissolve.

Allow the reconstituted solution to stand for 5 minutes.

Inspect the solution visually; it should be a clear, colorless to opalescent liquid free of visible particles.

Use the solution immediately after reconstitution.

If storage is necessary, hold at room temperature (up to 25°C/77°F) for a maximum of 60 minutes before administration.

Do not administer if the solution is discolored or contains particulate matter.

Adverse Reactions

Infections and parasitic diseases Very common – infections, in particular, nasopharyngitis, sinusitis (viral), upper respiratory tract infections, bronchitis, influenza, urinary tract infections, gastroenteritis, panniculitis, pneumonia, pharyngitis, ear infections.

Nervous system disorders Common – dizziness/vertigo.

Musculoskeletal and connective tissue disorders Common – back pain.

Blood and lymphatic system disorders Common – thrombocytopenia, leukopenia; Uncommon – neutropenia.

Metabolism and nutrition disorders Common – dyslipidemia; possible transient increase in uric acid concentration.

Ear and labyrinth disorders Common – dizziness.

Gastrointestinal disorders Common – vomiting; Uncommon – gastroesophageal reflux disease; In some cases, during therapy with the drug, patients with CAPS experienced asymptomatic slight increases in serum bilirubin levels, not accompanied by an increase in the activity of liver transaminases.

Hepatobiliary disorders Common – increased bilirubin level, increased AST activity.

Allergic reactions: No development of anaphylactoid or anaphylactic reactions was observed, however, the risk of developing severe hypersensitivity reactions, which may occur with injectable administration of protein-based drugs, cannot be ruled out.

Immunological reactions 1% – in patients receiving Canakinumab for gouty arthritis, antibodies to canakinumab were detected; these antibodies were not detected in patients with CAPS.

General disorders Uncommon – general weakness.

Local reactions Common – injection site reaction.

Contraindications

Acute infectious diseases; pregnancy; lactation period (breastfeeding); children under 4 years of age and weighing less than 15 kg (safety and efficacy for this category of patients have not been sufficiently studied); hypersensitivity to canakinumab.

Use in Pregnancy and Lactation

Contraindicated for use during pregnancy and lactation (breastfeeding).

Special Precautions

Experience with the use of canakinumab in patients without an established mutation in the NLRP3 gene is limited.

Canakinumab should be used with caution in elderly patients; with a history of recurrent infections or any conditions predisposing to the development of infection.

The use of canakinumab may be accompanied by an increased frequency of serious infections, so patients should be under medical supervision to detect symptoms of infection during and after therapy with the drug. If severe infections develop, treatment with canakinumab should not be started or continued.

The development of severe and systemic infectious diseases during therapy with the drug was accompanied by clinical symptoms (fever) and increased production of inflammatory markers (serum CRP levels). However, since the possibility of developing infectious processes without these manifestations cannot be excluded, adequate monitoring of the patient’s condition should be ensured when using the drug.

Before starting treatment, 1-2 months after the start, and periodically during therapy, a standard clinical blood test should be performed to detect neutropenia. In patients with neutropenia, treatment with canakinumab should be started only after the neutrophil count has normalized. If a decrease in ANC is detected during therapy, adequate monitoring of the patient’s condition should be ensured and, if necessary, the issue of discontinuing treatment with the drug should be considered.

Cases of malignant neoplasms have been reported in clinical trials in patients receiving Canakinumab, but the risk of developing malignant neoplasms during therapy with antibodies that bind IL-1 is unknown.

When using canakinumab, approximately 12% of patients with various CAPS phenotypes had positive tuberculin test results without any signs of tuberculosis infection (latent or active). There are no data on an increased risk of reactivation of tuberculosis or opportunistic infections during treatment with monoclonal antibodies to IL-1 (including canakinumab).

Before starting treatment with canakinumab, all patients should be examined to identify active or latent tuberculosis infection (including medical history and appropriate screening tests, such as tuberculin test, IGRA (Interferon-Gamma-Release-Assay) tests, or chest X-ray). During treatment, the condition of patients should be carefully monitored to identify tuberculosis infection. In case of conversion of the tuberculin test from negative to positive, especially in high-risk patients, alternative screening tests should be performed. If tuberculosis infection is detected, treatment with canakinumab should not be started or continued.

Vaccination of patients receiving treatment with canakinumab with live vaccines should be carried out only when the benefit of vaccination outweighs the possible risk. If necessary, vaccination with live vaccines is carried out after the start of therapy (at least 3 months after the last injection of the drug and 3 months before the next one).

Effect on ability to drive vehicles and operate machinery

Patients who experience vertigo while using canakinumab should not drive vehicles or operate machinery until this adverse reaction has completely resolved.

Drug Interactions

Since the expression of cytochrome P450 isoenzymes in the liver can be suppressed by cytokines that stimulate chronic inflammation, such as IL-1β, the administration of potent cytokine inhibitors may normalize the expression of cytochrome P450 isoenzymes in the liver. This is clinically significant for drugs metabolized by cytochrome P450 isoenzymes and having a narrow therapeutic index, when the drug dose is individually selected. When using canakinumab in patients receiving such drugs, their dose should be adjusted if necessary (depending on their clinical effect and plasma concentration of the active substance).

Clinical studies have noted the safe use of canakinumab with anti-gout agents.

Canakinumab is not recommended for concurrent use with TNF inhibitors and other IL-1β blockers, as this combination increases the risk of severe infections.

Data on the effect of vaccination with live vaccines, as well as on the possible secondary transmission of infection, in patients receiving treatment with the drug are not available.

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.