Ilsira^® (Solution) Instructions for Use

Marketing Authorization Holder

Biocad, JSC (Russia)

Contact Information

BIOCAD JSC (Russia)

ATC Code

L04AC (Interleukin inhibitors)

Active Substance

Levilimab (Rec.INN registered by WHO)

Dosage Form

Ilsira®

Solution for subcutaneous injection 180 mg/1 ml: 0.9 ml syringes 2 or 4 pcs. with wipes

Dosage Form, Packaging, and Composition

Solution for subcutaneous injection transparent, yellow-brown in color; slight opalescence is possible.

* pre-filled syringe.

Excipients: sodium acetate trihydrate – 0.392 mg, glycine – 6.8 mg, mannitol – 20.7 mg, glacial acetic acid – to pH 5.0, water for injections – to 0.9 ml.

0.9 ml – three-component sterile syringes made of colorless glass (1) – contour cell packaging (2) complete with alcohol wipes (2 pcs.) – cardboard packs.
0.9 ml – three-component sterile syringes made of colorless glass (1) – contour cell packaging (4) complete with alcohol wipes (4 pcs.) – cardboard packs.

A self-adhesive label is affixed to each syringe.

Clinical-Pharmacological Group

Immunosuppressive drug. Interleukin receptor antagonist

Pharmacotherapeutic Group

Immunosuppressants, interleukin inhibitors

Pharmacological Action

Levilimab is a recombinant monoclonal antibody of the IgG₁ subclass, highly homologous to native human antibodies, that binds to the α-subunit of the interleukin-6 (IL-6) receptor.

The levilimab molecule contains deeply optimized light and heavy chain variable fragments and constant domains with a fully human sequence. Levilimab binds and blocks both soluble (sIL-6R) and membrane-bound IL-6 receptors (mIL-6R).

Blockade of both receptor forms prevents the realization of the IL-6-associated pro-inflammatory cascade, inhibits the activation of antigen-presenting cells, B- and T-lymphocytes, monocytes and macrophages, endothelial cells and fibroblasts, and the excessive production of other pro-inflammatory cytokines.

IL-6 is a key element of the cytokine release syndrome (cytokine storm syndrome, hemophagocytic lymphohistiocytosis or macrophage activation syndrome), which can lead to acute respiratory distress syndrome, multiple organ failure and be fatal.

Massive cytokine release (cytokine storm) is observed in patients receiving immunosuppressive therapy, including depleting agents (in particular, monoclonal antibodies to T- and B-lymphocyte receptors), as well as in severe infectious diseases, including in patients with COVID-19.

A high level of IL-6 in the blood is associated with a more severe course of the novel coronavirus infection and pronounced lung changes, which necessitates intensive therapy and increases the risk of death from COVID-19.

IL-6 is the only cytokine that directly induces the synthesis of acute-phase proteins in hepatocytes: C-reactive protein (CRP), fibrinogen, serum amyloid A protein (SAA), hepcidin, leptin.

Furthermore, IL-6 is involved in the activation and maintenance of local inflammatory reactions (formation of pannus in the synovium, stimulation of osteoclastogenesis – erosion of cartilage tissue, osteoporosis), which is observed in the pathogenesis of rheumatoid arthritis.

The specific anti-inflammatory activity of levilimab has been demonstrated in in vitro and in vivo tests.

Levilimab has an antiproliferative effect on DS-1 cell culture, causing dose-dependent inhibition of cell growth.

In a model of collagen-induced arthritis in cynomolgus macaques (Macaca fascicularis), repeated (once a week for 7 weeks) subcutaneous administration of levilimab was accompanied by a decrease in the severity of the inflammatory reaction in the joints, confirmed by histological examination (significant reduction in the severity of inflammatory and degenerative changes in cartilage tissue).

Changes in the parameters of pharmacodynamic markers (increase in the concentration of sIL-6R, saturation of mIL-6R, increase in the concentration of IL-6) indicate highly effective dose-dependent neutralization of both forms of the IL-6 receptor by the drug Levilimab, which in turn is accompanied by a rapid and pronounced decrease in serum CRP concentration, reflecting effective suppression of the inflammatory process.

In clinical studies of levilimab, blockade of up to 90% of membrane-bound IL-6 receptors within the first 2 hours after a single subcutaneous administration of the drug at a dose of 1.6 mg/kg or more was demonstrated.

Pharmacokinetics

Absorption and Distribution

After a single subcutaneous administration of levilimab, a dose-dependent increase in its serum concentration is observed.

After administration, the drug begins to be detected in the serum of patients within 2-12 hours, and its concentration increases, reaching maximum values after 96 [72-168] hours.

Doses of the drug exceeding 2.0 mg/kg demonstrated a biphasic pattern of concentration increase: the first peak was observed in the period of 48-72 hours, the second – by 168 hours, followed by a decrease to undetectable values by day 70.

After a single subcutaneous administration of the drug at a dose of 162 mg, the C_max of levilimab in serum was 17543 [10975; 28323] ng/ml, and the values of the AUC indicator calculated over the period 0-168 hours (AUC_0-168) were 1866231 [1297632-3719014] ng/ml×h.

With repeated administration of levilimab to patients with rheumatoid arthritis, the values of the total AUC calculated over the period 0-2016 hours after administration (AUC_0-2016) were 189580779 [134794695; 230680771] ng/ml×h when administered once a week and 50763951 [34465213.5; 65810194.5] ng/ml×h when administered once every 2 weeks.

The C_max-mult indicator with repeated administrations increased and reached values of 201024 [151563-246408] ng/ml with weekly administration of the drug and 51570 [37201-71740] ng/ml with administration once every 2 weeks.

At the same time, T_max was 1848 [1512; 2016] hours with weekly administration of the drug and 1848 [1512; 1848] hours with administration once every 2 weeks, respectively.

The steady-state V_d was 7871.029 [4226.795; 13363.547] ml when the drug was administered once a week and 7130.453 [5532.978; 11387.959] ml when administered once every 2 weeks.

With repeated administrations, accumulation of the drug is noted, with an increase in C_max by 6.5-14.2 times with weekly administration and by 1.9-4.2 times with administration of the drug once every 2 weeks.

The accumulation ratio (AR) was 10.932 [6.446; 14.178] for weekly administration of the drug and 2.593 [1.902; 4.164] for administration once every 2 weeks.

Thus, in patients with rheumatoid arthritis, multiple subcutaneous administration of levilimab once a week provides higher serum concentration and exposure compared to administration once every 2 weeks.

Elimination

The total clearance (Cl) of levilimab after a single administration at a dose of 2.2 mg/kg was 35.288±11.7 ml/h, and at a dose of 2.9 mg/kg the Cl indicator was 25.974±1.1 ml/h.

T_1/2 of a single subcutaneous dose of 2.9 mg/kg was 133.683 [92.754; 197.197] hours.

The values of the parameters characterizing the elimination period are dose-dependent (the indicators of mean residence time of the drug in the body (MRT) and T_1/2 increase with increasing administered dose, and Cl decreases), which indicates the nonlinear pharmacokinetics of the drug, due to target-mediated distribution and elimination.

Pharmacokinetics in Special Patient Groups

Patients with renal and hepatic impairment No specific studies have been conducted in this category of patients; pharmacokinetic data in patients with renal and hepatic impairment are not available.

Patients over 65 years of age Pharmacokinetic data in individuals over 65 years of age are not available.

Indications

Novel coronavirus infection (COVID-19)

• Pathogenetic therapy of cytokine release syndrome in severe novel coronavirus infection (COVID-19).

Rheumatoid arthritis

• Moderate or high activity rheumatoid arthritis in adults with an inadequate response to therapy with one or more disease-modifying antirheumatic drugs, including for slowing radiographic progression. Levilimab is used in combination therapy with methotrexate and/or other synthetic basic anti-inflammatory drugs.

ICD codes

Dosage Regimen

For subcutaneous administration.

The drug Ilsira^® is intended for administration both in outpatient clinics and in hospital settings.

The use of levilimab should be carried out under the supervision of a physician.

In case of long-term use of the drug, in particular for the therapy of rheumatoid arthritis, if the doctor considers it possible, after appropriate training in the technique of subcutaneous injections, patients can independently administer the drug to themselves.

The drug Ilsira^® is administered subcutaneously using a pre-filled syringe into the area of the anterior abdominal wall (at least 5 cm away from the navel), the anterior and lateral surface of the thigh, or the middle third of the outer part of the upper arm.

Do not administer the drug into areas with damaged or altered skin (with indurations, redness, neoplasms, hyperpigmentation or hypersensitivity).

For the purpose of pathogenetic therapy of cytokine release syndrome in severe novel coronavirus infection (COVID-19) the recommended dose of the drug Ilsira^® is 324 mg once as two subcutaneous injections of 162 mg each.

In case of insufficient effect of the first dose of levilimab, repeated administration of the drug after 48-96 hours at a dose of 324 mg as two subcutaneous injections of 162 mg each is possible.

The decision on the need for repeated administration is made exclusively by the doctor.

For the therapy of rheumatoid arthritis the recommended dose of the drug Ilsira^® is 162 mg subcutaneously once a week.

Upon achieving disease remission, administration in the regimen of 162 mg subcutaneously once every 2 weeks is possible.

Patients who have not achieved remission are recommended to continue using the drug at a dose of 162 mg subcutaneously once a week.

Patients who have an increase in disease activity after reducing the frequency of administrations are recommended to resume using the drug at a dose of 162 mg subcutaneously once a week.

If adverse events develop during rheumatoid arthritis therapy associated with changes in laboratory parameters, the dose and administration regimen should be adjusted in accordance with the recommendations in Tables 1, 2 and 3.

Table 1. Recommendations for dose adjustment with increased activity of liver enzymes ALT or AST

Table 2. Recommendations for dose adjustment with a decrease in the absolute neutrophil count (ANC)

Table 3. Recommendations for dose adjustment with a decrease in platelet count

Missed dose in rheumatoid arthritis therapy

If a scheduled administration is missed for any reason, the injection of the drug Ilsira^® should be performed as soon as possible.

A new count for the date of the next administration begins from the moment of the actually performed injection of the drug Ilsira^®.

Instructions for use

Preparation for subcutaneous injection

• Wash your hands thoroughly.

• Remove the package with the syringe from the refrigerator. Then remove the syringe with the medicinal product from the cardboard pack. Inspect the syringe and the medicinal product in it. Do not use the syringe if:
  • The solution is cloudy, there are foreign visible particles in the drug;
  • The color has changed;
  • Any parts of the syringe are damaged;
  • The expiration date (expires on …) indicated on the cardboard pack and on the syringe label has passed.

• Leave the syringe at room temperature for approximately 25-30 minutes. Do not warm the syringe with the drug in any other way.

• Prepare an alcohol wipe/cotton ball.

At this stage, do not remove the syringe cap.

Technique for performing subcutaneous injection of the drug Ilsira^® in a pre-filled syringe

1. Choose the injection site (anterior abdominal wall (at least 5 cm away from the navel), anterior and lateral surface of the thigh or middle third of the outer part of the upper arm (possible injection sites are shaded in the figure below)).

2. Do not inject the drug into an area of skin that is painful, reddened, indurated, or bruised. These signs may indicate an infection. Also, do not inject the drug into areas with moles, hyperpigmentation, and scars.

3. The injection site must be treated with an alcohol wipe using circular motions.

4. Do not shake the syringe.

5. Remove the needle cap without touching the needle and avoiding contact with other surfaces.

6. With one hand, grasp the treated skin into a fold.

7. Take the syringe in the other hand, holding it with the graduated surface facing up. The drug should be administered at a 45 or 90 degree angle to the skin surface, depending on the skin thickness and the severity of the subcutaneous fat layer (in lean patients, the drug is administered at a 45-degree angle; in patients with a skin fold thickness of more than 1.5 cm, administration at a 90-degree angle is acceptable).

8. With one quick movement, insert the needle completely into the skin fold.

9. After inserting the needle, release the skin fold.

10. Inject the entire solution with slow, constant pressure on the syringe plunger over 2-5 seconds.

11. When the syringe is empty, remove the needle from the skin at the same angle.

12. With a piece of gauze, lightly press the injection area for 10 seconds, but do not rub the surface. A small amount of blood may come out of the injection site. If desired, you can use a plaster.

13. Do not reuse the syringe after injection.

14. Perform the second injection of the drug Ilsira^® to achieve a total dose of 324 mg in a similar manner.

15. For subsequent injections, the injection site should be changed.

Disposal of consumables

Unused drug solution, used syringes, wipes/cotton balls and other consumables are subject to disposal using a closable, puncture-resistant container for sharp objects made of plastic or glass.

Do not allow used syringes to be stored in places accessible to children.

Adverse Reactions

Within the framework of conducted clinical studies in healthy volunteers, patients with rheumatoid arthritis and severe novel coronavirus infection (COVID-19), the drug Ilsira^® showed a favorable safety profile.

The most frequent adverse reactions in the conducted clinical studies were increased activity of ALT and AST, neutropenia and increased blood lipid levels.

The spectrum of registered adverse events associated with the use of the drug Ilsira^® was expected for the class of IL-6 receptor inhibitors.

There were no fatal outcomes associated with therapy with the drug Ilsira^® during clinical studies.

In this instruction, adverse reactions are presented in accordance with the international dictionary of adverse reactions MedDRA.

Below is a list of adverse reactions registered in patients receiving Levilimab within the framework of clinical studies and having a definite, probable or possible degree of connection with taking the drug.

Frequency is indicated taking into account the following criteria: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (≤10000).

* In clinical studies, local reactions in the form of erythema and skin itching were recorded.

** This adverse reaction manifested as increased AST and ALT and was not accompanied by other symptoms of toxic hepatitis against the background of multiple drug therapy.

Also, during clinical development, isolated adverse events were recorded for which a reliable causal relationship with the use of levilimab has not been established to date inflammation of the skin lesion focus, asthenia, anemia, lymphadenitis, lymphocytosis, abnormal lung imaging procedure, decreased AST activity.

As immune system disorders, isolated hypersensitivity reactions (anaphylactic shock, angioedema) were observed in the post-registration period, which is consistent with the known safety profile of IL-6 receptor inhibitor class drugs.

Contraindications

• Hypersensitivity to levilimab, or to any of the excipients of the drug;
• Clinically significant active infections, including tuberculosis;
• Sepsis caused by pathogens other than COVID-19;
• Viral hepatitis B;
• Neutropenia less than 0.5×10⁹/L;
• Thrombocytopenia less than 50×10⁹/L;
• Increase in AST or ALT activity more than 5 times;
• Severe hepatic impairment (Child-Pugh class C);
• Severe and end-stage renal impairment (GFR less than 30 ml/min);
• Children and adolescents under 18 years of age;
• Pregnancy;
• Breastfeeding period;
• Combined use with TNFα inhibitors or use within 1 month after therapy with monoclonal antibodies to TNFα.

With caution

Caution should be exercised when prescribing levilimab to the following categories of patients

• With chronic and recurrent infections or with a history of them;
• With concomitant diseases predisposing to the development of infections;
• In the early convalescence period after severe and moderate infectious diseases;
• After recent vaccination with live attenuated vaccines;
• With mild and moderate hepatic impairment (Child-Pugh class A and B);
• With moderate renal impairment (GFR <60 ml/min and ≥30 ml/min);
• With diverticulitis, diverticulosis and ulcerative lesions of the gastrointestinal tract, including in the medical history, due to the risk of gastrointestinal perforation;
• With demyelinating diseases;
• Receiving immunosuppressive therapy after organ transplantation.

Due to the ability of levilimab to suppress the acute phase inflammatory reactions, special caution should be exercised regarding the early detection of infectious diseases during therapy.

Due to limited clinical data on the use of levilimab in elderly patients, caution should be exercised when prescribing the drug to patients of this age group.

Use in Pregnancy and Lactation

Pregnancy

No studies on the effect on the fetus in pregnant women have been conducted. It is known that monoclonal antibodies can cross the placental barrier. The drug Ilsira^® is contraindicated for use during pregnancy. Women of childbearing potential and their sexual partners should use effective contraception during therapy with levilimab.

Breastfeeding period

It is unknown whether Levilimab passes into breast milk. Given that immunoglobulins of the G class, to which Levilimab belongs, can be excreted in breast milk, the drug Ilsira^® is contraindicated for use during breastfeeding.

Fertility

There are no data on the effect of the drug on fertility in humans.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment (Child-Pugh class C).

The drug should be prescribed with caution to patients with mild and moderate hepatic impairment (Child-Pugh class A and B).

Use in Renal Impairment

The use of the drug is contraindicated in severe and end-stage renal impairment (GFR less than 30 ml/min).

The drug should be prescribed with caution to patients with moderate renal impairment (GFR <60 ml/min and ≥30 ml/min).

Pediatric Use

The use of the drug is contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Caution should be exercised when prescribing the drug to elderly patients.

Special Precautions

Traceability

In order to improve the traceability of biotechnological medicinal products, the name and batch number of the prescribed medicinal product Levilimab must be recorded in the patient’s medical documentation.

Infections

The presence of potentially severe infections such as HIV, active hepatitis B, syphilis, tuberculosis, is a contraindication for prescribing levilimab. Levilimab should not be used in patients with active infectious diseases, including localized infections. Given the immunosuppressive effect of levilimab, therapy with this drug may potentially lead to exacerbation of chronic infections and an increased risk of primary infection.

In case of hepatitis B reactivation or development of serious infections, therapy with levilimab should be discontinued and appropriate etiotropic therapy should be prescribed.

Caution is required regarding patients with a history of recurrent infectious diseases, as well as individuals with risk factors for infections in the form of concomitant diseases or concomitant therapy.

Given the suppression of acute phase inflammatory reactions by levilimab, the symptoms of an infectious disease may be masked, which should be taken into account when early detection of serious infections in patients receiving the drug Ilsira^®. If any symptoms appear that indicate the development of an infectious disease during the use of levilimab, the patient should immediately consult a doctor for timely diagnosis and prescription of therapy.

Tuberculosis

Therapy with the drug Ilsira^® is contraindicated in patients with active tuberculosis. Before prescribing the drug Ilsira^® and during therapy, standard screening for tuberculosis should be performed. Patients with latent tuberculosis are recommended to undergo a standard course of anti-tuberculosis therapy before starting therapy with the drug Ilsira^®.

Laboratory parameters

Neutropenia. In clinical studies of the drug Ilsira^®, a decrease in neutrophil count was observed. During long-term therapy of patients with rheumatoid arthritis, the decrease in ANC was not accompanied by a higher frequency of infections, including serious ones. Caution should be exercised when treating with the drug Ilsira^® in patients with ANC <2×10⁹/L. If ANC decreases to <0.5×10⁹/L, therapy with the drug Ilsira^® should be discontinued. Neutrophil count should be assessed 4-8 weeks after the start of therapy, and thereafter according to clinical practice.

Thrombocytopenia. In clinical studies of the drug Ilsira^®, a decrease in platelet count was observed. During long-term therapy of patients with rheumatoid arthritis, the decrease in platelet count was not accompanied by the development of bleeding. Caution should be exercised when prescribing therapy with the drug Ilsira^® when the platelet count is below 100×10³/µL. Treatment is not recommended when the platelet count is <50×10³/µL. Platelet count should be assessed 4-8 weeks after the start of therapy, and thereafter according to clinical practice.

Liver enzymes. In clinical studies of the drug Ilsira^®, an increase in the activity of liver transaminases without signs of hepatic insufficiency was observed. The frequency of such changes may increase when used concomitantly with drugs that have potential hepatotoxic effects (e.g., methotrexate, antibacterial drugs and others). Caution should be exercised when prescribing therapy with the drug Ilsira^® in patients with ALT or AST levels exceeding the ULN by more than 1.5 times. Liver transaminase activity (ALT and AST) should be assessed 4-8 weeks after the start of therapy, and thereafter according to clinical practice.

Changes in lipid metabolism parameters. In clinical studies of the drug Ilsira^®, an increase in lipid concentrations (total cholesterol and/or triglycerides) was observed. Lipid metabolism parameters should be assessed 4-8 weeks after the start of therapy with levilimab, and thereafter according to clinical practice. When managing patients with hyperlipidemia, national guidelines should be taken into account.

Hypersensitivity reactions

The development of hypersensitivity reactions is potentially possible when using levilimab. Within the framework of the conducted clinical studies of levilimab, no hypersensitivity reactions were registered. During the post-registration evaluation period of the drug Ilsira^®, isolated cases of anaphylactic reactions and hypersensitivity reactions have been described. If anaphylactic or other serious allergic reactions occur, the use of the drug Ilsira^® should be immediately discontinued and appropriate symptomatic therapy initiated.

Malignancies

Patients with RA have an increased risk of malignancies, which may be exacerbated by long-term use of immunosuppressive drugs. The volume of clinical data on IL-6 receptor inhibitor class drugs in general and levilimab in particular is insufficient to establish the frequency of malignancy development and to confirm a causal relationship with therapy. The safety of levilimab during long-term use continues to be studied.

Presence of alcohol or drug dependence

The presence of alcohol or drug dependence, as well as mental disorders, may cause the patient’s non-compliance with the levilimab treatment schedule, which, in turn, may lead to reduced therapy effectiveness. More careful monitoring of patients with these conditions is necessary due to the lack of clinical study results in this category of patients and the possibility of an increased risk of hepatotoxicity and other adverse consequences.

Immunogenicity

During clinical studies of the drug Ilsira^®, including during long-term (for one year) treatment of rheumatoid arthritis, no production of binding antibodies to levilimab was detected.

Patients over 65 years of age

Data on the efficacy and safety of the drug in patients over 65 years of age are limited. No significant age-related differences in the distribution and elimination of the drug are assumed.

Patients with impaired renal and hepatic function

The efficacy and safety of the drug in this category of patients have not been studied.

Use in pediatrics

The efficacy and safety of the drug in children and adolescents under 18 years of age have not been studied.

Vaccination

Immunization with live attenuated vaccines should not be carried out during treatment with the drug Ilsira^®, since clinical assessment of the safety of this interaction has not been conducted within the framework of clinical studies. Vaccination with live attenuated vaccines before starting therapy with the drug Ilsira^®, as well as the interval between vaccination and the start of therapy, must comply with current clinical guidelines.

Demyelinating diseases

Given the data on the safety profile of IL-6 receptor inhibitor class drugs, caution should be exercised when using levilimab in patients with demyelinating diseases. It is necessary to carefully monitor the appearance of symptoms indicating the development of a demyelinating disease of the CNS, despite the fact that the ability of levilimab to cause demyelinating diseases of the CNS has not been established to date.

Effect on ability to drive vehicles and machinery

There are no data on the effect of the drug Ilsira^® on the ability to drive vehicles and operate machinery and/or mechanisms. Given that episodes of dizziness have been observed with therapy with other IL-6 receptor inhibitors, patients experiencing dizziness when using the drug Ilsira^® are not recommended to drive vehicles and machinery until the dizziness stops.

Overdose

There are no clinical data on overdose of the drug Ilsira^®. The maximum tolerated dose of levilimab for humans has not been established. In clinical studies, with subcutaneous administration of levilimab at the maximum daily dose of 324 mg twice with an interval of 48-96 hours, no new adverse reactions that change the understanding of the drug’s safety profile were registered.

Treatment there is no specific antidote. Symptomatic therapy is carried out.

Drug Interactions

No information on adverse drug interactions of levilimab with other medicinal products has been received to date.

Mixing the drug with other medicinal products is strictly prohibited.

Storage Conditions

The drug should be stored in a light-protected place, out of the reach of children, at a temperature from 2°C (35.6°F) to 8°C (46.4°F); do not freeze.

Shelf Life

Shelf life – 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.