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A novel treatment to manage RA
Patient care
is the finest
of arts
is the finest
of arts
IL-6 Receptor or Ligand? How to treat the
population with active RA inadequately
controlled by practice?
population with active RA inadequately
controlled by practice?
Olokizumab is a novel interleukin 6 (IL-6) inhibitor,
a humanized monoclonal antibody of Ig G4/ϰ isotype
a humanized monoclonal antibody of Ig G4/ϰ isotype
Solution for subcutaneous injection, 160 mg/mL, 0.4 mL vial, shelf life is 3 years, manufactured by R-Pharm JSC (marketing authorization in Russia No. ЛП-006218 dd 21/05/2020). It is the Rx drug that should be administered at the physician's prescription. Before starting olokizumab, please see the Full Prescribing Information
Olokizumab mode of action is blocking the 3 IL-6 axis, which differs from the interaction points of other inhibitors¹’²
- Olokizumab efficacy and safety were studied as part of a large-scale program of clinical trials, CREDO, which included 2,444 adult patients with Rheumatoid Arthritis from 19 countries worldwide. The study of olokizumab continues in the general, open-label, long-term extension.
- Olokizumab was included into the Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation for treatment of patients over 18 years old with mild to critical COVID-19.
- The particular feature of olokizumab action mode is blocking of IL-6, rather than its receptor.
- Olokizumab administration in patients with COVID-19 ensures the optimum use of budget funds.
General Information of the drug
Therapeutic Indications:
Therapy of patients over 18 years of age with moderate to severe rheumatoid arthritis in combination with methotrexate and who have an inadequate response to methotrexate or tumor necrosis inhibitors (TNFi).*
Posology and method of administration:
Olokizumab is injected subcutaneously, into the thigh or anterior abdominal wall, 0.4 mL of the solution at the concentration of 160 mg/mL. Before administration, the solution should be warmed up to room temperature. Storage of the product at >8 ˚С should not exceed 4 hours.
Dosage mode:
The recommended dose is 64 mg once every 4 weeks. In patients with severe rheumatoid arthritis and DAS28 ≥ 6.9, an increase in the dosing frequency to 64 mg once every 2 weeks subcutaneously may be considered.
BEFORE STARTING OLOKIZUMAB, PLEASE SEE THE FULL PRESCRIBING INFORMATION.
* Full prescribing information (marketing authorization No. ЛП-006218 dd 21/05/2020).
Therapy of patients over 18 years of age with moderate to severe rheumatoid arthritis in combination with methotrexate and who have an inadequate response to methotrexate or tumor necrosis inhibitors (TNFi).*
Posology and method of administration:
Olokizumab is injected subcutaneously, into the thigh or anterior abdominal wall, 0.4 mL of the solution at the concentration of 160 mg/mL. Before administration, the solution should be warmed up to room temperature. Storage of the product at >8 ˚С should not exceed 4 hours.
Dosage mode:
The recommended dose is 64 mg once every 4 weeks. In patients with severe rheumatoid arthritis and DAS28 ≥ 6.9, an increase in the dosing frequency to 64 mg once every 2 weeks subcutaneously may be considered.
BEFORE STARTING OLOKIZUMAB, PLEASE SEE THE FULL PRESCRIBING INFORMATION.
* Full prescribing information (marketing authorization No. ЛП-006218 dd 21/05/2020).
Therapeutic Indications:
Pathogenetic therapy of cytokine release syndrome in patients with moderate to severe new coronavirus infection (COVID-19).1
Criteria for prescribing according to the Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 17 of 14.12.2022 in Russ.)2:
Adult patients with mild to moderate COVID-19 and risk factors of severe course, with CT 1-2 or moderate pneumonia3, in combination with two or more of the following symptoms:
• SpO2 – 97% or higher, no signs of shortness of breath
• 3N ≤ CRP ≤ 6N;
• fever 37,5-37,9°С for 3-5 days;
• white blood cell count – 3,5-4,0*109/l;
• absolute lymphocyte count – 1,5-2,0*109/l
Adult patients with CT 1-2 or moderate pneumonia3, in combination with two or more of the following symptoms:
• SpO2 – 94%-97%, shortness of breath on exertion
• 6N ≤ CRP < 9N;
• fever ≥ 38°С for 3-5 days;
• white blood cell count – 3,0-3,5*109/l;
• absolute lymphocyte count – 1,0-1,5*109/l
Adult patients with CT 1-4 or moderate3 to severe4 pneumonia, in combination with two or more of the following symptoms:
• SpO2 ≤ 93% dyspnea at rest / progressive dyspnea during the first 2-3 days
• fever >38°С for 2-3 days;
• CRP ≥ 9N or an increase in CRP levels by 3 times for 3-5 days of illness;
• white blood cell count < 3,0*109/l;
• absolute lymphocyte count < 1,0*109/l
• Serum ferritin level* ≥ 2 normal for 3-5 days of illness
• Serum LDH level ≥ 1.5 norms for 3-5 days of illness
• IL-6 level* > 40 pk / ml.
Posology and method of administration:
Mild:
64 mg (1 vial 160 mg/mL, 0,4 мл) subcutaneously1,2
If there is an insufficient effect, repeat the injection intravenously after 24 hours. In total, no more than 256 mg should be administered.**
Moderate**:
64 – 128 mg (1 or 2 vials of 160 mg/mL, 0,4 mL) intravenously
Dilute in 100 mL of 0.9% NaCl solution (duration – 60 minutes). If there is an insufficient effect, repeat the injection intravenously after 24 hours. In total, no more than 256 mg should be administered.
Severe and critical**:
256 mg (4 vials of 160 mg/mL, 0,4 mL) intravenously
Dilute in 100 mL of 0.9% NaCl solution (duration – 60 minutes).
* Serum ferritin and IL-6 levels are determined when studies are held
** This method is not included in full prescribing information for Olokizumab. According to Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 13.1 of 17/11/2021) (in Russ.)
1. Instruction for the medical use of Artlegia, ЛП-006218 dated May 21, 2020, the owner of the registration certificate – R-Pharm JSC
2. Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 17 of 14/12/2022) (in Russ.)
3. According to the X-ray examination: homogeneous blackening of round shape and different extent, involvement of lung parenchyma ≤ 50%
4. According to the X-ray examination: blackening by type of infiltration (symptom of "white lungs") involvement of lung parenchyma ≥ 50%
Pathogenetic therapy of cytokine release syndrome in patients with moderate to severe new coronavirus infection (COVID-19).1
Criteria for prescribing according to the Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 17 of 14.12.2022 in Russ.)2:
Adult patients with mild to moderate COVID-19 and risk factors of severe course, with CT 1-2 or moderate pneumonia3, in combination with two or more of the following symptoms:
• SpO2 – 97% or higher, no signs of shortness of breath
• 3N ≤ CRP ≤ 6N;
• fever 37,5-37,9°С for 3-5 days;
• white blood cell count – 3,5-4,0*109/l;
• absolute lymphocyte count – 1,5-2,0*109/l
Adult patients with CT 1-2 or moderate pneumonia3, in combination with two or more of the following symptoms:
• SpO2 – 94%-97%, shortness of breath on exertion
• 6N ≤ CRP < 9N;
• fever ≥ 38°С for 3-5 days;
• white blood cell count – 3,0-3,5*109/l;
• absolute lymphocyte count – 1,0-1,5*109/l
Adult patients with CT 1-4 or moderate3 to severe4 pneumonia, in combination with two or more of the following symptoms:
• SpO2 ≤ 93% dyspnea at rest / progressive dyspnea during the first 2-3 days
• fever >38°С for 2-3 days;
• CRP ≥ 9N or an increase in CRP levels by 3 times for 3-5 days of illness;
• white blood cell count < 3,0*109/l;
• absolute lymphocyte count < 1,0*109/l
• Serum ferritin level* ≥ 2 normal for 3-5 days of illness
• Serum LDH level ≥ 1.5 norms for 3-5 days of illness
• IL-6 level* > 40 pk / ml.
Posology and method of administration:
Mild:
64 mg (1 vial 160 mg/mL, 0,4 мл) subcutaneously1,2
If there is an insufficient effect, repeat the injection intravenously after 24 hours. In total, no more than 256 mg should be administered.**
Moderate**:
64 – 128 mg (1 or 2 vials of 160 mg/mL, 0,4 mL) intravenously
Dilute in 100 mL of 0.9% NaCl solution (duration – 60 minutes). If there is an insufficient effect, repeat the injection intravenously after 24 hours. In total, no more than 256 mg should be administered.
Severe and critical**:
256 mg (4 vials of 160 mg/mL, 0,4 mL) intravenously
Dilute in 100 mL of 0.9% NaCl solution (duration – 60 minutes).
* Serum ferritin and IL-6 levels are determined when studies are held
** This method is not included in full prescribing information for Olokizumab. According to Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 13.1 of 17/11/2021) (in Russ.)
1. Instruction for the medical use of Artlegia, ЛП-006218 dated May 21, 2020, the owner of the registration certificate – R-Pharm JSC
2. Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 17 of 14/12/2022) (in Russ.)
3. According to the X-ray examination: homogeneous blackening of round shape and different extent, involvement of lung parenchyma ≤ 50%
4. According to the X-ray examination: blackening by type of infiltration (symptom of "white lungs") involvement of lung parenchyma ≥ 50%
Contraindications:
- A medical history of hypersensitivity to olokizumab or any drug component.
- Active infectious diseases (including TB).
- Children under 18.
- Hereditary fructose intolerance (the drug contains sorbitol).
- Pregnancy. Breastfeeding.
- In patients with a medical history of severe or opportunistic infections; in co-morbidities and conditions, including risk factors of infections (diabetes mellitus, renal failure, admission of immunosuppressive drugs, old age, etc.).
- In patients who contacted TB patients. Before the administration of olokizumab in such patients, the risk and the benefit of using the drug should be weighed.
- In patients with a medical history of diverticulitis or intestinal perforation and other risk factors of intestinal perforation.
- In patients with hepatic impairment and hepatic failure.
Clinical trials
Efficacy and safety of olokizumab drug are studied:
- In non-clinical studies;
- As part of Phase I and II clinical trials (CTs);
- In three international Phase III clinical trials with 2,444 adult patients diagnosed with rheumatoid arthritis of moderate to severe activity (CREDO 1, 2, 3)
- In the general, open-label, long-term study in patients who completed one of Phase III clinical trials.
- 96% of patients decided to continue treatment with olokizumab in the general, open-label, long-term trial.
Phase III program of clinical trials for patients with rheumatoid arthritis
Phase III, randomized, double-blind, placebo-controlled, multi-center study in parallel groups to assess efficacy and safety of olokizumab safety in patients with moderate to severe rheumatoid arthritis that is not sufficiently controlled with Methotrexate (CREDO 1), protocol No. CL04041022; permission of the Russian Health Ministry No. 324 dd 13/05/2016.
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Phase III, randomized, double-blind, multi-center study in parallel groups with placebo and active control for assessment of efficacy and safety of olokizumab in patients with moderate to severe rheumatoid arthritis, which is insufficiently controlled with Methotrexate (CREDO 2), protocol No. CL04041023; permission of the Russian Ministry of Health No. 356 dd 24/05/2016.
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Phase III, randomized, double-blind, placebo-controlled, multi-center study in parallel groups to assess efficacy and safety of olokizumab in patients with moderate to severe rheumatoid arthritis that is not sufficiently controlled with alpha tumor necrosis factor inhibitors (CREDO 3), protocol No. CL04041025; permission of the Russian Ministry of Health No. 389 dd 07/06/2016.
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Multi-center, open-label, Phase III study to assess olokizumab efficacy and safety in patients with moderate to severely active rheumatoid arthritis (CREDO 4), protocol CL04041024; permission of the Russian Ministry of Health No. 670 dd 20/09/2016.
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Clinical experience of olokizumab administration in Covid-19
"International, multi-center, randomized, double-blind adaptive, placebo-controlled study of efficacy and safety of the single administration of olokizumab and RPH-104 in the setting of conventional treatment in patients with a severe infection caused by SARS-CoV-2 (COVID-19)", protocol No. CL04041078; permission of the Russian Ministry of Health No. 147 dd 03/04/2020 г.
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Reference to: National Register of Clinical Studies
Reference to: U.S. National Library of Medicine
Administration of olokizumab in patients infected with SARS-CoV-2 (COVID-19) demonstrated its efficacy in real clinical practice.
The general condition of patients is improving on the first day of treatment
Body temperature decrease to normal by Day 7
Significant impact on the systemic inflammatory response
Scientific program design
Goal: to analyze the data of olokizumab administration in patients with COVID-19 in real clinical practice
Inclusion criteria:
- Patient's age: ≥18
- Confirmed COVID-19 diagnosis
- Thoracic multislice computed tomography (КТ1‑3) or changes in the thoracic X-ray image of 0% to 75% in combination with 2‑and more criteria: Fever ≥ 38°C, oxygen treatment, c-reactive protein ≥30 mg/L
Exclusion criteria:
- Patient's enrollment in any of the clinical trials
- Hemodialysis
- Severe kidney failure: creatinine clearance of <30 ml/min
- Septic shock
Olokizumab is included into treatment regimens of patients with COVID-19, depending on the severity of the disease in a hospital setting, according to the Temporary guidelines "Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)" of the Ministry of Health of the Russian Federation (version 17 of 14.12.2022 in Russ.):
· Favipiravir / Remdesivir / Molnupiravir / Human Immunoglobulin against COVID-19 / synthetic siRNA (double-stranded)
· Olokizumab
· Anticoagulant for parenteral administration
· Olokizumab
· Anticoagulant for parenteral administration
· Remdesivir / Human Immunoglobulin against COVID-19
· Methylprednisolone / Dexamethasone
· Olokizumab
· Anticoagulant for parenteral administration
· Antibacterial, antimycotic therapy
· Methylprednisolone / Dexamethasone
· Olokizumab
· Anticoagulant for parenteral administration
· Antibacterial, antimycotic therapy
Mild:
Regimen 1
Regimen 1
Moderate:
Regimen 1
Regimen 1
Severe and critical:
Regimen 4
Regimen 4
5
5
6
5
· Favipiravir / Remdesivir / Molnupiravir / Human Immunoglobulin against COVID-19 / synthetic siRNA (double-stranded)
· Olokizumab
· Methylprednisolone / Dexamethasone
· Anticoagulant for parenteral administration
· Olokizumab
· Methylprednisolone / Dexamethasone
· Anticoagulant for parenteral administration
5
5
6
5
7
7
5
8
Scientific program data analysis
1. Patients with a high risk of severe course of the disease (age over 65 years, presence of concomitant diseases (diabetes mellitus, obesity, chronic diseases of the cardiovascular system) during the first 7 days of the disease or with a positive result of laboratory examination for SARS-CoV-2 RNA
2. Oral administration of molnupiravir can be effective for COVID-19 treatment if patients start taking this medical drug after COVID-19 diagnosis confirmation and within five days from the onset of the first symptoms in adult patients with mild and moderate disease with a high risk of progression to severe disease
3. In case of respiratory failure
4. Prescribed when fever (t > 38.0 °C) for more than 3 days according to indications in section 5.4 of Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” of the Ministry of Health of the Russian Federation (version 17 of 14.12.2022) (in Russ)
siRNA - small interfering RNA
2. Oral administration of molnupiravir can be effective for COVID-19 treatment if patients start taking this medical drug after COVID-19 diagnosis confirmation and within five days from the onset of the first symptoms in adult patients with mild and moderate disease with a high risk of progression to severe disease
3. In case of respiratory failure
4. Prescribed when fever (t > 38.0 °C) for more than 3 days according to indications in section 5.4 of Temporary guidelines “Prevention, diagnosis and treatment of new coronavirus infection (COVID-19)” of the Ministry of Health of the Russian Federation (version 17 of 14.12.2022) (in Russ)
siRNA - small interfering RNA
Comparison groups parameters
Safety
- Olokizumab has a positive safety and tolerability profile conforming the data described in the literature for IL-6 inhibitors.
- Olokizumab safety was assessed in Phase III large-scale program (CREDO 1, 2, 3), involving 2,444 patients older than 18 years old, with rheumatoid arthritis of moderate to severe activity, and is still being studied in the general, open-label, long-term extension of the program for patients completed one of the Phase III clinical trials, CREDO 4, involving 2,105 patients.
- The most frequent adverse reactions were infections as well as changes in certain hematological and biochemical parameters (leukopenia, neutropenia, increase in hepatic transaminases).
- Submission of messages concerning the suspected adverse reactions is significant after the marketing authorization for the medicinal product is received. This allows continuous monitoring of the benefit-risk ratio for this medicinal product.
- If you learned about any adverse reaction to olokizumab, solution for subcutaneous injection, 160 mg/mL, please notify R-Pharm JSC accordingly. Please notify the Pharmacovigilance Unit by email, safety@rpharm.ru
- You can also notify the Federal Service for Surveillance in Healthcare by email: pharm@roszdravnadzor.ru or at the address: 4, Slavyanskaya Square, Bldg 1, Moscow 109074, Russia
Full Prescribing Information
Further information
Nasonov E, Fatenejad S, Feist E, et al. Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study [published online ahead of print, 2021 Aug 3]. Ann Rheum Dis. 2021;annrheumdis-2021-219876 (in Eng)
Scientific events
Get answers to questions on olokizumab at:
olokizumab@r-pharm.ru
Information on adverse reactions to olokizumab should be sent by email: safety@rpharm.ru
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