Tofacitinib

Serious infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving immunomodulators, including biologics and tofacitinib. The most common serious infections reported with tofacitinib include pneumonia, subcutaneous inflammation, herpes zoster, and urinary tract infection. Among the opportunistic infections with the use of tofacitinib, cases of the development of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, herpes zoster with damage to various dermatomes, cytomegalovirus infection, and BK virus infection were noted. Some patients have had disseminated disease, most often with the simultaneous use of immunomodulators - methotrexate or corticosteroids, which themselves and in addition to the underlying disease rheumatoid arthritis can predispose to the development of infections. It is also possible to develop other serious infections that were not reported in clinical studies (for example, histoplasmosis, coccidioidomycosis and listeriosis).

Tofacitinib should not be used in patients with active infection, including local infections. Before using tofacitinib, the risk/benefit ratio of therapy should be assessed in patients with chronic or recurrent infection, after contact with a patient with tuberculosis, a history of severe or opportunistic infection, in patients who have lived in or recently visited areas where tuberculosis or mycoses are endemic, and in patients with a predisposition to developing infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after therapy with tofacitinib. Tofacitinib should be temporarily discontinued if the patient develops a serious infection, opportunistic infection, or sepsis. If a new infection develops while receiving tofacitinib, the patient should undergo a rapid and complete diagnostic evaluation, similar to a patient suffering from immunodeficiency. The appointment of appropriate antibacterial therapy, as well as careful dynamic monitoring, is indicated.

Since older patients usually have a higher incidence of infections, caution should also be exercised in such cases.

Tuberculosis

Before using tofacitinib, patients should be screened for signs of latent or active tuberculosis infection.

Before initiating tofacitinib therapy in patients with a history of latent or active tuberculosis, in the absence of evidence of an adequate course of antituberculosis therapy, as well as in patients with a negative test result for latent tuberculosis, but the presence of risk factors for tuberculosis infection, appropriate antituberculosis therapy should be administered. When making a decision regarding the need for anti-tuberculosis therapy for each individual patient, it is recommended to consult with a TB specialist.

Patients should be closely monitored for development of signs of tuberculosis, including patients who test negative for latent tuberculosis before initiating therapy.

The incidence of tuberculosis with tofacitinib in the global clinical development program was 0.1-0.2%. Patients with latent tuberculosis should receive standard antimycobacterial therapy before initiating tofacitinib therapy.

Reactivation of viral infections

Reactivation of viral infections has been described with the use of therapy with basic anti-inflammatory drugs. Cases of herpes virus reactivation (eg, herpes zoster) have also been reported in clinical studies of tofacitinib. The effect of tofacitinib on reactivation of chronic viral hepatitis is unknown. Patients testing positive for hepatitis B and C were excluded from clinical studies. Before initiating tofacitinib therapy, screening for viral hepatitis should be performed.

Malignant and lymphoproliferative diseases (except non-melanoma skin cancer)

There is a possibility that tofacitinib affects the body's defense against cancer. The effect of tofacitinib therapy on the development and course of malignant neoplasms is unknown, however, in clinical studies of this drug, cases of the development of malignant neoplasms were recorded.

Skin cancer other than melanoma

Cases of non-melanoma skin cancer have been reported in patients receiving tofacitinib therapy. Periodic skin examination is recommended in patients at increased risk of developing skin cancer.

Cases of perforation of the gastrointestinal tract

Clinical studies of patients with rheumatoid arthritis have reported cases of gastrointestinal perforation, although the role of Janus kinase inhibition in these events is unknown. Such cases have mainly been described as diverticulum perforation, peritonitis, abscess and appendicitis. All patients who developed gastrointestinal perforation received concomitant therapy with NSAIDs and/or glucocorticosteroids. The relative contribution of concomitant therapy and tofacitinib in the development of gastrointestinal perforation is unknown.

Tofacitinib should be used with caution in patients at increased risk of GI perforation (eg, patients with a history of diverticulitis). Patients with new GI symptoms should be immediately evaluated for early detection of GI perforation.

Laboratory indicators

Neutrophils: Treatment with tofacitinib was associated with an increased incidence of neutropenia (<2000/mm3) compared with placebo. Treatment with tofacitinib in patients with low neutrophil counts (absolute neutrophil count less than 1000/µL) is not recommended. In patients with a persistent decrease in the absolute neutrophil count to 500-1000 cells/μL, reduce the dose of tofacitinib or discontinue treatment until the absolute neutrophil count reaches a concentration of more than 1000 cells/μL. In patients with an absolute neutrophil count less than 500/µl, treatment is not recommended. Neutrophil levels should be monitored after 4-8 weeks of therapy and then every 3 months.

Hemoglobin: It is not recommended to initiate tofacitinib therapy in patients with low hemoglobin levels (less than 90 g/L). Treatment with tofacitinib should be discontinued in patients with hemoglobin levels less than 80 g/L, or if hemoglobin levels decrease by 20 g/L or more during treatment. Hemoglobin should be monitored initially, after 4-8 weeks of therapy, and then every 3 months.

Lipids: Treatment with tofacitinib is accompanied by an increase in blood lipid levels - total cholesterol, LDL cholesterol, and HDL cholesterol. Maximum effect was usually observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4-8 weeks after the start of therapy. The use of statins in patients with elevated concentrations of total cholesterol and LDL cholesterol during tofacitinib therapy allows achieving baseline values.

Vaccination

There is currently no information on vaccine response or secondary transmission of infection when live vaccines are administered to patients receiving tofacitinib. It is not recommended to administer live vaccines concomitantly with tofacitinib. It is recommended that all patients receive required immunizations in accordance with current vaccination guidelines before initiating tofacitinib.

Patients with impaired renal function

Tofacitinib was not studied in clinical trials in patients with baseline creatinine clearance <40 mL/min.

Impact on the ability to drive vehicles and operate machinery

Studies of the effect of tofacitinib on the ability to drive a car and use machines have not been conducted.

Jakvinus

Serious infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving immunomodulators, including biologics and Jaquinus. The most common serious infections reported with use of Jaquinus include pneumonia, subcutaneous inflammation, herpes zoster, and urinary tract infection. Among the opportunistic infections when using the drug Yaquinus, cases of the development of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, herpes zoster with damage to various dermatomes, cytomegalovirus infection, and BK virus infection were noted. In some patients, disseminated diseases were noted, most often with the simultaneous use of immunomodulators - methotrexate or corticosteroids. which in themselves and in addition to the underlying disease rheumatoid arthritis can predispose to the development of infections. It is also possible to develop other serious infections that were not reported in clinical studies (for example, histoplasmosis, coccidioidomycosis and listeriosis).

Javius should not be used in patients with active infection, including localized infections. Before using Yaquinus, the risk/benefit ratio of therapy should be assessed in patients with chronic or recurrent infection, after contact with a patient with tuberculosis, a history of severe or opportunistic infection, in patients who have lived in or recently visited areas where tuberculosis or mycoses are endemic, and in patients with a predisposition to developing infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after therapy with Jaquinus. Jaquinus should be temporarily discontinued if the patient develops a serious infection, opportunistic infection, or sepsis until the patient's condition is controlled. If a new infection develops while using the drug Yaquinus, the patient is subject to a rapid and complete diagnostic examination in the same way as a patient suffering from immunodeficiency. The appointment of appropriate antibacterial therapy, as well as careful dynamic monitoring, is indicated.

Since older patients usually have a higher incidence of developing

infections, in such cases caution should also be exercised.

Tuberculosis

Before using Yaquinus, you should be screened for signs of latent or active tuberculosis infection.

Before initiating therapy with Yaquinus in patients with a history of latent or active tuberculosis, in the absence of confirmation of an adequate course of anti-tuberculosis therapy, as well as in patients with a negative test result for latent tuberculosis, but the presence of risk factors for tuberculosis infection, appropriate anti-tuberculosis therapy should be administered. When making a decision regarding the need for anti-tuberculosis therapy for each individual patient, it is recommended to consult with a TB specialist.

Patients should be closely monitored for development of signs of tuberculosis, including patients who test negative for latent tuberculosis before initiating therapy.

The incidence of tuberculosis with the use of the drug Yaquinus within the framework of the global clinical development program was 0.1 - 0.2%. Patients with latent tuberculosis are subject to standard antimycobacterial therapy before starting therapy with Yaquinus.

Reactivation of viral infections

Reactivation of viral infections has been described with DMARD therapy. Cases of reactivation of the herpes virus (for example, herpes zoster) have also been described in clinical studies of Jakvius. The effect of Yaquinus on the reactivation of chronic viral hepatitis is unknown. Patients testing positive for hepatitis B and C were excluded from clinical studies. Screening for the presence of viral hepatitis should be performed before initiating therapy with Yaquinus.

Malignant and lymphoproliferative diseases (except non-melanoma skin cancer (NSMC))

There is a possibility that Jaquinus affects the body's defense against malignant neoplasms. The effect of therapy with Yaquinus on the development and course of malignant neoplasms is unknown, however, in clinical studies of this drug, cases of the development of malignant neoplasms were recorded. Cases of lymphoma have been reported in patients treated with Jaquinus. Although patients with rheumatoid arthritis, especially those with highly active disease, have a higher risk (several times higher) of developing lymphoma compared with the general population, the role, if any, of Janus kinase (JAK) inhibition in the development lymphoma is unknown.

Non-melanoma skin cancer (NSMC)

Cases of development of SCNM have been reported in patients receiving tofacitinib therapy. Periodic skin examination is recommended in patients at increased risk of developing skin cancer.

Cases of perforation of the gastrointestinal tract

Clinical studies of patients with rheumatoid arthritis have reported cases of gastrointestinal perforation, although the role of Janus kinase inhibition in these events is unknown. Such cases have mainly been described as diverticulum perforation, peritonitis, abdominal abscess and appendicitis. All patients who developed gastrointestinal perforation received concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or glucocorticoids. The relative contribution of concomitant therapy and the use of Yaquinus in the development of gastrointestinal perforation is unknown.

Jaquinus should be used with caution in patients at increased risk of gastrointestinal perforation (eg, patients with a history of diverticulitis). Patients with new GI symptoms should be immediately evaluated for early detection of GI perforation.

Laboratory indicators

Lymphocytes: "cases of lymphocyte counts falling to less than 500 cells/mm" were associated with an increase in the incidence of serious infections that required therapy. It is not recommended to initiate therapy with Yaquinus in patients with low lymphocyte counts (i.e., less than 500 cells/mm3). If the patient has a confirmed decrease in the absolute number of lymphocytes to a level of less than 500 cells/mm3, treatment with the drug

Jaquinus is not recommended. Lymphocyte levels should be monitored at baseline and then every 3 months (see section "Dosage and Administration").

Neutrophils: Treatment with Yaquinus was associated with an increased incidence of neutropenia (<2000 cells/mm3) compared to placebo. Treatment with Yaquinus in patients with low neutrophil counts (ANC less than 1000 cells/mm3) is not recommended. In patients with a persistent decrease in ANC to 500-1000 cells/mm3, the dose of Yaquinus should be reduced or treatment should be discontinued until the ANC concentration reaches more than 1000 cells/mm3. In patients with a confirmed absolute neutrophil count of less than 500 cells/mm3, treatment is not recommended. Neutrophil levels should be monitored at baseline and after 4-8 weeks of therapy, and then every 3 months (see sections “Dosage and Administration”, “Side Effects”).

Hemoglobin: It is not recommended to initiate therapy with Yaquinus in patients with low hemoglobin levels (less than 9 g/dL). Treatment with Yaquinus should be discontinued in patients with hemoglobin levels less than 8 g/dL, or if hemoglobin levels decrease by 2 g/dL or more during treatment. Hemoglobin should be monitored at the initial stage of therapy, after 4-8 weeks of therapy, and then every 3 months (see section "Dosage and Administration").

Lipids: treatment with Yaquinus is accompanied by an increase in blood lipid levels - total cholesterol, LDL cholesterol, and high-density lipoprotein cholesterol (HDL). Maximum effect was usually observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4-8 weeks after the start of therapy. The use of statins in patients with elevated concentrations of total cholesterol and LDL cholesterol during therapy with Jakvius allows one to achieve baseline values.

Vaccinations

Information on vaccination response or secondary transmission of infection when live vaccines are administered to patients receiving Jaquinus is not yet available. It is not recommended to administer live vaccines at the same time as Jaquinus. It is recommended that all patients receive required immunizations in accordance with current vaccination recommendations before starting Yaquinus.

Patients with nocturnal dysfunction

In clinical studies, Javius was not studied in patients with initial creatinine clearance less than 40 ml/min (calculated using the Cockcroft-Gault formula) (see section “Contraindications”).

Yaquinus, 5 mg, film-coated tablets, 56 pcs.

Serious infections

Serious and sometimes fatal infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving immunomodulators, including biologics and Jaquinus. The most common serious infections reported with use of Jaquinus include pneumonia, subcutaneous inflammation, herpes zoster, and urinary tract infection. Among the opportunistic infections when using the drug Yaquinus, cases of the development of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, herpes zoster with damage to various dermatomes, cytomegalovirus infection, and BK virus infection were noted. Some patients have had disseminated disease, most often with the simultaneous use of immunomodulators - methotrexate or corticosteroids, which themselves and in addition to the underlying disease rheumatoid arthritis can predispose to the development of infections. It is also possible to develop other serious infections that were not reported in clinical studies (for example, histoplasmosis, coccidioidomycosis and listeriosis).

Jaquinus should not be used in patients with active infection, including localized infections. Before using Yaquinus, the risk/benefit ratio of therapy should be assessed in patients with chronic or recurrent infection, after contact with a patient with tuberculosis, a history of severe or opportunistic infection, in patients who have lived in or recently visited areas where tuberculosis or mycoses are endemic, and in patients with a predisposition to developing infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after therapy with Jaquinus. Jaquinus should be temporarily discontinued if the patient develops a serious infection, opportunistic infection, or sepsis. If a new infection develops while using the drug Yaquinus, the patient is subject to a rapid and complete diagnostic examination, similar to a patient suffering from immunodeficiency. The appointment of appropriate antibacterial therapy, as well as careful dynamic monitoring, is indicated.

Since older patients usually have a higher incidence of infections, caution should also be exercised in such cases.

Tuberculosis

Before using Yaquinus, you should be screened for signs of latent or active tuberculosis infection.

Patients should be closely monitored for development of signs of tuberculosis, including patients who test negative for latent tuberculosis before initiating therapy.

The incidence of tuberculosis with the use of the drug Yaquinus in the global clinical development program was 0.1-0.2%. Patients with latent tuberculosis are subject to standard antimycobacterial therapy before starting therapy with Yaquinus.

Reactivation of viral infections

Reactivation of viral infections has been described with DMARD therapy. Cases of reactivation of the herpes virus (for example, herpes zoster) have also been described in clinical studies of the drug Jaquinus. The effect of Yaquinus on the reactivation of chronic viral hepatitis is unknown. Patients testing positive for hepatitis B and C were excluded from clinical studies. Screening for the presence of viral hepatitis should be performed before initiating therapy with Yaquinus.

Malignant and lymphoproliferative diseases (except non-melanoma skin cancer)

Non-melanoma skin cancer (NSMC)

Cases of development of SCNM have been reported in patients receiving tofacitinib therapy. Periodic skin examination is recommended in patients at increased risk of developing skin cancer.

Cases of perforation of the gastrointestinal tract

Clinical studies of patients with rheumatoid arthritis have reported cases of gastrointestinal perforation, although the role of Janus kinase inhibition in these events is unknown. Such cases have mainly been described as diverticulum perforation, peritonitis, abscess and appendicitis. All patients who developed perforation of the gastrointestinal tract received concomitant therapy with NSAIDs and/or corticosteroids. The relative contribution of concomitant therapy and the use of Yaquinus in the development of gastrointestinal perforation is unknown.

Laboratory indicators

Neutrophils: Treatment with Yaquinus was associated with an increased incidence of neutropenia (less than 2000/mcL) compared to placebo. Treatment with Yaquinus in patients with low neutrophil concentrations (ANC less than 1000/mcL) is not recommended. In patients with a persistent decrease in ANC to 500-1000 cells/µl, the dose of Yaquinus should be reduced or treatment should be discontinued until the ANC concentration reaches more than 1000 cells/µl. In patients with an absolute neutrophil count less than 500/µl, treatment is not recommended. Neutrophil levels should be monitored after 4-8 weeks of therapy and then every 3 months.

Hemoglobin: It is not recommended to initiate therapy with Yaquinus in patients with low hemoglobin levels (less than 90 g/l). Treatment with Yaquinus should be discontinued in patients with a hemoglobin level of less than 80 g/L, or if the hemoglobin level decreases by 20 g/L or more during treatment. Hemoglobin should be monitored initially, after 4-8 weeks of therapy, and then every 3 months.

Lipids: treatment with Yaquinus is accompanied by an increase in blood lipid levels - total cholesterol, LDL cholesterol, and HDL cholesterol. Maximum effect was usually observed within 6 weeks. Assessment of lipid parameters should be performed approximately 4-8 weeks after the start of therapy. The use of statins in patients with elevated concentrations of total cholesterol and LDL cholesterol during therapy with Yaquinus allows achieving baseline values.

Vaccination

Patients with impaired renal function

In clinical studies, Yaquinus was not studied in patients with initial creatinine clearance <40 ml/min.

Impact on the ability to drive vehicles and operate machinery

Studies of the effect of the drug Yaquinus on the ability to drive a car and operate machinery have not been conducted.