Tofacitinib (Tofacitinibum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation
  • Yaqurinus
    pills inwards 
    Pfizer Manufakchuring Deutschland GmbH     Germany
    • АТХ:

    L.04.A.A.29   Tofacitinib

    Pharmacodynamics:

    Immunosuppressant, a selective inhibitor of the family of Janus kinases, which has a high selectivity for other kinases of the human genome. Inhibition of janus kinase-1 results in a weakening of signal transmission under the action of additional pro-inflammatory cytokines, such as IL-6 and IFN-γ. At a higher exposure of the drug, inhibition of the transfer of the signal of Janus kinase-2 leads to inhibition of erythropoietin signaling.

    Pharmacokinetics:

    Maximum concentration is achieved within 0.5-1 h, rapid elimination (half-life about 3 hours) and a proportional dose increase in systemic exposure. Tofacitinib well absorbed, its bioavailability is 74%. The excretion of tofacitinib by approximately 70% is accomplished by metabolism in the liver and by 30% by kidney excretion in an unchanged form.

    Indications:Moderate or severe active rheumatoid arthritis in adults with an inadequate response to one or more basic anti-inflammatory drugs.
    ICD-10

    XIII.M05-M14.M05   Seropositive rheumatoid arthritis

    Contraindications:
    • Severe liver dysfunction.
    • Infection with hepatitis B and / or C viruses (presence of serological markers of HBV and HCV infection).
    • Creatinine clearance less than 40 ml / min.
    • Simultaneous use of live vaccines.
    • The simultaneous use of the drug with biological preparations, such as tumor necrosis factor inhibitors, interleukin antagonists (IL-1R, IL-6R), monoclonal anti-CD20 antibodies, selective co-stimulatory modulators, and potent immunosuppressants such as azathioprine, ciclosporin and tacrolimus, since this combination increases the likelihood of pronounced immunosuppression and the risk of infection.
    • Severe infections, active infections, including local infections.
    • Pregnancy (safety and efficacy not studied).
    • Breastfeeding period.
    • Children and adolescents under 18 years of age (safety and efficacy not studied).
    • Deficiency of lactase, lactose intolerance, glucose-galactose malabsorption.
    • Hypersensitivity to tofacitinib or to any other component of the drug.
    Carefully:

    At increased risk of perforation of the digestive tract (for example, in patients with a history of diverticulitis).

    In elderly patients due to the high risk of developing infectious diseases.

    Pregnancy and lactation:

    Adequate, well-controlled studies of the use of tofacitinib in pregnant women have not been conducted.

    The ability of tofacitinib to penetrate breast milk in humans has not been studied. You should stop breastfeeding during therapy with tofacitinib.

    Recommendations for FDA - category D.

    Dosing and Administration:

    Inside, regardless of food intake.

    Tofacitinib can be used as a monotherapy or in combination with methotrexate or other non-biological basic anti-inflammatory drugs.

    The recommended dose is 5 mg 2 times a day. Some patients may need to increase the dose to 10 mg twice a day, depending on the clinical response to therapy.

    Side effects:

    Infections and parasitic infestations: very often - nasopharyngitis; often - pneumonia, herpes zoster, bronchitis, influenza, sinusitis, urinary tract infections, pharyngitis; infrequent - sepsis, bacterial pneumonia, pneumococcal pneumonia, pyelonephritis, inflammation of subcutaneous fat,viral gastroenteritis, viral infection, herpes simplex; rarely - tuberculosis of the central nervous system, encephalitis, necrotizing fasciitis, cryptococcal meningitis, disseminated tuberculosis, urosepsis, pneumonia caused by Pneumocystis jiroveci, staphylococcal bacteremia, tuberculosis, bacterial arthritis, atypical infection caused by mycobacteria, infection caused by the complex Mycobacterium avium, cytomegalovirus infection, bacteremia.

    From the side of cardio-vascular system: often - increased blood pressure.

    From the side digestive system: often - abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia; infrequently, steatosis of the liver.

    From the side metabolism: often - hyperlipidemia, dyslipidemia; infrequently - dehydration.

    From the side nervous system: often - headache, insomnia; infrequently paresthesia.

    From the side musculoskeletal system: often - pain in muscles and bones, arthralgia; infrequently - tendonitis, swelling of the joints, muscle tension.

    From the side hemostasis systems: often - leukopenia, anemia; infrequently - neutropenia.

    From the side respiratory system: often shortness of breath, cough; infrequently, stagnation in the paranasal sinuses.

    From the side skin integument: often - a rash; infrequently - erythema, itchy skin.

    Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequently skin cancer not associated with melanoma.

    Laboratory and instrumental indicators: often - increased activity of liver enzymes, creatine phosphokinase, increased concentrations of LDL, blood cholesterol (in clinical trials first observed after the first month of therapy and remained stable in the future), weight gain; infrequently - an increase in the activity of transaminases, an increase in the concentration of creatinine in the blood plasma, an increase in concentration gamma-glutamyl transpeptidase, impaired functional liver tests.

    Other: often - fever, fatigue, peripheral edema.

    Overdose:

    Experience of overdose with the use of tofacitinib is absent. Treatment is symptomatic and supportive. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of unwanted reactions. If unwanted reactions develop, appropriate therapy should be prescribed. There is no specific antidote.

    Data on the pharmacokinetics in healthy volunteers,who received single doses up to 100 mg, indicate that about 95% of the administered dose is excreted within 24 hours.

    Interaction:

    Research in vitro showed that tofacitinib in concentrations that are even more than 150 times the equilibrium maximum concentration achieved when used at the recommended therapeutic doses, does not substantially inhibit or induce the activity of the main drugs metabolized by the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. These results were confirmed by in vitro studies of drug interaction, which showed no changes in the pharmacokinetics of midazolam, a highly selective substrate of the CYP3A4 isoenzyme, when used simultaneously with tofacitinib. Data in vitro showed that the ability of tofacitinib at therapeutic concentrations to inhibit carriers such as P-glycoprotein, organic anionic or cationic carriers is very low.

    Simultaneous use with tofacitinib had no effect on the pharmacokinetics of oral contraceptives, levonorgestrel and ethinylestradol in healthy women.

    The simultaneous use of tofacitinib with methotrexate at a dose of 15-25 mg once a week reduced the systemic exposureand maximum concentration methotrexate by 10% and 13%, respectively. These changes in the pharmacokinetics of methotrexate did not require dose adjustment, or the selection of individual doses of methotrexate.

    In patients with rheumatoid arthritis, the clearance of tofacitinib did not change over time. This indicates that tofacitinib does not affect the activity of CYP isoenzymes in patients with rheumatoid arthritis. Thus, the simultaneous use of substrates of CYP isoenzymes with tofacitinib is unlikely to lead to a clinically significant increase in their metabolism in patients with rheumatoid arthritis.

    Special instructions:

    Serious infections

    In patients with rheumatoid arthritis receiving immunomodulators, including biological agents and tofacitinib, serious and sometimes fatal infections are noted, caused by bacterial, mycobacterial, fungal, viral or other opportunistic pathogens. The most frequent serious infections noted with the use of tofacitinib include pneumonia, inflammation of the subcutaneous tissue, herpes zoster and urinary tract infection.Of the opportunistic infections with the use of tofacitinib, there have been cases of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, shingles with lesions of various dermatomes, cytomegalovirus infection, and VC-virus infection. In some patients, disseminated diseases were noted, most often with simultaneous use of immunomodulators - methotrexate or corticosteroids, which alone and in addition to the underlying disease of rheumatoid arthritis can predispose to the development of infections. It is also possible to develop other serious infections that have not been documented in clinical studies (eg, histoplasmosis, coccidioidomycosis and listeriosis).

    Tofacitinib should not be used in patients with active infection, including local infections. Before applying tofacitinib should evaluate the risk / benefit ratio of therapy in patients with chronic or recurrent infection after contact with TB patients, the presence of severe opportunistic infections or a history of patients who lived or visited recently endemic areas for TB or fungal infections, as well as in patients with a predisposition to developing infection.Patients should be closely monitored for signs and symptoms of infection during and after therapy with tofacitinib. Tofacitinib should be temporarily discontinued if the patient develops a serious infection, an opportunistic infection or sepsis. With the development of a new infection with the use of tofacitinib, the patient is subject to a rapid and complete diagnostic examination similar to a patient suffering from immunodeficiency. The appointment of appropriate antibiotic therapy as well as careful dynamic observation is shown.

    Since elderly patients usually have a higher incidence of infection, caution is also necessary in such cases.

    Tuberculosis

    Before applying tofacitinib, a check should be made for signs of latent or active tuberculosis infection.

    Before beginning therapy with tofacitinib in patients with latent or active tuberculosis in the history, in the absence of confirmation of an adequate course of antituberculous therapy, as well as in patients with a negative result of the study for latent tuberculosis, but presence of risk factors for tuberculosis infection, appropriate anti-tuberculosis therapy should be conducted.When deciding on the need for antituberculous therapy, it is recommended that in each individual patient, a consultation with the TB specialist is recommended.

    Patients should be closely monitored for signs of tuberculosis, including patients with negative latency tuberculosis before initiating therapy.

    The incidence of tuberculosis in the application of tofacitinib within the world clinical development program was 0.1-0.2%. Patients with latent tuberculosis before the initiation of therapy with tofacitinib are subject to standard antimycobacterial therapy.

    Reactivation of viral infections

    Reactivation of viral infections is described when using basic anti-inflammatory drugs. Cases of reactivation of the herpes virus (eg herpes zoster) have also been described in clinical studies of tofacitinib. The effect of tofacitinib on the reactivation of chronic viral hepatitis is unknown. Patients with a positive test result for hepatitis B and C were excluded from clinical trials. Before starting therapy with tofacitinib, screening for the presence of viral hepatitis should be carried out.

    Malignant and lymphoproliferative diseases (with the exception of skin cancer, not related to melanoma)

    There is a possibility that tofacitinib affects the protection of the body from malignant neoplasms. The effect of therapy with tofacitinib on development and course of malignant neoplasms is unknown, however, in clinical trials of this drug, cases of development of malignant neoplasms were recorded.

    Skin cancer not related to melanoma

    Cases of development have been reported skin cancer, not related to melanoma, in patients receiving therapy with tofacitinib. It is recommended to conduct periodic skin examination in patients with an increased risk of developing skin cancer.

    Cases of perforation of the digestive tract

    In clinical studies of patients with rheumatoid arthritis, cases of perforation of the gastrointestinal tract have been described, although the role of inhibition of the Yanus kinase is unknown in these phenomena. Such cases were mainly described as perforation of diverticula, peritonitis, abscess and appendicitis. All patients who developed perforation of the gastrointestinal tract received concomitant therapy with NSAIDs and / or glucocorticosteroids.The relative contribution of concomitant therapy and the use of tofacitinib in the development of perforation of the gastrointestinal tract is unknown.

    Tofacitinib should be used with caution in patients with an increased risk of perforation of the gastrointestinal tract (for example, in patients with a history of diverticulitis). Patients with new symptoms from the gastrointestinal tract are subject to immediate examination for early detection of perforation of the digestive tract.

    Laboratory indicators

    Neutrophils: treatment with tofacitinib was accompanied by an increase in the incidence of neutropenia (<2000 / μl) compared with placebo. Treatment with tofacitinib patients with a low concentration of neutrophils (absolute number of neutrophils less than 1000 / μl) is not recommended. In patients with a steady decrease in the absolute number of neutrophils to 500-1000 / μL, the dose of tofacitinib should be reduced or discontinued until the absolute neutrophil count exceeds 1,000 cells / μl. In patients with an absolute neutrophil count of less than 500 / μl, treatment is not recommended. The level of neutrophils should be monitored after 4-8 weeks of therapy, and then every 3 months.

    Hemoglobin: It is not recommended to begin therapy with tofacitinib in patients with low hemoglobin levels (less than 90 g / l).Treatment with tofacitinib should be discontinued in patients with a hemoglobin level of less than 80 g / l, or with a decrease in hemoglobin level by 20 g / l or more on the background of treatment. Hemoglobin should be monitored at the initial stage of therapy, after 4-8 weeks of therapy, and then every 3 months.

    Lipids: treatment with tofacitinib is accompanied by an increase in the level of blood lipids - total cholesterol, LDL cholesterol, and HDL cholesterol. The maximum effect was usually observed within 6 weeks. Evaluation of lipid parameters should be performed after about 4-8 weeks after initiation of therapy. The use of statins in patients with elevated concentrations of total cholesterol and LDL cholesterol on the background of therapy with tofacitinib allows achieving baseline values.

    Vaccination

    Information on the response to vaccination or secondary transmission of infection when live vaccines are administered to patients receiving tofacitinib, is absent until now. It is not recommended to administer live vaccines simultaneously with tofacitinib. It is recommended that before the start of tofacitinib, all patients perform the necessary immunizations in accordance with current vaccination recommendations.

    Patients with impaired renal function

    In clinical trials tofacitinib Not studied in patients with baseline creatinine clearance <40 mL / min.

    Impact on the ability to drive vehicles and manage mechanisms

    Impact studies tofacitinib the ability to drive and work with machinery have not been carried out.

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