Yakvinus (Tofacitinib)

Composition, release form and packaging

Tablets - 1 tab.:

• active substance: tofacitinib 5/10 mg as tofacitinib citrate 8.078 /16.155 mg;
• excipients: microcrystalline cellulose 122.615/245.230 mg, lactose monohydrate 61.307/122.615 mg, sodium croscarmellose 6/12 mg, magnesium stearate 2/4 mg;
• Film coating: Opadry White 6 mg (hypromellose 2.4 mg, titanium dioxide 1.5 mg, lactose monohydrate 1.26 mg, macrogol 0.48 mg, triacetin 0.36 mg. Opadry Blue 12 mg (hypromellose 4.8 mg, titanium dioxide 2.724 mg, lactose monohydrate 2.52 mg, macrogol 0.96 mg, triacetin 0.24 mg, indigo carmine aluminum lake 0.24 mg, brilliant blue aluminum lake 0.036 mg.

14 tablets in an aluminum foil blister.

4 blisters together with instructions for use in a cardboard box.

Description of the dosage form

White, round, film-coated tablets engraved with "Pfizer" on one side and "JKI 5" on the other. The tablet core is white or almost white. Two layers are visible on the cross-section. The tablet core is white or almost white.

Pharmacotherapeutic group

Selective immunosuppressants.

Pharmacokinetics

The pharmacokinetic profile of tofacitinib is characterized by rapid absorption (maximum plasma concentration is achieved within 0.5-1 hour), rapid elimination (half-life approximately 3 hours), and dose-proportional increase in systemic exposure. Steady-state concentrations are achieved within 24-48 hours, with little accumulation after twice-daily dosing.

Absorption and distribution

Tofacitinib is well absorbed and its bioavailability is 74%. Administration of tofacitinib with a high-fat meal did not result in changes in the area under the concentration-time curve (AUC), while the maximum concentration (Cmax) in plasma was reduced by 32%. In clinical studies, tofacitinib was administered regardless of food intake.

Plasma protein binding of tofacitinib is approximately 40%. Tofacitinib is predominantly bound to albumin and does not bind to α1-acid glycoprotein. Tofacitinib is equally distributed between red blood cells and plasma.

Metabolism and excretion

Tofacitinib clearance is approximately 70% via hepatic metabolism and 30% via renal excretion as unchanged tofacitinib. Tofacitinib metabolism is primarily mediated by CYP3A4 and to a lesser extent CYP2C19. In a study of radiolabeled tofacitinib, more than 65% of the total circulating radioactivity was due to unchanged tofacitinib and the remaining 35% was due to 8 metabolites (each less than 8% of the total radioactivity). The pharmacologic activity is due to unmetabolized tofacitinib.

Pharmacokinetics in patients with rheumatoid arthritis

In patients with rheumatoid arthritis, the AUC of tofacitinib at minimum and maximum body weights (40 and 140 kg) was found to be similar to that in patients weighing 70 kg.

In elderly patients aged 80 years, the AUC was less than 5% higher compared to patients aged 55 years.

In women, the AUC of tofacitinib is 7% lower compared to men. The data also showed no significant differences (<5%) in the AUC of tofacitinib between Caucasian, Black, and Asian patients. A nearly linear relationship was observed between body weight and volume of distribution, resulting in higher Cmax and lower minimum plasma concentration (Cmax) in patients with lower body weight. However, this difference is not considered clinically significant. The interindividual variability (% CV) in AUC for tofacitinib was approximately 27%.

Impaired renal function

In patients with mild, moderate, and severe renal impairment, AUC values ​​were 37%, 43%, and 123% higher, respectively, compared to healthy volunteers. In patients with end-stage renal disease, the contribution of dialysis to the total clearance of tofacitinib is relatively small.

Impaired liver function

In patients with mild to moderate hepatic impairment, AUC values ​​were reduced by 3%

and 65% exceeded similar indicators in healthy volunteers.

Patients with severe hepatic impairment or patients with positive

HBV or HCV serological tests have not been studied.

Childhood

Studies of the pharmacokinetics, safety, and efficacy of tofacitinib in children have not been conducted.

Pharmacodynamics

Mechanism of action

Tofacitinib is a potent, selective inhibitor of the Janus kinase family, with high selectivity for other kinases in the human genome. In a kinase assay, tofacitinib inhibits Janus kinases 1, 2, 3, and to a lesser extent tyrosine kinase 2. In cells where Janus kinases signal in pairs, tofacitinib preferentially inhibits signaling through heterodimeric receptors associated with Janus kinase 3 and/or Janus kinase 1, with functional selectivity for receptors that signal through Janus kinase 2 pairs. Inhibition of Janus kinase 1 and Janus kinase 3 by tofacitinib blocks signaling through common gamma-chain-containing receptors for several cytokines, including IL-2, -4, -7, -9, -15, and -21. These cytokines play an integrative role in lymphocyte activation, proliferation, function, and inhibition of signaling, resulting in modulation of multiple aspects of the immune response. In addition, inhibition of JAK-1 results in attenuation of signaling by additional proinflammatory cytokines such as IL-6 and IFN-γ. At higher drug exposures, inhibition of JAK-2 signaling results in inhibition of erythropoietin signaling.

Pharmacodynamic effects

Treatment with Yaquinus was associated with a dose-dependent reduction in circulating CD16/56+ natural killer cells. The estimated maximum reduction was achieved approximately 8-10 weeks after initiation of therapy. These changes usually resolved 2-6 weeks after completion of therapy. Treatment with Yaquinus was associated with a dose-dependent increase in B-cell counts. Changes in circulating T-lymphocyte counts and their subsets were small and variable. The clinical significance of these changes is unknown. The change in total serum IgG, M, and A levels over the 6-month treatment period in patients with rheumatoid arthritis was small, dose-independent, and similar to placebo.

Following treatment with Yakvinus in patients with rheumatoid arthritis, a rapid decrease in serum C-reactive protein (CRP) was observed, which was maintained throughout the treatment period. The changes in CRP levels observed during treatment with Yakvinus did not resolve within 2 weeks after discontinuation of therapy, indicating a longer duration of pharmacodynamic activity compared to the half-life.

Indications for use

Yakvius is indicated for the treatment of adult patients with moderate to severe active rheumatoid arthritis who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

Contraindications for use

• hypersensitivity to tofacitinib or to any other component of the drug;
• 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;
• concomitant use of live vaccines;
• Concomitant use of Yakvinus with biological agents such as tumor necrosis factor (TNF) inhibitors, interleukin (IL-IR, IL-6R) antagonists, monoclonal anti-CD20 antibodies, selective co-stimulatory modulators, and potent immunosuppressants such as azathioprine, cyclosporine, and tacrolimus should be avoided, since such a combination increases the likelihood of severe immunosuppression and the risk of infection;
• severe infections, active infections, including local, severe infectious diseases;
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• pregnancy (safety and efficacy have not been studied);
• breastfeeding period;
• children under 18 years of age (safety and efficacy have not been studied).

The drug Yakvinus should be used with caution:

• in cases of increased risk of gastrointestinal (GI) organ perforation (e.g., in patients with a history of diverticulitis).
• in elderly people due to the high risk of developing infectious diseases.

Pregnancy and lactation

There are no adequate, well-controlled studies of the use of Yaquinus in pregnant women. Yaquinus should not be used during pregnancy.

The ability of tofacitinib to penetrate into human breast milk has not been studied. Breastfeeding should be discontinued during therapy with Yaquinus.

Side effects

The most common serious adverse reactions reported with tofacitinib therapy were serious infections.

The most common adverse reactions during the first 3 months of controlled clinical trials (occurring in more than 2% of patients receiving Yaquinus monotherapy or in combination with DMARDs) included upper respiratory tract infection, headache, nasopharyngitis, and diarrhea. Discontinuation of therapy during the first 3 months due to any adverse reaction in double-blind, placebo-controlled trials was required in 4.2% of patients in the Yaquinus group and 3.2% of patients in the placebo group. The most common adverse reactions leading to Yaquinus discontinuation were infections. The most common infections leading to discontinuation of therapy included herpes zoster and pneumonia.

The frequency of adverse reactions is presented according to the following classification: Very common >10%; Common >1% and <10%; Uncommon >0.1% and <1%; Rare >0.01% and <0.1%; Very rare <0.01%.

No information can not be determined from the available data

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Infectious and parasitic diseases: very common - nasopharyngitis; common - pneumonia, herpes zoster, bronchitis, influenza, sinusitis, urinary tract infection, pharyngitis; uncommon - sepsis, bacterial pneumonia, pneumococcal pneumonia, pyelonephritis, subcutaneous fat inflammation, viral gastroenteritis, viral infection, herpes simplex; rare - tuberculosis of the central nervous system (CNS), encephalitis, necrotizing fasciitis, cryptococcal meningitis, disseminated tuberculosis, urosepsis, Pneumocystis jiroveci pneumonia, staphylococcal bacteremia, tuberculosis, bacterial arthritis, atypical mycobacterium infection, Mycobacterium avium complex infection, cytomegalovirus infection, bacteremia. Among patients taking Jaquinus, the rate of serious infections was higher in those over 65 years of age than in those under 65 years of age.

From the cardiovascular system: common - increased blood pressure.

From the digestive system: common - abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia.

From the side of metabolism: frequent - hyperlipidemia, dyslipidemia; uncommon - dehydration.

From the nervous system: frequent - headache; uncommon - paresthesia. Mental disorders: frequent - insomnia.

From the musculoskeletal system and connective tissue: common - muscle and bone pain, arthralgia; uncommon - teidipitis, joint swelling, muscle tension.

From the blood and lymphatic system: common - leukopenia, anemia; uncommon - neutropenia, lymphopenia.

Confirmed cases of lymphocyte counts <500 cells/mm3 were associated with an increased incidence of treated and serious infections. No clear relationship was found between neutropenia and the occurrence of serious infections.

From the respiratory system: common - shortness of breath, cough; uncommon - congestion in the paranasal sinuses.

From the skin: common - rash; uncommon - erythema, itching. From the liver and biliary tract: uncommon - fatty hepatosis. Benign, malignant and unspecified neoplasms (including cysts and polyps): uncommon - skin cancer, not associated with melanoma.

Violations revealed in clinical and laboratory studies: common - increased activity of liver enzymes, creatine phosphokinase (CPK), increased concentration of low-density lipoproteins (LDL), blood cholesterol (in clinical studies, they were first noted after the first month of therapy and subsequently remained stable), increased body weight; uncommon - increased activity of transaminases, increased concentration of creatinine in blood plasma, increased concentration of gamma-glutamyl transferase (GGT), impaired liver function tests. With increased activity of liver enzymes, a decrease in the dose of concomitant DMARDs, cancellation or reduction of the dose of Yakvinus led to a decrease or normalization of this parameter.

General disorders and reactions at the injection site: common - fever, fatigue, peripheral edema.

Trauma, intoxication and complications of manipulation: common - sprained ligaments; uncommon - muscle strain.

Interaction with medicinal products

Interactions affecting the use of the drug Yakvinus

Since tofacitinib is metabolized by CYP3A4, interactions with drugs that inhibit or induce this isoenzyme are highly likely. When co-administered with strong CYP3A4 inhibitors (e.g. ketoconazole), as well as with one or more moderate CYP3A4 inhibitors and strong CYP2C19 inhibitors (e.g. fluconazole), tofacitinib exposure increases (see section "Dosage and administration"). Co-administration of ketoconazole (a strong CYP3A4 inhibitor) and a single dose of tofacitinib increased the AUC and Cmax of tofacitinib by 103% and 16%, respectively. Concomitant use of fluconazole (a moderate inhibitor of CYP3A4 and a strong inhibitor of CYP2C19) increases the AUC and Cmax of tofacitinib by 79% and 27%, respectively.

When co-administered with strong CYP3A4 inducers (e.g. rifampicin), tofacitinib exposure is reduced. Co-administration of rifamnicin (a strong CYP3A4 inducer) reduces tofacitinib AUC and Cmax by 84% and 74%, respectively (see section "Dosage and Administration").

The likelihood of an effect of CYP2C19 or P-glycoprotein inhibitors on the pharmacokinetics of tofacitinib is low.

Concomitant use of tacrolimus (a weak inhibitor of the CYP3A4 isoenzyme) increases the AUC of tofacitinib by 21% and decreases the Cmax of tofacitinib by 9%. Concomitant use of cyclosporine (a moderate inhibitor of the CYP3A4 isoenzyme) increases the AUC of tofacitinib by 73% and decreases the Cmax of tofacitinib by 17%. Concomitant multiple use of tofacitinib and potent immunosuppressants in patients with rheumatoid arthritis has not been studied.

Co-administration with methotrexate (15-25 mg methotrexate once weekly) does not affect the pharmacokinetics of tofacitinib.

Interactions in which Yaquinus affects the pharmacokinetics of other drugs In vitro studies have shown that tofacitinib at concentrations even more than 150 times higher than the steady-state Cmax achieved with the use of recommended therapeutic doses does not significantly inhibit or induce the activity of the main drugs metabolized by cytochromes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). These results were confirmed by in vitro drug interaction studies, which showed no change in the pharmacokinetics of midazolam, a highly selective substrate of the CYP3A4 isoenzyme, when co-administered with tofacitinib. In vitro data have shown that the ability of tofacitinib at therapeutic concentrations to inhibit transporters such as P-glycoprotein, organic anion or cation transporters is very low.

Co-administration with tofacitinib had no effect on the pharmacokinetics of oral contraceptives, levonorgestrel, and ethinyl estradiol in healthy women. Co-administration of tofacitinib with methotrexate 15-25 mg once weekly decreased methotrexate AUC and Cmax by 10% and 13%, respectively. These changes in methotrexate pharmacokinetics did not require dose adjustment or individual dose adjustment of methotrexate.

In patients with rheumatoid arthritis, tofacitinib clearance did not change over time, indicating that tofacitinib does not affect CYP activity in patients with rheumatoid arthritis. Therefore, co-administration of CYP substrates with tofacitinib is unlikely to result in a clinically significant increase in their metabolism in patients with rheumatoid arthritis. Co-administration of Jaquinus did not affect the pharmacokinetics of metformin, indicating that tofacitinib does not affect the organic cation transporter (OCT2) in healthy volunteers.

Method of administration and dosage

Orally, regardless of food intake.

Jaquinus can be used as monotherapy or in combination with methotrexate or other non-biologic DMARDs.

The recommended dose is 5 mg twice daily. Some patients may require an increase in the dose to 10 mg twice daily, depending on the clinical response to therapy.

Dose adjustments due to laboratory abnormalities

Dose adjustment or discontinuation of therapy may be required if dose-related laboratory abnormalities develop, including lymphopenia, neutropenia, and anemia (see Tables 1, 2, and 3).

It is not recommended to initiate therapy in patients with an absolute neutrophil count (ANC) of less than 1000/mm3 and/or a hemoglobin level of less than 9 g/dL. It is not recommended to initiate therapy with the drug in patients with a lymphocyte count of less than 500 cells/mm3.

Table 1. Dose adjustment for lymphopenia

Table 2. Dose adjustment for neutropenia

Table 3. Dose adjustment for anemia

Special categories of patients

Impaired renal function

No dosage adjustment is required for patients with mild to moderate renal impairment.

The dose of Yaquinus should not exceed 5 mg twice daily in patients with severe renal impairment.

Impaired liver function

In patients with mild hepatic impairment, no dose adjustment is required. Yaquinus should not be used in patients with severe hepatic impairment. The dose of Yaquinus should not exceed 5 mg twice daily in patients with moderate hepatic impairment.

Concomitant use with inhibitors of cytochrome P450 (CYP3A4) and the CYP2C19 isoenzyme

In patients receiving strong inhibitors of the CYP3A4 isoenzyme (e.g. ketoconazole), the dose of Yaquinus should not exceed 5 mg twice daily. In patients receiving one or more concomitant drugs that can moderately inhibit the CYP3A4 isoenzyme and actively inhibit the CYP2C19 isoenzyme (e.g. fluconazole), the dose of Yaquinus should not exceed 5 mg twice daily.

Concomitant use of Yakvinus and strong inducers of the CYP3A4 isoenzyme (e.g. rifampicin) may result in a decrease or loss of clinical efficacy (see section "Interaction with other medicinal products").

Elderly patients (> 65 years)

No dose adjustment is required in patients aged 65 years and older.

Overdose

There is no experience of overdose with Yakvinus. Treatment is symptomatic and supportive. In case of overdose, it is recommended to monitor the patient's condition for the development of signs and symptoms of adverse reactions. If adverse reactions develop, appropriate therapy should be prescribed. There is no specific antidote.

Pharmacokinetic data in healthy volunteers receiving single doses up to 100 mg indicate that approximately 95% of the administered dose is excreted within 24 hours.

Precautions and special instructions

Serious infections

Serious and sometimes fatal infections caused by bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving immunomodulators, including biologics and Yakvinus. The most common serious infections reported with Yakvinus include pneumonia, cellulitis, herpes zoster, and urinary tract infection. Opportunistic infections reported with Yakvinus include tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, herpes zoster involving various dermatomes, cytomegalovirus infection, and BK virus infection. Disseminated disease has been reported in some patients, most often with concomitant use of immunomodulators, such as methotrexate or corticosteroids. which in themselves and in addition to the underlying disease rheumatoid arthritis may predispose to the development of infections. It is also possible to develop other serious infections that have not been recorded in clinical studies (e.g. histoplasmosis, coccidioidomycosis and listeriosis).

Jaquinus should not be used in patients with active infection, including local infections. Before using Jaquinus, the risk/benefit ratio of therapy should be assessed in patients with chronic or recurrent infection, after exposure to a patient with tuberculosis, with a history of severe or opportunistic infection, in patients who have lived in or recently visited endemic areas for tuberculosis or fungal infections, and in patients with a predisposition to infection. Patients should be closely monitored for signs and symptoms of infection during and after therapy with Jaquinus. Jaquinus should be temporarily discontinued if a patient develops a serious infection, opportunistic infection, or sepsis until the patient's condition is controlled. If a new infection develops while using Jaquinus, the patient should undergo prompt and complete diagnostic evaluation as for an immunocompromised patient. Appropriate antibacterial therapy and close dynamic monitoring are indicated.

Since elderly patients are generally characterized by a higher incidence of

infections, in such cases caution should also be exercised.

Tuberculosis

Before using Yakvinus, you should be examined for signs of latent or active tuberculosis infection.

Before starting therapy with Yakvinus 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 with risk factors for tuberculosis infection, appropriate anti-tuberculosis therapy should be administered. When deciding on the need for anti-tuberculosis therapy in each individual patient, it is recommended to consult a phthisiatrician.

Patients should be closely monitored for the development of signs of tuberculosis, including patients with a negative latent tuberculosis test result, prior to initiation of therapy.

The incidence of tuberculosis with the use of Yakvinus 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 Yakvinus.

Reactivation of viral infections

Reactivation of viral infections has been reported with DMARD therapy. Cases of herpes virus reactivation (eg, herpes zoster) have also been reported in clinical studies with Yakvinus. The effect of Yakvinus on reactivation of chronic viral hepatitis is unknown. Patients who tested positive for hepatitis B and C were excluded from clinical studies. Screening for viral hepatitis should be performed before initiating Yakvinus therapy.

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

There is a possibility that Yaquinus affects the body's defense against malignancies. The effect of Yaquinus therapy on the development and course of malignancies is unknown, but malignancies have been reported in clinical trials of this drug. Lymphoma has been reported in patients treated with Yaquinus. Although patients with rheumatoid arthritis, particularly those with highly active disease, have a higher risk (several-fold higher) of developing lymphoma compared with the general population, the role, if any, of Janus kinase (JAK) inhibition in the development of lymphoma is unknown.

Non-melanoma skin cancer (NMSC)

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

Cases of perforation of the gastrointestinal tract

Gastrointestinal perforation has been reported in clinical studies in patients with rheumatoid arthritis, although the role of Janus kinase inhibition in these events is unknown. The main events reported were diverticulum perforation, peritonitis, abdominal abscess, and appendicitis. All patients who developed gastrointestinal perforation were receiving concomitant therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and/or glucocorticoids. The relative contribution of concomitant therapy and JAKVINUS in the development of gastrointestinal perforation is unknown.

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

Laboratory indicators

Lymphocytes: Lymphocyte counts below 500 cells/mm" have been associated with an increased incidence of serious infections requiring treatment. It is not recommended to initiate therapy with Jaquinus in patients with low lymphocyte counts (i.e. below 500 cells/mm3). If a patient has a confirmed absolute lymphocyte count below 500 cells/mm3, treatment with Jaquinus

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

Neutrophils: Treatment with YAQUINUS was associated with an increased incidence of neutropenia (< 2000 cells/mm3) compared with placebo. Treatment with YAQUINUS is not recommended in patients with low neutrophil counts (ANC < 1000 cells/mm3). 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 is > 1000 cells/mm3. Treatment is not recommended in patients with confirmed absolute neutrophil counts < 500 cells/mm3. Neutrophil counts should be monitored at baseline and after 4-8 weeks of therapy, and then every 3 months (see sections 4.2 and 4.8).

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 start of therapy, after 4-8 weeks of therapy, and then every 3 months (see section "Dosage and administration").

Lipids: Treatment with Yakvinus results in an increase in blood lipid levels - total cholesterol, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol. The maximum effect is usually observed within 6 weeks. Lipid parameters should be assessed approximately 4-8 weeks after the start of therapy. The use of statins in patients with elevated total cholesterol and LDL cholesterol during therapy with Yakvinus allows the baseline values ​​to be achieved.

Vaccinations

There is currently no information on the response to vaccination or secondary transmission of infection when live vaccines are administered to patients receiving Jaquinus. It is not recommended to administer live vaccines concurrently with Jaquinus. It is recommended that all patients receive the required immunizations according to current vaccination recommendations before starting Jaquinus.

Patients with impaired renal function

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

Impact on the ability to drive vehicles and operate machinery

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

Storage conditions

Conditions of dispensing from pharmacies

According to the recipe