Jaquinus, 5 mg 56 pcs.

Jaquinus is a selective immunosuppressant. Tofacitinib is a potent, selective inhibitor of the Janus kinase family with high selectivity against other kinases of the human genome. According to the results of kinase studies, tofacitinib inhibits Janus kinases 1, 2, 3 and, to a lesser extent, tyrosine kinase 2.

In those cells where janus kinases transmit signals in pairs, tofacitinib preferentially inhibits the signal transduction of heterodimeric receptors associated with janus kinase-3 and/or janus kinase-1, with functional selectivity for receptors that transmit signals via janus kinase-2 pairs. Inhibition of janus kinase-1 and janus kinase-3 by tofacitinib blocks signaling through common receptors containing gamma chains against several cytokines including IL-2, -4, -7, -9, -15 and -21.

These cytokines have an integrating role in the processes of lymphocyte activation, proliferation, function and inhibition of signal transduction, leading to modulation of diverse aspects of the immune response. In addition, inhibition of Janus kinase-1 leads to attenuation of signal transduction by additional proinflammatory cytokines, such as IL-6 and IFN-γ. At higher drug exposure, inhibition of Janus kinase-2 signaling leads to inhibition of erythropoietin signaling.

Pharmacodynamic effects

The treatment with Jaquinus is accompanied by a dose-dependent decrease in circulating CD16/56+ natural killer cells. The estimated maximum reduction is achieved after about 8-10 weeks of therapy. The described changes usually resolve 2-6 weeks after the end of therapy. Treatment with Jaquinus was accompanied by a dose-dependent increase in the number of B-cells. Changes in the number of circulating T-lymphocytes and their subpopulations were insignificant and inconstant. The clinical significance of these changes is unknown. The change in total serum IgG, M and A levels during the 6-month treatment period in patients with rheumatoid arthritis was small, dose-independent and similar to that with placebo.

After treatment with Jaquinus, patients with rheumatoid arthritis experienced a rapid decrease in serum C-reactive protein (CRP) that persisted throughout the treatment period. The changes in C-RB levels observed during treatment with Jaquinus did not persist for 2 weeks after discontinuation of therapy, indicating a longer duration of pharmacodynamic activity compared to the half-life.

Pharmacokinetics

Absorption and distribution

The pharmacokinetics profile of tofacitinib is characterized by rapid absorption (Cmax is reached within 05-1 h), rapid excretion (T1/2 about 3 h) and dose-proportional increase in systemic exposure. Css is reached within 24-48 h with slight accumulation after administration 2 times/day.

Tofacitinib is well absorbed with a bioavailability of 74%. Administration of tofacitinib with fat-rich foods was not accompanied by changes in AUC, while Cmax in plasma is reduced by 32%. In clinical trials tofacitinib was used regardless of food intake.

The binding of tofacitinib to plasma proteins is approximately 40%. Tofacitinib predominantly binds to1-acid glycoprotein.

It is equally distributed between erythrocytes and blood plasma.

Metabolism and excretion

The excretion of tofacitinib is approximately 70% by metabolism in the liver and 30% by excretion by the kidneys as unchanged tofacitinib. Metabolism of tofacitinib is predominantly mediated by CYP3A4 isoenzyme and to a lesser extent by CYP2C19 isoenzyme. In a study of radioactively labeled 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). Pharmacological activity was associated with unmetabolized tofacitinib.

Pharmacokinetics in patients with rheumatoid arthritis

The AUC of tofacitinib at minimum and maximum body weight (40 and 140 kg) was found to be similar to that of 70 kg in patients with rheumatoid arthritis.

The AUC was less than 5% higher in elderly patients aged 80 years compared to patients aged 55 years.

The AUC of tofacitinib was 7% lower in women compared to men.

The data also showed no significant difference (< 5%) in the AUC of tofacitinib in Caucasian, Negroid and Asian patients.

A nearly linear relationship between body weight and Vd was observed, resulting in a higher Cmax and lower Cmin in plasma in patients with lower body weight. However, this difference is not considered clinically significant. The interindividual variability (% coefficient of variability) of the AUC for tofacitinib is approximately 27%.

Pharmacokinetics in Special Clinical Cases

Patients with mild, moderate or severe renal impairment had higher AUCs of 37%, 43% and 123%, respectively, compared to healthy volunteers. In patients with end-stage renal failure, the contribution of dialysis to the total clearance of tofacitinib is relatively small.

In patients with mild to moderate hepatic impairment, AUCs were 3% and 65% higher than in healthy volunteers. Patients with severe hepatic impairment have not been studied.

Tofacitinib pharmacokinetics, safety and efficacy in children have not been studied.

Indications

Moderate to severe active rheumatoid arthritis in adults with inadequate response to one or more baseline anti-inflammatory drugs (BART).

Active ingredient

Composition

1 film-coated tablet contains:

the active ingredient:

Tofacitinib citrate 8.078 mg, which corresponds to the content of tofacitinib 5 mg,

excipients:

Microcrystalline cellulose – 122.615 mg,

Lactose monohydrate – 61.307 mg,

croscarmellose sodium – 6 mg,

magnesium stearate – 2 mg.

coating composition:

Opadray 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).

How to take, the dosage

Orally, regardless of meals.

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

The recommended dose is 5 mg twice daily. In some patients, it may be necessary to increase the dose to 10 mg 2 times/day, depending on the clinical response to therapy.

Dose adjustment due to laboratory abnormalities

Dose adjustment or discontinuation of therapy may be required if dose-dependent abnormal laboratory values develop, including neutropenia and anemia (Tables 1 and 2).

It is not recommended to initiate therapy in patients with an absolute neutrophil count (ANR) of less than 1000/μL and/or with a hemoglobin level less than 90 g/L.

Table 1. Dose adjustment for neutropenia

Low BUNLaboratory value (cells/μL)RecommendationsA BUN > 1000Dose remains the same.BUN 500-1000If persistent decrease in this range, dose should be reduced or administration should be stopped.
If there is an increase in AFN over 1000 cells/μL, therapy may be resumed at a dose of 5 mg twice daily; thereafter, depending on clinical response, the dose may be increased to 10 mg twice daily.AFN < 500 (confirmed by reassessment)Cancel therapy.

Table 2. Dose adjustment for anemia

Low hemoglobinLaboratory value (g/L)Recommendation≥ 90 and decrease of less than 20 g/LDose remains the same.< 80 or decrease of 20 g/L or more (confirmed on reassessment)Jaquinus should be stopped until hemoglobin levels normalize.

Patients with mild to moderate renal dysfunction do not require dose adjustment. In patients with severe renal impairment, the dose of Jaquinus should not exceed 5 mg 2 times daily.

Yaquinus should not be used in patients with severe hepatic impairment. The dose of Jaquinus should not exceed 5 mg 2 times/day in patients with moderate hepatic impairment.

In elderly patients 65 years of age and older, no dose adjustment is required.

In patients receiving potent CYP3A4 isoenzyme inhibitors, the dose of Jaquinus should not exceed 5 mg 2 times/day.

In patients receiving one or more concomitant drugs capable of moderately inhibiting the CYP3A4 isoenzyme and actively inhibiting the CYP2C19 isoenzyme (e.g., fluconazole), the dose of Jaquinus should not exceed 5 mg 2 times daily.

The concomitant use of Jaquinus and potent CYP3A4 isoenzyme inhibitors may lead to a reduction or loss of clinical efficacy.

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Interaction

Interactions affecting the use of the drug Jaquinus

As tofacitinib is metabolized under the action of CYP3A4 isoenzyme, it is very likely that there is interaction with drugs that inhibit or induce this isoenzyme. When concomitant use with potent CYP3A4 isoenzyme inhibitors (e.g., ketoconazole), as well as when used with one or more moderate CYP3A4 isoenzyme inhibitors and potent CYP2C19 isoenzyme inhibitors (e.g., fluconazole) exposure tofacitinib is increased. Concomitant use of ketoconazole (a potent CYP3A4 isoenzyme inhibitor) and a single dose of tofacitinib increases AUC and Cmax of tofacitinib by 103% and 16%, respectively. Concomitant use of fluconazole (a moderate inhibitor of CYP3A4 isoenzyme as well as a potent inhibitor of CYP2C19 isoenzyme) increases AUC and Cmax of tofacitinib by 79% and 27% respectively.

Concomitant use with potent inducers of CYP3A4 isoenzyme (e.g., rifampicin) decreases tofacitinib exposure. Concomitant use of rifampicin (a potent inducer of CYP3A4 isoenzyme) reduces AUC and Cmax of tofacitinib by 84% and 74% respectively.

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

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

Concomitant use with methotrexate (15-25 mg of methotrexate once weekly) has no effect on the pharmacokinetics of tofacitinib.

Interactions in which Jaquinus affects the pharmacokinetics of other drugs

. In vitro studies have shown that tofacitinib at concentrations, even more than 150 times the Cssmax that is achieved when used at recommended therapeutic doses, does not significantly inhibit or induce the activity of major drugs metabolized by the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 isozymes. These results were confirmed by in vitro drug interaction studies, which showed no changes in the pharmacokinetics of midazolam, a highly selective substrate of the CYP3A4 isoenzyme, when used concomitantly with tofacitinib. In vitro data have shown that the ability of tofacitinib at therapeutic concentrations to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters is very low.

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

Concomitant use of tofacitinib with methotrexate at a dose of 15-25 mg once a week reduced the AUC and Cmax of methotrexate by 10% and 13%, respectively. These changes in methotrexate pharmacokinetics did not require dose adjustments or selection of individual methotrexate doses.

In patients with rheumatoid arthritis, tofacitinib clearance did not change over time. This indicates that tofacitinib has no effect on CYP isoenzyme activity in patients with rheumatoid arthritis. Thus, it is unlikely that concomitant use of CYP isoenzyme substrates with tofacitinib will result in a clinically significant increase in their metabolism in patients with rheumatoid arthritis.

Special Instructions

Serious infections

In patients with rheumatoid arthritis receiving immunomodulators, including biologics and Jaquinus, serious and sometimes fatal infections due to bacterial, mycobacterial, fungal, viral, or other opportunistic pathogens have been reported. The most frequent serious infections reported with Jaquinus include pneumonia, subcutaneous inflammation, herpes zoster, and urinary tract infection. Among opportunistic infections, cases of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, shingles with various dermatomes, cytomegalovirus infection, and BV virus infection have been reported with Jaquinus. Disseminated, disease has been noted in some patients, most often with the simultaneous use of immunomodulators – methotrexate or corticosteroids, which by themselves and in addition to the underlying disease rheumatoid arthritis can predispose to the development of infections. Other serious infections that have not been reported in clinical trials (e.g., histoplasmosis, coccidioidomycosis, and listeriosis) are also possible.

Yaquinus should not be used in patients with active infections, including localized infections. Before using Jaquinus, the risk/benefit ratio of therapy should be evaluated in patients with chronic or recurrent infection, after contact with a patient with tuberculosis with a history of severe or opportunistic infection, in patients who have lived or recently visited endemic areas for tuberculosis or mycoses, and in patients with a predisposition to develop infection. Patients should be closely monitored for signs and symptoms of infection during and after therapy with Jaquinus. Jaquinus should be temporarily discontinued if the patient develops a serious infection, an opportunistic infection, or sepsis. If a new infection develops during the use of Jaquinus, the patient is subject to prompt and complete diagnostic evaluation similar to that of an immunodeficient patient. The prescription of appropriate antibiotic therapy is indicated, as well as careful dynamic monitoring.

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

Tuberculosis

Ahead of the use of Jaquinus, evaluation for signs of latent or active tuberculosis infection should be performed.

In patients with a history of latent or active tuberculosis, in the absence of evidence of adequate antituberculosis therapy, or in patients who test negative for latent tuberculosis but have risk factors for tuberculosis infection, appropriate antituberculosis therapy should be given before starting therapy with Yaquinus. It is advisable to consult a phthisiatrician in deciding whether TB therapy is necessary in each individual patient.

Patients should be closely monitored for signs of TB, including patients who test negative for latent TB prior to initiation of therapy.

The incidence of tuberculosis with Jaquinus 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 Jaquinus.

Reactivation of viral infections

Reactivation of viral infections has been described when using BPV therapy. Reactivation of herpes virus infections (e.g., herpes zoster) has also been described in clinical studies of Jaquinus. The effect of Jaquinus on reactivation of chronic viral hepatitis is unknown. Patients who tested positive for hepatitis B and C have been excluded from clinical trials. Screening for viral hepatitis should be performed before starting therapy with Jaquinus.

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

Yaquinus has the potential to affect the body’s defense against malignancies. The effect of Jaquinus therapy on the development and course of malignancies is unknown, but clinical studies of the drug have documented cases of malignancies.

Non-melanoma skin cancer (RSCC)

The development of RSCC has been reported in patients receiving therapy with tofacitinib. Periodic skin examinations are recommended in patients who are at increased risk of developing skin cancer.

In cases of GI organ perforation

In clinical studies of patients with rheumatoid arthritis, cases of GI organ perforation have been described, although the role of Janus kinase inhibition in these phenomena is unknown. Such cases have mainly been described as diverticular perforation, peritonitis, abscess and appendicitis. All patients who developed gastrointestinal perforation received concomitant therapy with NSAIDs and/or GCS. The relative contribution of concomitant therapy and use of Jaquinus in the development of gastrointestinal perforation is unknown.

Yaquinus should be used with caution in patients with an increased risk of gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients with new gastrointestinal symptoms should be evaluated immediately for early detection of gastrointestinal perforation.

Laboratory measures

Neutrophils: Treatment with Jaquinus was associated with an increased incidence of neutropenia (less than 2000/μL) compared to placebo. Treatment with Jaquinus is not recommended in patients with a low concentration of neutrophils (AFP less than 1000/μL). In patients with persistent decrease of BFN to 500-1000/μL, the dose of Jaquinus should be decreased or treatment should be stopped until BFN concentration of more than 1000 cells/μL is achieved. In patients with absolute neutrophil counts 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: Therapy with Yaquinus is not recommended for patients with low hemoglobin levels (less than 90 g/l). The treatment with the drug Yaquinus should be stopped in patients with a hemoglobin level less than 80 g/l or when the hemoglobin level decreases by 20 g/l or more during the treatment. Hemoglobin should be monitored at the beginning of therapy, after 4-8 weeks of therapy and then every 3 months.

Lipids: treatment with Jaquinus is accompanied by increase in blood lipids – total cholesterol, LDL cholesterol, and HDL cholesterol. Maximum effect was usually observed within 6 weeks. Assessment of lipid parameters should be performed after about 4-8 weeks after the start of therapy. Use of statins in patients with elevated concentrations of total cholesterol and LDL cholesterol during therapy with Jaquinus helps to achieve baseline values.

Vaccination

There is currently no information on response to vaccination or secondary transmission of infection when administering live vaccines to patients receiving Jaquinus. Live vaccines should not be administered at the same time as Jaquinus. It is recommended that all patients complete the required immunizations in accordance with current vaccination recommendations before starting Jaquinus.

Patients with impaired renal function

Yaquinus has not been studied in patients with a baseline CK < 40 ml/min in clinical studies.

Impact on driving and operating ability

There have been no studies of the effect of Jaquinus on driving and operating ability.

Contraindications

Side effects

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

The most common adverse reactions during the first 3 months of controlled clinical trials (with development in more than 2% of patients treated with Jaquinus monotherapy or its combination with DMARDs) included upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.

Cancellation of therapy for any adverse reaction during double-blind, placebo-controlled trials was required in 6.8% of patients in the Jaquinus group and 3.7% of patients in the placebo group.

The most common adverse reactions that led to withdrawal of Jaquinus were infections. The most frequent infections leading to therapy withdrawal included herpes zoster and pneumonia.

In each frequency group, adverse reactions are presented in decreasing order of severity.

Infections and parasitic infestations: very common – nasopharyngitis; common – pneumonia, herpes zoster, bronchitis, influenza, sinusitis, urinary tract infections, pharyngitis; infrequent – sepsis, bacterial pneumonia, pneumococcal pneumonia, pyelonephritis, inflammation of subcutaneous fatty tissue, viral gastroenteritis, viral infection, herpes simplex; rare – CNS tuberculosis, 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 Mycobacterium avium complex, cytomegalovirus infection, bacteremia.

Cardiovascular system disorders: often – BP increase.

The digestive system: frequently – abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia; infrequently – hepatic steatosis.

Metabolism: frequently – hyperlipidemia, dislipidemia; infrequently – dehydration.

Nervous system disorders: frequently – headache, insomnia; infrequent – paresthesia.

Muscular system: often – muscle and bone pain, arthralgia; infrequent – tendinitis, joint swelling, muscle tension.

Hemostatic system: frequently – leukopenia, anemia; infrequently – neutropenia.

Respiratory system: often – shortness of breath, cough; infrequent – nasal sinus congestion.

The skin: often – rash; infrequent – erythema, pruritus.

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

Laboratory and instrumental parameters: often – increased activity of liver enzymes, CPK, increased concentration of LDL, blood cholesterol (in clinical trials first observed after the first month of therapy and subsequently remained stable), increased body weight; infrequent – increased activity of transaminases, increased concentration of creatinine in plasma, increased concentration of GGTP, impaired liver function tests.

Others: often – fever, fatigue, peripheral edema.

Overdose

There is no experience of overdose with the drug Jaquinus. Treatment is symptomatic and supportive. In case of overdose, it is recommended to monitor the patient for signs and symptoms of adverse reactions. In case of development of adverse reactions, 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.

Pregnancy use

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

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