Jaquinus^® (Tablets, Solution) Instructions for Use

ATC Code

L04AA29 (Tofacitinib)

Active Substance

Tofacitinib

Clinical-Pharmacological Group

Immunosuppressive drug

Pharmacotherapeutic Group

Immunosuppressants, selective immunosuppressants

Pharmacological Action

Tofacitinib is a potent, selective inhibitor of the Janus kinase family, possessing high selectivity for other kinases in the human genome. Based on kinase profiling results, Tofacitinib inhibits Janus kinases 1, 2, 3 and, to a lesser extent, Tyrosine kinase 2. In cells where Janus kinases transmit signals in pairs, Tofacitinib preferentially inhibits signaling through heterodimeric receptors associated with Janus kinase 3 and/or Janus kinase 1, exhibiting functional selectivity for receptors that signal through Janus kinase 2 pairs. Inhibition of Janus kinase 1 and Janus kinase 3 by tofacitinib blocks signaling via 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 signal transduction inhibition, leading to the modulation of various aspects of the immune response. Furthermore, inhibition of Janus kinase 1 leads to attenuation of signaling by additional proinflammatory cytokines, such as IL-6 and IFN-γ. At higher drug exposures, inhibition of Janus kinase 2 signaling leads to inhibition of erythropoietin signaling.

Pharmacodynamic effects

Treatment with Jaquinus^® is accompanied by a dose-dependent decrease in circulating natural killer CD16/56+ cells. The estimated maximum reduction is achieved after approximately 8-10 weeks of therapy initiation. The described changes usually resolve within 2-6 weeks after therapy cessation. Treatment with Jaquinus^® was accompanied by a dose-dependent increase in B-cell counts. Changes in circulating T-lymphocyte counts and their subpopulations were minor and inconsistent. The clinical significance of these changes is unknown. The change in total serum levels of IgG, M, and A over a 6-month treatment period in patients with rheumatoid arthritis was small, dose-independent, and similar to that with placebo.

Following treatment with Jaquinus^® in patients with rheumatoid arthritis, a rapid decrease in serum C-reactive protein (CRP) was observed, which persisted throughout the treatment period. Changes in CRP levels observed during treatment with Jaquinus^® did not resolve within 2 weeks after therapy discontinuation, indicating a longer duration of pharmacodynamic activity compared to T_1/2.

Similar changes were observed in patients with psoriasis.

Similar changes in T-cells, B-cells, and serum CRP were observed in patients with active psoriatic arthritis; however, reversibility was not assessed. The sum of serum immunoglobulins was not assessed in patients with active psoriatic arthritis.

Pharmacokinetics

Absorption and Distribution

The pharmacokinetic profile of tofacitinib is characterized by rapid absorption (C_max is reached within 0.5-1 h), rapid elimination (T_1/2 about 3 h), and a dose-proportional increase in systemic exposure. C_ss is achieved within 24-48 h with minimal accumulation after twice-daily administration.

Tofacitinib is well absorbed, with a bioavailability of 74%. Administration of tofacitinib with a high-fat meal did not result in changes in AUC, whereas plasma C_max decreases by 32%. In clinical studies, Tofacitinib was administered without regard to meals.

The binding of tofacitinib to plasma proteins is approximately 40%. Tofacitinib predominantly binds to albumin and does not bind to α₁-acid glycoprotein.

It is equally distributed between erythrocytes and plasma.

Metabolism and Excretion

Elimination of tofacitinib is approximately 70% via hepatic metabolism and 30% via renal excretion of unchanged tofacitinib. The metabolism of tofacitinib is primarily mediated by the CYP3A4 isoenzyme and to a lesser extent by the CYP2C19 isoenzyme. In a radiolabeled tofacitinib study, more than 65% of the total circulating radioactivity was attributed to unchanged Tofacitinib, and the remaining 35% to 8 metabolites (each less than 8% of total radioactivity). All metabolites detected in animals are presumed to have ≤10% potential for JAK1/3 inhibition. Pharmacological activity is associated with 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 tofacitinib AUC among Caucasian, Black, and Asian patients.

A nearly linear relationship was observed between body weight and V_d, leading to higher C_max and lower C_min plasma concentrations in patients with lower body weight. However, this difference is not considered clinically significant. The interindividual variability (% coefficient of variation) of the AUC for tofacitinib is about 27%.

Pharmacokinetics in patients with active psoriatic arthritis

A population pharmacokinetic analysis of patients with active psoriatic arthritis showed that the systemic exposure (AUC) of tofacitinib at extreme body weight values [(61 kg, 109 kg) (10^th and 90^th percentile in the patient population dataset)] was similar to that in patients weighing 83.3 kg.

In elderly patients aged 80 years, the estimated AUC value was 10% higher than in patients with a median age of 50 years.

In women, the estimated AUC was 5% lower than in men.

Available data also showed no significant differences in tofacitinib AUC values between Caucasian, Black, and Mongoloid patients.

Inter-patient variability (percentage coefficient of variation) of AUC values for Jaquinus^® is estimated to be about 32%.

Pharmacokinetics in patients with psoriasis

In patients with psoriasis, the clearance of tofacitinib (26.7 L/h) was found to be approximately 45% higher than in patients with rheumatoid arthritis (18.4 L/h). This corresponds to the AUC of tofacitinib in patients with psoriasis being approximately 30% lower than in patients with rheumatoid arthritis. Interindividual variability in AUC is approximately 28%.

Body weight does not affect the clearance of tofacitinib, while V_d increases with increasing body weight. This results in patients with lower body weight having a similar mean C_ss of tofacitinib as patients with higher body weight, but a higher C_max and lower C_min than patients with higher body weight. However, this difference is not considered clinically significant.

No differences in tofacitinib exposure were noted when assessing renal function (CrCl) in patients of different ages, body weights, sexes, races, ethnicities, and severity of the underlying disease.

Pharmacokinetics in patients with active ulcerative colitis

A population pharmacokinetic analysis of patients with ulcerative colitis did not reveal clinically significant changes in tofacitinib exposure levels (AUC) depending on age, body weight, sex, or race.

Exposure in women was 15% higher than in men, and exposure in Asian patients was 7.3% higher than in patients of other races.

There was a dependence between body weight and V_d, leading to higher C_max and lower C_min concentrations in patients with lower body weight. Nevertheless, this difference is not considered clinically significant.

The variability of tofacitinib AUC values among patients with ulcerative colitis (coefficient of variation in %) is estimated to be approximately 23% and 25% when taking the drug at a dose of 5 mg twice daily and 10 mg twice daily, respectively.

Pharmacokinetics in special clinical cases

In patients with mild, moderate, or 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.

In patients with mild and moderate hepatic impairment, AUC values exceeded those in healthy volunteers by 3% and 65%, respectively. Patients with severe hepatic impairment or patients with positive HBV or HCV serology have not been studied.

No pharmacokinetic, safety, or efficacy studies of tofacitinib have been conducted in children.

Indications

• Moderate or severe active rheumatoid arthritis in adult patients with an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs);
• Active psoriatic arthritis in adult patients with an inadequate response to one or more DMARDs;
• Moderate or severe chronic plaque psoriasis in adult patients when systemic therapy or phototherapy is indicated;
• Induction and maintenance therapy in adult patients with moderate or severe active ulcerative colitis with insufficient response, loss of response, or intolerance to corticosteroids, azathioprine, 6-mercaptopurine, or TNF inhibitors.

ICD codes

Dosage Regimen

Tablets

The drug is taken orally without regard to meals.

Rheumatoid arthritis

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

The recommended dose is 5 mg twice daily. In some patients, a dose increase to 10 mg twice daily may be required, depending on the clinical response to therapy.

Psoriatic arthritis

The recommended dose of Jaquinus^® is 5 mg twice daily in combination with standard synthetic DMARDs (csDMARDs).

Plaque psoriasis

The recommended dose of Jaquinus^® for the treatment of moderate or severe plaque psoriasis is 10 mg twice daily.

Ulcerative colitis

The recommended dose of Jaquinus^® for the treatment of adult patients with moderate or severe active ulcerative colitis is 10 mg twice daily for induction therapy for at least 8 weeks and 5 mg twice daily for maintenance therapy.

Induction therapy should be discontinued in patients who have not achieved a therapeutic effect by week 16.

For refractory patients, such as those who have not responded to previous TNF inhibitor therapy, continuation of treatment with a dose of 10 mg twice daily should be considered.

For patients in whom the therapeutic effect of Jaquinus^® at a dose of 5 mg twice daily is not maintained, it may be achieved by taking Jaquinus^® at a dose of 10 mg twice daily.

Dose adjustment due to laboratory abnormalities

Dose adjustment or therapy discontinuation may be required in case of development of dose-dependent laboratory abnormalities, including neutropenia and anemia (Tables 1, 2, and 3).

It is not recommended to initiate therapy in patients with an absolute neutrophil count (ANC) less than 1000/µL and/or a hemoglobin level less than 90 g/L. It is not recommended to initiate therapy with the drug in patients with a lymphocyte count less than 500/µL.

Table 1. Dose adjustment for lymphopenia

Table 2. Dose adjustment for neutropenia

Table 3. Dose adjustment for anemia

Special patient categories

Renal impairment

For indications with a maximum recommended dose of Jaquinus^® of 5 mg twice daily in patients with severe renal impairment, the recommended dose of Jaquinus^® is 5 mg twice daily. Specific recommendations for each indication are provided below.

Rheumatoid arthritis

No dose adjustment is required for patients with mild or moderate renal impairment. The dose of Jaquinus^® should not exceed 5 mg once daily in patients with severe renal impairment (including, but not limited to, patients on hemodialysis).

Psoriatic arthritis

No dose adjustment is required for patients with mild or moderate renal impairment. The recommended dose of Jaquinus^® is 5 mg once daily for patients with severe renal impairment (including, but not limited to, patients on hemodialysis).

Plaque psoriasis

No dose adjustment is required for patients with mild or moderate renal impairment. In patients with severe renal impairment, the dose of Jaquinus^® should not exceed 5 mg twice daily (including, but not limited to, patients on hemodialysis).

Ulcerative colitis

No dose adjustment is required for patients with mild or moderate renal impairment. In patients with severe renal impairment (including, but not limited to, patients on hemodialysis), the recommended dose of Jaquinus^® is 5 mg twice daily if the patient with normal renal function would have been prescribed 10 mg twice daily; the recommended dose is 5 mg once daily if the patient with normal renal function would have been prescribed 5 mg twice daily.

Hepatic impairment

For indications with a maximum recommended dose of Jaquinus^® of 5 mg twice daily in patients with moderate hepatic impairment, the recommended dose is 5 mg once daily. Specific recommendations for each indication are provided below.

Rheumatoid arthritis

No dose adjustment is required for patients with mild hepatic impairment. Jaquinus^® should not be used in patients with severe hepatic impairment. The dose of Jaquinus^® should not exceed 5 mg once daily in patients with moderate hepatic impairment.

Psoriatic arthritis

No dose adjustment is required for patients with mild hepatic impairment. Jaquinus^® is not recommended for patients with severe hepatic impairment. The recommended dose of Jaquinus^® is 5 mg once daily in patients with moderate hepatic impairment.

Plaque psoriasis

No dose adjustment is required for patients with mild hepatic impairment. Jaquinus^® is not recommended for patients with severe hepatic impairment. In patients with moderate hepatic impairment, the dose of Jaquinus^® should not exceed 5 mg twice daily.

Ulcerative colitis

No dose adjustment is required for patients with mild hepatic impairment. Jaquinus^® is not recommended for patients with severe hepatic impairment. In patients with moderate hepatic impairment, the recommended dose of Jaquinus^® is 5 mg twice daily if 10 mg twice daily would be prescribed with normal hepatic function; the recommended dose is 5 mg once daily if 5 mg twice daily would be prescribed with normal hepatic function.

Concomitant use with CYP3A4 and CYP2C19 inhibitors

For indications with a maximum recommended dose of Jaquinus^® of 5 mg twice daily in patients receiving strong CYP3A4 inhibitors (e.g., ketoconazole) or one or more concomitant medications resulting in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole), the recommended dose of Jaquinus^® is 5 mg once daily. Specific recommendations for each indication are provided below.

Rheumatoid arthritis

In patients receiving potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole), the dose of Jaquinus^® should not exceed 5 mg once daily. In patients receiving one or more concomitant medications that can moderately inhibit the CYP3A4 isoenzyme and potently inhibit the CYP2C19 isoenzyme (e.g., fluconazole), the dose of Jaquinus^® should not exceed 5 mg once daily.

Psoriatic Arthritis

For patients receiving strong CYP3A4 inhibitors (e.g., ketoconazole), the recommended dose of Jaquinus^® is 5 mg twice daily. For patients receiving one or more concomitant medications resulting in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole), the recommended dose of Jaquinus^® is 5 mg once daily.

Plaque Psoriasis

The dose of Jaquinus^® should not exceed 5 mg twice daily for patients receiving strong CYP3A4 inhibitors (e.g., ketoconazole). For patients receiving one or more concomitant medications resulting in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole), the dose of Jaquinus^® should not exceed 5 mg twice daily.

Ulcerative Colitis

For patients receiving strong CYP3A4 inhibitors (e.g., ketoconazole) or one or more concomitant medications resulting in both moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (e.g., fluconazole), the dose of Jaquinus^® should be reduced to 5 mg twice daily if the patient is taking 10 mg twice daily. If the patient is taking the drug at a dose of 5 mg twice daily, the dose should be reduced to 5 mg once daily.

Concomitant Use with CYP3A4 Inducers

Concomitant use of Jaquinus^® and potent CYP3A4 inducers (e.g., rifampicin) may lead to a reduction or loss of clinical efficacy; therefore, such a drug combination is not recommended.

Plaque Psoriasis in Patients of Japanese and Korean Ethnicity

Patients in this category have an increased risk of developing herpes zoster. Consideration should be given to using the drug at a dose of 5 mg twice daily.

Elderly Patients (≥65 years)

Dose adjustment in patients aged 65 years and older is not required.

Solution

Orally, regardless of food intake.

Tofacitinib can be used as monotherapy or in combination with methotrexate or other non-biological DMARDs.

The recommended dose is 5 mg twice daily. In some patients, a dose increase to 10 mg twice daily may be required, depending on the clinical response to therapy.

Dose adjustment or discontinuation of therapy may be required in case of dose-dependent laboratory abnormalities, including neutropenia and anemia.

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

In patients with severe renal and/or hepatic impairment, in patients receiving potent inhibitors of the CYP3A4 isoenzyme, in patients receiving one or more concomitant medications that can moderately inhibit the CYP3A4 isoenzyme and potently inhibit the CYP2C19 isoenzyme (e.g., fluconazole), the dose of tofacitinib should not exceed 5 mg twice daily.

Adverse Reactions

The most frequent serious adverse reactions observed during therapy with tofacitinib in patients with rheumatoid arthritis, psoriatic arthritis, and psoriasis were serious infections.

In induction and maintenance therapy studies across all treatment groups, the most common categories of serious adverse reactions in ulcerative colitis were gastrointestinal disorders and infections.

Rheumatoid Arthritis

In patients with rheumatoid arthritis, the most common adverse reactions during the first 3 months of controlled clinical studies (occurring in more than 2% of patients receiving Jaquinus^® monotherapy or its combination with DMARDs) included headache, upper respiratory tract infections, nasopharyngitis, hypertension, nausea, and diarrhea.

Discontinuation of therapy within the first 3 months due to any adverse reaction during double-blind, placebo-controlled studies or studies with methotrexate as a control drug was required in 3.8% of cases for patients in the Jaquinus^® group and 3.2% for patients in the placebo group. The most common adverse reactions leading to discontinuation of Jaquinus^® were infections. The most common infections leading to therapy discontinuation included herpes zoster and pneumonia.

Psoriatic Arthritis

In active psoriatic arthritis, the most frequently reported adverse reactions during the first 12 weeks in placebo-controlled clinical studies (occurring in ≥2% of patients receiving Jaquinus^®, with a frequency at least 1% higher than in patients receiving placebo) were bronchitis, diarrhea, dyspepsia, increased fatigue, headache, nasopharyngitis, pharyngitis.

The percentage of patients who discontinued treatment due to any adverse reactions during the first 12 weeks of the double-blind, placebo-controlled study was 3.2% for patients taking Jaquinus^® and 2.5% for patients taking placebo. The most common infection leading to therapy discontinuation was sinusitis.

The overall safety profile observed in patients with active psoriatic arthritis treated with Jaquinus^® is consistent with the safety profile in patients with rheumatoid arthritis.

Plaque Psoriasis

In patients with psoriasis, the most common adverse reactions during the first 12-16 weeks (occurring in more than 2% of patients receiving therapy with Jaquinus^®, and at least 1% higher than observed in patients receiving placebo) during the use of tofacitinib were diarrhea, upper respiratory tract infections, increased creatine phosphokinase (CPK) activity, plasma cholesterol concentrations, hypercholesterolemia, hyperlipidemia, and headache.

The number of patients in whom Jaquinus^® therapy had to be discontinued due to adverse reactions during the first 12-16 weeks of therapy in clinical studies was 3% compared to 4% of patients receiving placebo.

The most common infections leading to therapy discontinuation were pneumonia, urinary tract infections, and herpes zoster.

Ulcerative Colitis

Adverse reactions that were reported in ≥2% of patients receiving Jaquinus^® 10 mg twice daily, with a frequency at least 1% higher than in patients receiving placebo, in induction therapy studies (OCTAVE Induction-I, OCTAVE Induction-II, and OCTAVE SUSTAIN studies) were increased blood CPK level, nasopharyngitis, pyrexia, and headache.

In induction and maintenance therapy studies across all treatment groups, the most common categories of serious adverse reactions were gastrointestinal disorders and infections, with the most common serious adverse reaction being worsening of ulcerative colitis. In controlled clinical studies of ulcerative colitis, 1 case of breast cancer was reported in a patient receiving placebo; cases of solid malignant neoplasms or lymphomas in patients receiving Jaquinus^® were absent. In the long-term extension study, malignant neoplasms, including solid malignant neoplasms and lymphomas, were detected in patients with ulcerative colitis receiving Jaquinus^®.

In induction and maintenance therapy studies, the most common reason for study discontinuation was worsening of ulcerative colitis. Excluding discontinuation due to worsening of ulcerative colitis, the proportion of patients who discontinued treatment due to any adverse reactions was less than 5% in any of the groups taking Jaquinus^® or placebo in these studies.

The overall safety profile observed in patients with ulcerative colitis treated with Jaquinus^® is consistent with the safety profile for all indications of Jaquinus^®.

The frequency of adverse reactions was defined as follows: very common (≥10%), common (≥1% and <10%), uncommon (≥0.1% and <1%), rare (≥0.01% and <0.1%), very rare (<0.01%), not known (cannot be estimated from the available data). Within each frequency group, adverse reactions are presented in order of decreasing severity.

Infections and infestations Common – pneumonia, herpes zoster, bronchitis, influenza, sinusitis, urinary tract infections, nasopharyngitis, pharyngitis; Uncommon – tuberculosis (including disseminated tuberculosis), diverticulitis, pyelonephritis, cellulitis, viral infection, herpes simplex, viral gastroenteritis; Rare – sepsis, CNS tuberculosis^a, encephalitis^a, necrotizing fasciitis^a, cryptococcal meningitis^a, disseminated tuberculosis, urosepsis^a, Pneumocystis jirovecii pneumonia, pneumococcal pneumonia^a, bacterial pneumonia, staphylococcal bacteremia^a, atypical mycobacterial infection^a, Mycobacterium avium complex infection^a, cytomegalovirus infection, bacteremia^a, bacterial arthritis^b. Among patients taking Jaquinus^®, the frequency of serious infections was higher in individuals over 65 years of age than in those under 65 years of age.

Cardiac disorders Common – increased blood pressure.

Gastrointestinal disorders Common – abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia; Uncommon – hepatic steatosis.

Metabolism and nutrition disorders Common – hyperlipidemia; Uncommon – dyslipidemia, dehydration.

Nervous system disorders Common – headache; Uncommon – paresthesia.

Psychiatric disorders Uncommon – insomnia.

Musculoskeletal and connective tissue disorders Common – arthralgia; Uncommon – pain in extremity, tendonitis, joint swelling, muscle tightness.

Blood and lymphatic system disorders Common – anemia; Uncommon – leukopenia, neutropenia, lymphopenia. Confirmed cases of lymphocyte count decrease to a level less than 500 cells/µL were associated with an increased frequency of treated and serious infections. No clear association was found between neutropenia and the occurrence of serious infections.

Immune system disorders Uncommon – hypersensitivity^d.

Respiratory, thoracic and mediastinal disorders Common – cough; Uncommon – dyspnea, sinus congestion.

Skin and subcutaneous tissue disorders Common – rash; Uncommon – pruritus, erythema.

Benign, malignant and unspecified neoplasms (including cysts and polyps) Uncommon – non-melanoma skin cancer^c.

Investigations Common – increased GGT, CPK, blood cholesterol (in clinical studies, first noted after the first month of therapy and subsequently remained stable), increased body weight; Uncommon – increased hepatic enzymes, increased transaminases, increased plasma creatinine, impaired liver function tests, increased LDL concentration. When hepatic enzyme activity increased, reducing the dose of the concomitant DMARD, discontinuing or reducing the dose of Jaquinus^® led to a decrease or normalization of this parameter.

General disorders and administration site conditions Common – pyrexia, fatigue, peripheral edema; Uncommon – ligament sprain, muscle strain.

^a These adverse drug reactions were reported only in open-label, long-term, extension studies; therefore, the frequency of these adverse drug reactions was assessed from the phase 3 randomized studies.

^b The frequency of bacterial arthritis was determined by the combined frequency for the preferred terms of bacterial and infectious arthritis.

^c Non-melanoma skin cancer was established as an adverse drug reaction in 2013. Non-melanoma skin cancer is not a preferred term: frequency is determined by combining the frequencies for the preferred terms basal cell carcinoma and squamous cell carcinoma of skin.

^d Data from spontaneous reports (reactions such as angioedema and urticaria were observed). Some reactions were also observed in clinical studies.

Contraindications

• Severe hepatic impairment;
• 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 with biological drugs, such as TNF inhibitors, interleukin antagonists (IL-1R, IL-6R), monoclonal anti-CD20 antibodies, selective co-stimulatory modulators, as well as potent immunosuppressants such as azathioprine, cyclosporine, and tacrolimus, since such a combination increases the likelihood of pronounced immunosuppression and the risk of infection;
• Severe infections, active infections, including localized infections;
• Pregnancy (safety and efficacy have not been studied);
• Breastfeeding period;
• Age under 18 years (safety and efficacy have not been studied);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
• Hypersensitivity to tofacitinib or to any other component of the drug.

Use with caution in patients with an increased risk of gastrointestinal perforation (e.g., in patients with a history of diverticulitis); in elderly patients due to the high risk of developing infectious diseases.

Use in Pregnancy and Lactation

Adequate, well-controlled studies of the use of Jaquinus^® in pregnant women have not been conducted. Jaquinus^® should not be used during pregnancy.

Women of reproductive potential should be advised to use effective contraception during therapy with Jaquinus^® and for at least 4 weeks after taking the last dose of the drug.

The ability of tofacitinib to pass into human breast milk has not been studied. Breastfeeding should be discontinued during therapy with Jaquinus^®.

Use in Hepatic Impairment

The use of the drug is contraindicated in severe hepatic impairment.

Use in Renal Impairment

The use of the drug is contraindicated in creatinine clearance less than 40 ml/min.

Pediatric Use

The use of the drug is contraindicated in children under 18 years of age.

Geriatric Use

Dose adjustment in patients aged 65 years and older is not required; however, the drug should be used with caution in elderly patients due to the high risk of developing infectious diseases.

Special Precautions

Combined use with other antirheumatic agents

In patients with rheumatoid arthritis, the use of Jaquinus^® in combination with bDMARDs, such as TNF inhibitors, IL-1R antagonists, IL-6R antagonists, monoclonal antibodies to CD20, selective co-stimulation modulators, and potent immunosuppressants, for example, azathioprine, cyclosporine, and tacrolimus, has not been studied. Since there is a risk of enhanced immunosuppression with a subsequent increase in the risk of infection, the use of such combinations should be avoided.

When using Jaquinus^® in combination with MTX, a higher frequency of adverse events was observed than when using Jaquinus^® as monotherapy.

General infections

The most common infections noted during the use of tofacitinib in patients with rheumatoid arthritis were upper respiratory tract infections and nasopharyngitis (4.1% and 3.4%, respectively).

The most common infections noted during the first 12-16 weeks of tofacitinib therapy in patients with psoriasis were nasopharyngitis and upper respiratory tract infections (nasopharyngitis in 7% and 8% of cases with tofacitinib 5 mg and 10 mg twice daily, respectively, upper respiratory tract infections in 4% and 5% of cases with tofacitinib 5 mg and 10 mg twice daily, respectively).

Serious infections

In patients receiving immunomodulators, including biological drugs and Jaquinus^®, serious and sometimes fatal infections caused by bacterial, mycobacterial, fungal, viral, or other pathogens have been observed. The most common serious infections noted with the use of Jaquinus^® include pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections observed with the use of Jaquinus^® are cases of tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, herpes zoster involving various dermatomes, cytomegalovirus infection, BK virus infection, and listeriosis. Some patients with rheumatoid arthritis had disseminated diseases, most often with the concomitant use of immunomodulators – methotrexate or glucocorticoids, which themselves, in addition to the underlying disease (rheumatoid arthritis), may predispose to the development of infections. The development of other serious infections not registered in clinical studies (e.g., coccidioidomycosis) is also possible.

Jaquinus^® should not be used in patients with an active infection, including localized infections. Before using Jaquinus^®, the risk/benefit ratio of therapy should be assessed in patients with chronic or recurrent infection, after contact with a tuberculosis patient, with a history of severe or opportunistic infection, in patients who have lived in or recently visited tuberculosis or mycosis endemic areas, and in patients predisposed to developing infections. Patients should be carefully monitored for the development of 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 during the use of Jaquinus^®, the patient should undergo prompt and complete diagnostic evaluation similar to a patient with immunodeficiency. Appropriate antimicrobial therapy and careful follow-up are indicated.

Since elderly patients and patients with diabetes usually have a higher frequency of infections, caution should also be exercised in such cases.

Caution is also recommended when using the drug in patients with chronic lung diseases, as they may be more susceptible to infections. In clinical studies and during post-marketing use, cases of interstitial lung disease (some with fatal outcome) have been reported in patients receiving therapy with Jaquinus^®, a Janus kinase inhibitor. However, the role of Janus kinase inhibition is unknown.

The risk of infection may increase with increasing severity of lymphopenia. In this case, the lymphocyte count should be taken into account when assessing the individual risk of developing an infection.

Tuberculosis

Before using Jaquinus^®, the risk/benefit ratio of therapy should be assessed in patients with a history of tuberculosis, and in patients who have lived in or recently visited tuberculosis-endemic areas.

Before using Jaquinus^®, an examination for signs of latent or active tuberculosis infection should be performed in accordance with local guidelines.

Patients with latent tuberculosis should receive standard antimycobacterial therapy before starting treatment with Jaquinus^®.

Before initiating therapy with Jaquinus^® in patients with a history of latent or active tuberculosis, in the absence of confirmation of an adequate course of anti-tuberculosis therapy, and in patients with a negative test 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 a particular patient, it is recommended to consult with a phthisiatrician.

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

Reactivation of viral infections

Reactivation of viral infections has been described with DMARD therapy. Cases of herpes virus reactivation (e.g., herpes zoster) have also been described in clinical studies of Jaquinus^®. Post-marketing studies have reported cases of hepatitis B virus reactivation in patients receiving Jaquinus^® therapy. The effect of Jaquinus^® on the reactivation of chronic viral hepatitis is unknown. Patients with positive test results for hepatitis B and C were excluded from clinical studies. Screening for viral hepatitis should be performed before starting therapy with Jaquinus^®.

In clinical studies of Jaquinus^®, Japanese and Korean patients experienced more frequent cases of herpes zoster compared to patients of other ethnicities.

The frequency of herpes zoster may be increased in patients with a long history of rheumatoid arthritis who have previously received two or more biological DMARDs; in patients with an ANC of less than 1000 cells/µL.

Malignant and lymphoproliferative disorders (excluding non-melanoma skin cancer (NMSC))

Before initiating therapy in patients with an existing malignancy or a history of malignancy, except for cured NMSC, or when considering the possibility of continuing Jaquinus^® therapy in patients with a malignancy, the risk and benefits of treatment with Jaquinus^® should be taken into account. It is possible that Jaquinus^® affects the body’s defense against malignancies.

Cases of lymphoma have been reported in patients treated with Jaquinus^®. Although patients with rheumatoid arthritis, especially those with highly active disease, and patients with psoriasis may have a higher risk (several times higher) of developing lymphoma compared to the general population, the role of Jaquinus^®, if any, in the development of lymphoma has not been established.

Cases of other malignancies, including but not limited to lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer, have been reported in clinical studies and in the post-registration period.

The effect of Jaquinus^® therapy on the development and course of malignancies is unknown.

Non-melanoma skin cancer (NMSC)

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

Cases of gastrointestinal perforation

Cases of gastrointestinal perforation have been described in clinical studies, although the role of Janus kinase inhibition in these events is unknown. These cases were mainly described as diverticulum perforation, peritonitis, abdominal abscess, and appendicitis. All rheumatoid arthritis patients who developed gastrointestinal perforation were receiving concomitant therapy with NSAIDs and/or corticosteroids. The relative contribution of concomitant therapy and the use of Jaquinus^® in the development of gastrointestinal perforation is unknown. The frequency of such complications in patients with psoriasis, according to clinical study data, is 0.09 cases/100 patient-years.

Jaquinus^® should be used with caution in patients at increased risk of gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients with new gastrointestinal symptoms should be immediately examined for early detection of gastrointestinal perforation.

Risk of cardiovascular disease

Patients with rheumatoid arthritis are at an increased risk of cardiovascular disorders, so risk factors (e.g., hypertension and hyperlipidemia) should be controlled in these patients as part of routine standard care.

Liver enzymes

During treatment with Jaquinus^®, an increased frequency of elevated liver enzyme activity was observed in some patients. Caution should be exercised when initiating treatment with Jaquinus^® in patients with elevated ALT or AST, especially when initiating the drug in combination with potentially hepatotoxic drugs such as methotrexate. After initiation of treatment, biochemical parameters of liver function should be continuously monitored to detect potential cases of drug-induced liver injury, and possible causes of elevated liver enzymes should be promptly identified. If drug-induced liver injury is suspected, treatment with Jaquinus^® should be suspended until this diagnosis is ruled out.

Hypersensitivity

Hypersensitivity reactions such as angioedema and urticaria have been observed in patients taking Jaquinus^®. Some cases were assessed as serious. Most reactions occurred in patients with a history of multiple allergies. In case of a serious hypersensitivity reaction, the use of tofacitinib should be discontinued immediately until the cause is identified.

Laboratory parameters

Lymphocytes cases of decreased lymphocyte count to a level of less than 500 cells/µL were associated with an increased frequency of serious infections requiring therapy. It is not recommended to initiate therapy with Jaquinus^® in patients with a low lymphocyte count (i.e., less than 500 cells/µL). If a patient has a confirmed decrease in absolute lymphocyte count to a level of less than 500 cells/µL, treatment with Jaquinus^® is not recommended. Lymphocyte levels should be monitored at baseline and then every 3 months.

Neutrophils treatment with Jaquinus^® was associated with an increased frequency of neutropenia (< 2000/µL) compared to placebo. Initiating treatment with Jaquinus^® in patients with a low neutrophil count (ANC less than 1000/µL) is not recommended. In patients with a persistent decrease in ANC to 500-1000/µL, the dose of Jaquinus^® should be reduced or treatment discontinued until the ANC reaches more than 1000 cells/µL. In patients with an absolute neutrophil count of less than 500/µL, treatment is not recommended. Neutrophil levels should be monitored before starting therapy and after 4-8 weeks of therapy, and then every 3 months.

Hemoglobin it is not recommended to initiate therapy with Jaquinus^® in patients with a low hemoglobin level (less than 90 g/L). Treatment with Jaquinus^® 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 at the initial stage of therapy, after 4-8 weeks of therapy, and then every 3 months.

Lipids treatment with Jaquinus^® is accompanied by an increase in blood lipid levels – total cholesterol, LDL cholesterol, and HDL cholesterol. The maximum effect was usually observed within 6 weeks. Lipid parameters should be assessed after approximately 4-8 weeks after initiation of therapy. The use of statins in patients with elevated total cholesterol and LDL cholesterol during therapy with Jaquinus^® allows achieving baseline levels.

Vaccination

Information on secondary transmission of infection upon administration of live vaccines to patients receiving Jaquinus^® is currently unavailable. It is not recommended to administer live vaccines simultaneously with Jaquinus^®. It is recommended that all patients complete the necessary immunization according to current vaccination guidelines before starting Jaquinus^®. The interval between vaccination with live vaccines and the start of tofacitinib therapy should correspond to existing vaccination guidelines for patients receiving immunomodulatory therapy. According to these guidelines, if a live herpes zoster vaccine is administered, it should only be given to patients with a documented history of chickenpox or patients seropositive for varicella zoster virus. Vaccination should be performed at least 2 weeks, but preferably 4 weeks, before starting immunomodulatory therapy, such as Tofacitinib.

Patients with renal impairment

In clinical studies, Jaquinus^® was not studied in patients with baseline CrCl <40 mL/min (calculated using the Cockcroft-Gault formula).

Elderly patients

Elderly patients, in general, are at an increased risk of adverse events, which are more severe, so caution should be exercised when treating elderly patients.

Effect on ability to drive and operate machinery

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

Overdose

There is no experience with overdose with Jaquinus^®.

Treatment symptomatic and supportive therapy should be provided. In case of overdose, it is recommended to monitor the patient 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 from healthy volunteers receiving single doses of up to 100 mg indicate that approximately 95% of the administered dose is eliminated within 24 hours.

Drug Interactions

Interactions affecting the use of Jaquinus^®

Since Tofacitinib is metabolized by the CYP3A4 isoenzyme, interaction with drugs that inhibit or induce this isoenzyme is highly probable. When used concomitantly with potent inhibitors of the CYP3A4 isoenzyme (e.g., ketoconazole), as well as when used concomitantly with one or more moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (e.g., fluconazole), the exposure to tofacitinib increases. Concomitant use of ketoconazole (a potent CYP3A4 isoenzyme inhibitor) and a single dose of tofacitinib increased the AUC and C_max of tofacitinib by 103% and 16%, respectively. Concomitant use of fluconazole (a moderate CYP3A4 isoenzyme inhibitor and a potent CYP2C19 isoenzyme inhibitor) increased the AUC and C_max of tofacitinib by 79% and 27%, respectively.

When used concomitantly with potent inducers of the CYP3A4 isoenzyme (e.g., rifampicin), the exposure to tofacitinib decreases. Concomitant use of rifampicin (a potent CYP3A4 isoenzyme inducer) reduced the AUC and C_max of tofacitinib by 84% and 74%, respectively.

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

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

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

Interactions where Jaquinus^® affects the pharmacokinetics of other drugs

In vitro studies have shown that Tofacitinib, at concentrations even more than 80 times the C_ss^max of total tofacitinib achieved with tofacitinib doses of 5 mg and 10 mg twice daily in patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, and ulcerative colitis, does not significantly inhibit or induce the activity of major drugs metabolized by the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 isoenzymes. These results were confirmed by in vitro drug interaction studies, which showed no changes in the pharmacokinetics of midazolam, a highly selective CYP3A4 isoenzyme substrate, when used concomitantly with tofacitinib.

In vitro data indicate that Tofacitinib does not inhibit the activity of the major human drug-metabolizing enzyme, uridine 5′-diphosphate-glucuronosyltransferase (UGT) – UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7, at concentrations 250 times the C_ss^max of total tofacitinib occurring with tofacitinib doses of 5 mg and 10 mg twice daily in patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, and ulcerative colitis.

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.

Concomitant use with tofacitinib did not affect the pharmacokinetics of oral contraceptives, levonorgestrel and ethinyl estradiol, in healthy women.

Concomitant use of tofacitinib with methotrexate at a dose of 15-25 mg once weekly reduced the AUC and C_max of methotrexate by 10% and 13%, respectively. These changes in the pharmacokinetics of methotrexate did not require dose adjustment or individual methotrexate dosing.

In patients with rheumatoid arthritis, psoriasis, and ulcerative colitis, the clearance of tofacitinib did not change over time. This indicates that Tofacitinib does not affect the activity of CYP isoenzymes in these patients. Thus, it is unlikely that concomitant use of CYP isoenzyme substrates with tofacitinib will lead to a clinically significant increase in their metabolism in patients with rheumatoid arthritis, psoriasis, and ulcerative colitis. Concomitant administration of Jaquinus^® did not affect the pharmacokinetics of metformin, indicating that Tofacitinib does not affect the organic cation transporter (OCT2) in healthy volunteers.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.