Expiration date: 10/2026

Release form, composition and packaging

White film-coated tablets, round, biconvex, with the inscription "Pfizer" on one side and "JKI 5" on the other; the core of the tablet is white or almost white.

1 tab;et of 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.

The composition of the film shell: 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).

14 pcs. - blisters (4) - cardboard packs with the control of the first opening.

Pharmacological action

Tofacitinib is a powerful, selective inhibitor of the Janus kinase family, with high selectivity against other kinases of the human genome. According to the results of the study of kinases, tofacitinib inhibits janus kinases 1, 2, 3 and to a lesser extent tyrosine kinase-2. In those cells where janus kinases transmit a signal in pairs, tofacitinib preferably inhibits the signal transmission of heterodimer receptors associated with janus kinase-3 and/or janus kinase-1, having functional selectivity for receptors that transmit signals through janus kinase-2 pairs. Inhibition of janus kinase-1 and janus kinase-3 under the action of tofacitinib blocks signal transmission via common receptors containing gamma chains against several cytokines, including IL-2, -4, -7, -9, -15 and -21. These cytokines play an integrating role in the processes of activation of lymphocytes, their proliferation, functioning and inhibition of signal transmission, which leads to the modulation of various aspects of the immune response. In addition, the inhibition of janus kinase-1 leads to a weakening of signal transmission under the action of additional pro-inflammatory cytokines, such as IL-6 and IFN-?. At higher drug exposure, inhibition of janus kinase-2 signal transmission leads to inhibition of erythropoietin signal transmission.

Pharmacodynamic effects

Treatment with the drug Jaquinus is accompanied by a dose-dependent decrease in circulating natural killers CD16/56+. The estimated maximum reduction is achieved after about 8-10 weeks after the start of therapy. The described changes are usually resolved 2-6 weeks after the end of therapy. Treatment with the drug 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 unstable. The clinical significance of these changes is unknown. The change in the total serum levels of IgG, M and A during the 6-month period of treatment of patients with rheumatoid arthritis was small, dose-independent and similar to that with placebo.

After treatment with Jaquinus in patients with rheumatoid arthritis, there was a rapid decrease in serum C-reactive protein (C-RB), which persisted throughout the entire treatment period. Changes in the level of C-RB noted during treatment with the drug Jaquinus did not occur within 2 weeks after discontinuation of therapy, which indicates a longer duration of pharmacodynamic activity compared to T1/2.

Similar changes were observed in patients with psoriasis.

Similar changes in T-cells, B-cells and C-RB in blood serum were observed in patients with active psoriatic arthritis, but reversibility was not evaluated. The amount of serum immunoglobulins was not evaluated in patients with active psoriatic arthritis.

Pharmacokinetics

Suction and distribution

The pharmacokinetics profile of tofacitinib is characterized by rapid absorption (Cmax is reached within 0.5-1 h), rapid excretion (T1/2 about 3 h) and a dose-proportional increase in systemic exposure. Css is achieved within 24-48 hours with a slight accumulation after taking 2 times / day.

Tofacitinib is well absorbed, its bioavailability is 74%. The use of tofacitinib with a fat-rich diet was not accompanied by changes in AUC, while Cmax in blood plasma decreased by 32%. In clinical studies, tofacitinib was used regardless of food intake.

The binding of tofacitinib to plasma proteins is approximately 40%. Tofacitinib mainly binds to albumin and does not bind to ?1-acid glycoprotein.

It is equally distributed between red blood cells and blood plasma.

Metabolism and excretion

Excretion of tofacitinib by about 70% is carried out by metabolism in the liver and by 30% by excretion by the kidneys in the form of unchanged tofacitinib. The metabolism of tofacitinib is mainly mediated by the CYP3A4 isoenzyme and to a lesser extent by the CYP2C19 isoenzyme. In the study of tofacitinib labeled with a radioactive isotope, more than 65% of the total circulating radioactivity accounted for unchanged tofacitinib, and the remaining 35% - for 8 metabolites (each - less than 8% of the total radioactivity). It is assumed that all metabolites that are found in animals have a 10% potential inhibition of JAK1/3. Pharmacological activity is associated with unmetabolized tofacitinib.

Pharmacokinetics in patients with rheumatoid arthritis

It was found that in patients with rheumatoid arthritis, the AUC of tofacitinib at minimum and maximum body weight (40 and 140 kg) were similar to those in patients with a body weight of 70 kg.

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

In women, the AUC of tofacitinib is 7% lower compared to men.

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

There is an almost linear relationship between body weight and Vd, which leads to the achievement of higher Cmax and lower Cmin in blood plasma in patients with lower body weight. However, this difference is not considered to be clinically significant. The interindividual variability (% coefficient of variability) of the AUC index for tofacitinib is about 27%.

Pharmacokinetics in patients with active psoriatic arthritis

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

In elderly patients aged 80 years, the AUC value was estimated to be 10% higher than in patients with an average age of 50 years.

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

The available data also showed that there were no significant differences in the AUC values of tofacitinib between patients of the Caucasian, Negroid and Mongoloid races.

The variability in different patients (percentage coefficient of variation) of AUC values for the drug Jaquinus is estimated to be about 32%.

Pharmacokinetics in patients with psoriasis

It was found that in patients with psoriasis, the clearance of tofacitinib (26.7 l/h) is approximately 45% higher than in patients with rheumatoid arthritis (18.4 l/h). This corresponds to the fact that the AUC of tofacitinib in patients with psoriasis is approximately 30% lower than in patients with rheumatoid arthritis. The interindividual variability of AUC is approximately 28%.

Body weight does not affect the clearance of tofacitinib, while Vd increases with increasing body weight. This leads to the fact that in patients with a lower body weight, the average Css of tofacitinib corresponds to that of patients with a higher body weight, the Cmax of tofacitinib is higher, and the Cmin is lower than in patients with a higher body weight. However, this difference is not taken into account as clinically significant.

There were no differences in the exposure of tofacitinib when assessing renal function (CC) in patients of different ages, body weight, gender, race, ethnicity and severity of the underlying disease.

Pharmacokinetics in patients with active ulcerative colitis

Population pharmacokinetic analysis of patients with ulcerative colitis did not reveal clinically significant changes in the level of exposure to tofacitinib (AUC) depending on age, body weight, gender and 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.

A relationship between body weight and Vd was observed, leading to higher Cmax and lower Cmin concentrations in patients with lower body weight. However, this difference is not considered clinically significant.

It is estimated that the variability of AUC values of tofacitinib between patients with ulcerative colitis (coefficient of variation in %) is approximately 23% and 25% when taking the drug at a dose of 5 mg 2 times / day and at a dose of 10 mg 2 times / day, respectively.

Pharmacokinetics in special clinical cases

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

In patients with mild and moderate hepatic impairment, AUC values were 3% and 65% higher than those in healthy volunteers. Patients with severe hepatic impairment or patients with positive HBV or HCV serological tests were not studied.

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

Indications

• moderate or severe active rheumatoid arthritis in adult patients with an inadequate response to one or more basic anti-inflammatory drugs (HDL);
• active psoriatic arthritis in adult patients with an inadequate response to one or more HDL;
• chronic plaque psoriasis of moderate or severe severity 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.

Dosage regimen

The drug is taken orally regardless of food intake.

Rheumatoid arthritis

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

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

Psoriatic arthritis

The recommended dose of the drug Jaquinus is 5 mg 2 times / day in combination with standard synthetic BMARP (ssBMARP).

Plaque psoriasis

The recommended dose of the drug Jaquinus for the treatment of plaque psoriasis of moderate or severe degree is 10 mg 2 times / day.

Ulcerative colitis

The recommended dose of the drug Jaquinus for the treatment of adult patients with moderate or severe active ulcerative colitis is 10 mg 2 times / day for induction therapy for at least 8 weeks and 5 mg 2 times / day for maintenance therapy.

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

For refractory patients, such as patients who have not responded to previous TNF inhibitor therapy, consideration should be given to continuing treatment with a dose of 10 mg 2 times / day.

Patients for whom the therapeutic effect of the drug Jaquinus at a dose of 5 mg 2 times / day has not been preserved, it can be achieved by taking the drug Jaquinus at a dose of 10 mg 2 times / day.

Dose adjustment due to laboratory abnormalities

It is not recommended to start therapy in patients with an absolute neutrophil count (AHN) of less than 1000 / ml and / or with a hemoglobin level of less than 90 g / l. It is not recommended to start therapy with the drug in patients with a lymphocyte count of less than 500 / ml.

Low acnlaboratory value (cells/ml)The recommendation HH >1000 dose remains at the same level.ACN 500-1000P with a persistent decrease in this range, the dose should be reduced or discontinued until the ACN reaches more than 1000 cells / ml.

For patients receiving Jaquinus at a dose of 5 mg 2 times / day, stop taking the drug. If the AHN is more than 1000, resume taking the drug Jaquinus at a dose of 5 mg 2 times / day.

For patients receiving Jaquinus at a dose of 10 mg 2 times / day, reduce the dose of the drug to 5 mg 2 times / day.

With an AHN of more than 1000, increase the dose of the drug Jaquinus to 10 mg 2 times / day, based on the clinical response to treatment.AHN <500 (confirmed upon re-evaluation)Cancel therapy.

Low hemoglobin level Laboratory value (g/l)Recommendations?90 and a reduction of less than 20 g/lDose remains at the same level.<80 or a decrease of 20 g/l or more (confirmed upon re-evaluation)The use of the drug Jaquinus should be discontinued until the hemoglobin level normalizes.

Special categories of patients

Impaired renal function

For indications with the maximum recommended dose of the drug Jaquinus 5 mg 2 times / day in patients with severe renal impairment, the recommended dose of the drug Jaquinus is 5 mg 2 times / day. Specific recommendations for each indication are presented below.

Rheumatoid arthritis

Patients with mild or moderate renal impairment do not require dose adjustment. The dose of the drug Jaquinus should not exceed 5 mg 1 time / day in patients with severe renal impairment (including, but not limited to, patients on hemodialysis).

Psoriatic arthritis

In patients with mild or moderate renal impairment, dose adjustment is not required. The recommended dose of the drug Jaquinus is 5 mg 1 time / day for patients with severe renal impairment (including, but not limited to, patients on hemodialysis).

Plaque psoriasis

In patients with mild or moderate renal impairment, dose adjustment is not required. In patients with severe renal impairment, the dose of the drug Jaquinus should not exceed 5 mg 2 times / day (including, but not limited to, patients on hemodialysis).

Ulcerative colitis

In patients with mild or moderate renal impairment, dose adjustment is not required. In patients with severe renal impairment (including, but not limited to, patients on hemodialysis), the recommended dose of the drug Jaquinus is 5 mg 2 times / day if, with normal renal function, the patient would have been prescribed 10 mg 2 times / day; the recommended dose is 5 mg 1 time / day if, with normal renal function, the patient would have been prescribed 5 mg 2 times / day.

Impaired liver function

For indications with the maximum recommended dose of the drug Jaquinus 5 mg 2 times / day in patients with moderate hepatic impairment, the recommended dose is 5 mg 1 time / day. Specific recommendations for each indication are presented below.

Rheumatoid arthritis

In patients with mild hepatic impairment, dose adjustment is not required. Jaquinus should not be used in patients with severe hepatic impairment. The dose of the drug Jaquinus should not exceed 5 mg 1 time / day in patients with moderate hepatic impairment.

Psoriatic arthritis

In patients with mild hepatic impairment, dose adjustment is not required. The drug Jaquinus is not recommended for patients with severe hepatic impairment. The recommended dose of the drug Jaquinus is 5 mg 1 time / day in patients with moderate hepatic impairment.

Plaque psoriasis

In patients with mild hepatic impairment, dose adjustment is not required. The drug Jaquinus  is not recommended for patients with severe hepatic impairment. In patients with moderate hepatic impairment, the dose of the drug Jaquinus should not exceed 5 mg 2 times / day.

Ulcerative colitis

In patients with mild hepatic impairment, dose adjustment is not required. The drug Jaquinus is not recommended for patients with severe hepatic impairment. In patients with moderate hepatic impairment, the recommended dose of the drug Jaquinus is 5 mg 2 times / day, if 10 mg 2 times / day is prescribed for normal liver function; the recommended dose is 5 mg 1 time / day, if 5 mg 2 times / day is prescribed for normal liver function.

Concomitant use with CYP3A4 and CYP2C19 inhibitors

For indications with the maximum recommended dose of the drug Jaquinus 5 mg 2 times / day in patients receiving strong inhibitors of CYP3A4 (eg, ketoconazole) or one or more concomitant drugs, which leads in both cases to moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (eg, fluconazole), the recommended dose of the drug Jaquinus is 5 mg 1 time / day. Specific recommendations for each indication are presented below.

Rheumatoid arthritis

In patients receiving powerful inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole), the dose of the drug Jaquinus should not exceed 5 mg 1 time / day. In patients receiving one or more concomitant medications capable of moderately inhibiting the CYP3A4 isoenzyme and actively inhibiting the CYP2C19 isoenzyme (for example, fluconazole), the dose of the drug Jaquinus should not exceed 5 mg 1 time / day.

Psoriatic arthritis

For patients receiving strong CYP3A4 inhibitors (for example, ketoconazole), the recommended dose of the drug Jaquinus is 5 mg 2 times / day. For patients receiving one or more concomitant medications, which leads in both cases to moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (for example, fluconazole), the recommended dose of the drug Jaquinus  is 5 mg 1 time / day.

Plaque psoriasis

The dose of the drug Jaquinus should not exceed 5 mg 2 times / day for patients receiving strong CYP3A4 inhibitors (for example, ketoconazole). For patients receiving one or more concomitant medications, which leads in both cases to moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (for example, fluconazole), the dose of the drug Jaquinus should not exceed 5 mg 2 times / day.

Ulcerative colitis

For patients receiving strong CYP3A4 inhibitors (for example, ketoconazole) or one or more concomitant medications, which leads in both cases to moderate inhibition of CYP3A4 and strong inhibition of CYP2C19 (for example, fluconazole), the dose of the drug Jaquinus should be reduced to 5 mg 2 times / day if the patient takes 10 mg 2 times / day. If the patient takes the drug at a dose of 5 mg 2 times / day, the dose should be reduced to 5 mg 1 time / day.

Simultaneous use with CYP3A4 inducers

Simultaneous use of the drug Jaquinus and powerful inducers of CYP3A4 (for example, rifampicin) may lead to a decrease or loss of clinical efficacy, therefore, such a combination of drugs is not recommended.

Plaque psoriasis in patients of Japanese and Korean nationalities

Patients in this category have an increased risk of developing herpes zoster. The possibility of using the drug at a dose of 5 mg 2 times / day should be considered.

Elderly patients (?65 years)

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

Side effect

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

In studies of induction and maintenance therapy in 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 frequent adverse reactions during the first 3 months of controlled clinical trials (with the development of more than 2% of patients receiving Jaquinus monotherapy or its combination with HDL) included headache, upper respiratory tract infections, nasopharyngitis, hypertension, nausea and diarrhea.

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

Psoriatic arthritis

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

The percentage of patients who stopped treatment due to any adverse reactions during the first 12 weeks of the double-blind placebo-controlled trial was 3.2% for patients taking Jaquinus and 2.5% for patients taking placebo. The most common infection that led to discontinuation of therapy was sinusitis.

The general safety profile observed in patients with active psoriatic arthritis treated with the drug Jaquinus corresponds to the safety profile in patients with rheumatoid arthritis.

Plaque psoriasis

In patients with psoriasis, the most frequent adverse reactions during the first 12-16 weeks (with the development of more than 2% of patients receiving therapy with Jaquinus, and at least 1% higher than was observed in patients receiving placebo) against the background 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 the development of adverse reactions during the first 12-16 weeks of therapy in clinical trials was 3% compared with 4% of patients receiving placebo.

The most frequent infections leading to the cancellation of therapy were pneumonia, urinary tract infections and herpes zoster.

Ulcerative colitis

Adverse reactions that were observed in ?2% of patients receiving Jaquinus at a dose of 10 mg 2 times / day, with a frequency of at least 1% higher than the frequency in patients receiving placebo in induction therapy studies (OCTAVE Induction-I, OCTAVE lnduction-II and OCTAVE SUSTAIN studies) were an increase in the level of CPK in the blood, nasopharyngitis, pyrexia and headache.

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

The general safety profile observed in patients with ulcerative colitis treated with the drug Jaquinus corresponds to the safety profile for all indications of the drug Jaquinus.

The frequency of adverse reactions was determined as follows: very often (?10%), often (?1% and <10%), infrequently (?0.1% and <1%), rarely (?0.01% and <0.1%), very rarely (<0.01%), no information (impossible to determine based on available data). In each frequency group, adverse reactions are presented in order of decreasing severity.

Infectious and parasitic diseases: often - pneumonia, herpes zoster, bronchitis, flu, sinusitis, urinary tract infections, nasopharyngitis, pharyngitis; infrequently - tuberculosis (including disseminated tuberculosis), diverticulitis, pyelonephritis, inflammation of subcutaneous fat, viral infection, herpes simplex, viral gastroenteritis; rarely - sepsis, tuberculosis of the Central nervous system, encephalitis, necrotizing fasciitis, cryptococcal meningitis, disseminated tuberculosis, urosepsis, pneumonia caused by Pneumocystis jiroveci, pneumococcal pneumonia, bacterial pneumonia, staphylococcal bacteremia, atypical infection caused by mycobacteria, infection caused by Mycobacterium complex aviuma, cytomegalovirus infection, bacteremia, bacterial arthritis. Among patients taking Jaquinus, the incidence of serious infections was higher in those over 65 years of age than in those under 65 years of age.

From the cardiovascular system: often - an increase in blood pressure.

From the digestive system: often - abdominal pain, vomiting, gastritis, diarrhea, nausea, dyspepsia; infrequently - fatty hepatosis.

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

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

Mental disorders: infrequently - insomnia.

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

From the hematopoietic system: often - anemia; infrequently - leukopenia, neutropenia, lymphopenia. Confirmed cases of a decrease in the number of lymphocytes to less than 500 cells/ml were accompanied by an increase in the frequency of treated and serious infections. There was no clear relationship between neutropenia and the occurrence of serious infections.

From the immune system: infrequently - hypersensitivity.

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

From the skin: often - rash; infrequently - itching, erythema.

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

From laboratory and instrumental studies: often - an increase in the concentration of GGT, CK, blood cholesterol (in clinical studies, they were first noted after the first month of therapy and remained stable in the future), an increase in body weight; infrequently - an increase in the activity of liver enzymes, an increase in the activity of transaminases, an increase in the concentration of creatinine in blood plasma, a violation of liver functional tests, an increase in LDL concentration. With an increase in the activity of liver enzymes, a decrease in the dose of concomitant HDL, cancellation or reduction of the dose of the drug Jaquinus led to a decrease or normalization of this parameter.

Other: often - fever, fatigue, peripheral edema; infrequently - sprained ligaments, muscle stretching.

and undesirable drug reactions were reported only in open, long-term, complementary studies; therefore, the frequency of these undesirable drug reactions was evaluated during randomized phase 3 trials.

The frequency of bacterial arthritis was determined by the combined frequency for the preferred term bacterial and infectious arthritis.

Skin cancer unrelated to melanoma was identified as an undesirable drug reaction in 2013. Non-melanoma skin cancer is not a preferred term: frequency is determined by combining frequencies for the preferred terms basal cell carcinoma and squamous cell carcinoma of the skin.

Data of spontaneous messages (reactions such as angioedema and urticaria were observed). Some reactions have also been observed in clinical trials.

Contraindications to use

• severe liver dysfunction;
• infection with hepatitis B and/or C viruses (presence of serological markers of HBV and HCV infection);
  
• CC less than 40 ml/min;
  
• simultaneous use of live vaccines;
  
• simultaneous use with biological drugs such as TNF inhibitors, interleukin antagonists (IL-1R, IL-6R), monoclonal anti-CD20 antibodies, selective co-stimulating modulators, as well as powerful immunosuppressants such as azathioprine, cyclosporine and tacrolimus, since such a combination increases the likelihood of severe immunosuppression and the risk of infection;
  
• severe infections, active infections, including local;
  
• pregnancy (safety and efficacy have not been investigated);
  
• breastfeeding period;
  
• age up to 18 years (safety and efficacy have not been investigated);
  
• lactase deficiency, lactose intolerance, glucose-galactose malabsorption;
  
• hypersensitivity to tofacitinib or to any other component of the drug.
  

With caution: with an increased risk of perforation of the gastrointestinal tract (for example, in patients with a history of diverticulitis); in elderly patients due to a high risk of infectious diseases.

Use during pregnancy and lactation

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

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

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

Use in cases of impaired liver function

The use of the drug is contraindicated in severe liver dysfunction.

Use in cases of impaired renal function

It is contraindicated to use the drug with a CC of less than 40 ml / min.

Use in children

The use of the drug is contraindicated at the age of 18 years.

Use in elderly patients

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

Special instructions

Combined use with other antirheumatic agents

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

When using the drug Jaquinus in combination with MTT, a higher frequency of adverse events was observed than when using the drug Jaquinus in the form of monotherapy.

Common infections

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

The most frequent infections observed during the first 12-16 weeks of therapy with tofacitinib in patients with psoriasis were nasopharyngitis and upper respiratory tract infections (nasopharyngitis in 7% and 8% of cases when using tofacitinib at doses of 5 mg and 10 mg 2 times / day, respectively, upper respiratory tract infections in 4% and 5% of cases when using tofacitinib at doses of 5 mg and 10 mg 2 times / day, respectively).

Serious infections

Patients receiving immunomodulators, including biological drugs and Jaquinus, have serious and sometimes fatal infections caused by bacterial, mycobacterial, fungal, viral or other pathogens. The most frequent serious infections noted with the use of the drug Jaquinus include pneumonia, inflammation of the subcutaneous tissue, herpes zoster, urinary tract infection, diverticulitis and appendicitis. Cases of tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, shingles with lesions of various dermatomes, cytomegalovirus infection, VC-viral infection and listeriosis have been noted among the opportunistic infections when using the drug Jaquinus. In some patients with rheumatoid arthritis, disseminated diseases have been noted, most often with the simultaneous use of immunomodulators - methotrexate or glucocorticoids, which by themselves and in addition to the underlying disease (rheumatoid arthritis) can predispose to the development of infections. It is also possible to develop other serious infections that have not been reported in clinical studies (for example, coccidioidomycosis).

Jaquinus should not be used in patients with active infection, including local infections. Before using the drug 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 or recently visited endemic areas for tuberculosis or mycoses, as well as in patients with a predisposition to infection. Patients should be closely monitored for signs and symptoms of infection during and after therapy with the drug Jaquinus. Jaquinus should be temporarily discontinued if the patient has developed a serious infection, opportunistic infection or sepsis, until control over the patient's condition is established. With the development of a new infection against the background of the use of the drug Jaquinus, the patient is subject to a rapid and complete diagnostic examination by analogy with a patient suffering from immunodeficiency. The appointment of appropriate antibacterial therapy, as well as careful dynamic monitoring, is shown.

Since elderly patients and patients with diabetes mellitus are usually characterized by a higher incidence of infections, caution should also be exercised in such cases.

It is also recommended to be careful when using the drug in patients with chronic lung diseases, because they may be more susceptible to infections. In clinical studies and during post-registration use of the drug, cases of interstitial lung disease (in some cases fatal) 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 an increase in the severity of lymphopenia. In this case, when assessing the individual risk of infection, the number of lymphocytes should be taken into account.

Tuberculosis

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

Before using the drug, Jaquinus should be examined for signs of latent or active tuberculosis infection in accordance with local recommendations.

Patients with latent tuberculosis are subject to standard antimicobacterial therapy before starting therapy with Jaquinus.

Before starting therapy with the drug Jaquinus in patients with latent or active tuberculosis in the anamnesis, in the absence of confirmation of an adequate course of anti-tuberculosis therapy, as well as in patients with a negative test result for latent tuberculosis, but the presence of risk factors for tuberculosis infection, appropriate anti-tuberculosis therapy should be performed. When deciding on the need for TB therapy in each individual patient, it is recommended to consult with a phthisiologist.

Patients should be closely monitored for signs of tuberculosis, including patients with a negative test result for latent tuberculosis before starting therapy.

Reactivation of viral infections

Reactivation of viral infections is described when using HDL therapy. Cases of reactivation of the herpes virus (for example, herpes zoster) also described in clinical studies of the drug Jaquinus. In post-marketing studies, cases of hepatitis B virus reactivation have been reported in patients treated with the drug Jaquinus. The effect of the drug Jaquinus on the reactivation of chronic viral hepatitis is unknown. Patients who tested positive for hepatitis B and C were excluded from clinical trials. Before starting therapy with the drug Jaquinus, screening for the presence of viral hepatitis should be carried out.

In clinical studies of the drug Jaquinus, representatives of Japanese and Korean nationalities have more frequent cases of herpes zoster than representatives of other nationalities.

The incidence of herpes zoster may increase in patients with a long history of rheumatoid arthritis who previously received two or more biological HDL; in patients with AHN less than 1000 cells / ml.

Malignant and lymphoproliferative diseases (with the exception of non-melanoma skin cancer (RKNM))

Before starting therapy for patients with an existing malignant neoplasm or a history of malignant neoplasm, except for cured NSCLC, or when considering the possibility of continuing therapy with Jaquinus in patients with a malignant neoplasm, the risk and benefits of treatment with Jaquinus should be taken into account. There is a possibility that Jaquinus  affects the body's defense against malignant neoplasms.

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

In clinical studies and the post-registration period, cases of the development of other malignant neoplasms have been reported, including (but not limited to) lung cancer, breast cancer, melanoma, prostate cancer and pancreatic cancer.

The effect of therapy with the drug Jaquinus on the development and course of malignant neoplasms is unknown.

Non-melanoma skin cancer (RKNM)

There have been reported cases of RKNM in patients receiving tofacitinib therapy. It is recommended to conduct periodic skin examination in patients with an increased risk of developing skin cancer.

Cases of perforation of the gastrointestinal tract

Cases of gastrointestinal perforation have been described in clinical studies, although the role of janus kinase inhibition in these phenomena is unknown. Such cases were mainly described as diverticular perforation, peritonitis, abscess in the abdominal cavity and appendicitis. All patients with rheumatoid arthritis who developed perforation of the gastrointestinal tract received concomitant therapy with NSAIDs and/or GCS. The relative contribution of concomitant therapy and the use of the drug Jaquinus in the development of perforation of the gastrointestinal tract is unknown. The incidence of such complications in patients with psoriasis, according to clinical studies, is 0.09 cases / 100 patient-years.

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

Risk of cardiovascular diseases

Patients with rheumatoid arthritis are at increased risk of cardiovascular disorders, therefore, risk factors (for example, hypertension and hyperlipidemia) should be monitored in such patients as part of the usual standard treatment.

Liver enzymes

When treated with the drug Jaquinus, an increase in the frequency of increased activity of liver enzymes was observed in some patients. Attention should be paid to the question of starting treatment with Jaquinus in patients with increased ALT or ACT activity, especially when starting the drug in combination with potentially hepatotoxic drugs such as methotrexate. After the start of treatment, in order to identify potential cases of drug damage to the liver, it is recommended to monitor the biochemical parameters of liver function on an ongoing basis and quickly identify possible causes of increased activity of liver enzymes. If medicinal liver damage is suspected, treatment with Jaquinus should be suspended until this diagnosis is excluded.

Hypersensitivity

Hypersensitivity reactions such as angioedema and urticaria have been observed in patients taking the drug Jaquinus. Some cases were assessed as serious. Most of the reactions occurred in patients with a history of multiple allergies. In the event of a serious hypersensitivity reaction, it is necessary to immediately discontinue the use of tofacitinib until the causes are identified.

Laboratory indicators

Lymphocytes: cases of a decrease in the number of lymphocytes to less than 500 cells/ml were associated with an increase in the frequency of serious infections that required therapy. It is not recommended to start therapy with Jaquinus in patients with a low number of lymphocytes (i.e. less than 500 cells / ml). If the patient has confirmed a decrease in the absolute number of lymphocytes to a level of less than 500 cells / ml, treatment with Jaquinus is not recommended. The level of lymphocytes should be monitored at the initial level and then every 3 months.

Neutrophils: treatment with Jaquinus was accompanied by an increase in the incidence of neutropenia (< 2000/ µl) compared with placebo. It is not recommended to start treatment with Jaquinus in patients with a low concentration of neutrophils (ACP less than 1000 / µl). In patients with a persistent decrease in AHN to 500-1000 / ml, the dose of the drug Jaquinus should be reduced or treatment should be discontinued until the AHN concentration reaches more than 1000 cells / ml. In patients with an absolute number of neutrophils 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 start therapy with Jaquinus in patients with low hemoglobin levels (less than 90 g /l). Treatment with the drug Jaquinus should be discontinued in patients with hemoglobin levels less than 80 g / l, or with a decrease in hemoglobin levels 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 the drug Jaquinus is accompanied by an increase in the level of blood lipids - total cholesterol, LDL cholesterol, and HDL cholesterol. The maximum effect was usually observed within 6 weeks. Assessment of lipid parameters should be performed after about 4-8 weeks after the start of therapy. The use of statins in patients with an increased concentration of total cholesterol and LDL cholesterol against the background of therapy with the drug Jaquinus allows to achieve baseline values.

Vaccination

Information on secondary transmission of infection when live vaccines are administered to patients receiving Jaquinus is still missing. It is not recommended to administer live vaccines simultaneously with the drug Jaquinus. It is recommended that all patients complete the necessary immunization in accordance with current vaccination recommendations before starting the use of the drug Jaquinus. The interval between vaccination with live vaccines and the start of therapy with tofacitinib should comply with the available vaccination guidelines for patients receiving immunomodulatory therapy. According to these guidelines, if a live herpes zoster vaccine is administered, it should only be administered to patients with a documented history of chickenpox disease or to patients seropositive against chickenpox virus. Vaccination should be carried out at least 2 weeks in advance, but preferably 4 weeks before the start of therapy with immunomodulatory agents such as tofacitinib.

Patients with impaired renal function

In clinical studies, the drug Jaquinus was not studied in patients with baseline CC < 40 ml / min (calculated according to the Cockcroft-Gault formula).

Elderly patients

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

Influence on the ability to drive vehicles and manage mechanisms

Studies of the effect of the drug Jaquinus on the ability to drive a car and work with mechanisms have not been conducted.

Overdose

There is no experience of overdose when using the drug Jaquinus.

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

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

Drug interaction

Interaction affecting the use of the drug Jaquinus

Since tofacitinib is metabolized by the CYP3A4 isoenzyme, interaction with drugs that inhibit or induce this isoenzyme is very likely. When used simultaneously with potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole), as well as when used simultaneously with one or more moderate inhibitors of the CYP3A4 isoenzyme and potent inhibitors of the CYP2C19 isoenzyme (for example, fluconazole), the exposure of tofacitinib increases. Simultaneous use of ketoconazole (a powerful inhibitor of the CYP3A4 isoenzyme) and a single dose of tofacitinib increases the AUC and Cmax of tofacitinib by 103% and 16%, respectively. Concomitant use of fluconazole (a moderate inhibitor of the CYP3A4 isoenzyme, as well as a powerful inhibitor of the CYP2C19 isoenzyme) increases the AUC and Cmax of tofacitinib by 79% and 27%, respectively.

When used simultaneously with powerful inducers of the CYP3A4 isoenzyme (for example, rifampicin), the exposure of tofacitinib decreases. Simultaneous use of rifampicin (a powerful inducer of the CYP3A4 isoenzyme) reduces the AUC and Cmax of tofacitinib by 84% and 74%, respectively.

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

Concomitant use of tacrolimus (a weak inhibitor of the CYP3A4 isoenzyme) increases the AUC of tofacitinib by 21% and reduces 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 reduces the Cmax of tofacitinib by 17%. Simultaneous repeated use of tofacitinib and powerful immunosuppressants in patients with rheumatoid arthritis has not been studied.

Concomitant use with methotrexate (15-25 mg of methotrexate 1 time per week) has no effect on the pharmacokinetics of tofacitinib.

Interaction in which Jaquinus affects the pharmacokinetics of other drugs

In vitro studies have shown that tofacitinib in concentrations even more than 80 times higher than the Cssmax of total tofacitinib, which is achieved with the use of tofacitinib at doses of 5 mg and 10 mg 2 times / day in patients with rheumatoid arthritis, psoriatic arthritis, psoriasis and ulcerative colitis, does not significantly inhibit or induce the activity of the main drugs metabolized by CYP1A2, CYP2B6 isoenzymes, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. 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 show that tofacitinib does not inhibit the activity of the main human enzyme metabolizing drugs, uridine 5-diphosphate-glucuronosyltransferase (UGT) - UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7, in concentrations 250 times higher than the Cssmax of total tofacitinib, which occurs when tofacitinib is administered at doses of 5 mg and 10 mg 2 times /day in patients with rheumatoid arthritis, psoriatic arthritis, psoriasis and ulcerative colitis.

In vitro data have shown that the ability of tofacitinib in therapeutic concentrations to inhibit such transporters 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 ethinylestradiol in healthy women.

Simultaneous use of tofacitinib with methotrexate at a dose of 15-25 mg 1 time / week. reduced the AUC and Cmax of methotrexate by 10% and 13%, respectively. These changes in the pharmacokinetics of methotrexate did not require dose adjustment or selection of individual doses of methotrexate.

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 the simultaneous 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 the drug Jaquinus  had no effect on the pharmacokinetics of metformin, indicating that tofacitinib does not affect the carrier of organic cations (OST2) in healthy volunteers.

Storage conditions and terms

The drug should be stored out of the reach of children at a temperature no higher than 25 ° C. The shelf life is 3 years. Do not use the drug after the expiration date indicated on the package.