Instruction for use: Tofacitinib

Trade name of the drug – Jakvinus

The Latin name of the substance Tofacitinib

Tofacitinibum (genus. Tofacitinibi)

Chemical name

3 - [(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidin-1-yl] -3-oxopropanitrile (as citrate )

Gross formula

C16H20N6O

Pharmacological group:

Immunosuppressive drugs

The nosological classification (ICD-10)

M06.8 Other specified rheumatoid arthritis: Active rheumatoid arthritis

M06.9 Rheumatoid arthritis, unspecified: Rheumatoid arthritis; Pain syndrome in rheumatic diseases; Pain in rheumatoid arthritis; Inflammation in rheumatoid arthritis; Degenerative forms of rheumatoid arthritis; Children's rheumatoid arthritis; Exacerbation of rheumatoid arthritis; Acute articular rheumatism; Rheumatic arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatic polyarthritis; Rheumatoid arthritis; Rheumatoid arthritis; Rheumatoid arthritis of active course; Rheumatoid periarthritis; Rheumatoid polyarthritis; Acute rheumatoid arthritis; Acute rheumatism

CAS code

477600-75-2

Characteristics of the substance Tofacitinib

A selective inhibitor of the Janus kinase family (JAK), which also has a high selectivity for other kinases of the human genome.

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Tofacitinib citrate is a white to off-white powder with a water solubility of 2.9 mg / ml. The molecular mass of tofacitinib citrate is 504.5 Da (free base 312.4 Da).

Pharmacology

Mode action - Immunosuppressive.

Mechanism of action

Tofacitinib inhibits JAK1, -2, -3 and to a lesser extent tyrosine kinase 2. In those cells where JAK is signaled in pairs, tofacitinib preferably inhibits the signaling of heterodimeric receptors associated with JAK3 and / or JAK1, with functional selectivity for receptors, Which transmit signals through pairs of JAK2. Inhibition of JAK1 and JAK3 under the influence of tofacitinib blocks the signaling through common receptors containing gamma chains for several cytokines, including IL-2, -4, -7, -9, -15 and -21. These cytokines perform an integrating role in the processes of activation and proliferation of lymphocytes, their functioning and inhibition of signal transmission, which leads to modulation of various aspects of the immune response. In addition, inhibition of JAK1 results in impaired signal transmission under the action of additional pro-inflammatory cytokines, such as IL-6 and gamma-interferon. At higher exposure to tofacitinib, inhibition of JAK2 signaling results in inhibition of erythropoietin signaling.

Pharmacodynamic effects

Treatment with tofacitinib 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 initiation of therapy. The described changes are usually resolved after 2-6 weeks after the end of therapy. Treatment with tofacitinib 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 minor and unstable. The clinical significance of these changes is unknown. The change in total serum levels of IgG, -M and -A over the 6-month treatment period of patients with rheumatoid arthritis was small, dose independent and similar to that of placebo.

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

Pharmacokinetics

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

Absorption and distribution. Tofacitinib is well absorbed, its bioavailability is 74%.

The use of tofacitinib with food rich in fats is not accompanied by changes in AUC, while Cmax in blood plasma is reduced by 32%. In clinical studies, tofacitinib was used regardless of food intake.

The binding of tofacitinib with plasma proteins is approximately 40%. Tofacitinib predominantly binds to albumin and does not bind to the αl-acid glycoprotein. Tofacitinib is equally distributed between erythrocytes and blood plasma.

Metabolism and excretion. The clearance of tofacitinib by approximately 70% is accomplished by metabolism in the liver and by 30% by excretion through the kidneys in the form of unchanged tofacitinib. The metabolism of tofacitinib is predominantly mediated by the isoenzyme CYP3A4 and, to a lesser extent, by the isoenzyme CYP2C19. In the study of radiolabeled tofacitinib, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, and the remaining 35% by 8 metabolites (each less than 8% of total radioactivity). Pharmacological activity is associated with nonmetabolized tofacitinib.

Pharmacokinetics in patients with rheumatoid arthritis. It was found that in patients with rheumatoid arthritis AUC, tofacitinib with a 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 at the age of 80 years, the AUC was less than 5% higher than in patients aged 55 years.

In women, the AUC of tofacitinib is 7% lower than that of men.

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

An almost linear relationship between body weight and Vd is noted, which leads to a higher Cmax and lower Cmin in the blood plasma in patients with a lower body weight. However, this difference is not considered clinically significant. Interindividual variability (coefficient of variability) of AUC for tofacitinib is about 27%.

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

Violation of the function of the liver. In patients with mild and moderate impairment of liver function, AUC values were 3 and 65% higher than those of healthy volunteers. Patients with severe hepatic impairment or patients with positive serological tests of hepatitis B or hepatitis C have not been studied.

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

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Drug Interactions

Effect of tofacitinib on the pharmacokinetics of other drugs

In vitro studies show that tofacitinib at concentrations exceeding 160 times the CSS when taken at a dose of 5 mg 2 times a day does not have a significant inhibitory or inducing effect on the basic isoenzymes of human cytochrome P450 involved in the metabolism of drugs (CYP1A2, CYP2B6, CYP2C8 , CYP2C9, CYP2C19, CYP2D6 and CYP3A4). These results are confirmed by the study of drug interaction in humans, showing no changes in the pharmacokinetics of midazolam, the highly sensitive substrate CYP3A4, when it is used together with tofacitinib.

In patients with rheumatoid arthritis, the oral clearance of tofacitinib does not change with time, indicating that tofacitinib in these patients does not normalize the activity of cytochrome P450 isoenzymes. Therefore, co-administration with tofacitinib is not expected to cause a clinically relevant increase in the metabolism of CYP substrates in patients with rheumatoid arthritis.

In vitro data indicate a low ability of tofacitinib at therapeutic concentrations to inhibit carriers such as P-glycoprotein, organic anionic or cationic vectors.

Based on the results of the study of the effect of tofacitinib on the pharmacokinetics of other drugs (AUC, Cmax, 90% confidence interval), the dose adjustment of the following jointly used drugs is not recommended: methotrexate, midazolam, levonorgestrel, ethinyl estradiol, metformin.

The effect of other drugs on the pharmacokinetics of tofacitinib

Since tofacitinib is metabolized by CYP3A4, it may interact with drugs that inhibit or induce this isoenzyme. It is unlikely that inhibitors of CYP2C19 or P-glycoprotein had a significant effect on the pharmacokinetics of tofacitinib. Based on the results of the study of the effect of other drugs on the pharmacokinetics of tofacitinib (AUC, Cmax, 90% confidence interval), it is recommended to reduce the dose of tofacitinib up to 5 mg once a day when combined with ketoconazole and fluconazole. When combined with rifampicin, the effectiveness of tofacitinib may decrease; Do not need a dose adjustment in the combined use of methotrexate with tofacitinib. The simultaneous use of tacrolimus and cyclosporine with tofacitinib can enhance the immunosuppressive effect.

Application of the substance Tofacitinib

Treatment of adult patients with moderate or severe active rheumatoid arthritis with an inadequate response to one or more basic anti-inflammatory drugs (DMAP).

Contraindications

Increased sensitivity to tofacitinib, severe liver dysfunction, infection with hepatitis B and / or C viruses (presence of serological markers of HBV and HCV infection), Cl creatinine <40 ml / min, simultaneous application of live vaccines, simultaneous use with biological agents (such Such as TNF inhibitors, IL-1R antagonists, IL-6R, monoclonal anti-CD20 antibodies, selective costimulatory modulators), as well as strong immunosuppressants (such as azathioprine, cyclosporin and tacrolimus), since such combinations are increased in The likelihood of severe immunosuppression and the risk of infection; Severe infections, active infections, including local, severe infectious diseases; Pregnancy (safety and efficacy not studied); The period of breastfeeding; Children under 18 years of age (safety and efficacy not studied).

Restrictions

Tofacitinib should be used with caution at an increased risk of perforation of the gastrointestinal tract (for example, in patients with a history of diverticulitis), in the elderly due to a high risk of developing infectious diseases.

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It is not recommended to use tofacitinib in combination with biological BVP or strong immunosuppressants, such as azathioprine and cyclosporine.

Pregnancy and breast-feeding

The action category for fetus by FDA is C.

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

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

Side effects of Tofacitinib

The most frequent serious undesirable reactions, noted against the background of therapy with tofacitinib, were serious infections.

The most frequent adverse reactions during the first 3 months of controlled clinical trials (with development in more than 2% of patients receiving tofacitinib monotherapy or a combination of it with DMARD) included upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.

The withdrawal of therapy during the first 3 months due to any adverse reaction during double-blind, placebo-controlled trials was required in 4.2% of cases for patients in the tofacitinib group and 3.2% for patients in the placebo group. The most frequent undesirable reactions that led to the abolition of tofacitinib were infections. The most frequent infections leading to the abolition of therapy included herpes zoster and pneumonia.

The frequency of adverse reactions listed below is presented by the following classification: very often - ≥10%; Often - ≥1 and <10%; Infrequently - ≥0.1 and <1%; Rarely - ≥0.01 and <0.1%; Very rarely - <0.01%; No information - cannot be determined from the available data.

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

Infectious and parasitic diseases: very often - nasopharyngitis; Often - pneumonia, herpes zoster, bronchitis, influenza, sinusitis, urinary tract infections, pharyngitis; Infrequently - sepsis, bacterial pneumonia, pneumococcal pneumonia, pyelonephritis, inflammation of subcutaneous fat, viral gastroenteritis, viral infection, herpes simplex; Rare - tuberculosis of the central nervous system, encephalitis, necrotizing fasciitis, cryptococcal meningitis, disseminated tuberculosis, urosepsis, pneumonia caused by Pneumocystis jiroveci, staphylococcal bacteremia, tuberculosis, bacterial arthritis, atypical infection caused by mycobacteria, infection caused by the Mycobacterium avium complex, CMV infection, bacteremia . Among patients who took tofacitinib, the incidence of serious infections was higher in people older than 65 years than in persons younger than 65 years.

From the CVS: often - an increase in blood pressure.

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

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

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

Mental disorders: often - insomnia.

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

On the part of the blood and lymphatic system: often - leukopenia, anemia; Infrequently - a neutropenia, a lymphopenia.

Confirmed cases of a decrease in the number of lymphocytes to less than 500 cells / mm3 were accompanied by an increase in the incidence of treatment and serious infections.

There was no clear correlation between neutropenia and the occurrence of serious infections.

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

From the skin: often - a rash; Infrequently - erythema, itchy skin.

From the liver and biliary tract; Infrequently - fatty hepatosis.

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

Violations revealed in clinical and laboratory studies: often - increased activity of liver enzymes, CK, increased concentrations of LDL, blood cholesterol (in clinical trials first observed after the first month of therapy and remained stable in the future), weight gain; Infrequently - an increase in the activity of transaminases, an increase in the concentration of creatinine in the blood plasma, an increase in the concentration of GGT, a violation of functional liver tests. With an increase in the activity of hepatic enzymes, a reduction in the dose of concomitant DMARD, cancellation or reduction of the dose of tofacitinib led to a decrease or normalization of this parameter.

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

Trauma, intoxication and complications of manipulation: often - sprain; Infrequent - stretching of the muscles.

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Since clinical studies have been conducted with a different set of conditions, the frequency of occurrence of adverse reactions observed in these studies cannot be directly compared with the frequency in other studies and cannot predict the occurrence of side effects in a larger population of patients in clinical practice.

The data of 7 protocols of double-blind placebo-controlled multicenter clinical trials are summarized: two, performed in the second phase of clinical trials, and five - in the third. In these trials, patients were randomized into groups: two groups received tofacitinib in the form of monotherapy at a dose of 5 or 10 mg twice daily (292 and 306 patients respectively), two groups - tofacitinib at a dose of 5 or 10 mg twice daily in combination With DMARD (including methotrexate) (1044 and 1043 patients, respectively) and one group - placebo (809 patients).

The most frequent adverse reactions were severe infections (see "Precautions").

As a result of serious adverse reactions of any profile during the first 3 months of use in double-blind, placebo-controlled clinical trials, 4% of patients taking tofacitinib and 3% of those taking placebo discontinued treatment.

Infections in general. In seven controlled trials, during the first 3 months of use, the overall incidence of infections was 20 and 22% for groups of patients receiving 5 or 10 mg of tofacitinib per day, respectively, and 18% for the placebo group. Most often, when taking tofacitinib, upper respiratory tract infections, nasopharyngitis and urinary tract infections (4, 3, and 2%, respectively) were observed.

Severe infections. In seven trials, during the first 3 months of use, a severe infection in one patient from the placebo group (lethality 0.5 cases per 100 patient-years of follow-up) and 11 patients receiving tofacitinib at a dose of 5 or 10 mg twice daily (lethality 1.7 cases per 100 patient-years of follow-up). The difference (corresponding to 95% confidence interval) between the combined group of patients receiving 5 and 10 mg of tofacitinib 2 times a day and the placebo group was 1.1 (-0.4, 2.5) cases per 100 patient-years.

In patients who had been observed for 12 months, severe infections were noted in 34 patients (lethality 2.7 cases per 100 patient-years of follow-up) receiving tofacitinib 5 mg twice daily and in 33 patients (lethality 2.7 cases For 100 patient-years of observation) who received 10 mg of tofacitinib twice daily. The difference (corresponding to 95% confidence interval) between the groups of patients receiving 10 mg of tofacitinib 2 times a day and 5 mg tofacitinib 2 times a day was -0.1 (-1.3, 1.2) cases per 100 patient-years .

The most common of the serious infections were pneumonia, cellulitis, shingles and urinary tract infection (see "Precautions").

Tuberculosis. In seven controlled trials, during the first 3 months of use, no cases of tuberculosis were seen in patients taking placebo and 5 or 10 mg of tofacitinib twice daily. In patients taking tofacitinib for 12 months, there were no cases of tuberculosis in the group receiving 5 mg twice a day, and 6 cases were noted in patients receiving 10 mg twice a day (mortality 0.5 cases per 100 patient-years of follow-up) Development of tuberculosis. The difference (corresponding to 95% confidence interval) between groups of patients receiving 10 mg of tofacitinib 2 times a day and 5 mg tofacitinib twice daily was 0.5 (0.1; 0.9) per 100 patient-years.

There are also cases of development of disseminated tuberculosis. The medication exposure of tofacitinib before the diagnosis of "tuberculosis" was 10 months (fluctuation from 152 to 960 days) (see "Precautions").

Opportunistic infections (excluding tuberculosis). Opportunistic infections were not observed in patients who received placebo and 5 or 10 mg of tofacitinib twice daily for the first 3 months of testing. In patients taking tofacitinib for 12 months, opportunistic infections were registered in 4 patients who received 5 mg twice daily (lethality 0.3 cases per 100 patient-years of follow-up) and 4 patients who received 10 mg twice daily Day (lethality 0.3 cases per 100 patient-years of follow-up). The difference (corresponding to 95% confidence interval) between groups of patients receiving 10 mg of tofacitinib 2 times a day and 5 mg tofacitinib 2 times a day was 0 (-0.5, 0.5) cases per 100 patient-years.

The medication of tofacitinib exposure before the diagnosis of "opportunistic infection" was 8 months (fluctuation from 41 to 698 days).

Influence on the development of malignant diseases. Malignant diseases (with the exception of non-melanoma skin cancer) in controlled studies were not observed during the first 3 months of placebo-treated patients and were recorded in 2 patients (lethality 0.3 cases per 100 patient-years of follow-up) Tofacitinib as in a dose of 5 mg 2 times a day, and in a dose of 10 mg 2 times a day. The difference (corresponding to 95% confidence interval) between the combined group of patients receiving 5 and 10 mg of tofacitinib 2 times a day and the placebo group was 0.3 (-0.1, 0.7) cases per 100 patient-years.

During the observation period of 12 months, malignant diseases (with the exception of skin cancer that was not associated with melanoma) were recorded in 5 patients taking tofacitinib 5 mg twice daily (mortality 0.4 cases per 100 patient-years of follow-up), and 7 Patients who received 10 mg twice a day (lethality 0.6 cases per 100 patient-years of follow-up). The difference (corresponding to 95% confidence interval) between groups of patients receiving 10 mg of tofacitinib 2 times a day and 5 mg tofacitinib twice daily was 0.2 (-0.4, 0.7) cases per 100 patient-years. One of the cases of malignancy was the development of lymphoma, which occurred when taking tofacitinib in a dose of 10 mg 2 times a day during the first 12 months.

The most frequent manifestations of malignancy, observed in t.ch. With long-term use, included lung and breast cancer, stomach, colorectal and renal cell carcinoma, prostate cancer, lymphoma and malignant melanoma (see "Precautions").

Deviations of laboratory indicators

Lymphopenia. In the controlled clinical trials, confirmed cases of a decrease in the absolute number of lymphocytes <500 cells / mm3 were observed in total in 0.04% of patients receiving tofacitinib at a dose of 5 or 10 mg twice a day in the first 3 months of treatment. These cases were associated with an increase in the incidence of treated and severe infections (see "Precautions").

Neutropenia. In the controlled clinical trials, confirmed cases of absolute absolute neutrophil count decrease of <1000 cells / mm3 were observed in 0.07% of patients receiving tofacitinib at a dose of 5 or 10 mg twice a day in the first 3 months of treatment. There were no confirmed cases of a decrease in the absolute number of neutrophils <500 cells / mm3 in any of the groups receiving treatment. There is no exact relationship between neutropenia and the incidence of severe infections. In the population of long-term safety assessment, the nature and frequency of confirmed cases of absolute absolute neutrophil reduction were consistent with data obtained during controlled clinical trials (see "Precautions").

Increased level of hepatic enzymes. In patients treated with tofacitinib, cases of confirmed elevation of the level of hepatic enzymes were observed to be higher than 3-fold in comparison with vaginal hypertension (> 3 x VGN). In such patients, a modification of the treatment regimen, such as a reduction in the dose of the co-administered HDL, a break in the use of tofacitinib, or a decrease in its dose, led to a decrease or normalization of the level of hepatic enzymes.

In controlled studies using monotherapy with tofacitinib in the first 3 months, there was no difference in the incidence of elevated ALT or AST between the placebo groups and those receiving 5 or 10 mg twice daily. In studies with combined use of DMARD in the first 3 months, the ALT level was> 3 × VGN observed in 1; 1.3 and 1.2% of patients receiving placebo, 5 or 10 mg of tofacitinib, respectively, and an increase in the AST level above> 3 x VGN - in 0.6; 0.5 and 0.4% of patients in the same groups.

One case of tofacitinib-induced liver damage was observed in a patient who received 10 mg of tofacitinib twice daily for approximately 2.5 months. This patient developed a symptomatic increase in the level of AST and ALT higher than 3 x VGN and bilirubin level higher than 2 x HNG, which required hospitalization and liver biopsy.

Increase in lipid levels. In controlled clinical trials, a dose-related increase in lipid levels (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) was observed in the first month of treatment and remained stable thereafter. Changes in lipid content during the first 3 months of treatment in these studies are summarized below:

- the average level of LDL cholesterol increased by 15 and 19%, respectively, in patients taking 5 and 10 mg of tofacitinib 2 times a day;

- the average level of HDL cholesterol increased by 10 and 12%, respectively, in patients taking 5 and 10 mg of tofacitinib 2 times a day;

- the average LDL / HDL ratio did not change significantly in patients treated with tofacitinib.

The level of LDL cholesterol and apolipoprotein B was reduced to the level observed before the start of treatment, in response to statin therapy.

In the long-term safety assessment population, the increase in lipid levels remained at the level observed in controlled clinical trials.

Increased serum creatinine. In controlled clinical trials, there was a dose-related increase in serum creatinine with tofacitinib. In the 12-month follow-up period, the mean increase in serum creatinine was <0.1 mg / dL, while with long-term use of tofacitinib, up to 2% of patients discontinued treatment due to an increase in creatinine levels of more than 50% of baseline. The clinical significance of this phenomenon is unknown.

Other adverse reactions.

Adverse reactions that occurred in ≥2% of patients who took 5 mg (n = 1336) or 10 mg (n = 1349) of tofacitinib twice daily in monotherapy or in combination with DMARD in the first 3 months of therapy and occurred at a frequency above 1 %, Than in the placebo group (n = 809), included (data in percentage, the first figure - patients taking 5 mg tofacitinib twice a day, the second - 10 mg tofacitinib 2 times a day and the third - placebo): diarrhea - 4 %; 2.9% and 2.3%; Nasopharyngitis - 3.8%; 2.8% and 2.8%; Upper respiratory tract infection - 4.5%; 3.8% and 3.3%; Headache - 4,3%; 3.4% and 2.1%; Hypertension - 1.6%; 2.3% and 1.1%.

Other adverse reactions that have occurred during prolonged controlled and open trials are given below.

On the part of the blood and lymphatic system: anemia.

From the side of metabolism and eating disorders: dehydration.

Mental disturbances: insomnia.

From the side of the nervous system: paresthesia.

Respiratory, thoracic and mediastinal disorders: shortness of breath, cough, congestion of the paranasal sinuses.

From the gastrointestinal tract: abdominal pain, dyspepsia, vomiting, gastritis, nausea.

From the hepatobiliary system: hepatosteatosis.

From the skin and subcutaneous tissue: rash, erythema, itching.

From the musculoskeletal system and connective tissues: musculoskeletal pain, arthralgia, tendonitis, swelling of the joints.

Benign, malignant and unspecified neoplasms (including cysts and polyps): skin cancer, not related to melanoma.

General disorders and reactions at the site of administration: fever, fatigue, peripheral edema.

Interaction

Interactions that affect the use of tofacitinib

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

With the simultaneous use of CYP3A4 isoenzyme (eg rifampicin) with powerful inducers, the exposure to tofacitinib decreases. The simultaneous use of rifampicin (a powerful inductor of the isoenzyme CYP3A4) reduces AUC and Cmax of tofacitinib by 84% and 74%, respectively.

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

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

Concurrent use with methotrexate (15-25 mg methotrexate once a week) does not affect the pharmacokinetics of tofacitinib.

Interactions in which tofacitinib affects the pharmacokinetics of other drugs

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

Simultaneous use with tofacitinib did not affect the pharmacokinetics of oral contraceptives, levonorgestrel and ethinyl estradiol in healthy women. The simultaneous use of tofacitinib with methotrexate at a dose of 15-25 mg once a week reduced the AUC and Cmax values of methotrexate by 10 and 13%, respectively. These changes in the pharmacokinetics of methotrexate did not require dose adjustment or the selection of individual doses of methotrexate.

In patients with rheumatoid arthritis, the clearance of tofacitinib did not change over time. This indicates that tofacitinib does not affect the activity of CYP isoenzymes in patients with rheumatoid arthritis. Thus, it is unlikely that simultaneous application of substrates of CYP isoenzymes with tofacitinib leads to a clinically significant increase in their metabolism in patients with rheumatoid arthritis. The concomitant reception of tofacitinib did not affect the pharmacokinetics of metformin, indicating that tofacitinib does not affect the carrier of organic cations (OCT2) in healthy volunteers.

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Strong inhibitors of CYP3A4

Exposure tofacitinib increases with its combined use with strong inhibitors of CYP3A4 (eg ketonazole).

Moderate inhibitors of CYP3A4 and strong inhibitors of CYP2C19

Exposure tofacitinib increases with its concomitant use with drugs that are both moderate inhibitors of CYP3A4 and strong inhibitors of CYP2C19 (eg, fluconazole).

Strong inductors CYP3A4

Exposure tofacitinib decreases when it is used together with strong inducers CYP3A4 (eg rifampicin).

Immunosuppressive drugs

There is a risk of additive immunodepression in the combined use of tofacitinib and strong immunosuppressants (eg azathioprine, tacrolimus, cyclosporine). The combined use of multiple doses of tofacitinib and strong immunosuppressants in patients with rheumatoid arthritis has not been studied. It is not recommended to use tofacitinib in combination with biological BVP or strong immunosuppressants, such as azathioprine and cyclosporine.

Overdose

The experience of an overdose with the use of tofacitinib is absent.

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

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

Routes of administration

Inside.

Precautionary measures

Serious infections

In patients with rheumatoid arthritis receiving immunomodulators, including biological agents and tofacitinib, serious and, in some cases, fatal infections caused by bacterial, mycobacterial, fungal, viral or other opportunistic pathogens have been noted. The most frequent serious infections noted with the use of tofacitinib include pneumonia, inflammation of the subcutaneous tissue, herpes zoster and urinary tract infection. Of the opportunistic infections with the use of tofacitinib, cases of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, shingles with various dermatitis, CMV infection, and poliomavirus (BK virus) infection were noted. Some patients reported disseminated diseases, most often with the simultaneous use of immunosuppressants (methotrexate or GCS), which in 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 documented in clinical studies (eg, histoplasmosis, coccidiomycosis and listeriosis).

Tofacitinib should not be used in patients with active infection, including local infection. Before tofacitinib, the risk / benefit ratio of patients with a chronic or recurrent infection should be assessed, 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, and In patients with a predisposition to infection. Patients should be closely monitored for signs and symptoms of infection during and after therapy with tofacitinib.

Tofacitinib should be temporarily discontinued if the patient develops a serious infection, an opportunistic infection or sepsis, until the patient's condition is established. When a new infection develops with the use of tofacitinib, the patient is subject to a rapid and complete diagnostic examination similar to a patient suffering from immunodeficiency. The appointment of appropriate antibiotic therapy, as well as careful dynamic observation, is shown.

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

Tuberculosis

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

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

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

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

Reactivation of viral infections

Reactivation of viral infections is described in the application of therapy with BPD. Cases of reactivation of the herpes virus (eg herpes zoster) are also described in clinical studies of tofacitinib. The effect of tofacitinib on the reactivation of chronic viral hepatitis is unknown. Patients with a positive test result for hepatitis B and C were excluded from clinical studies. Before starting therapy with tofacitinib, screening for the presence of viral hepatitis should be carried out.

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

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

In patients treated with tofacitinib, cases of lymphoma have been reported. Although patients with rheumatoid arthritis, especially those with a highly active form of the disease, have a higher risk (several times higher) of lymphoma than the general population, the role of inhibition of JAK, if any, in the development of lymphoma is unknown.

PKNM. Cases of the development of FCNM in patients receiving therapy with tofacitinib have been reported. It is recommended to conduct periodic skin examination in patients with an increased risk of developing skin cancer.

Cases of perforation of the digestive tract

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

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

Laboratory indicators

Lymphocytes: cases of a decrease in the number of lymphocytes to <500 cells / mm3 were associated with an increase in the frequency of serious infections that required therapy. It is not recommended to begin therapy with tofacitinib in patients with a low number of lymphocytes (ie <500 cells / mm3). If the patient has confirmed a decrease in the absolute number of lymphocytes to a level of <500 cells / mm3, treatment with the drug tofacitinib is not recommended. The number of lymphocytes must be monitored at baseline and then every 3 months.

Neutrophils: treatment with tofacitinib was accompanied by an increase in the incidence of neutropenia (<2000 cells / mm3) compared with placebo. Treatment with tofacitinib of patients with a low neutrophil concentration (absolute number of neutrophils (ACHP) <1000 cells / mm3) is not recommended. In patients with a sustained decrease in AFN to 500-1000 cells / mm3, a dose of tofacitinib should be reduced or treatment discontinued until ACH concentration> 1000 cells / mm3. In patients with confirmed ACHN <500 cells / mm3 treatment is not recommended. The level of neutrophils should be monitored at baseline and after 4-8 weeks of therapy, and then every 3 months.

Hemoglobin: It is not recommended to start therapy with tofacitinib in patients with low hemoglobin (<9 g / dl). Treatment with tofacitinib should be discontinued in patients with a hemoglobin level <8 g / dL, or with a decrease in hemoglobin level by 2 g / dL or more on the background of treatment. Hemoglobin should be monitored at the initial stage of therapy, after 4-8 weeks of therapy, and then every 3 months.

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

Vaccination

Information on the response to vaccination or secondary transmission of infection when administering live vaccines to patients receiving tofacitinib is not available to date. Do not administer live vaccines at the same time as tofacitinib. It is recommended that before the start of tofacitinib, all patients undergo the necessary immunization in accordance with current vaccination recommendations.

Patients with impaired renal function

In clinical studies, tofacitinib was not studied in patients with baseline Cl creatinine <40 mL / min (calculated using the Cockcroft-Gault formula) (see "Contraindications").

Influence on ability to drive a car and other complex mechanisms. Studies of the effects of tofacitinib on the ability to drive and work with machinery have not been carried out.

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Severe infections

There are reports of severe and, in some cases, fatal infections caused by bacterial, mycobacterial, invasive fungal, viral or other opportunistic pathogens, in patients with rheumatoid arthritis receiving tofacitinib. The most common of the serious infections were pneumonia, cellulitis, shingles and urinary tract infection (see "Side effects"). Of the opportunistic infections associated with the use of tofacitinib, there have been cases of tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatitis zoster, CMV infection and BK virus infection. In some patients, the disease was more likely in disseminated than local form, and often with the concomitant use of immunosuppressants, such as methotrexate or GCS. Other serious infections that have not been reported in clinical trials (eg, histoplasmosis, coccidioidomycosis, and listeriosis) may also occur.

It should be excluded the use of tofacitinib in patients with active severe infection, including localized forms. The risk / benefit ratio should be assessed before starting the use of tofacitinib in patients under the following conditions:

- presence of chronic or recurrent infection;

- the risk of contracting tuberculosis;

- a history of severe or opportunistic infection;

- living or traveling in a region endemic for tuberculosis or mycoses;

- a predisposition to the above infections.

During and after treatment with tofacitinib, patients should be carefully monitored for signs and symptoms of infection. Treatment with tofacitinib should be discontinued with the development of severe infection, opportunistic infection or sepsis. If a new infection develops during treatment with tofacitinib, an urgent and complete diagnostic examination should be performed, appropriate antimicrobial therapy should be prescribed and the patient carefully monitored.

Tuberculosis

Before the appointment of tofacitinib, patients should be examined and tested for latent or active tuberculosis.

Anti-tuberculosis therapy should be prescribed before the appointment of tofacitinib in patients with a latent or active form of tuberculosis in the history who have not received a proper adequate course of treatment, as well as in patients with a negative reaction to latent tuberculosis, but who have risk factors for tuberculosis infection. To decide on the appointment of anti-tuberculosis therapy in a particular patient, it is recommended to consult a specialist with experience in the treatment of tuberculosis.

It is necessary to closely monitor the appearance of signs and symptoms of tuberculosis in patients, including those who before the start of treatment had negative tests for the latent form of tuberculosis infection. Patients with a latent form of tuberculosis before the appointment of tofacitinib should undergo a course of standard antimycobacterial therapy.

Viral reactivation

In clinical studies using tofacitinib, cases of viral reactivation have been observed, including the reactivation of the herpes virus (eg, herpes zoster). The effect of tofacitinib on the reactivation of chronic viral hepatitis is unknown. Patients with a positive sample for hepatitis B or C were excluded from clinical trials. Before starting therapy with tofacitinib, according to clinical guidelines, screening for the presence of viral hepatitis should be performed. In patients receiving tofacitinib, the risk of development of herpes zoster is increased, and this risk appears to be higher in patients receiving tofacitinib in Japan.

Malignant and lymphoproliferative diseases

The risk / benefit ratio of tofacitinib should be considered before initiating therapy in patients with a known malignant neoplasm (with the exception of successfully treated skin cancer that is not associated with melanoma) or continuing therapy with tofacitinib in patients with advanced malignancy. In clinical studies of tofacitinib, there have been cases of development of malignant neoplasms (see "Side effects").

In seven controlled clinical trials involving patients with rheumatoid arthritis, 11 cases of solid tumors and 1 case of lymphoma were diagnosed in 3328 patients who received tofacitinib in combination with or without or with or without DMARD during the first 12 months of observation, compared with 0 cases of solid tumors and 0 cases Lymphoma in 809 patients who received a placebo in combination with or without BPD. Cases of lymphoma and solid tumors have also been observed in prolonged extended trials involving patients with rheumatoid arthritis receiving tofacitinib.

In the phase 2B controlled trials with two or more doses in patients with a constant drug intake after kidney transplantation, each receiving induction therapy with basiliximab, high doses of GCS and mycophenolic acid preparations, post-transplant lymphoproliferative disease associated with the Epstein-Barr virus was observed. Such cases were observed in 5 of 218 patients receiving tofacitinib (2.3%), compared with 0 of 111 patients receiving cyclosporine.

In patients receiving tofacitinib, cases of skin cancer that are not associated with melanoma are noted. For patients with an increased risk of developing skin cancer, periodic examination of the skin is recommended.

Perforation of the gastrointestinal tract

In clinical studies using tofacitinib in patients with rheumatoid arthritis, there have been cases of perforation of the gastrointestinal tract, but the role of inhibition of JAK kinases in these cases is unknown.

Caution should be exercised when using tofacitinib in patients at increased risk of gastrointestinal perforation (eg, patients with a history of diverticulitis). Patients with newly identified abdominal symptoms should be urgently examined for early identification of the gastrointestinal perforation (see also "Side effects").

Deviations of laboratory indicators

Lymphopenia. Treatment with tofacitinib was associated with lymphocytosis, beginning in the first month of use, and was accompanied by a consistent decrease in the absolute number of lymphocytes below the norm by approximately 10% within 12 months of therapy. The number of lymphocytes less than 500 cells / mm3 was associated with a higher incidence of treated and severe infections.

It should be excluded the use of tofacitinib in patients with a low number of lymphocytes (ie <500 cells / mm3). It is not recommended treatment with tofacitinib in patients with a confirmed absolute number of lymphocytes <500 cells / mm3.

Control of the number of lymphocytes should be performed at the beginning of treatment and every 3 months of therapy.

Neutropenia. Treatment with tofacitinib was associated with an increase in the number of cases of development of neutropenia (<2000 cells / mm3) compared with placebo.

It should be excluded the use of tofacitinib in patients with a low number of neutrophils (ie, with an absolute number of neutrophils <1000 cells / mm3). Patients who developed persistent neutropenia with an absolute neutrophil count of 500-1000 cells / mm3 should discontinue the use of tofacitinib until the absolute number of neutrophils is restored to> 1,000 cells / mm3. It is not recommended treatment with tofacitinib in patients with an absolute neutrophil count of <500 cells / mm3.

The control of the number of neutrophils should be carried out at the beginning of treatment, after 4-8 weeks and every 3 months from the beginning of therapy.

Anemia. Tofacitinib should be avoided in patients with low hemoglobin levels (ie <9 g / dl). Treatment with tofacitinib should be stopped in patients whose hemoglobin levels fell to <8 g / dL or fell by more than 2 g / dL during treatment.

It is necessary to determine the level of hemoglobin before treatment, 4-8 weeks after the start of treatment and every 3 months in the future.

Increased level of hepatic enzymes

Treatment with tofacitinib was associated with an increase in the incidence of elevated hepatic enzyme levels compared with placebo. Most of these abnormalities arose in studies using background therapy for BPH (mainly methotrexate).

To identify potential drug damage to the liver, regular monitoring of liver parameters and the urgent study of cases of elevation of hepatic enzyme levels are recommended. If it is assumed that liver damage has occurred as a result of the use of drugs, the appointment of tofacitinib should be suspended until the deletion of this diagnosis.

Increase in lipid levels

Treatment with tofacitinib was associated with an increase in lipid parameters, such as total cholesterol, LDL cholesterol and HDL cholesterol. The maximum effects were usually observed within 6 weeks. The effect of increasing lipid parameters on cardiovascular morbidity and mortality is not established.

Evaluation of lipid parameters should be carried out approximately 4-8 weeks after initiation of therapy with tofacitinib.

To control hyperlipidemia, the patient should be led according to clinical guidelines (eg National Education Program for Cholesterol, NCEP).

Vaccination

There is no data on the response to vaccination or secondary transmission of infection when using live vaccines in patients receiving tofacitinib. The simultaneous use of live vaccines and tofacitinib should be avoided. Before initiation of therapy with tofacitinib, the necessary vaccinations should be performed in accordance with the current immunization instructions.

Special instructions

Since film-coated tablets contain lactose, they are contraindicated in individuals with lactase deficiency, lactose intolerance, glucose-galactose malabsorption.