tofacent

Instructions for use of Tofacitinib

Common name: Tofacitinib

Trade name: Tofacinix

Full names: Tofacitinib, Tofacitinib, tofacitinib, Tofacinix, Tofanib, Tofaxen

[Tofacitinib Indications]

Tofacinix is suitable for adult patients with moderately to severely active rheumatoid arthritis (RA) who have insufficient efficacy or intolerance to methotrexate. It can be used in combination with methotrexate or other non-biological disease-modifying antirheumatic drugs (DMARDs).

Restrictions on use: It is not recommended to use Tofacinix with biologic DMARDs or strong immunosuppressives (such as azathioprine and cyclosporine).

[Tofacitinib specifications]

5 mg (based on Tofacitinib)

[Tofacitinib usage and dosage]

Rheumatoid arthritis

Tofacinix can be used in combination with methotrexate or other non-biological DMARD drugs. The recommended dose of Tofacinix is ​​5 mg twice daily. Administer orally, with or without food.

Dose adjustment due to serious infection and cytopenias

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

Dose adjustment or treatment interruption is recommended when lymphopenia, neutropenia, and anemia occur [see Precautions and Adverse Reactions]

If a patient develops a serious infection, administration of Tofacinix should be avoided until the infection is controlled.

Dose adjustments due to drug interactions

In patients who:

are concurrently treated with a strong inhibitor of cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole), or who are receiving one or more agents that result in moderate inhibition of both CYP3A4 and CYP2C19 For concomitant use of highly suppressive medications (eg, fluconazole), the recommended dose of Tofacinix should be 5 mg once daily.

Coadministration of Tofacinix with strong CYP3A4 inducers (such as rifampicin) may result in loss or reduction of clinical response. Coadministration of strong CYP3A4 inducers with Tofacinix is ​​not recommended.

Dose adjustments in patients with renal or hepatic impairment

In patients with:

Moderate or severe renal insufficiency, or moderate hepatic impairment, the recommended dose of Tofacinix should be 5 mg once daily. Tofacinix is ​​not recommended for patients with severe hepatic impairment.

[Tofacitinib Adverse Reactions]

Clinical Trial Experience

Because different clinical studies are conducted under different conditions, the incidence of adverse reactions observed in clinical studies of one drug cannot be directly compared with the incidence of adverse reactions in clinical studies of another drug and therefore cannot predict the incidence observed in clinical practice in the broader patient population.

Although other doses have been studied, the recommended dose of Tofacinix is ​​5 mg twice daily.

The data below include two Phase 2 and five Phase 3 double-blind, controlled, multicenter clinical trials. In these trials, patients were randomized to Tofacinix monotherapy: 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients); in combination: Tofacinix 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with a DMARD (including methotrexate); and placebo (809 patients). The protocols of all seven studies were based on the premise that patients taking placebo would receive tofacinix at month 3 or 6, depending on the patient's response status (uncontrolled disease activity) or the study design, so that adverse events could not always be accurately attributed to a given treatment. Therefore, some analyzes followed the inclusion of patients from the placebo and tofacinix groups at given intervals who had a change in treatment based on study design or patient response. Comparisons were made between placebo and Tofacinix based on drug exposure in the previous 3 months, and between Tofacinix 5 mg twice daily and Tofacinix 10 mg twice daily based on drug exposure in the previous 12 months.

The long-term safety population included all patients who participated in a double-blind, controlled trial (early development phase study) and then participated in one of two long-term safety studies. The study design of the long-term safety study allows for dose adjustments of Tofacinix based on clinical judgment. This limits the interpretation of long-term safety data in terms of dosage.

The most common serious adverse reaction is serious infection (see Precautions).

In a double-blind, placebo-controlled trial, the proportion of patients who discontinued treatment due to any adverse reaction during 0 to 3 months of drug exposure was 4% in the Tofacinix group and 3% in the placebo group.

Overall infections

In the seven controlled trials, the overall incidence of infections during 0 to 3 months of drug exposure was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most common infections reported with Tofacinix were upper respiratory tract infection, nasopharyngitis, and urinary tract infection (4%, 3%, and 2% of patients, respectively).

Serious Infections

In the seven controlled trials, during 0 to 3 months of drug exposure, one serious infection was reported in patients in the placebo group (0.5 per 100 patient-years) and 11 serious infections were reported in patients receiving Tofacinix 5 mg or 10 mg twice daily (1.7 per 100 patient-years). The 5 mg twice daily tofacinix treatment group and the 10 mg twice daily tofacinix treatment group were combined and subtracted from the placebo group, resulting in an incidence rate difference (and corresponding 95% confidence interval) between treatment groups of 1.1 (-0.4, 2.5) events per 100 patient-years.

In these seven controlled trials, during 0 to 12 months of drug exposure, 34 serious infections (2.7 per 100 patient-years) were reported in the 5 mg twice daily tofacinix group and 33 serious infections (2.7 per 100 patient-years) were reported in the 10 mg twice daily tofacinix group. Subtracting the 5 mg twice daily Tofacinix treatment group from the 10 mg twice daily treatment group, the resulting incidence rate difference between the treatment groups (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years.

The most common serious infections include pneumonia, cellulitis, shingles, and urinary tract infections (see Precautions).

Tuberculosis

In these seven controlled trials, no cases of tuberculosis were reported in the placebo, 5 mg twice daily Tofacinix, or 10 mg twice daily Tofacinix groups during 0 to 3 months of drug exposure.

In these seven controlled trials, 0 cases of tuberculosis were reported in patients treated with 5 mg twice daily tofacinix and 6 cases were reported in patients treated with 10 mg twice daily during 0 to 12 months of drug exposure (0.5 events per 100 patient-years). Subtracting the 10 mg twice daily tofacinix treatment group from the 5 mg twice daily treatment group, the resulting incidence rate difference (and corresponding 95% confidence interval) between treatment groups was 0.5 (0.1, 0.9) events per 100 patient-years. Cases of disseminated tuberculosis have also been reported. The median duration of Tofacinix exposure before tuberculosis diagnosis was 10 months (152 days, 960 days) (see Precautions).

Opportunistic infections (excluding tuberculosis)

In these seven controlled trials, no opportunistic infections were reported in the placebo, 5 mg twice daily Tofacinix, or 10 mg twice daily Tofacinix groups during the 0 to 3 months of drug exposure.

In these seven controlled trials, during 0 to 12 months of drug exposure, 4 opportunistic infections (0.3 per 100 patient-years) were reported in patients treated with 5 mg twice daily Tofacinix and 4 cases (0.3 per 100 patient-years) were reported in patients treated with 10 mg twice daily Tofacinix. Subtracting the 10 mg twice daily Tofacinix treatment group from the 5 mg twice daily treatment group, the resulting incidence rate difference between treatment groups (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years.

The median duration of Tofacinix exposure before diagnosis of opportunistic infection was 8 months (range, 41 to 698 days) (see Precautions).

Malignancy

In these seven controlled trials, 0 cases of malignancy (excluding NMSC) were reported in the placebo group and 2 cases (0.3 per 100 patient-years) in patients treated with 5 mg twice daily Tofacinix and 10 mg twice daily Tofacinix during the 0 to 3 months of drug exposure. Tofacinix 5 mg twice daily and 10 mg twice daily were combined and subtracted from placebo, resulting in an incidence rate difference (and corresponding 95% confidence interval) between treatment groups of 0.3 (-0.1, 0.7) events per 100 patient-years.

Among the seven controlled trials, during 0 to 12 months of drug exposure, 5 cases of malignancy (excluding NMSC) were reported in patients treated with 5 mg twice daily Tofacinix (0.4 per 100 patient-years) and 7 cases (0.6 per 100 patient-years) were reported in the 10 mg twice daily Tofacinix group. Subtracting the 10 mg twice daily tofacinix treatment group from the 5 mg twice daily tofacinix treatment group resulted in an incidence rate difference (and corresponding 95% confidence interval) between treatment groups of 0.2 (-0.4, 0.7) events per 100 patient-years. One of these malignancies was a case of lymphoma that occurred in 1 patient in the Tofacinix 10 mg twice daily treatment group between 0 and 12 months.

The most common malignancies, including those observed during long-term extension studies, were lung and breast cancer, followed by gastric cancer, colorectal cancer, renal cell carcinoma, prostate cancer, lymphoma, and malignant melanoma (see Precautions).

Abnormal laboratory tests

Lymphopenia

In controlled clinical trials, absolute lymphocyte counts decreased to less than 500 cells/mm in 0.04% of patients treated with Tofacinix 5 mg twice daily and Tofacinix 10 mg twice daily combined during the first 3 months of drug exposure.

Lymphocyte counts below 500 cells/mm3 have been associated with treatment and an increased incidence of serious infections (see Precautions).

Neutropenia

A decline in ANC to less than 1000 cells/mm3 has been demonstrated in 0.07% of patients in the combined Tofacinix 5 mg twice daily and 10 mg twice daily Tofacinix treatment groups during the first 3 months of drug exposure in controlled clinical trials.

No decrease in ANC below 500 cells/mm3 was observed in any treatment group. There is no clear relationship between neutropenia and the development of serious infections.

The pattern and incidence of definitive decline in ANC in the long-term safety population were consistent with the incidence observed in controlled clinical trials (see Precautions).

Elevated Liver Enzymes

A definite increase in liver enzymes to greater than 3 times the upper limit of normal (3xULN) was observed in patients treated with Tofacinix. In patients who experience elevated liver enzymes, adjustments to the treatment regimen, such as reducing the dose of DMARD concomitant medication, interrupting tofacinix therapy, or reducing the dose of tofacinix, can reduce or normalize liver enzymes.

In controlled, monotherapy trials (0-3 months), no significant differences were observed in the incidence of elevated ALT or AST between the placebo, 5 mg tofacinix twice daily, and 10 mg twice daily tofacinix treatment groups.

In controlled trials of DMARDs as background therapy (0-3 months), ALT elevations above 3 times the upper limit of normal were observed in 1.0%, 1.3%, and 1.2% of patients in the placebo, 5 mg twice daily Tofacinix, and 10 mg twice daily Tofacinix groups, respectively. In these trials, the proportion of patients with AST elevations above 3 times the upper limit of normal was 0.6% in the placebo group, 0.5% in the 5 mg twice daily Tofacinix group, and 0.4% in the 10 mg twice daily Tofacinix group.

One case of drug-induced liver injury was reported in the Tofacinix 10 mg twice daily treatment group for approximately 2.5 months. The patient developed symptomatic elevations in AST and ALT values ​​greater than 3 times the ULN and bilirubin elevation greater than 2 times the ULN, requiring hospitalization and liver biopsy. Increased blood lipids

In controlled clinical trials, a dose-related increase in blood lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) was observed at one month of drug exposure and remained stable thereafter. In controlled clinical trials, changes in lipid parameters during the first 3 months of drug exposure are summarized as follows: Mean LDL cholesterol increased by 15% in the 5 mg twice daily Tofacinix treatment group and by 19% in the 10 mg twice daily Tofacinix treatment group.

Mean HDL cholesterol increased by 10% in the 5 mg twice daily Tofacinix group and by 12% in the 10 mg twice daily Tofacinix group.

The mean LDL/HDL ratio remained essentially unchanged among patients treated with Tofacinix.

In controlled clinical trials, elevated LDL cholesterol and ApoB resolved with statin therapy, returning to pretreatment levels.

In the long-term safety population, increases in lipid parameters were consistent with those observed in controlled clinical trials.

Elevated serum creatinine

Dose-related increases in serum creatinine were observed in Tofacinix-treated groups in controlled clinical trials. The mean increase in serum creatinine in the 12-month pooled safety analysis was <0.1 mg/dL; however, as exposure increased in the long-term extension study, up to 2% of patients discontinued Tofacinix treatment due to protocol-specified discontinuation criteria, that is, an increase in creatinine greater than 50% of baseline. The clinical significance of the observed increase in serum creatinine has not been determined. Other adverse reactions occurred in 2% or more of patients treated with tofacinix 5 mg twice daily or tofacinix 10 mg twice daily, with or without DMARDs, and were at least 1% greater than the incidence observed in patients treated with placebo.

Other adverse reactions that occurred in controlled and open-label extension studies include:

Hematological and lymphatic system abnormalities: anemia

Infections and infestations: diverticulitis Metabolic and nutritional Nutritional abnormalities: dehydration Mental abnormalities: insomnia

Nervous system abnormalities: paresthesia

Respiratory, thoracic and mediastinal abnormalities: dyspnea, cough, sinus congestion Gastrointestinal abnormalities: abdominal pain, indigestion, vomiting, gastritis, nausea Cardiac

Hepatobiliary abnormalities: hepatic steatosis

Skin and subcutaneous tissue abnormalities: rash, erythema, pruritus

Musculoskeletal, connective tissue and bone abnormalities: musculoskeletal pain, arthralgia, tendonitis, joint Swelling of benign, malignant, and unspecified tumors (including cysts and polyps): Non-melanoma skin cancer

Systemic abnormalities and administration site symptoms: Fever, fatigue, peripheral edema Clinical experience in methotrexate-naïve patients.

[Tofacitinib contraindications]

None

[Tofacitinib precautions]

Severe, and occasionally fatal, infections caused by bacteria, mycobacteria, invasive fungi, viruses, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis receiving Tofacinix. The most common serious infections reported with Tofacinix include pneumonia, cellulitis, shingles, urinary tract infection, and diverticulitis (see Adverse Reactions). Among the opportunistic infections reported with Tofacinix are tuberculosis and other mycobacterial infections, cryptococcus, esophageal candidiasis, pneumocystosis, multiple cutaneous herpes zoster, cytomegalovirus, and BK virus. Some patients present with disseminated infection rather than localized disease and are often concurrently taking immunosuppressants such as methotrexate or corticosteroids.

Other serious infections not reported in clinical studies (e.g., histoplasmosis, coccidioidomycosis, listeriosis) may also occur.

Avoid initiating Tofacinix in patients with severe active infection, including localized infection. The risks and benefits of treatment should be considered before initiating Tofacinix in patients who:

Have chronic or recurrent infections

Have a history of exposure to tuberculosis

Have a history of serious or opportunistic infections

Have lived in or traveled to an area where tuberculosis or mycobacteria are endemic

Have underlying conditions that may make them susceptible to infection

All patients should be closely monitored for signs and symptoms of infection during and after treatment with Tofacinix. Dosing of Tofacinix should be interrupted if a patient develops serious infection, opportunistic infection, or sepsis. Patients who develop a new infection while being treated with Tofacinix should undergo prompt and complete diagnostic testing as appropriate for immunocompromised patients; appropriate antimicrobial therapy should be initiated, and the patient should be monitored closely.

Tuberculosis

Prior to initiating administration of Tofacinix, patients should be evaluated and tested for latent or active infection.

Antituberculosis therapy should also be considered before initiating Tofacinix administration in patients with a past history of latent or active tuberculosis, in whom an adequate course of therapy cannot be confirmed and in whom risk factors for tuberculosis infection remain despite a negative latent tuberculosis test result. Consultation with a specialist in tuberculosis treatment is recommended to help decide whether it is appropriate to initiate anti-tuberculosis treatment for an individual patient.

Patients should be closely monitored for signs and symptoms of tuberculosis, including those who test negative for latent tuberculosis infection before starting treatment.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy prior to administration of Tofacinix.

Viral Reactivation

Viral reactivation has been observed in clinical studies of Tofacinix, including cases of herpes virus reactivation (e.g., shingles). The effect of Tofacinix on chronic viral hepatitis reactivation has not been established. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Before starting treatment with Tofacinix, screening for viral hepatitis should be performed in accordance with clinical guidelines. The risk of herpes zoster is increased in patients treated with Tofacinix, and the risk appears to be higher in Japanese patients treated with Tofacinix.

Malignant Neoplasms and Lymphoproliferative Disorders

Consider the risks and benefits of Tofacinix therapy before initiating treatment in patients with a known malignancy other than successfully treated non-melanoma skin cancer (NMSC) or when considering continuing Tofacinix therapy in patients who have developed a malignancy. Malignancies have been observed in clinical studies of tofacinix (see Adverse Reactions). In seven controlled clinical studies in rheumatoid arthritis, 11 cases of solid cancer and 1 case of lymphoma were diagnosed in 3328 patients who received tofacinix with or without DMARDs during the first 12 months of drug exposure, compared with 0 cases of solid cancers and 0 cases of lymphoma in 809 patients who received placebo with or without DMARDs. Lymphoma and solid cancers were also observed in long-term extension studies of Tofacinix in patients with rheumatoid arthritis.

In Phase 2B, a controlled dose-ranging study was conducted in first-time renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid. Five cases (2.3%) of Epstein-Barr virus-associated post-transplant lymphoproliferative disease were observed in 218 patients treated with Tofacinix, compared with 0 cases in 111 patients treated with cyclosporine.

Non-melanoma skin cancer

Non-melanoma skin cancer (NMSC) has been reported in patients treated with Tofacinix. Regular skin examinations are recommended for patients at increased risk of skin cancer.

Gastrointestinal perforation

Events of gastrointestinal perforation have been reported in clinical studies of Tofacinix in patients with rheumatoid arthritis, but the role of JAK inhibition in these events is unknown.

Tofacinix should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis). Patients with new abdominal symptoms should be promptly evaluated to allow early identification of gastrointestinal perforation (see Adverse Reactions).

Laboratory Abnormalities

Lymphocyte Abnormalities

During the 12-month treatment period, an initial Tofacinix treatment-related lymphocytosis occurred at one month of drug exposure, followed by a gradual decline, with the mean absolute lymphocyte count approximately 10% below baseline. Lymphocyte counts below 500 cells/mm3 are associated with an increased incidence of serious infections.

Avoid initiating Tofacinix therapy in patients with low lymphocyte counts (i.e., less than 500 cells/mm3). Treatment with Tofacinix is ​​not recommended in patients who develop definitive absolute lymphocyte counts below 500 cells/mm3.

Monitor lymphocyte counts at baseline and every 3 months thereafter. See Dosage and Administration for recommended dosage adjustments based on lymphocyte count.

Neutropenia

Tofacinix treatment is associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared with placebo.

Avoid initiating Tofacinix therapy in patients with low neutrophil counts (i.e., ANC less than 1000 cells/mm3). For patients who develop ANC that persists between 500 and 1000 cells/mm3, interrupt tofacinix administration until ANC is greater than or equal to 1000 cells/mm3. Treatment with Tofacinix is ​​not recommended in patients who develop an ANC less than 500 cells/mm3. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. See Dosage and Administration for recommended dosage adjustments based on ANC results.

Anemia

Avoid initiating Tofacinix therapy in patients with low hemoglobin levels (i.e., less than 9 g/dL). Tofacinix therapy should be discontinued in patients who experience a hemoglobin level less than 8 g/dL or a decrease in hemoglobin level greater than 2 g/dL during treatment.

Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. See Dosage and Administration for recommended dosage adjustments based on hemoglobin results.

Elevated liver enzymes

Tofacinix treatment was associated with an increased incidence of elevated liver enzymes compared with placebo. Most of these abnormalities occurred in studies using DMARDs (mainly methotrexate) as background therapy.

It is recommended to conduct routine monitoring of liver function test items and quickly investigate the cause of elevated liver enzymes to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, tofacinix administration should be interrupted until this diagnosis is ruled out.

Elevated blood lipids

Tofacinix treatment is associated with an increase in blood lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects are generally observed within 6 weeks. The impact of these elevated lipid parameters on cardiovascular morbidity and mortality has not yet been determined.

Assessment of lipid parameters should be performed approximately 4-8 weeks after starting Tofacinix treatment. Patients were managed for hyperlipidemia according to clinical guidelines.

Vaccination

No data are available on the response to vaccination or secondary transmission of live vaccine infections in patients receiving Tofacinix. Avoid administering live vaccines at the same time as Tofacinix.

Before starting treatment with Tofacinix, the immunization regimen should be updated in accordance with current immunization guidelines.

Medications in Diabetic Patients

Because the incidence of infections is generally higher in the diabetic population, caution should be used when treating patients with diabetes.

Liver function damage

Tofacinix concentrations were higher in patients with moderate hepatic impairment who received tofacinix compared to patients with normal hepatic function who received tofacinix. Higher plasma concentrations may increase the risk of certain adverse reactions, so the recommended dose of Tofacinix in patients with moderate hepatic impairment is 5 mg once daily [see Dosage and Administration]. Tofacinix has not been studied in patients with severe hepatic impairment and therefore its use is not recommended in patients with severe hepatic impairment. No dose adjustment is required in patients with mild hepatic impairment. The safety and effectiveness of Tofacinix have not been studied in patients with positive hepatitis B virus or hepatitis C virus serological tests.

Renal Impairment

Tofacinix plasma concentrations are higher in patients with moderate and severe renal impairment who receive Tofacinix than in patients with normal renal function who receive Tofacinix; therefore, the recommended dose of Tofacinix in patients with moderate and severe renal impairment is 5 mg once daily [see Dosage and Administration]. In clinical trials, Tofacinix has not been evaluated in patients with rheumatoid arthritis who had baseline creatinine clearance values ​​less than 40 mL/minute (estimated using the Cockroft-Gault formula). No dose adjustment is required in patients with mild renal impairment.

[Tofacitinib for pregnant and lactating women]

Pregnant women

Teratogenic effects:

Category C pregnancy. There are no adequate and well-controlled studies in pregnant women. Tofacinix should be used during pregnancy only if the potential benefits can be demonstrated to outweigh the potential risks to the fetus. Tofacinix was shown to be fetal lethal and teratogenic in rats and rabbits at 146 and 13 times the maximum recommended human dose (MRHD), respectively. In a rat embryo-fetal development study, tofacinix was teratogenic at a drug exposure level of approximately 146 times the MRHD (based on AUC at an oral dose of 100 mg/kg/day). Teratogenic effects include external and soft tissue deformities, respectively, generalized edema and septal defects, as well as skeletal deformities or variations (missing cervical vertebral arch; curvature of femur, fibula, humerus, radius, scapula, tibia and ulna; sternum cleft; missing ribs; femoral deformity; rib ramus; fused ribs; fused sternal segments; hemicentric thoracic vertebrae). In addition, there is an increase in post-implantation miscarriage, including early and late resorption, resulting in a decrease in the number of viable fetuses. Average fetal weight decreased. No developmental toxicity was observed in rats at exposure levels approximately 58 times the MRHD (based on AUC at an oral dose of 30 mg/kg/day). In embryo-fetal development studies in rabbits, tofacinix was teratogenic at drug exposure levels approximately 13 times the MRHD (based on AUC at an oral dose of 30 mg/kg/day) with no signs of maternal toxicity. Teratogenic effects include thoracogastric schisis, omphalocele, ventricular septal defects, cranial/skeletal malformations (microstomia, microphthalmos), midline and caudal defects. In addition, there is an increase in postimplantation miscarriage associated with late resorption. No developmental toxicity was observed in rabbits at drug exposure levels approximately 3 times the MRHD (based on AUC at an oral dose of 10 mg/kg/day).

Non-teratogenic effects:

In studies in perinatal and postnatal rats, there were reduced litter size, reduced postnatal survival, and reduced pup weight at exposure levels approximately 73 times the MRHD (based on AUC at an oral dose of 50 mg/kg/day). Drug exposure at approximately 17 times the MRHD (based on AUC at an oral dose of 10 mg/kg/day) had no effect on behavioral and learning outcomes, sexual maturation of F1 rats, or the ability to mate and produce live F2 rat fetuses.

Breastfeeding women

Tofacinix is ​​secreted in the milk of lactating rats. It is not known whether Tofacinix is ​​excreted in human milk. Because many drugs are excreted in human milk and Tofacinix has the potential to cause serious adverse reactions in a nursing infant, the decision whether to discontinue breastfeeding or to discontinue the drug should take into account the importance of the drug to the mother.

[Tofacinib Pediatric Medication]

The safety and effectiveness of Tofacinix in pediatric patients have not been established.

[Tofacitinib for the Elderly]

Among the 3,315 patients participating in five global clinical studies, a total of 505 patients with rheumatoid arthritis were 65 years old and above, including 71 patients over 75 years old. The incidence of serious infections was higher in subjects 65 years and older in the Tofacinix treatment group than in subjects younger than 65 years. Since the incidence of infection is generally higher in the elderly, caution should be used in the treatment of the elderly.

[Drug Interactions with Tofacitinib]

Strong CYP3A4 Inhibitors

Tofacinix exposure increases when Tofacinix is ​​coadministered with strong inhibitors of cytochrome P450 (CYP) 3A4 (such as ketoconazole) (see Dosage and Administration).

Moderate CYP3A4 and strong CYP2C19 inhibitors

Tofacinix exposure is increased when Tofacinix is ​​coadministered with drugs that cause moderate CYP3A4 inhibition and strong CYP2C19 inhibition (such as fluconazole) (see Administration and Dosage).

Potent CYP3A4 inducers

Tofacinix exposure is decreased when Tofacinix is ​​coadministered with strong CYP3A4 inducers (such as rifampicin) (see Administration and Dosage).

Immunosuppressants

When Tofacinix is ​​combined with strong immunosuppressants (such as azathioprine, tacrolimus, cyclosporine), there is a risk of increased immunosuppressive effects. The concomitant use of multiple doses of Tofacinix with strong immunosuppressants has not been studied in rheumatoid arthritis. It is not recommended to use Tofacinix with biologic DMARDs or strong immunosuppressives (such as azathioprine and cyclosporine).

[Tofacinib Overdose]

Symptoms, signs, and laboratory findings in acute overdose situations in humans There is no experience with Tofacinix overdose.

Treatment or Management of Overdose

Pharmacokinetic data in healthy volunteers at doses up to and including single doses of 100 mg indicate that more than 95% of the administered dose is expected to be eliminated within 24 hours.

There is no specific antidote for Tofacinix overdose. In case of overdose, it is recommended to monitor the patient for signs and symptoms of adverse reactions. Patients who experience adverse reactions should receive appropriate treatment.

[Tofacitinib Storage]

Store in a cool and dry place, not exceeding 30°C. Protected from light and out of reach of children.

[Tofacitinib packaging]

Aluminum film strip blister packaging. 30 tablets/box

[Tofacitinib validity period]

24 months