Date of approval.
Date of revision.
Tofacitib Citrate Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Tofacitinib Citrate Tablets
English name: Tofacitinib Citrate Tablets
Hanyu Pinyin: Juyuansuan Tuofatibu Pian
Ingredients
Active ingredient: Tofacitinib Citrate.
Chemical name: (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropionitrile citrate
Chemical structure formula.
Molecular formula: C16H20N6O-C6H8O7
Molecular weight: 504.5
Properties
This product is a white round film-coated tablet, which appears white to off-white after removing the coating.
Indications
Tofacitab is indicated for adult patients with moderately to severely active rheumatoid arthritis (RA) for whom methotrexate is not effective or is intolerable, and may be used in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARD).
Limitations on use: Tofacitab is not recommended in combination with biologic DMARD drugs or potent immunosuppressants (e.g., azathioprine and cyclosporine).
Specification
5mg (based on C16H20N6O)
Dosage and Administration
Important Medication Instructions
Do not start tofacitab in patients with absolute lymphocyte count less than 500 cells/mm3, absolute neutrophil count (ANC) less than 1000 cells/mm3, or hemoglobin level less than 9 g/dL.
● Interruption of dosing is recommended in the presence of lymphocytopenia, neutropenia, and anemia (see PRECAUTIONS, Adverse Reactions).
If a patient develops a serious infection, tofacitab administration should be interrupted until the infection is controlled (see PRECAUTIONS).
Tofacitab may be taken with or without food.
Recommended doses for rheumatoid arthritis
Table 1 lists the recommended adult daily dose of tofacitab and dose adjustments for patients treated with CYP2C19 and/or CYP3A4 inhibitors; moderate or severe renal impairment (including but not limited to patients with severe renal insufficiency on hemodialysis) or moderate hepatic impairment; and concomitant lymphopenia, neutropenia, or anemia.
Table 1: Recommended dose of tofacitab for patients with rheumatoid arthritis1
Tofacitib 5 mg twice daily in adult patients receiving
a potent CYP3A4 inhibitor (e.g., ketoconazole), or
an intermediate CYP3A4 inhibitor and a potent
CYP2C19 inhibitor (e.g., fluconazole)
[see Drug Interactions] 5 mg once daily in patients with
Moderate or severe renal impairment (see Precautions)
Moderate hepatic impairment
(see Precautions)* 5 mg once daily
For patients undergoing hemodialysis, dose should be administered after dialysis on the day of dialysis. If administered prior to dialysis operations, supplemental dosing after the patient is on dialysis is not recommended. Lymphocyte counts below 500 cells confirmed by repeat testing
/Patients with ANC between 500 and 1000 cells/mm3 discontinue dosing
When ANC is above 1000, re-dose 5 mg twice daily Patients with ANC below 500 cells/mm3 discontinue dosing Patients with hemoglobin levels below 8 g/dL or reduced by more than 2 g/dL discontinue dosing until hemoglobin values return to normal.1 Tofacitab may be used in combination with methotrexate or other non-biologic disease-modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis. Use.
*Tofacitab is not recommended for use in patients with severe hepatic impairment.
Adverse Reactions
As reported in foreign literature.
The following clinically significant adverse reactions are described in other sections of the instruction.
Serious infections (see precautions)
Malignancy and lymphoproliferative disorders (see precautions)
Thrombosis (see precautions)
Gastrointestinal perforation (see Precautions)
Hypersensitivity reactions (see precautions)
Abnormal laboratory tests (see precautions)
Clinical trial experience
Because different clinical studies were conducted under different conditions, the incidence of adverse reactions observed with one drug in clinical studies cannot be directly compared with the incidence of another drug in clinical studies and therefore cannot predict the incidence observed in clinical practice in a broader population of patients.
Although other doses have been studied, the recommended dose of tofacitib is 5 mg twice daily. Tofacitib 10 mg twice daily should not be used in rheumatoid arthritis.
The data below include two Phase 2 and five Phase 3 double-blind, controlled, multicenter clinical trials. In these trials, patients were randomized to tofacitib monotherapy: 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients); combinations: tofacitib 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with a DMARD class (including methotrexate); and a placebo group ( 809 patients). The protocols of all seven studies were based on the premise that patients on placebo were to receive tofacitab at month 3 or month 6 depending on whether the patient was in remission (with uncontrolled disease activity) or the study design, such that adverse events could not always be accurately attributed to a specified treatment. Therefore, certain analyses followed the inclusion of patients in both the placebo and tofacitab groups who had changed treatment based on study design or patient remission from the placebo group to the tofacitab group at a given time interval. Comparisons were made between placebo and tofacitab based on drug exposure during the first 3 months and between tofacitab 5 mg twice daily and tofacitab 10 mg twice daily based on drug exposure during the first 12 months.
The long-term safety population included all patients who participated in a double-blind, controlled trial (including early development phase studies) and were then enrolled in one of two long-term safety studies. The study design of the long-term safety study allowed for adjustment of tofacitib dosing based on clinical judgment. This limits the interpretation of long-term safety data in terms of dose.
The most common serious adverse reaction was a serious infection (see PRECAUTIONS).
The proportion of patients in the double-blind, placebo-controlled trial who discontinued treatment for any adverse reaction during the 0 to 3-month drug exposure was 4% in the tofacitib group and 3% in the placebo group.
Overall Infection Status
The overall incidence of infections within the 5 mg twice daily treatment group and the 10 mg twice daily treatment group during the 0 to 3 month drug exposure period in these seven controlled trials was 20% and 22%, respectively, compared with 18% in the placebo group.
The most common infections reported with tofacitab were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).
Serious infections
In these seven controlled trials, 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 tofacitib 5 mg or 10 mg twice daily (1.7 per 100 patient-years) during drug exposure of 0 to 3 months. 5 mg twice daily tofacitib treatment group and 10 mg twice daily tofacitib treatment combination and subsequently subtracted from the placebo group, yielded an incidence difference (and corresponding 95% confidence interval) of 1.1 (-0.4, 2.5) episodes per 100 patient-years between treatment groups.
In these seven controlled trials, 34 serious infections (2.7 per 100 patient-years) were reported in the 5 mg twice daily tofacitab treatment group and 33 serious infections (2.7 per 100 patient-years) were reported in the 10 mg twice daily tofacitab treatment group during 0 to 12 months of drug exposure. 10 mg twice daily tofacitab treatment group minus the 5 mg twice daily treatment group yielded The difference in incidence (and corresponding 95% confidence interval) between the treatment groups was -0.1 (-1.3, 1.2) episodes per 100 patient-years.
The most common serious infections included pneumonia, cellulitis, and herpes zoster, and urinary tract infections (see Caution).
Tuberculosis
No tuberculosis was reported in patients in the placebo group, the 5 mg twice-daily tofacitab treatment group, and the 10 mg twice-daily tofacitab treatment group in these seven controlled trials during drug exposure of 0 to 3 months.
In these seven controlled trials, 0 cases of TB were reported by patients in the 5 mg twice daily tofacitab treatment group and 6 cases of TB were reported by patients in the 10 mg twice daily tofacitab treatment group during the 0 to 12 month drug exposure period (0.5 episodes per 100 patient-years).The difference in incidence between treatment groups obtained for the 10 mg twice daily tofacitab treatment group minus the 5 mg twice daily treatment group ( and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) episodes per 100 patient-years.
Cases of disseminated TB were also reported. The median duration of tofacitab exposure prior to the diagnosis of TB was 10 months (range from 152 to 960 days) (see Caution).
Opportunistic infections (excluding tuberculosis)
None of the patients in these seven controlled trials reported opportunistic infections in the placebo group, the 5 mg twice-daily tofacitib treatment group, or the 10 mg twice-daily tofacitib treatment group during drug exposure of 0 to 3 months.
In these seven controlled trials, four opportunistic infections (0.3 per 100 patient-years) were reported by patients in the 5 mg twice daily tofacitab treatment group and four opportunistic infections (0.3 per 100 patient-years) were reported by patients in the 10 mg twice daily tofacitab treatment group during the 0 to 12 month drug exposure period. The difference in incidence (and corresponding 95% confidence interval) between treatment groups was 0 (-0.5, 0.5) infections per 100 patient-years for the 10 mg twice daily tofacitab treatment group minus the 5 mg twice daily treatment group.
The median duration of tofacitab exposure prior to diagnosis of opportunistic infection was 8 months (range from 41 to 698 days) (see Caution).
Malignancies
In these seven controlled trials, 0 malignancies (excluding NMSC) were reported in the placebo group and a total of 2 in patients in the 5 mg twice-daily tofacitib treatment group and the 10 mg twice-daily tofacitib treatment group during drug exposure of 0 to 3 months (0.3 episodes per 100 patient-years). the 5 mg twice-daily tofacitib treatment group and the 10 mg twice-daily tofacitib treatment combination and subsequently subtracted from the placebo group, yielded an incidence difference (and corresponding 95% confidence interval) of 0.3 (-0.1, 0.7) episodes per 100 patient-years between treatment groups.
In these seven controlled trials, five cases of malignancy (excluding NMSC) were reported in the 5 mg twice-daily tofacitab treatment group (0.4 episodes per 100 patient-years) and seven cases in the 10 mg twice-daily tofacitab treatment group (0.6 episodes per 100 patient-years) during 0 to 12 months of drug exposure. 10 mg twice-daily tofacitab treatment group minus the 5 mg twice-daily The difference in incidence (and corresponding 95% confidence interval) between the treatment groups was 0.2 (-0.4, 0.7) episodes per 100 patient-years for the 10 mg twice daily tofacitab treatment group. One of these malignancies was a case of lymphoma that presented in one patient in the tofacitab 10 mg twice daily treatment group between 0 and 12 months.
The most common malignancies, including those observed during the long-term extension study, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate, lymphoma, and malignant melanoma (see Caution).
Laboratory test abnormalities
Lymphocytopenia
In clinical controlled trials, the number of patients with a test-confirmed decline in absolute lymphocyte counts to less than 500 cells/mm3 was 0.04% in the 5 mg twice-daily tofacitab treatment group and the 10 mg twice-daily tofacitab treatment group after the combination during the first 3 months of drug exposure.
Assay-confirmed lymphocyte counts below 500 cells/mm3 were associated with increased incidence of treatment and serious infections (see Caution).
Neutropenia
In clinical controlled trials, the decrease in ANC confirmed by testing to less than 1000 cells/mm3 was 0.07% of patients in the 5 mg twice-daily tofacitab treatment group and after the 10 mg twice-daily tofacitab treatment combination during the first 3 months of drug exposure.
No decrease in ANC to less than 500 cells/mm3 was observed in any treatment group.
There was no clear relationship between neutropenia and the development of serious infections.
In the long-term safety population, the pattern and incidence of definitive decreases in ANC remained consistent with the incidence observed in clinical controlled trials (see Caution).
Elevated Liver Enzymes
Definitive increases in liver enzymes to greater than 3 times the upper limit of normal (3xULN) were observed in patients in the tofacitab-treated group. In patients who developed elevated liver enzymes, treatment regimen modifications such as dose reduction of DMARD combination, interruption of tofacitab therapy, or dose reduction of tofacitab resulted in a reduction or normalization of liver enzymes.
In controlled, monotherapy trials (0-3 months), there was no significant difference in the incidence of ALT or AST elevations observed in the placebo group, the 5 mg twice-daily tofacitib treatment group, and the 10 mg twice-daily tofacitib treatment group.
In controlled trials (0-3 months) using DMARD as background treatment, 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 group, the 5 mg twice daily tofacitib treatment group and the 10 mg twice daily tofacitib treatment group, respectively. In these trials, the percentage of patients with AST elevations above 3 times the upper limit of normal in the placebo group, the 5 mg twice daily tofacitib treatment group and the 10 mg twice daily tofacitib treatment group were 0.6%, 0.5% and 0.4%, respectively.
One case of pharmacogenic liver injury was reported in the 10 mg twice-daily tofacitab treatment group, and the duration of treatment was approximately 2.5 months. This patient developed symptomatic AST and ALT values elevated more than 3 times ULN and had bilirubin elevations more than 2 times ULN, requiring hospitalization and liver biopsy.
Elevated lipids
In controlled clinical trials, a dose-related increase in 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 were summarized as follows.
Mean LDL cholesterol increased by 15% in the 5 mg twice-daily tofacitab treatment group and by 19% in the 10 mg twice-daily tofacitab treatment group.
Mean HDL cholesterol increased by 10% in the 5 mg twice-daily tofacitab treatment group and by 12% in the 10 mg twice-daily tofacitab treatment group.
The mean LDL/HDL ratio in patients in the tofacitab-treated group remained essentially unchanged.
In controlled clinical trials, elevated LDL cholesterol and ApoB decreased to pretreatment levels with corresponding remission with statin therapy.
In the long-term safety population, the elevated lipid parameters remained consistent with those observed in the controlled clinical trials.
Elevated serum creatinine
In controlled clinical trials, dose-related elevations in serum creatinine were observed in the tofacitab-treated group. The mean increase in serum creatinine in the 12-month combined safety analysis was <0.1 mg/dL; however, with increasing exposure time in the long-term extension study, up to 2% of patients discontinued tofacitib treatment due to the discontinuation criteria specified in the study protocol, i.e., creatinine increases above 50% of baseline values. The clinical significance of the observed phenomenon of elevated serum creatinine has not been clarified.
Other adverse reactions
Adverse reactions occurring at an incidence of ≥2% and reported at a rate at least 1% higher than the placebo group in patients in the 5 mg twice-daily tofacitib treatment group or the 10 mg twice-daily tofacitib treatment group, with or without DMARD, are shown in Table 2.
Table 2: Common adverse reactions* in clinical trials of tofacitib with or without DMARD (0-3 months) for rheumatoid arthritis
Tofacitib
5 mg twice daily tofacitib
10 mg twice daily** Placebo preferred term N = 1336 (%) N = 1349 (%) N = 809 (%) Upper respiratory tract infection 443 Nasopharyngitis 433 Diarrhea 432 Headache 432 Hypertension 221N represents patients from seven clinical trials who were randomized to and received treatment.
* Reported by ≥ 2% of patients treated with either tofacitab dose and reported by ≥ 1% more than the placebo group.
** The recommended dose of tofacitib for the treatment of rheumatoid arthritis is 5 mg twice daily (see Dosage and Administration). Other adverse reactions that occurred in controlled and open extension studies include
Abnormalities of the blood and lymphatic system: anemia
Infections and infestations: diverticulitis
Metabolic and nutritional abnormalities: dehydration
Mental abnormalities: insomnia
Neurological abnormalities: sensory abnormalities
Respiratory, thoracic and mediastinal abnormalities: dyspnea, cough, sinus congestion, interstitial lung disease (limited to patients with rheumatoid arthritis, and some are fatal)
Gastrointestinal abnormalities: abdominal pain, indigestion, vomiting, gastritis, nausea
Hepatobiliary abnormalities: hepatic steatosis
Skin and subcutaneous tissue abnormalities: rash, erythema, pruritus
Musculoskeletal, connective tissue and bone abnormalities: musculoskeletal pain, arthralgia, tendonitis, joint swelling
Benign, malignant and tumors of unknown nature (including cysts and polyps): non-melanoma skin cancer
Systemic abnormalities and administration site symptoms: fever, fatigue, peripheral edema
Dose-dependent adverse reactions were observed in patients treated with tofacitab 10 mg twice daily compared to those receiving 5 mg twice daily and included the following: herpes zoster infection, severe infection and NMSC.
Post-marketing Experience
The following adverse reactions have been identified during post-approval use of tofacitab. Because these adverse reactions were spontaneously reported by populations of uncertain size, it was not always possible to reliably estimate their frequency or determine a causal relationship with drug exposure.
Immune system abnormalities: drug-related hypersensitivity reactions (events such as angioedema and urticaria have been observed).
[Contraindication
None
[Precautions].
As reported in foreign literature.
Severe infection
Serious infections caused by bacteria, mycobacteria, invasive fungi, viruses, or other opportunistic pathogens have been reported in patients with rheumatoid arthritis treated with tofacitab, and occasionally fatal infections. The most common serious infections reported with tofacitab include pneumonia, cellulitis, herpes zoster, urinary tract infections, diverticulitis, and appendicitis. Among the opportunistic infections reported with tofacitab are tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal Candida infection, pneumocystis, multiple cutaneous herpes zoster, cytomegalovirus infection, BK virus infection, and listeriosis. Some patients present with disseminated infection rather than localized disease and are often taking concomitant immunosuppressive drugs such as methotrexate or corticosteroids.
Other serious infections not reported in clinical studies (e.g., coccidioidomycosis) may also occur.
Avoid starting tofacitab in patients with severe active infections, including those with localized infections. The risks and benefits of treatment should be considered before starting tofacitab in patients who
Have chronic or recurrent infections
Have a history of previous exposure to tuberculosis
Have a history of severe or opportunistic infections
Have lived or traveled in an area where tuberculosis or mycobacteria are endemic
Have an underlying medical condition that may make them susceptible to infection
All patients should be monitored closely for signs and symptoms of infection during and after treatment with tofacitab. If a patient develops a serious infection, opportunistic infection, or sepsis, tofacitab administration should be interrupted. Patients who develop new infections during treatment with tofacitab should undergo prompt and complete diagnostic testing as indicated for immunocompromised patients; appropriate antimicrobial therapy should be initiated and the patient should be closely monitored.
Caution is also advised in patients with a history of chronic lung disease or with interstitial lung disease, as these patients are more likely to develop infections.
The risk of infection may increase with increasing lymphopenia, and lymphocyte counts should be considered when assessing the risk of infection in individual patients. For lymphopenia, discontinuation and monitoring according to the lymphocyte count criteria under [DOSAGE AND ADMINISTRATION] is recommended.
Tuberculosis
Prior to initiation of tofacitab administration and during administration, patients should be evaluated and tested for latent or active infection according to applicable guidelines.
Antituberculosis treatment should also be considered prior to initiating tofacitab 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 test result for latent tuberculosis. Consultation with a TB treatment specialist is recommended to help determine whether it is appropriate to initiate anti-TB treatment for a particular individual patient.
Patients should be monitored closely for signs and symptoms of TB disease, including those who test negative for latent TB infection prior to initiating treatment.
Patients with latent TB should be treated with standard anti-mycobacterial therapy prior to totofacitab administration.
Viral reactivation
Viral reactivation has been observed in clinical studies with tofacitab, including cases of herpesvirus reactivation (e.g., herpes zoster). Post-marketing cases of hepatitis B reactivation have been reported in patients treated with tofacitab. The effect of tofacitab on reactivation of chronic viral hepatitis has not been clarified. Patients with positive screening results for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed according to clinical guidelines prior to initiation of tofacitib therapy. The risk of herpes zoster is elevated in patients treated with tofacitab and appears to be higher in Japanese and Korean patients treated with tofacitab.
Malignancies and lymphoproliferative disorders
Consider the risks and benefits of tofacitab treatment before starting treatment in patients with a known malignancy other than successfully treated non-melanoma skin cancer (NMSC) or when considering continuation of tofacitab treatment in patients who develop a malignancy. Malignancies have been observed in clinical studies with tofacitib (see Adverse Reactions).
In seven controlled clinical studies in rheumatoid arthritis, 11 cases of solid cancer and 1 case of lymphoma were diagnosed in 3,328 patients treated with tofacitib with or without DMARD during the first 12 months of drug exposure, compared with 0 cases of both solid cancer and lymphoma in 809 patients treated with placebo with or without DMARD. in the treatment with tofacitib Lymphomas and solid cancers were also observed in a long-term extension study of patients with rheumatoid arthritis.
In phase 2B, a controlled dose-ranging study was conducted in patients undergoing first-time renal transplantation, all of whom received baliximab induction therapy, high-dose corticosteroids, and mycophenolic acid analogs. 5 cases (2.3%) of EBV-associated post-transplant lymphoproliferative disease were observed in 218 patients treated with tofacitab compared to 0 cases in the 111 patients in the cyclosporine treatment group.
Other malignancies, including but not limited to lung, breast, melanoma, prostate and pancreatic cancers, were observed in clinical studies and post-marketing.
Non-melanoma skin cancers
Non-melanoma skin cancer (NMSC) has been reported in patients treated with tofacitab. Regular skin examinations are recommended for patients with an increased risk of skin cancer.
Thrombosis
Thrombosis (including pulmonary embolism, deep vein thrombosis, and arterial thrombosis) has occurred in patients treated with tofacitab and other Janus kinase (JAK) inhibitors (for the treatment of inflammatory states). In a large ongoing post-marketing safety study, a higher incidence of these events was observed in patients with rheumatoid arthritis aged 50 years and older treated with tofacitab 10 mg twice daily who had at least one cardiovascular risk factor than in patients treated with tofacitab 5 mg twice daily or TNF blockers. Most of these events were serious and some resulted in death (see Caution).
Tofacitab 10 mg twice daily should not be used in rheumatoid arthritis.
Evaluate patients with symptoms of thrombosis immediately and discontinue tofacitib in patients who develop symptoms of thrombosis.
Tofacitab should be avoided in patients who may be at increased risk of thrombosis.
Gastrointestinal Perforation
Gastrointestinal perforation events have been reported in clinical studies of tofacitab in patients with rheumatoid arthritis, but the role of JAK inhibition in these events is unknown. In these studies, many patients with rheumatoid arthritis were receiving background treatment with nonsteroidal anti-inflammatory drugs (NSAIDs).
Tofacitab should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or who are receiving an NSAID). Patients with new onset of abdominal symptoms should be evaluated promptly for early recognition of gastrointestinal perforation (see Adverse Reactions).
Hypersensitivity reactions
Reactions such as angioedema and urticaria that may reflect drug-related hypersensitivity reactions have been observed in patients treated with tofacitab. Some of these are serious events. If a serious hypersensitivity reaction occurs, tofacitab should be discontinued immediately while possible triggers or causes of the reaction are evaluated (see Adverse Reactions).
Laboratory test abnormalities
Lymphocyte abnormalities
During the 12-month treatment period, there was a tofacitab treatment-related initial lymphocytosis at one month of drug exposure followed by a gradual decline with a mean absolute lymphocyte count approximately 10% lower than baseline. Lymphocyte counts below 500 cells/mm3 caused an increased incidence of serious infections.
Avoid starting tofacitab therapy in patients with low lymphocyte counts (i.e., below 500 cells/mm3). Treatment with tofacitab is not recommended in patients who develop a deterministic absolute lymphocyte count below 500 cells/mm3.
Lymphocyte counts were monitored at baseline and every 3 months thereafter. See Dosage for recommended dose adjustments based on lymphocyte counts.
Neutropenia
Tofacitab treatment was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared with placebo.
Avoid starting tofacitab therapy in patients with low neutrophil counts (i.e., ANC less than 1000 cells/mm3). Interrupt tofacitab administration until ANC is greater than or equal to 1000 cells/mm3 in patients presenting with persistent ANC of 500-1000 cells/mm3. tofacitab therapy is not recommended in patients presenting with 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 for recommended dose adjustments based on ANC results.
Anemia
Avoid initiating tofacitib therapy in patients with low hemoglobin levels (i.e., less than 9 g/dL). Tofacitab therapy should be interrupted in patients who develop a hemoglobin level below 8 g/dL or a decrease in hemoglobin level greater than 2 g/dL at the time of treatment.
Monitor hemoglobin at baseline and after 4-8 weeks of treatment, and every 3 months thereafter. See Dosage and Administration for recommended dose adjustments based on hemoglobin results.
Elevated liver enzymes
Tofacitab treatment was associated with an increased incidence of elevated liver enzymes compared to the placebo group. The majority of these abnormalities were seen in the study program using DMARD (primarily methotrexate) as background therapy.
Routine monitoring of liver function tests is recommended to promptly investigate the cause of liver enzyme elevations to identify potential cases of drug-related liver injury. If pharmacologic liver injury is suspected, tofacitab administration should be interrupted until this diagnosis is ruled out.
Elevated lipids
Tofacitab treatment was associated with a dose-dependent increase in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. No clinically relevant changes in the LDL/HDL cholesterol ratio were observed. The impact of these elevated lipid parameters on cardiovascular morbidity and mortality has not been determined.
Evaluation of lipid parameters should be performed approximately 4-8 weeks after initiation of tofacitab therapy.
Manage patients for hyperlipidemia according to clinical guidelines.
Vaccination
Avoid concurrent administration of live vaccinations with tofacitab. The interval between live vaccination and tofacitab treatment initiation should be in accordance with current vaccination guidelines for immunosuppressive drugs.
A patient developed varicella zoster virus vaccine strain infection 2 days after starting tofacitab (5 mg twice daily) treatment 16 days after live attenuated vaccination (Zostavax). The patient had not been exposed to varicella virus, as the patient had no history of prior varicella infection and no anti-varicella antibodies at baseline examination. The patient recovered after discontinuation of tofacitab and treatment with standard doses of antivirals.
Immunizations were administered in accordance with current immunization guidelines prior to initiation of tofacitab therapy.
Medication for diabetic patients
Caution should be exercised when treating patients with diabetes because of the typically high incidence of infection in the diabetic population.
Renal impairment
Moderate and severe impairment
Tofacitab blood levels are higher in patients with moderate and severe renal impairment treated with tofacitab compared to patients with normal renal function treated with tofacitab. Therefore, in patients with moderate or severe renal impairment (including but not limited to patients with severe renal insufficiency who are on hemodialysis), dose adjustment of tofacitib is recommended (see DOSAGE AND ADMINISTRATION).
Mild Impairment
No dose adjustment is required in patients with mild renal impairment.
Hepatic Impairment
Severe impairment
Tofacitab has not been studied in patients with severe hepatic impairment; therefore, tofacitab is not recommended for use in patients with severe hepatic impairment.
Moderate Impairment
Tofacitib blood levels are higher in patients with moderate hepatic impairment treated with tofacitib compared to patients with normal liver function treated with tofacitib (see Pharmacokinetics). Elevated blood levels may increase the risk of certain adverse reactions. Therefore, in patients with moderate hepatic impairment, dose adjustment of tofacitib is recommended (see Dosage and Administration).
Mild Impairment
Dose adjustment of tofacitib is not required in patients with mild hepatic impairment.
Hepatitis B or C serology
The safety and efficacy of tofacitib have not been studied in patients with positive serology for hepatitis B virus or hepatitis C virus.
For Pregnant and Lactating Women
Pregnant women
Risk Summary
The available data on tofacitab use in pregnant women are insufficient to establish the risk of significant drug-related birth defects, miscarriage, or adverse maternal or fetal outcomes. During pregnancy, both the mother and fetus are at risk associated with rheumatoid arthritis (see Clinical Considerations).
Background risk for major birth defects and miscarriage has not been estimated in the applicable population. All pregnant women are at background risk for birth defects, miscarriage, or other adverse outcomes. In the general U.S. population, the background risks of clinically confirmed pregnancies for major birth defects and miscarriage are 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-Related Maternal and/or Embryonic/Fetal Risks
Published data suggest that in women with rheumatoid arthritis, increased disease activity is associated with an increased risk of adverse pregnancy outcomes. Adverse pregnancy outcomes include preterm delivery (delivery before 37 weeks of gestation), low birth weight infants (less than 2500 g), and small size at birth relative to gestational age.
Lactation
Risk Summary
There are no data on the presence of tofacitib in human milk, its effect on breastfed infants, or its effect on lactation. In view of the serious adverse effects observed in adults treated with tofacitab, such as an increased risk of serious infection, patients should be advised that breast-feeding during treatment and for at least 18 hours (approximately 6 elimination half-lives) of the last tofacitab dose is not recommended.
Fertility
For women of childbearing potential, family planning and contraception should be used.
[Pediatric Dosage].
The safety and efficacy of tofacitib in pediatric patients have not been established.
[Geriatric use].
According to foreign literature.
Of the 3315 patients who participated in five clinical studies worldwide, a total of 505 patients with rheumatoid arthritis were 65 years of age or older, including 71 patients who were 75 years of age or older. The incidence of serious infections was higher in subjects 65 years of age and older in the tofacitab treatment group than in those younger than 65 years of age. Because of the higher incidence of infection in the elderly population in general, caution should be exercised when using it for the treatment of the elderly (see Precautions).
Drug Interactions]
Table 3 lists drugs that have clinically important drug interactions when combined with tofacitab and instructions for preventing or managing drug interactions.
Table 3: Clinically relevant interactions affecting tofacitib when combined with other drugs
Potent CYP3A4 inhibitors (e.g., ketoconazole) clinically affect tofacitib exposure with increased interventions suggesting tofacitib dose adjustment
(See Dosage, Pharmacokinetics Figure 3) Combination of moderate CYP3A4 inhibitors with potent CYP2C19 inhibitors (e.g., fluconazole) clinically affects increased tofacitib exposure Intervention suggests adjusting tofacitib dose
(see Dosage, Pharmacokinetics, Figure 3) Potent CYP3A4 inducers (e.g., rifampin) clinically affect tofacitib exposure and may result in missing or reduced clinical responses Interventions are not recommended in combination with tofacitib
(see Pharmacokinetic Figure 3) Immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine) clinical impact increased risk of immunosuppression; combination with biologic DMARD or potent immunosuppression has not been studied in patients with rheumatoid arthritis Interventions are not recommended in combination with tofacitib
(see Indications, Pharmacokinetics Figure 3) [Overdose
There is no specific antidote for tofacitab overdose. In the event of an overdose, monitoring of patient signs and symptoms of adverse reactions is recommended.
In a study of subjects with end-stage renal disease (ESRD) receiving hemodialysis, plasma tofacitib concentrations decreased more rapidly over the hemodialysis period and the dialysis efficiency calculated from dialysis machine clearance/total blood flow to the dialysis machine was higher [mean (standard deviation) = 0.73 (0.15)]. However, because tofacitib is mainly cleared by non-renal routes, the total elimination fraction produced by hemodialysis is low, thus limiting the value of hemodialysis in the treatment of tofacitib overdose.
Pharmacology and Toxicology
Pharmacological effects
Tofacitab is an inhibitor of Janus kinase (JAK), an intracellular enzyme that transduces signals from cytokine or growth factor-receptor interactions in the cell membrane, thereby affecting cellular hematopoiesis and cellular immune function. Within this signaling pathway, JAK phosphorylates and activates signal transducers and activators of transcription (STAT), thereby regulating intracellular activities, including gene expression. Tofacitab regulates this signaling pathway at this point in JAK, preventing STAT phosphorylation and activation, and JAK enzymes deliver cytokine signals via paired JAKs (e.g. JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitab inhibits the in vitro activity of JAK1/JAK2, JAK1/JAK3 and JAK2/JAK2 combinatorial enzymes with IC50s of 406, 56 and 1377 nM, respectively, but the relevance of specific JAK combinatorial enzymes to therapeutic efficacy has not been clarified.
Toxicological studies
Genotoxicity
Tofacitab is not mutagenic in bacterial revertant mutation assays. Tofacitib was positive in the human lymphocyte in vitro chromosomal aberration assay in the presence of metabolizing enzymes and negative in the absence of metabolizing enzymes. Tofacitib was negative in the Ames test, CHO-HGPRT test, rat micronucleus test and rat hepatocyte in-program DNA synthesis test.
Reproductive toxicity
Rats given toofacitab at exposure levels approximately 17 times the recommended dose of 5 mg twice daily and approximately 8.3 times the dose of 10 mg twice daily (as measured by the AUC of the oral dose of 10 mg/kg/day) showed increased post-fertilization loss and reduced fertility in females. No effect on fertility was seen in female rats at exposure levels equal to the recommended dose of 5 mg twice daily and approximately 0.5 times the dose of 10 mg twice daily (as measured by the AUC of the oral dose of 1 mg/kg/day) of tofacitib. No effects on male fertility, sperm motility, or sperm concentration were seen with tofacitab at approximately 133 times the recommended dose of 5 mg twice daily and at approximately 67 times the recommended dose of 10 mg twice daily (as measured by the AUC of an oral dose of 100 mg/kg/day).
In a rat embryo-fetus developmental toxicity assay, pregnant rats were exposed to approximately 146 times the recommended dose of tofacitib at 5 mg twice daily and approximately 73 times the maximum recommended dose of 10 mg twice daily (as measured by the AUC of the oral dose of 100 mg/kg/day in rats) during fetal organogenesis, which was teratogenic. The teratogenic effects included external deformities and soft tissue deformities, respectively generalized edema and septal membrane defects, and skeletal deformities or mutations (absence of cervical arch; curvature of femur, fibula, humerus, radius, scapula, tibia, and ulna; sternal fractures; absent ribs; femoral deformities; bifurcated ribs; fused ribs; fused sternal joints; and hemivertebral deformities of the thoracic spine). In addition, there was increased post-arrival loss, including early and late resorption, with a consequent decrease in the number of live fetuses and a decrease in mean litter weight. No developmental toxicity was observed in rats at approximately 58 times the recommended exposure level of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (based on an AUC of 30 mg/kg/day oral dose in pregnant rats).
In a rabbit embryo-fetal development study, pregnant rabbits receiving tofacitab at approximately 13 times the recommended dose of 5 mg twice daily and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (at an AUC of 30 mg/kg/day oral dose in rabbits) during fetal organogenesis had teratogenic effects with no maternal toxicity. Teratogenic effects included thoracoabdominal cleft, umbilical bulge, septal membrane defects, cranial/skeletal malformations (small mouth, small eyeballs), midline and caudal defects. In addition, there is an increase in post-arrival fetal loss associated with late resorption. Developmental toxicity was not observed in rabbits at drug exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the maximum recommended dose of 10 mg twice daily (based on the AUC of 10 mg/kg/day oral dose in pregnant rabbits).
In perinatal and postnatal studies in pregnant rats receiving tofacitab from day 6 of gestation to day 20 of lactation, reduced litter size, reduced postnatal survival, and reduced pup weights were observed at approximately 73 times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily (at an AUC of 50 mg/kg/day oral dose in rats). Exposure levels of approximately 17 times the recommended dose of 5 mg twice daily and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (at an AUC of 10 mg/kg/day in rats) had no effect on behavioral and learning outcomes, sexual maturation of the F1 generation of rats, and the ability to mate and produce live F2 generation rat fetuses.
Carcinogenicity
The carcinogenicity of tofacitab was evaluated in a 6-month carcinogenicity test in rasH2 transgenic mice and a 2-year carcinogenicity test in rats. Tofacitib was not seen to be carcinogenic in mice at approximately 34 times the recommended dose of 5 mg twice daily and at approximately 17 times the maximum recommended dose of 10 mg twice daily (based on the AUC of a dose of 200 mg/kg/day administered orally) levels.
In a 2-year oral carcinogenicity test in SD rats, benign testicular mesenchymal stromal cell tumors, hibernomas (malignant tumors of brown adipose tissue) and benign thymomas were seen at doses greater than or equal to 30 mg/kg/day (exposure levels approximately 42 times the AUC of the recommended dose of 5 mg twice daily and approximately 21 times the AUC of the dose of 10 mg twice daily). The risk of relevance of benign testicular mesenchymal cell tumors to humans has not been clarified.
Lymphomas were seen in monkeys exposed to tofacitab at levels approximately 6 times the recommended dose of 5 mg twice daily and approximately 3 times the dose of 10 mg twice daily (based on the AUC of an oral dose of 5 mg/kg twice daily) in a 39-week toxicology trial. No lymphoma was observed at exposure levels of 1 times the recommended dose of 5 mg twice daily and approximately 0.5 times the dose of 10 mg twice daily (based on the AUC of an oral dose of 1 mg/kg twice daily).
Pharmacokinetics]
After oral administration of tofacitab, peak plasma drug concentrations were reached within 0.5-1 h. The clearance half-life was approximately 3 h. An increase in systemic exposure proportional to the dose was observed in the therapeutic dose range. After twice-daily administration, steady-state concentrations are reached within 24-48 hours, and drug accumulation is negligible.
Absorption
The absolute oral bioavailability of tofacitib is 74%. When tofacitib was combined with a high-fat diet, there was no change in AUC, while Cmax was reduced by 32%. In clinical trials, tofacitib administration was not affected by food [see DOSAGE].
Distribution
The volume of distribution after intravenous administration was 87 L. The protein binding of tofacitib was approximately 40%. Tofacitib is primarily bound to albumin and does not appear to bind to alpha 1 acidic glycoprotein. Tofacitib is uniformly distributed between red blood cells and plasma.
Metabolism and excretion
The mechanism of clearance of tofacitib is approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitib is mainly mediated by CYP3A4, with a small contribution from CYP2C19. In human radiolabeling studies, the prototype tofacitib accounted for more than 65% of the total circulating radioactivity, with the remaining 35% attributed to eight metabolites, each accounting for less than 8% of the total radioactivity. The pharmacological activity of tofacitib is due to the parent molecule.
Pharmacokinetic characteristics of the patient population
Population pharmacokinetics showed similar pharmacokinetic characteristics between patients. The coefficient of variation (%) of tofacitib AUC was overall similar between patients suffering from different diseases, ranging from 22% to 34% (Table 4).
Table 4. exposure to tofacitib in the patient population receiving 5 mg twice-daily doses
Pharmacokinetic parametersa
Geometric mean (CV%) Tofacitib 5 mg
Twice daily rheumatoid arthritis AUC0-24,ss (ng-h/mL)504
(22.0%) Abbreviations: AUC0-24,ss = area under the blood concentration time curve at steady state over 24 hours; CV = coefficient of variation.
a. Pharmacokinetic parameters were estimated based on population pharmacokinetic analysis.
Special Populations
Considering the differences in renal function between patients (i.e., creatinine clearance), the evaluation of covariates as part of the population pharmacokinetics in the patient population according to age, weight, sex, and race showed no clinically relevant changes in tofacitib exposure (Figure 1). A roughly linear relationship between body weight and volume of distribution was observed, resulting in higher peak concentrations (Cmax) and lower troughs (Cmin) in patients with lower body weight. However, this difference is not considered to be clinically relevant.
The effects of renal and hepatic impairment of tofacitab and other intrinsic factors on tofacitab pharmacokinetics are shown in Figure 1.
Figure 1: Effect of intrinsic factors on the pharmacokinetics of tofacitib
Note: Reference comparison values for weight, age, sex and race are 70 kg, 55 years, male and Caucasian; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function.
a Dose adjustment (see Dosage and Administration).
In subjects with ESRD maintained by hemodialysis, the mean AUC was approximately 40% higher than previous data in healthy subjects, which is consistent with renal clearance of tofacitib being approximately 30% of the total clearance. Dose adjustments are recommended in patients with ESRD maintained by hemodialysis (see Dosage and Administration).
Drug Interactions
Potential for Tofacitab to Affect the Pharmacokinetics of Other Drugs
In vitro studies have shown that tofacitib does not significantly inhibit or induce the activity of the major human drug metabolizing CYP enzymes (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) at concentrations equivalent to steady-state Cmax at 10 mg administered twice daily. These in vitro results were confirmed by a human drug interaction study that showed no change in the pharmacokinetics of midazolam, a highly sensitive CYP3A4 substrate, when combined with tofacitab.
In vitro studies have shown that tofacitab does not significantly inhibit the activity of the major human drug metabolizing uridine 5′-diphosphate glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7] at concentrations above 250-fold steady-state Cmax at 10 mg administered twice daily.
In patients with rheumatoid arthritis, oral clearance of tofacitib did not change over time, suggesting that tofacitib does not normalize CYP enzyme activity in patients with rheumatoid arthritis. Therefore, coadministration with tofacitib is not expected to result in a clinically relevant increase in CYP substrate metabolism in patients with rheumatoid arthritis.
In vitro data suggest that tofacitib has a low potential to inhibit transporters, such as P-glycoprotein, organic anion or cation transporters, at therapeutic concentrations.
The recommended drugs for combined dosing after tofacitib administration are shown in Figure 2.
Figure 2: Effect of tofacitib on the pharmacokinetics of other drugs
Potential for other drugs to affect tofacitib pharmacokinetics
Because tofacitib is metabolized by CYP3A4, it may interact with drugs that inhibit or induce CYP3A4.
CYP2C19 inhibitors or P-glycoprotein inhibitors alone are unlikely to substantially alter the pharmacokinetics of tofacitib (see Figure 3).
Figure 3: Effect of other drugs on the pharmacokinetics of tofacitib
[Storage].
Seal and store at no more than 30°C.
Package】
Packed in high-density polyethylene bottles for oral solid dosage, 28 tablets/bottle.
Expiration date
18 months
Execution Standard
Approval number】
【Drug marketing license holder
Name: Nanjing Xiangsheng Dongyuan Pharmaceutical Co.
Registered address: No. 8 Xinglong Road, Pukou Economic Development Zone, Nanjing, Jiangsu Province
Zip code: 211800
Manufacturer
Company name: Nanjing Centron Dongyuan Pharmaceutical Co.
Production Address: No. 99, Huakang Road, Nanjing High-tech Industrial Development Zone
Tel: 025-58286999
Fax: 025-58285555
Website: www.simcere.com