Componentes:
Método de ação:
Opção de tratamento:
Medicamente revisado por Kovalenko Svetlana Olegovna, Farmácia Última atualização em 10.04.2022
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20 principais medicamentos com os mesmos componentes:
Artrite reumatóide
- Jakvinus / Jakvinus XR (tofacitinibe) é indicado para o tratamento de pacientes adultos com artrite reumatóide moderada a severamente ativa que tiveram uma resposta ou intolerância inadequada ao metotrexato. Pode ser usado em monoterapia ou em combinação com metotrexato ou outros medicamentos anti-reumáticos modificadores da doença não biológica (DMARDs).
- Limitações de uso: O uso de Jakvinus / Jakvinus XR em combinação com DMARDs biológicos ou com imunossupressores potentes, como azatioprina e ciclosporina, não é recomendado.
Artrite psoriática
- Jakvinus / Jakvinus XR (tofacitinibe) é indicado para o tratamento de pacientes adultos com artrite psoriática ativa que tiveram uma resposta ou intolerância inadequada ao metotrexato ou outros medicamentos anti-reumáticos modificadores da doença (DMARDs).
- Limitações de uso: O uso de Jakvinus / Jakvinus XR em combinação com DMARDs biológicos ou com imunossupressores potentes, como azatioprina e ciclosporina, não é recomendado.
Artrite reumatóide
- XELJANZ / XELJANZ XR (tofacitinibe) é indicado para o tratamento de pacientes adultos com artrite reumatóide moderada a severamente ativa que tiveram uma resposta ou intolerância inadequada ao metotrexato. Pode ser usado em monoterapia ou em combinação com metotrexato ou outros medicamentos anti-reumáticos modificadores da doença não biológica (DMARDs).
- Limitações de uso: O uso de XELJANZ / XELJANZ XR em combinação com DMARDs biológicos ou com imunossupressores potentes, como azatioprina e ciclosporina, não é recomendado.
Artrite psoriática
- XELJANZ / XELJANZ XR (tofacitinibe) é indicado para o tratamento de pacientes adultos com artrite psoriática ativa que tiveram uma resposta ou intolerância inadequada ao metotrexato ou outros medicamentos anti-reumáticos modificadores da doença (DMARDs).
- Limitações de uso: O uso de XELJANZ / XELJANZ XR em combinação com DMARDs biológicos ou com imunossupressores potentes, como azatioprina e ciclosporina, não é recomendado.
- A dose recomendada de Jakvinus é de 5 mg duas vezes ao dia e a dose recomendada de Jakvinus XR é de 11 mg uma vez ao dia.
- Jakvinus / Jakvinus XR é administrado por via oral com ou sem alimentos.
- Engula os comprimidos Jakvinus XR inteiros e intactos. Não esmague, separe ou mastigue.
Mudando de Jakvinus Tablets para Jakvinus XR Tablets
Os doentes tratados com Jakvinus 5 mg duas vezes por dia podem ser trocados para Jakvinus XR 11 mg uma vez por dia no dia seguinte à última dose de Jakvinus 5 mg.
Dosagem na artrite reumatóide
- Jakvinus / Jakvinus XR pode ser usado como monoterapia ou em combinação com metotrexato ou outros medicamentos anti-reumáticos modificadores da doença não biológica (DMARDs). A dose recomendada de Jakvinus é de 5 mg duas vezes ao dia e a dose recomendada de Jakvinus XR é de 11 mg uma vez ao dia.
Dosagem em artrite psoriática
A dose recomendada de Jakvinus é de 5 mg duas vezes ao dia, usada em combinação com DMARDs não biológicos.
A dose recomendada de Jakvinus XR é de 11 mg uma vez ao dia, usada em combinação com DMARDs não biológicos.
A eficácia do Jakvinus / Jakvinus XR como monoterapia não foi estudada na artrite psoriática.
Modificações de dosagem devido a infecções graves e citopenias (consulte as Tabelas 1, 2 e 3 abaixo)
- Recomenda-se que o Jakvinus / Jakvinus XR não seja iniciado em pacientes com uma contagem absoluta de linfócitos inferior a 500 células / mm3, uma contagem absoluta de neutrófilos (CAN) inferior a 1000 células / mm3 ou com níveis de hemoglobina inferiores a 9 g / dL
- A interrupção da dose é recomendada para o tratamento de linfopenia, neutropenia e anemia.
- Evite o uso de Jakvinus / Jakvinus XR se um paciente desenvolver uma infecção grave até que a infecção seja controlada.
Modificações de dosagem devido a interações medicamentosas
- Nos pacientes que recebem:
- inibidores potentes do citocromo P450 3A4 (CYP3A4) (por exemplo,., cetoconazol) ou
- um ou mais medicamentos concomitantes que resultam em inibição moderada do CYP3A4 e inibição potente do CYP2C19 (por exemplo,., fluconazol),
a dose recomendada é de Jakvinus 5 mg uma vez ao dia.
- Co-administração de indutores potentes do CYP3A4 (por exemplo,., rifampicina) com Jakvinus / Jakvinus XR pode resultar em perda ou redução da resposta clínica ao Jakvinus / Jakvinus XR .
- A administração concomitante de indutores potentes do CYP3A4 com Jakvinus / Jakvinus XR não é recomendada.
Modificações de dosagem em pacientes com comprometimento renal ou hepático
- Em pacientes com:
- insuficiência renal moderada ou grave, ou
- compromisso hepático moderado
a dose recomendada é de Jakvinus 5 mg uma vez ao dia.
- O uso de Jakvinus / Jakvinus XR em pacientes com insuficiência hepática grave não é recomendado.
Tabela 1: Ajustes de dose para linfopenia
Baixa contagem de linfócitos | |
Valor do laboratório (células / mm3) | Recomendação |
Contagem de linfócitos maior ou igual a 500 | Mantenha a dose |
Os linfócitos contam menos de 500 (Confirmado por repetição de testes) | Interrompa Jakvinus / Jakvinus XR |
Tabela 2: Ajustes de dose para neutropenia
ANC baixo | |
Valor do laboratório (células / mm3) | Recomendação |
ANC maior que 1000 | Mantenha a dose |
ANC 500-1000 | Para reduções persistentes nesse intervalo, interrompa a dosagem até ANC ser maior que 1000
|
ANC menor que 500 (Confirmado por repetição de testes) | Interrompa Jakvinus / Jakvinus XR |
Tabela 3: Ajustes de dose para anemia
Baixo valor de hemoglobina | |
Valor do laboratório (g / dL) | Recomendação |
Menos ou igual a 2 g / dL diminuem e maior ou igual a 9,0 g / dL | Mantenha a dose |
Maior que 2 g / dL diminuem ou menos que 8,0 g / dL (Confirmado por repetição de testes) | Interrompa a administração de Jakvinus / Jakvinus XR até que os valores de hemoglobina sejam normalizados |
- A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia e a dose recomendada de XELJANZ XR é de 11 mg uma vez ao dia.
- XELJANZ / XELJANZ XR é administrado por via oral com ou sem alimentos.
- Engula os comprimidos XELJANZ XR inteiros e intactos. Não esmague, separe ou mastigue.
Mudando de comprimidos XELJANZ para comprimidos XELJANZ XR
Os doentes tratados com XELJANZ 5 mg duas vezes por dia podem ser trocados para XELJANZ XR 11 mg uma vez por dia no dia seguinte à última dose de XELJANZ 5 mg.
Dosagem na artrite reumatóide
- XELJANZ / XELJANZ XR pode ser usado como monoterapia ou em combinação com metotrexato ou outros medicamentos anti-reumáticos modificadores da doença não biológica (DMARDs). A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia e a dose recomendada de XELJANZ XR é de 11 mg uma vez ao dia.
Dosagem em artrite psoriática
A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia, usada em combinação com DMARDs não biológicos.
A dose recomendada de XELJANZ XR é de 11 mg uma vez ao dia, usada em combinação com DMARDs não biológicos.
A eficácia do XELJANZ / XELJANZ XR como monoterapia não foi estudada na artrite psoriática.
Modificações de dosagem devido a infecções graves e citopenias (consulte as Tabelas 1, 2 e 3 abaixo)
- Recomenda-se que o XELJANZ / XELJANZ XR não seja iniciado em pacientes com uma contagem absoluta de linfócitos inferior a 500 células / mm3, uma contagem absoluta de neutrófilos (CAN) inferior a 1000 células / mm3 ou com níveis de hemoglobina inferiores a 9 g / dL
- A interrupção da dose é recomendada para o tratamento de linfopenia, neutropenia e anemia.
- Evite o uso de XELJANZ / XELJANZ XR se um paciente desenvolver uma infecção grave até que a infecção seja controlada.
Modificações de dosagem devido a interações medicamentosas
- Nos pacientes que recebem:
- inibidores potentes do citocromo P450 3A4 (CYP3A4) (por exemplo,., cetoconazol) ou
- um ou mais medicamentos concomitantes que resultam em inibição moderada do CYP3A4 e inibição potente do CYP2C19 (por exemplo,., fluconazol),
a dose recomendada é de XELJANZ 5 mg uma vez ao dia.
- Co-administração de indutores potentes do CYP3A4 (por exemplo,., rifampicina) com XELJANZ / XELJANZ XR pode resultar em perda ou redução da resposta clínica ao XELJANZ / XELJANZ XR .
- A administração concomitante de indutores potentes do CYP3A4 com XELJANZ / XELJANZ XR não é recomendada.
Modificações de dosagem em pacientes com comprometimento renal ou hepático
- Em pacientes com:
- insuficiência renal moderada ou grave, ou
- compromisso hepático moderado
a dose recomendada é de XELJANZ 5 mg uma vez ao dia.
- O uso de XELJANZ / XELJANZ XR em pacientes com insuficiência hepática grave não é recomendado.
Tabela 1: Ajustes de dose para linfopenia
Baixa contagem de linfócitos | |
Valor do laboratório (células / mm3) | Recomendação |
Contagem de linfócitos maior ou igual a 500 | Mantenha a dose |
Os linfócitos contam menos de 500 (Confirmado por repetição de testes) | Interrompa o XELJANZ / XELJANZ XR |
Tabela 2: Ajustes de dose para neutropenia
ANC baixo | |
Valor do laboratório (células / mm3) | Recomendação |
ANC maior que 1000 | Mantenha a dose |
ANC 500-1000 | Para reduções persistentes nesse intervalo, interrompa a dosagem até ANC ser maior que 1000
|
ANC menor que 500 (Confirmado por repetição de testes) | Interrompa o XELJANZ / XELJANZ XR |
Tabela 3: Ajustes de dose para anemia
Baixo valor de hemoglobina | |
Valor do laboratório (g / dL) | Recomendação |
Menos ou igual a 2 g / dL diminuem e maior ou igual a 9,0 g / dL | Mantenha a dose |
Maior que 2 g / dL diminuem ou menos que 8,0 g / dL (Confirmado por repetição de testes) | Interrompa a administração de XELJANZ / XELJANZ XR até que os valores de hemoglobina sejam normalizados |
Nenhum
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Serious Infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving Jakvinus. The most common serious infections reported with Jakvinus included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with Jakvinus. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.
Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).
Avoid use of Jakvinus/Jakvinus XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Jakvinus/Jakvinus XR in patients:
- with chronic or recurrent infection
- who have been exposed to tuberculosis
- with a history of a serious or an opportunistic infection
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Jakvinus/Jakvinus XR. Jakvinus/Jakvinus XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Jakvinus/Jakvinus XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are discussed in Dosage Modifications due to Serious Infections and Cytopenias.
Tuberculosis
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of Jakvinus /Jakvinus XR.
Anti-tuberculosis therapy should also be considered prior to administration of Jakvinus/Jakvinus XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering Jakvinus/Jakvinus XR.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with Jakvinus. The impact of Jakvinus/Jakvinus XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with Jakvinus/Jakvinus XR. The risk of herpes zoster is increased in patients treated with Jakvinus/Jakvinus XR and appears to be higher in patients treated with Jakvinus in Japan and Korea.
Malignancy And Lymphoproliferative Disorders
Consider the risks and benefits of Jakvinus/Jakvinus XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing Jakvinus/Jakvinus XR in patients who develop a malignancy. Malignancies were observed in clinical studies of Jakvinus.
In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving Jakvinus with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with Jakvinus.
In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving Jakvinus plus non-biologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with Jakvinus.
In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with Jakvinus (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs) have been reported in patients treated with Jakvinus. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Gastrointestinal Perforations
Events of gastrointestinal perforation have been reported in clinical studies with Jakvinus, although the role of JAK inhibition in these events is not known.
Jakvinus/Jakvinus XR 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 presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Laboratory Abnormalities
Lymphocyte Abnormalities
Treatment with Jakvinus was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
Avoid initiation of Jakvinus/Jakvinus XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with Jakvinus/Jakvinus XR is not recommended.
Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts.
Neutropenia
Treatment with Jakvinus was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
Avoid initiation of Jakvinus/Jakvinus XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt Jakvinus/Jakvinus XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with Jakvinus/Jakvinus XR is not recommended.
Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results.
Anemia
Avoid initiation of Jakvinus/Jakvinus XR treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with Jakvinus/Jakvinus XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results.
Liver Enzyme Elevations
Treatment with Jakvinus was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of Jakvinus/Jakvinus XR should be interrupted until this diagnosis has been excluded.
Lipid Elevations
Treatment with Jakvinus was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of Jakvinus/Jakvinus XR therapy.
Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
Vaccinations
Avoid use of live vaccines concurrently with Jakvinus/Jakvinus XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.
Update immunizations in agreement with current immunization guidelines prior to initiating Jakvinus/Jakvinus XR therapy.
General
Specific To Jakvinus XR
As with any other non-deformable material, caution should be used when administering Jakvinus XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Patient Counseling
Advise patients of the potential benefits and risks of Jakvinus/Jakvinus XR.
Serious Infection
Inform patients that Jakvinus/Jakvinus XR may lower the ability of their immune system to fight infections. Advise patients not to start taking Jakvinus/Jakvinus XR if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment.
Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with Jakvinus.
Malignancies And Lymphoproliferative Disorders
Inform patients that Jakvinus/Jakvinus XR may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking Jakvinus. Instruct patients to inform their healthcare provider if they have ever had any type of cancer.
Important Information On Laboratory Abnormalities
Inform patients that Jakvinus/Jakvinus XR may affect certain lab test results, and that blood tests are required before and during Jakvinus/Jakvinus XR treatment.
Pregnancy
Inform patients that Jakvinus/Jakvinus XR should not be used during pregnancy unless clearly necessary, and advise patients to inform their doctors right away if they become pregnant while taking Jakvinus/Jakvinus XR. Inform patients that Pfizer has a registry for pregnant women who have taken Jakvinus/Jakvinus XR during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll. Women of reproductive potential should be advised to use effective contraception during treatment with Jakvinus/Jakvinus XR and for at least 4 weeks after the last dose. Inform patients that they should not breastfeed while taking Jakvinus/Jakvinus XR.
Residual Tablet Shell
Patients receiving Jakvinus XR may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell.
This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the human dose (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the human dose (on an AUC basis at oral doses of 1 mg/kg twice daily).
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the human dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the human dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
In rats, tofacitinib at exposure levels approximately 17 times the human dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the human dose (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the human dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
Use In Specific Populations
All information provided in this section is applicable to Jakvinus and Jakvinus XR as they contain the same active ingredient (tofacitinib).
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Jakvinus/Jakvinus XR during pregnancy. Patients should be encouraged to enroll in the Jakvinus/Jakvinus XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.
Risk Summary
There are no adequate and well-controlled studies of Jakvinus/Jakvinus XR use in pregnant women.
The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. The background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively.
Based on animal studies, Jakvinus/Jakvinus XR has the potential to affect a developing fetus. Fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg twice daily, respectively. Further, in a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg twice daily.
Data
Human Data
In the tofacitinib clinical development programs, birth defects and miscarriages were reported.
Animal Data
In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).
In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).
In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Lactation
Risk Summary
Data
Human Data
There are no adequate and well-controlled studies of Jakvinus/Jakvinus XR use during breastfeeding.
Animal Data
Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.
Females And Males Of Reproductive Potential
Contraception
Females
Embryofetal toxicity including malformations occurred in embryofetal development studies in rats and rabbits.
Females of reproductive potential should be advised to use effective contraception during treatment with Jakvinus/Jakvinus XR and for at least 4 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with Jakvinus/Jakvinus XR.
Infertility
Females
Based on findings in rats, treatment with Jakvinus/Jakvinus XR may result in reduced fertility in females of reproductive potential.
Pediatric Use
The safety and effectiveness of Jakvinus/Jakvinus XR in pediatric patients have not been established.
Geriatric Use
Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among Jakvinus-treated subjects 65 years of age and older was higher than among those under the age of 65.
As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Use In Diabetics
As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.
Hepatic Impairment
Jakvinus-treated patients with moderate hepatic impairment had greater tofacitinib levels than Jakvinus-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions, therefore, the recommended dose is Jakvinus 5 mg once daily in patients with moderate hepatic impairment. Jakvinus/Jakvinus XR has not been studied in patients with severe hepatic impairment; therefore, use of Jakvinus/Jakvinus XR in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of Jakvinus/Jakvinus XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
Renal Impairment
Jakvinus-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than Jakvinus-treated patients with normal renal function; therefore, the recommended dose is Jakvinus 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, Jakvinus/Jakvinus XR was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/ min (or in patients with active psoriatic arthritis with creatinine clearance values less than 50 mL/min). No dose adjustment is required in patients with mild renal impairment.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Serious Infections
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.
Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).
Avoid use of XELJANZ/XELJANZ XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ/XELJANZ XR in patients:
- with chronic or recurrent infection
- who have been exposed to tuberculosis
- with a history of a serious or an opportunistic infection
- who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
- with underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ/XELJANZ XR. XELJANZ/XELJANZ XR should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ/XELJANZ XR should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are discussed in Dosage Modifications due to Serious Infections and Cytopenias.
Tuberculosis
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ /XELJANZ XR.
Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ/XELJANZ XR in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient.
Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.
Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ/XELJANZ XR.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. The impact of XELJANZ/XELJANZ XR on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ/XELJANZ XR. The risk of herpes zoster is increased in patients treated with XELJANZ/XELJANZ XR and appears to be higher in patients treated with XELJANZ in Japan and Korea.
Malignancy And Lymphoproliferative Disorders
Consider the risks and benefits of XELJANZ/XELJANZ XR treatment prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing XELJANZ/XELJANZ XR in patients who develop a malignancy. Malignancies were observed in clinical studies of XELJANZ.
In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving XELJANZ with or without DMARD, compared to 0 solid cancers and 0 lymphomas in 809 patients in the placebo with or without DMARD group during the first 12 months of exposure. Lymphomas and solid cancers have also been observed in the long-term extension studies in rheumatoid arthritis patients treated with XELJANZ.
In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ.
In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
Non-Melanoma Skin Cancer
Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.
Gastrointestinal Perforations
Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known.
XELJANZ/XELJANZ XR 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 presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Laboratory Abnormalities
Lymphocyte Abnormalities
Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3). In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.
Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts.
Neutropenia
Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3). For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ/XELJANZ XR dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ/XELJANZ XR is not recommended.
Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC results.
Anemia
Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with XELJANZ/XELJANZ XR should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.
Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter. For recommended modifications based on hemoglobin results.
Liver Enzyme Elevations
Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.
Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ/XELJANZ XR should be interrupted until this diagnosis has been excluded.
Lipid Elevations
Treatment with XELJANZ was associated with increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.
Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ/XELJANZ XR therapy.
Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.
Vaccinations
Avoid use of live vaccines concurrently with XELJANZ/XELJANZ XR. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.
Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ/XELJANZ XR therapy.
General
Specific To XELJANZ XR
As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Patient Counseling
Advise patients of the potential benefits and risks of XELJANZ/XELJANZ XR.
Serious Infection
Inform patients that XELJANZ/XELJANZ XR may lower the ability of their immune system to fight infections. Advise patients not to start taking XELJANZ/XELJANZ XR if they have an active infection. Instruct patients to contact their healthcare provider immediately during treatment if symptoms suggesting infection appear in order to ensure rapid evaluation and appropriate treatment.
Advise patients that the risk of herpes zoster, some cases of which can be serious, is increased in patients treated with XELJANZ.
Malignancies And Lymphoproliferative Disorders
Inform patients that XELJANZ/XELJANZ XR may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking XELJANZ. Instruct patients to inform their healthcare provider if they have ever had any type of cancer.
Important Information On Laboratory Abnormalities
Inform patients that XELJANZ/XELJANZ XR may affect certain lab test results, and that blood tests are required before and during XELJANZ/XELJANZ XR treatment.
Pregnancy
Inform patients that XELJANZ/XELJANZ XR should not be used during pregnancy unless clearly necessary, and advise patients to inform their doctors right away if they become pregnant while taking XELJANZ/XELJANZ XR. Inform patients that Pfizer has a registry for pregnant women who have taken XELJANZ/XELJANZ XR during pregnancy. Advise patients to contact the registry at 1-877-311-8972 to enroll. Women of reproductive potential should be advised to use effective contraception during treatment with XELJANZ/XELJANZ XR and for at least 4 weeks after the last dose. Inform patients that they should not breastfeed while taking XELJANZ/XELJANZ XR.
Residual Tablet Shell
Patients receiving XELJANZ XR may notice an inert tablet shell passing in the stool or via colostomy. Patients should be informed that the active medication has already been absorbed by the time the patient sees the inert tablet shell.
This product’s label may have been updated. For current full prescribing information, please visit www.pfizer.com.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In a 39-week toxicology study in monkeys, tofacitinib at exposure levels approximately 6 times the human dose (on an AUC basis at oral doses of 5 mg/kg twice daily) produced lymphomas. No lymphomas were observed in this study at exposure levels 1 times the human dose (on an AUC basis at oral doses of 1 mg/kg twice daily).
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib, at exposure levels approximately 34 times the human dose (on an AUC basis at oral doses of 200 mg/kg/day) was not carcinogenic in mice.
In the 24-month oral carcinogenicity study in Sprague-Dawley rats, tofacitinib caused benign Leydig cell tumors, hibernomas (malignancy of brown adipose tissue), and benign thymomas at doses greater than or equal to 30 mg/kg/day (approximately 42 times the exposure levels at the human dose on an AUC basis). The relevance of benign Leydig cell tumors to human risk is not known.
Tofacitinib was not mutagenic in the bacterial reverse mutation assay. It was positive for clastogenicity in the in vitro chromosome aberration assay with human lymphocytes in the presence of metabolic enzymes, but negative in the absence of metabolic enzymes. Tofacitinib was negative in the in vivo rat micronucleus assay and in the in vitro CHO-HGPRT assay and the in vivo rat hepatocyte unscheduled DNA synthesis assay.
In rats, tofacitinib at exposure levels approximately 17 times the human dose (on an AUC basis at oral doses of 10 mg/kg/day) reduced female fertility due to increased post-implantation loss. There was no impairment of female rat fertility at exposure levels of tofacitinib equal to the human dose (on an AUC basis at oral doses of 1 mg/kg/day). Tofacitinib exposure levels at approximately 133 times the human dose (on an AUC basis at oral doses of 100 mg/kg/day) had no effect on male fertility, sperm motility, or sperm concentration.
Use In Specific Populations
All information provided in this section is applicable to XELJANZ and XELJANZ XR as they contain the same active ingredient (tofacitinib).
Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ/XELJANZ XR during pregnancy. Patients should be encouraged to enroll in the XELJANZ/XELJANZ XR pregnancy registry if they become pregnant. To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.
Risk Summary
There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use in pregnant women.
The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. The background risks in the U.S. general population of major birth defects and miscarriages are 2-4% and 15-20% of clinically recognized pregnancies, respectively.
Data
Human Data
In the tofacitinib clinical development programs, birth defects and miscarriages were reported.
Animal Data
In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats). Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).
In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).
In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the human dose of 5 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).
Lactation
Risk Summary
It is not known whether tofacitinib is excreted in human milk. Additionally, there are no data to assess the effects of the drug on the breastfed child. However, tofacitinib is excreted in rat milk at concentrations higher than in maternal serum. Women should not breastfeed while treated with XELJANZ/XELJANZ XR. A decision should be made whether to discontinue breastfeeding or to discontinue XELJANZ/XELJANZ XR.
Data
Human Data
There are no adequate and well-controlled studies of XELJANZ/XELJANZ XR use during breastfeeding.
Animal Data
Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.
Females And Males Of Reproductive Potential
Contraception
Females
Embryofetal toxicity including malformations occurred in embryofetal development studies in rats and rabbits.
Females of reproductive potential should be advised to use effective contraception during treatment with XELJANZ/XELJANZ XR and for at least 4 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with XELJANZ/XELJANZ XR.
Infertility
Females
Based on findings in rats, treatment with XELJANZ/XELJANZ XR may result in reduced fertility in females of reproductive potential.
Pediatric Use
The safety and effectiveness of XELJANZ/XELJANZ XR in pediatric patients have not been established.
Geriatric Use
Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older. The frequency of serious infection among XELJANZ-treated subjects 65 years of age and older was higher than among those under the age of 65.
As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.
Use In Diabetics
As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.
Hepatic Impairment
XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib levels than XELJANZ-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions, therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate hepatic impairment. XELJANZ/XELJANZ XR has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ/XELJANZ XR in patients with severe hepatic impairment is not recommended. No dose adjustment is required in patients with mild hepatic impairment. The safety and efficacy of XELJANZ/XELJANZ XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
Renal Impairment
XELJANZ-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than XELJANZ-treated patients with normal renal function; therefore, the recommended dose is XELJANZ 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, XELJANZ/XELJANZ XR was not evaluated in rheumatoid arthritis patients with baseline creatinine clearance values (estimated by the Cockroft-Gault equation) less than 40 mL/ min (or in patients with active psoriatic arthritis with creatinine clearance values less than 50 mL/min). No dose adjustment is required in patients with mild renal impairment.
Experiência em ensaios clínicos
Como os estudos clínicos são conduzidos em condições muito variadas, as taxas de reação adversa observadas nos estudos clínicos de um medicamento não podem ser diretamente comparadas às taxas nos estudos clínicos de outro medicamento e podem não prever as taxas observadas em uma população mais ampla de pacientes na prática clínica.
Artrite reumatóide
Os estudos clínicos descritos nas seções a seguir foram conduzidos usando Jakvinus. Embora outras doses de Jakvinus tenham sido estudadas, a dose recomendada de Jakvinus é de 5 mg duas vezes ao dia.
A dose recomendada para Jakvinus XR é de 11 mg uma vez ao dia.
Os dados a seguir incluem dois ensaios multicêntricos, controlados e controlados, de fase 2 e cinco, de fase 3. Nestes ensaios, os pacientes foram randomizados para doses de Jakvinus 5 mg duas vezes ao dia (292 pacientes) e 10 mg duas vezes ao dia (306 pacientes) em monoterapia, Jakvinus 5 mg duas vezes ao dia (1044 pacientes) e 10 mg duas vezes ao dia (1043 pacientes) em combinação com DMARDs (incluindo metotrexato) e placebo (809 pacientes). Todos os sete protocolos incluíram disposições para pacientes que tomam placebo para receber tratamento com Jakvinus no mês 3 ou no mês 6, seja pela resposta do paciente (com base na atividade descontrolada da doença) ou por design, para que eventos adversos nem sempre possam ser atribuídos sem ambiguidade a um determinado tratamento. Portanto, algumas análises a seguir incluem pacientes que mudaram o tratamento por projeto ou pela resposta do paciente do placebo ao Jakvinus no grupo placebo e Jakvinus de um determinado intervalo. As comparações entre placebo e Jakvinus foram baseadas nos primeiros 3 meses de exposição, e as comparações entre Jakvinus 5 mg duas vezes ao dia e Jakvinus 10 mg duas vezes ao dia foram baseadas nos primeiros 12 meses de exposição.
A população de segurança a longo prazo inclui todos os pacientes que participaram de um estudo controlado, duplo-cego (incluindo estudos anteriores da fase de desenvolvimento) e depois participaram de um dos dois estudos de segurança a longo prazo. O desenho dos estudos de segurança a longo prazo permitiu a modificação das doses de Jakvinus de acordo com o julgamento clínico. Isso limita a interpretação dos dados de segurança a longo prazo em relação à dose.
As reações adversas graves mais comuns foram infecções graves.
A proporção de pacientes que interromperam o tratamento devido a qualquer reação adversa durante a exposição de 0 a 3 meses nos ensaios duplo-cegos controlados por placebo foi de 4% para pacientes que tomaram Jakvinus e de 3% para pacientes tratados com placebo.
Infecções gerais
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, a frequência geral de infecções foi de 20% e 22% nos grupos de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia, respectivamente, e 18% no grupo placebo.
As infecções mais comumente relatadas por Jakvinus foram infecções do trato respiratório superior, nasofaringite e infecções do trato urinário (4%, 3% e 2% dos pacientes, respectivamente).
Infecções graves
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, foram relatadas infecções graves em 1 paciente (0,5 eventos por 100 pacientes-ano) que receberam placebo e 11 pacientes (1,7 eventos por 100 pacientes-ano) que receberam Jakvinus 5 mg ou 10 mg duas vezes ao dia. A diferença de taxa entre os grupos de tratamento (e o intervalo de confiança correspondente de 95%) foi de 1,1 (-0,4, 2,5) eventos por 100 pacientes-ano para o grupo Jakvinus combinado de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia menos placebo.
Nos sete ensaios controlados, durante a exposição de 0 a 12 meses, foram relatadas infecções graves em 34 pacientes (2,7 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de Jakvinus e 33 pacientes (2,7 eventos por 100 pacientes-ano) que recebeu 10 mg duas vezes ao dia de Jakvinus. A diferença de taxa entre as doses de Jakvinus (e o intervalo de confiança correspondente de 95%) foi de -0,1 (-1,3, 1,2) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia Jakvinus menos 5 mg duas vezes ao dia Jakvinus.
As infecções graves mais comuns incluíram pneumonia, celulite, herpes zoster e infecção do trato urinário.
Tuberculose
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, não foi relatada tuberculose em pacientes que receberam placebo, 5 mg duas vezes ao dia de Jakvinus ou 10 mg duas vezes ao dia de Jakvinus.
Nos sete ensaios controlados, durante a exposição de 0 a 12 meses, foi relatada tuberculose em 0 pacientes que receberam 5 mg duas vezes ao dia de Jakvinus e 6 pacientes (0,5 eventos por 100 pacientes-ano) que receberam 10 mg duas vezes ao dia de Jakvinus. A diferença de taxa entre as doses de Jakvinus (e o intervalo de confiança correspondente de 95%) foi de 0,5 (0,1, 0,9) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia Jakvinus menos 5 mg duas vezes ao dia Jakvinus.
Casos de tuberculose disseminada também foram relatados. A exposição média a Jakvinus antes do diagnóstico de tuberculose foi de 10 meses (variação de 152 a 960 dias).
Infecções oportunistas (excluindo tuberculose)
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, não foram relatadas infecções oportunistas em pacientes que receberam placebo, 5 mg duas vezes ao dia de Jakvinus ou 10 mg duas vezes ao dia de Jakvinus.
Nos sete ensaios controlados, durante a exposição de 0 a 12 meses, foram relatadas infecções oportunistas em 4 pacientes (0,3 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de Jakvinus e 4 pacientes (0,3 eventos por 100 pacientes-ano) que recebeu 10 mg duas vezes ao dia de Jakvinus. A diferença de taxa entre as doses de Jakvinus (e o intervalo de confiança correspondente de 95%) foi de 0 (-0,5, 0,5) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia Jakvinus menos 5 mg duas vezes ao dia Jakvinus.
A exposição média a Jakvinus antes do diagnóstico de uma infecção oportunista foi de 8 meses (variação de 41 a 698 dias).
Malignidade
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, foram relatadas neoplasias excluindo NMSC em 0 pacientes que receberam placebo e 2 pacientes (0,3 eventos por 100 pacientes-ano) que receberam Jakvinus 5 mg ou 10 mg duas vezes ao dia. A diferença de taxa entre os grupos de tratamento (e o intervalo de confiança correspondente de 95%) foi de 0,3 (-0,1, 0,7) eventos por 100 pacientes-ano para o grupo Jakvinus combinado de 5 mg e 10 mg duas vezes ao dia menos o placebo.
Nos sete ensaios controlados, durante a exposição de 0 a 12 meses, foram relatadas neoplasias excluindo NMSC em 5 pacientes (0,4 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de Jakvinus e 7 pacientes (0,6 eventos por 100 pacientes-ano) que recebeu 10 mg duas vezes ao dia de Jakvinus. A diferença de taxa entre as doses de Jakvinus (e o intervalo de confiança correspondente de 95%) foi de 0,2 (-0,4, 0,7) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia Jakvinus menos 5 mg duas vezes ao dia Jakvinus. Uma dessas neoplasias foi um caso de linfoma que ocorreu durante o período de 0 a 12 meses em um paciente tratado com Jakvinus 10 mg duas vezes ao dia.
Os tipos mais comuns de malignidade, incluindo malignidades observadas durante a extensão a longo prazo, foram câncer de pulmão e mama, seguidos por gástrico, colorretal, célula renal, câncer de próstata, linfoma e melanoma maligno.
Anormalidades laboratoriais
Linfopenia
Nos ensaios clínicos controlados, as reduções confirmadas nas contagens absolutas de linfócitos são inferiores a 500 células / mm3 ocorreu em 0,04% dos pacientes para os grupos Jakvinus de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia combinados durante os primeiros 3 meses de exposição.
O linfócito confirmado conta menos de 500 células / mm3 foram associados a um aumento da incidência de infecções tratadas e graves.
Neutropenia
Nos ensaios clínicos controlados, as reduções confirmadas no ANC abaixo de 1000 células / mm3 ocorreu em 0,07% dos pacientes para os grupos Jakvinus de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia combinados durante os primeiros 3 meses de exposição.
Não houve reduções confirmadas no ANC abaixo de 500 células / mm3 observado em qualquer grupo de tratamento.
Não havia uma relação clara entre neutropenia e a ocorrência de infecções graves.
Na população de segurança a longo prazo, o padrão e a incidência de reduções confirmadas no ANC permaneceram consistentes com o que foi observado nos ensaios clínicos controlados.
Elevações da enzima hepática
Aumentos confirmados nas enzimas hepáticas superiores a 3 vezes o limite superior do normal (3x LSN) foram observados em pacientes tratados com Jakvinus. Em pacientes com elevação das enzimas hepáticas, a modificação do regime de tratamento, como redução na dose de DMARD concomitante, interrupção de Jakvinus ou redução na dose de Jakvinus, resultou em diminuição ou normalização das enzimas hepáticas.
Nos ensaios controlados de monoterapia (0-3 meses), não foram observadas diferenças na incidência de elevações da ALT ou AST entre o placebo e os grupos Jakvinus 5 mg e 10 mg duas vezes ao dia.
Nos ensaios controlados com DMARD (0-3 meses), foram observadas elevações da ALT superiores a 3x LSN em 1,0%, 1,3% e 1,2% dos pacientes que receberam placebo, 5 mg e 10 mg duas vezes ao dia, respectivamente. Nestes ensaios, foram observadas elevações do AST superiores a 3x LSN em 0,6%, 0,5% e 0,4% dos pacientes que receberam placebo, 5 mg e 10 mg duas vezes ao dia, respectivamente.
Um caso de lesão hepática induzida por medicamento foi relatado em um paciente tratado com Jakvinus 10 mg duas vezes ao dia por aproximadamente 2,5 meses. O paciente desenvolveu elevações sintomáticas de AST e ALT superiores a 3x elevações de LSN e bilirrubina superiores a 2x LSN, o que exigiu hospitalizações e biópsia hepática.
Elevações lipídicas
Nos ensaios clínicos controlados, foram observadas elevações relacionadas à dose nos parâmetros lipídicos (colesterol total, colesterol LDL, colesterol HDL, triglicerídeos) em um mês de exposição e permaneceram estáveis posteriormente. Alterações nos parâmetros lipídicos durante os primeiros 3 meses de exposição nos ensaios clínicos controlados estão resumidas abaixo :
- O colesterol médio LDL aumentou 15% no braço Jakvinus 5 mg duas vezes ao dia e 19% no braço Jakvinus 10 mg duas vezes ao dia.
- O colesterol HDL médio aumentou 10% no braço Jakvinus 5 mg duas vezes ao dia e 12% no braço Jakvinus 10 mg duas vezes ao dia.
- As razões médias de LDL / HDL permaneceram essencialmente inalteradas em pacientes tratados com Jakvinus.
Em um ensaio clínico controlado, as elevações no colesterol LDL e ApoB diminuíram para os níveis de pré-tratamento em resposta à terapia com estatina.
Na população de segurança a longo prazo, as elevações nos parâmetros lipídicos permaneceram consistentes com o que foi observado nos ensaios clínicos controlados.
Elevações de creatinina sérica
Nos ensaios clínicos controlados, foram observadas elevações relacionadas à dose na creatinina sérica com o tratamento com Jakvinus. O aumento médio da creatinina sérica foi <0,1 mg / dL na análise de segurança combinada de 12 meses; no entanto, com o aumento da duração da exposição nas extensões de longo prazo, até 2% dos pacientes foram descontinuados do tratamento com Jakvinus devido ao critério de descontinuação especificado pelo protocolo de um aumento na creatinina em mais de 50% da linha de base. O significado clínico das elevações séricas observadas da creatinina é desconhecido.
Outras reações adversas
As reações adversas que ocorrem em 2% ou mais dos pacientes em 5 mg duas vezes ao dia ou 10 mg duas vezes ao dia Jakvinus e pelo menos 1% maior que a observada em pacientes com placebo com ou sem DMARD estão resumidas na Tabela 4.
Tabela 4: Reações adversas que ocorrem em pelo menos 2% ou mais dos pacientes em 5 ou 10 mg Jakvinus duas vezes ao dia com ou sem DMARD (0-3 meses) e pelo menos 1% maior que o observado em pacientes com artrite reumatóide no placebo
Jakvinus 5 mg duas vezes ao dia | Jakvinus 10 mg duas vezes ao dia * | Placebo | |
Termo preferido | N = 1336 (%) | N = 1349 (%) | N = 809 (%) |
Diarréia | 4.0 | 2.9 | 2.3 |
Nasofaringite | 3.8 | 2.8 | 2.8 |
Infecção do trato respiratório superior | 4.5 | 3.8 | 3.3 |
Dor de cabeça | 4.3 | 3.4 | 2.1 |
Hipertensão | 1.6 | 2.3 | 1.1 |
N reflete pacientes randomizados e tratados dos sete ensaios clínicos * A dose recomendada de Jakvinus é de 5 mg duas vezes ao dia. |
Outras reações adversas que ocorreram em estudos de extensão controlados e abertos incluíram:
Doenças do sangue e do sistema linfático : Anemia
Infecções e infestações : Diverticulite
Distúrbios do metabolismo e nutrição : Desidratação
Distúrbios psiquiátricos : Insônia
Distúrbios do sistema nervoso: Parestesia
Distúrbios respiratórios, torácicos e mediastinais : Dispnéia, tosse, congestão sinusal, doença pulmonar intersticial (algumas fatais)
Distúrbios gastrointestinais : Dor abdominal, dispepsia, vômito, gastrite, náusea
Distúrbios hepatobiliares: Esteatose hepática
Afecções dos tecidos cutâneos e subcutâneos : Erupção cutânea, eritema, prurido
Afecções musculosqueléticas, dos tecidos conjuntivos e dos ossos : Dor musculoesquelética, artralgia, tendinite, inchaço das articulações
Neoplasias benignas, malignas e não especificadas (incluindo cistos e pólipos) : Cânceres de pele não melanoma
Perturbações gerais e alterações no local de administração : Pirexia, fadiga, edema periférico
Experiência clínica em pacientes com metotrexato ingênuo
O estudo VI foi um ensaio clínico controlado por ativos em pacientes sem metotrexato. A experiência de segurança nesses pacientes foi consistente com os estudos I-V
Artrite psoriática
Jakvinus 5 mg duas vezes ao dia e 10 mg duas vezes ao dia foram estudados em 2 ensaios clínicos de Fase 3 duplo-cegos em pacientes com artrite psoriática ativa (SCA).
O estudo PsA-I (NCT01877668) teve uma duração de 12 meses e registrou pacientes que tiveram uma resposta inadequada a um DMARD não biológico e que foram ingênuos ao tratamento com um inibidor de TNF (TNFi). O estudo PsA-I incluiu um período controlado por placebo de três meses e também incluiu adalimumab 40 mg por via subcutânea uma vez a cada 2 semanas por 12 meses.
O estudo PsA-II (NCT01882439) teve uma duração de 6 meses e registrou pacientes que tiveram uma resposta inadequada a pelo menos um TNFi aprovado. Este ensaio clínico incluiu um período controlado por placebo de três meses.
Nestes ensaios clínicos combinados de Fase 3, 238 pacientes foram randomizados e tratados com Jakvinus 5 mg duas vezes ao dia e 236 pacientes foram randomizados e tratados com Jakvinus 10 mg duas vezes ao dia. Todos os pacientes nos ensaios clínicos foram obrigados a receber tratamento com uma dose estável de um DMARD não biológico [a maioria (79%) recebeu metotrexato]. A população do estudo randomizada e tratada com Jakvinus (474 pacientes) incluiu 45 (9,5%) pacientes com 65 anos ou mais e 66 (13,9%) pacientes com diabetes no início do estudo.
O perfil de segurança observado em pacientes com artrite psoriática ativa tratados com Jakvinus foi consistente com o perfil de segurança observado em pacientes com artrite reumatóide.
Experiência em ensaios clínicos
Como os estudos clínicos são conduzidos em condições muito variadas, as taxas de reação adversa observadas nos estudos clínicos de um medicamento não podem ser diretamente comparadas às taxas nos estudos clínicos de outro medicamento e podem não prever as taxas observadas em uma população mais ampla de pacientes na prática clínica.
Artrite reumatóide
Os estudos clínicos descritos nas seções a seguir foram conduzidos usando XELJANZ. Embora outras doses de XELJANZ tenham sido estudadas, a dose recomendada de XELJANZ é de 5 mg duas vezes ao dia.
A dose recomendada para XELJANZ XR é de 11 mg uma vez ao dia.
Os dados a seguir incluem dois ensaios multicêntricos, controlados e controlados, de fase 2 e cinco, de fase 3. Nestes ensaios, os pacientes foram randomizados para doses de XELJANZ 5 mg duas vezes ao dia (292 pacientes) e 10 mg duas vezes ao dia (306 pacientes) em monoterapia, XELJANZ 5 mg duas vezes ao dia (1044 pacientes) e 10 mg duas vezes ao dia (1043 pacientes) em combinação com DMARDs (incluindo metotrexato) e placebo (809 pacientes). Todos os sete protocolos incluíram disposições para pacientes que tomaram placebo para receber tratamento com XELJANZ no mês 3 ou no mês 6, seja pela resposta do paciente (com base na atividade descontrolada da doença) ou por design, para que eventos adversos nem sempre possam ser inequivocamente atribuídos a um determinado tratamento. Portanto, algumas análises a seguir incluem pacientes que mudaram o tratamento por projeto ou pela resposta do paciente do placebo ao XELJANZ no grupo placebo e XELJANZ de um determinado intervalo. As comparações entre placebo e XELJANZ foram baseadas nos primeiros 3 meses de exposição, e as comparações entre XELJANZ 5 mg duas vezes ao dia e XELJANZ 10 mg duas vezes ao dia foram baseadas nos primeiros 12 meses de exposição.
A população de segurança a longo prazo inclui todos os pacientes que participaram de um estudo controlado, duplo-cego (incluindo estudos anteriores da fase de desenvolvimento) e depois participaram de um dos dois estudos de segurança a longo prazo. O desenho dos estudos de segurança a longo prazo permitiu a modificação das doses de XELJANZ de acordo com o julgamento clínico. Isso limita a interpretação dos dados de segurança a longo prazo em relação à dose.
As reações adversas graves mais comuns foram infecções graves.
A proporção de pacientes que interromperam o tratamento devido a qualquer reação adversa durante a exposição de 0 a 3 meses nos ensaios duplo-cegos controlados por placebo foi de 4% para pacientes que tomaram XELJANZ e 3% para pacientes tratados com placebo.
Infecções gerais
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, a frequência geral de infecções foi de 20% e 22% nos grupos de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia, respectivamente, e 18% no grupo placebo.
As infecções mais comumente relatadas com XELJANZ foram infecções do trato respiratório superior, nasofaringite e infecções do trato urinário (4%, 3% e 2% dos pacientes, respectivamente).
Infecções graves
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, foram relatadas infecções graves em 1 paciente (0,5 eventos por 100 pacientes-ano) que receberam placebo e 11 pacientes (1,7 eventos por 100 pacientes-ano) que receberam XELJANZ 5 mg ou 10 mg duas vezes ao dia. A diferença de taxa entre os grupos de tratamento (e o intervalo de confiança correspondente de 95%) foi de 1,1 (-0,4, 2,5) eventos por 100 pacientes-ano para o grupo combinado de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia XELJANZ menos placebo.
Nos sete ensaios controlados, durante os 0 a 12 meses de exposição, infecções graves foram relatadas em 34 pacientes (2,7 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de XELJANZ e 33 pacientes (2,7 eventos por 100 pacientes-ano) que receberam 10 mg duas vezes ao dia de XELJANZ. A diferença de taxa entre as doses de XELJANZ (e o intervalo de confiança correspondente de 95%) foi -0,1 (-1,3, 1.2) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia XELJANZ menos 5 mg duas vezes ao dia XELJANZ .
As infecções graves mais comuns incluíram pneumonia, celulite, herpes zoster e infecção do trato urinário.
Tuberculose
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, não foi relatada tuberculose em pacientes que receberam placebo, 5 mg duas vezes ao dia de XELJANZ ou 10 mg duas vezes ao dia de XELJANZ
Nos sete ensaios controlados, durante os 0 a 12 meses de exposição, tuberculose foi relatada em 0 pacientes que receberam 5 mg duas vezes ao dia de XELJANZ e 6 pacientes (0,5 eventos por 100 pacientes-ano) que receberam 10 mg duas vezes ao dia de XELJANZ. A diferença de taxa entre as doses de XELJANZ (e o intervalo de confiança correspondente de 95%) foi 0,5 (0.1, 0,9) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia XELJANZ menos 5 mg duas vezes ao dia XELJANZ .
Casos de tuberculose disseminada também foram relatados. A exposição média ao XELJANZ antes do diagnóstico de tuberculose foi de 10 meses (variação de 152 a 960 dias).
Infecções oportunistas (excluindo tuberculose)
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, não foram relatadas infecções oportunistas em pacientes que receberam placebo, 5 mg duas vezes ao dia de XELJANZ ou 10 mg duas vezes ao dia de XELJANZ
Nos sete ensaios controlados, durante os 0 a 12 meses de exposição, infecções oportunistas foram relatadas em 4 pacientes (0,3 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de XELJANZ e 4 pacientes (0,3 eventos por 100 pacientes-ano) que receberam 10 mg duas vezes ao dia de XELJANZ. A diferença de taxa entre as doses de XELJANZ (e o intervalo de confiança correspondente de 95%) foi 0 (-0,5, 0,5) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia XELJANZ menos 5 mg duas vezes ao dia XELJANZ .
A exposição média ao XELJANZ antes do diagnóstico de uma infecção oportunista foi de 8 meses (variação de 41 a 698 dias).
Malignidade
Nos sete ensaios controlados, durante a exposição de 0 a 3 meses, foram relatadas neoplasias excluindo NMSC em 0 pacientes que receberam placebo e 2 pacientes (0,3 eventos por 100 pacientes-ano) que receberam XELJANZ 5 mg ou 10 mg duas vezes ao dia. A diferença de taxa entre os grupos de tratamento (e o intervalo de confiança correspondente de 95%) foi de 0,3 (-0,1, 0,7) eventos por 100 pacientes-ano para o grupo XELJANZ combinado de 5 mg e 10 mg duas vezes ao dia menos placebo.
Nos sete ensaios controlados, durante os 0 a 12 meses de exposição, malignidades excluindo NMSC foram relatadas em 5 pacientes (0,4 eventos por 100 pacientes-ano) que receberam 5 mg duas vezes ao dia de XELJANZ e 7 pacientes (0,6 eventos por 100 pacientes-ano) que receberam 10 mg duas vezes ao dia de XELJANZ. A diferença de taxa entre as doses de XELJANZ (e o intervalo de confiança correspondente de 95%) foi 0,2 (-0,4, 0,7) eventos por 100 pacientes-ano por 10 mg duas vezes ao dia XELJANZ menos 5 mg duas vezes ao dia XELJANZ. Uma dessas neoplasias foi um caso de linfoma que ocorreu durante o período de 0 a 12 meses em um paciente tratado com XELJANZ 10 mg duas vezes ao dia.
Os tipos mais comuns de malignidade, incluindo malignidades observadas durante a extensão a longo prazo, foram câncer de pulmão e mama, seguidos por gástrico, colorretal, célula renal, câncer de próstata, linfoma e melanoma maligno.
Anormalidades laboratoriais
Linfopenia
Nos ensaios clínicos controlados, as reduções confirmadas nas contagens absolutas de linfócitos são inferiores a 500 células / mm3 ocorreu em 0,04% dos pacientes para os grupos XELJANZ de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia combinados durante os primeiros 3 meses de exposição.
O linfócito confirmado conta menos de 500 células / mm3 foram associados a um aumento da incidência de infecções tratadas e graves.
Neutropenia
Nos ensaios clínicos controlados, as reduções confirmadas no ANC abaixo de 1000 células / mm3 ocorreu em 0,07% dos pacientes para os grupos XELJANZ de 5 mg duas vezes ao dia e 10 mg duas vezes ao dia combinados durante os primeiros 3 meses de exposição.
Não houve reduções confirmadas no ANC abaixo de 500 células / mm3 observado em qualquer grupo de tratamento.
Não havia uma relação clara entre neutropenia e a ocorrência de infecções graves.
Na população de segurança a longo prazo, o padrão e a incidência de reduções confirmadas no ANC permaneceram consistentes com o que foi observado nos ensaios clínicos controlados.
Elevações da enzima hepática
Aumentos confirmados nas enzimas hepáticas superiores a 3 vezes o limite superior do normal (3x LSN) foram observados em pacientes tratados com XELJANZ. Em pacientes com elevação das enzimas hepáticas, modificação do regime de tratamento, como redução na dose de DMARD concomitante, interrupção do XELJANZ, ou redução na dose de XELJANZ, resultou em diminuição ou normalização de enzimas hepáticas.
Nos ensaios controlados de monoterapia (0-3 meses), não foram observadas diferenças na incidência de elevações da ALT ou AST entre o placebo e XELJANZ 5 mg e 10 mg grupos duas vezes ao dia.
Nos ensaios controlados com DMARD (0-3 meses), foram observadas elevações da ALT superiores a 3x LSN em 1,0%, 1,3% e 1,2% dos pacientes que receberam placebo, 5 mg e 10 mg duas vezes ao dia, respectivamente. Nestes ensaios, foram observadas elevações do AST superiores a 3x LSN em 0,6%, 0,5% e 0,4% dos pacientes que receberam placebo, 5 mg e 10 mg duas vezes ao dia, respectivamente.
Um caso de lesão hepática induzida por medicamento foi relatado em um paciente tratado com XELJANZ 10 mg duas vezes ao dia por aproximadamente 2,5 meses. O paciente desenvolveu elevações sintomáticas de AST e ALT superiores a 3x elevações de LSN e bilirrubina superiores a 2x LSN, o que exigiu hospitalizações e biópsia hepática.
Elevações lipídicas
Nos ensaios clínicos controlados, foram observadas elevações relacionadas à dose nos parâmetros lipídicos (colesterol total, colesterol LDL, colesterol HDL, triglicerídeos) em um mês de exposição e permaneceram estáveis posteriormente. Alterações nos parâmetros lipídicos durante os primeiros 3 meses de exposição nos ensaios clínicos controlados estão resumidas abaixo :
- O colesterol médio LDL aumentou 15% no braço XELJANZ 5 mg duas vezes ao dia e 19% no braço XELJANZ 10 mg duas vezes ao dia.
- O colesterol HDL médio aumentou 10% no braço XELJANZ 5 mg duas vezes ao dia e 12% no braço XELJANZ 10 mg duas vezes ao dia.
- As razões médias de LDL / HDL permaneceram essencialmente inalteradas em pacientes tratados com XELJANZ.
Em um ensaio clínico controlado, as elevações no colesterol LDL e ApoB diminuíram para os níveis de pré-tratamento em resposta à terapia com estatina.
Na população de segurança a longo prazo, as elevações nos parâmetros lipídicos permaneceram consistentes com o que foi observado nos ensaios clínicos controlados.
Elevações de creatinina sérica
Nos ensaios clínicos controlados, foram observadas elevações relacionadas à dose na creatinina sérica com o tratamento com XELJANZ. O aumento médio da creatinina sérica foi <0,1 mg / dL na análise de segurança combinada de 12 meses; no entanto, com o aumento da duração da exposição nas extensões de longo prazo, até 2% dos pacientes foram descontinuados do tratamento com XELJANZ devido ao critério de descontinuação especificado pelo protocolo de um aumento na creatinina em mais de 50% da linha de base. O significado clínico das elevações séricas observadas da creatinina é desconhecido.
Outras reações adversas
As reações adversas que ocorrem em 2% ou mais dos pacientes em 5 mg duas vezes ao dia ou 10 mg duas vezes ao dia XELJANZ e pelo menos 1% maior que a observada em pacientes com placebo com ou sem DMARD estão resumidas na Tabela 4.
Tabela 4: Reações adversas que ocorrem em pelo menos 2% ou mais dos pacientes em 5 ou 10 mg duas vezes ao dia XELJANZ com ou sem DMARD (0-3 meses) e pelo menos 1% maior do que o observado em pacientes com artrite reumatóide no placebo
XELJANZ 5 mg duas vezes ao dia | XELJANZ 10 mg duas vezes ao dia * | Placebo | |
Termo preferido | N = 1336 (%) | N = 1349 (%) | N = 809 (%) |
Diarréia | 4.0 | 2.9 | 2.3 |
Nasofaringite | 3.8 | 2.8 | 2.8 |
Infecção do trato respiratório superior | 4.5 | 3.8 | 3.3 |
Dor de cabeça | 4.3 | 3.4 | 2.1 |
Hipertensão | 1.6 | 2.3 | 1.1 |
N reflete pacientes randomizados e tratados dos sete ensaios clínicos * A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia. |
Outras reações adversas que ocorreram em estudos de extensão controlados e abertos incluíram:
Doenças do sangue e do sistema linfático : Anemia
Infecções e infestações : Diverticulite
Distúrbios do metabolismo e nutrição : Desidratação
Distúrbios psiquiátricos : Insônia
Distúrbios do sistema nervoso: Parestesia
Distúrbios respiratórios, torácicos e mediastinais : Dispnéia, tosse, congestão sinusal, doença pulmonar intersticial (algumas fatais)
Distúrbios gastrointestinais : Dor abdominal, dispepsia, vômito, gastrite, náusea
Distúrbios hepatobiliares: Esteatose hepática
Afecções dos tecidos cutâneos e subcutâneos : Erupção cutânea, eritema, prurido
Afecções musculosqueléticas, dos tecidos conjuntivos e dos ossos : Dor musculoesquelética, artralgia, tendinite, inchaço das articulações
Neoplasias benignas, malignas e não especificadas (incluindo cistos e pólipos) : Cânceres de pele não melanoma
Perturbações gerais e alterações no local de administração : Pirexia, fadiga, edema periférico
Experiência clínica em pacientes com metotrexato ingênuo
O estudo VI foi um ensaio clínico controlado por ativos em pacientes sem metotrexato. A experiência de segurança nesses pacientes foi consistente com os estudos I-V
Artrite psoriática
XELJANZ 5 mg duas vezes ao dia e 10 mg duas vezes ao dia foram estudados em 2 ensaios clínicos de Fase 3 em dupla ocultação em pacientes com artrite psoriática ativa (SPA).
O estudo PsA-I (NCT01877668) teve uma duração de 12 meses e registrou pacientes que tiveram uma resposta inadequada a um DMARD não biológico e que foram ingênuos ao tratamento com um inibidor de TNF (TNFi). O estudo PsA-I incluiu um período controlado por placebo de três meses e também incluiu adalimumab 40 mg por via subcutânea uma vez a cada 2 semanas por 12 meses.
O estudo PsA-II (NCT01882439) teve uma duração de 6 meses e registrou pacientes que tiveram uma resposta inadequada a pelo menos um TNFi aprovado. Este ensaio clínico incluiu um período controlado por placebo de três meses.
Nestes ensaios clínicos combinados de Fase 3, 238 pacientes foram randomizados e tratados com XELJANZ 5 mg duas vezes ao dia e 236 pacientes foram randomizados e tratados com XELJANZ 10 mg duas vezes ao dia. Todos os pacientes nos ensaios clínicos foram obrigados a receber tratamento com uma dose estável de um DMARD não biológico [a maioria (79%) recebeu metotrexato]. A população do estudo randomizada e tratada com XELJANZ (474 pacientes) incluiu 45 (9,5%) pacientes com 65 anos ou mais e 66 (13,9%) pacientes com diabetes no início do estudo.
O perfil de segurança observado em pacientes com artrite psoriática ativa tratados com XELJANZ foi consistente com o perfil de segurança observado em pacientes com artrite reumatóide.
Sinais, sintomas e resultados laboratoriais da sobredosagem aguda em seres humanos
Não há experiência com sobredosagem de Jakvinus / Jakvinus XR .
Tratamento ou tratamento de overdose
Dados farmacocinéticos até e incluindo uma dose única de 100 mg em voluntários saudáveis indicam que mais de 95% da dose administrada deve ser eliminada em 24 horas.
Não há antídoto específico para sobredosagem com Jakvinus / Jakvinus XR. Em caso de sobredosagem, recomenda-se que o paciente seja monitorado quanto a sinais e sintomas de reações adversas. Pacientes que desenvolvem reações adversas devem receber tratamento apropriado.
Sinais, sintomas e resultados laboratoriais da sobredosagem aguda em seres humanos
Não há experiência com sobredosagem de XELJANZ / XELJANZ XR .
Tratamento ou tratamento de overdose
Dados farmacocinéticos até e incluindo uma dose única de 100 mg em voluntários saudáveis indicam que mais de 95% da dose administrada deve ser eliminada em 24 horas.
Não existe antídoto específico para sobredosagem com XELJANZ / XELJANZ XR. Em caso de sobredosagem, recomenda-se que o paciente seja monitorado quanto a sinais e sintomas de reações adversas. Pacientes que desenvolvem reações adversas devem receber tratamento apropriado.
O tratamento com Jakvinus foi associado a reduções dependentes da dose das células assassinas naturais CD16 / 56+ circulantes, com reduções máximas estimadas ocorrendo aproximadamente 8 a 10 semanas após o início da terapia. Essas alterações geralmente foram resolvidas dentro de 2-6 semanas após a descontinuação do tratamento. O tratamento com Jakvinus foi associado a aumentos dependentes da dose na contagem de células B. Alterações na contagem de linfócitos T circulantes e subconjuntos de linfócitos T (CD3 +, CD4 + e CD8 +) foram pequenas e inconsistentes. O significado clínico dessas alterações é desconhecido.
Os níveis séricos totais de IgG, IgM e IgA após 6 meses de administração em pacientes com artrite reumatóide foram inferiores ao placebo; no entanto, as alterações foram pequenas e não dependem da dose.
Após o tratamento com Jakvinus em pacientes com artrite reumatóide, foram observadas e mantidas reduções rápidas na proteína C reativa sérica (PCR) durante a administração. As alterações na PCR observadas com o tratamento com Jakvinus não se revertem completamente dentro de 2 semanas após a descontinuação, indicando uma duração mais longa da atividade farmacodinâmica em comparação com a meia-vida farmacocinética.
Alterações semelhantes nas células T, células B e PCR sérica foram observadas em pacientes com artrite psoriática ativa, embora a reversibilidade não tenha sido avaliada. As imunoglobulinas séricas totais não foram avaliadas em pacientes com artrite psoriática ativa.
O tratamento com XELJANZ foi associado a reduções dependentes da dose das células assassinas naturais CD16 / 56+ circulantes, com reduções máximas estimadas ocorrendo aproximadamente 8 a 10 semanas após o início da terapia. Essas alterações geralmente foram resolvidas dentro de 2-6 semanas após a descontinuação do tratamento. O tratamento com XELJANZ foi associado a aumentos dependentes da dose na contagem de células B. Alterações na contagem de linfócitos T circulantes e subconjuntos de linfócitos T (CD3 +, CD4 + e CD8 +) foram pequenas e inconsistentes. O significado clínico dessas alterações é desconhecido.
Os níveis séricos totais de IgG, IgM e IgA após 6 meses de administração em pacientes com artrite reumatóide foram inferiores ao placebo; no entanto, as alterações foram pequenas e não dependem da dose.
Após o tratamento com XELJANZ em pacientes com artrite reumatóide, foram observadas e mantidas reduções rápidas na proteína C reativa sérica (PCR) durante a administração. As alterações na PCR observadas com o tratamento com XELJANZ não se revertem completamente dentro de 2 semanas após a descontinuação, indicando uma duração mais longa da atividade farmacodinâmica em comparação com a meia-vida farmacocinética.
Alterações semelhantes nas células T, células B e PCR sérica foram observadas em pacientes com artrite psoriática ativa, embora a reversibilidade não tenha sido avaliada. As imunoglobulinas séricas totais não foram avaliadas em pacientes com artrite psoriática ativa.
* Supplemental doses are not necessary in patients after dialysis. Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and White, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function. |
Drug Interactions
Potential For Jakvinus/Jakvinus XR To Influence The PK Of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with Jakvinus.
In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state Cmax of a 5 mg twice daily dose.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with Jakvinus/Jakvinus XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with Jakvinus/Jakvinus XR are shown in Figure 2.
Figure 2. Impact of Tofacitinib on PK of Other Drugs
Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion |
Potential For Other Drugs To Influence The PK Of Tofacitinib
Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the PK of tofacitinib. Dosing recommendations for Jakvinus/Jakvinus XR for administration with CYP inhibitors or inducers are shown in Figure 3.
Figure 3. Impact of Other Drugs on PK of Tofacitinib
Note: Reference group is administration of tofacitinib alone |
Clinical Studies
Rheumatoid Arthritis
The Jakvinus clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of Jakvinus is 5 mg twice daily.
Dose-Ranging Trials
Dose selection for Jakvinus was based on two pivotal dose-ranging trials.
Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: Jakvinus 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by Jakvinus 5 mg twice daily for 3 months, or placebo.
Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of Jakvinus (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
The results of Jakvinus-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and Jakvinus 1 mg groups compared to patients treated with the other Jakvinus doses. However, there was no difference in the proportion of responders among patients treated with Jakvinus 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
Figure 4: Proportion of Patients with ACR20 Response at Month 3 in Dose-Ranging Studies 1 and 2
Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.
Confirmatory Trials
Study I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received Jakvinus 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of Jakvinus 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received Jakvinus 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of Jakvinus 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received Jakvinus 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received Jakvinus 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS284( ESR) less than 2.6 at Month 6.
Study V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received Jakvinus 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of Jakvinus 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Study VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received Jakvinus 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.
Clinical Response
The percentages of Jakvinus-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In trials I-V, patients treated with either 5 or 10 mg twice daily Jakvinus had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in Jakvinus-treated patients were consistent at 6 and 12 months.
Table 5: Proportion of Patients with an ACR Response
Percent of Patients | |||||||||
Monotherapy in Nonbiologic or Biologic DMARD Inadequate Respondersc | MTX Inadequate Respondersd | TNF Inhibitor Inadequate Responderse | |||||||
Study I | Study IV | Study V | |||||||
Na | PBO | Jakvinus 5 mg Twice Daily | Jakvinus 10 mg Twice Dailyf | PBO + MTX | Jakvinus 5 mg Twice Daily + MTX | Jakvinus 10 mg Twice Daily + MTXf | PBO + MTX | Jakvinus 5 mg Twice Daily + MTX | Jakvinus 10 mg Twice Daily + MTXf |
122 | 243 | 245 | 160 | 321 | 316 | 132 | 133 | 134 | |
ACR20 | |||||||||
Month 3 | 26% | 59% | 65% | 27% | 55% | 67% | 24% | 41% | 48% |
Month 6 | NAb | 69% | 70% | 25% | 50% | 62% | NA | 51% | 54% |
ACR50 | |||||||||
Month 3 | 12% | 31% | 36% | 8% | 29% | 37% | 8% | 26% | 28% |
Month 6 | NA | 42% | 46% | 9% | 32% | 44% | NA | 37% | 30% |
ACR70 | |||||||||
Month 3 | 6% | 15% | 20% | 3% | 11% | 17% | 2% | 14% | 10% |
Month 6 | NA | 22% | 29% | 1% | 14% | 23% | NA | 16% | 16% |
a N is number of randomized and treated patients. b NA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement. c Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity. d Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria. e Inadequate response to a least one TNF inhibitor due to lack of efficacy and/or intolerance. f The recommended dose of Jakvinus is 5 mg twice daily. |
In Study IV, a greater proportion of patients treated with Jakvinus 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 6).
Table 6: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints
Study IV | |||
DAS28-4(ESR) Less Than 2.6 | Placebo + MTX | Jakvinus 5 mg Twice Daily + MTX | Jakvinus 10 mg Twice Daily + MTX* |
160 | 321 | 316 | |
Proportion of responders at Month 6 (n) | 1% (2) | 6% (19) | 13% (42) |
Of responders, proportion with 0 active joints (n) | 50% (1) | 42% (8) | 36% (15) |
Of responders, proportion with 1 active joint (n) | 0 | 5% (1) | 17% (7) |
Of responders, proportion with 2 active joints (n) | 0 | 32% (6) | 7% (3) |
Of responders, proportion with 3 or more active joints (n) | 50% (1) | 21% (4) | 40% (17) |
*The recommended dose of Jakvinus is 5 mg twice daily. |
The results of the components of the ACR response criteria for Study IV are shown in Table 7. Similar results were observed for Jakvinus in Studies I, II, III, V, and VI.
Table 7: Components of ACR Response at Month 3
Study IV | ||||||
Jakvinus 5 mg Twice Daily + MTX | Jakvinus 10 mgd Twice Daily + MTX | Placebo + MTX | ||||
N=321 | N=316 | N=160 | ||||
Component(mean) a | Baseline | Month 3a | Baseline | Month 3a | Baseline | Month 3a |
Number of tender | ||||||
joints | 24 | 13 | 23 | 10 | 23 | 18 |
(0-68) | (14) | (14) | (15) | (12) | (13) | (14) |
Number of swollen | ||||||
joints | 14 | 6 | 14 | 6 | 14 | 10 |
(0-66) | (8) | (8) | (8) | (7) | (9) | (9) |
Painb | 58 | 34 | 58 | 29 | 55 | 47 |
(23) | (23) | (24) | (22) | (24) | (24) | |
Patient global | 58 | 35 | 57 | 29 | 54 | 47 |
assessmentb | (24) | (23) | (23) | (20) | (23) | (24) |
Disability index | 1.41 | 0.99 | 1.40 | 0.84 | 1.32 | 1.19 |
(HAQ-DI)c | (0.68) | (0.65) | (0.66) | (0.64) | (0.67) | (0.68) |
Physician global | 59 | 30 | 58 | 24 | 56 | 43 |
assessmentb | (16) | (19) | (17) | (17) | (18) | (22) |
CRP (mg/L) | 15.3 | 7.1 | 17.1 | 4.4 | 13.7 | 14.6 |
(19.0) | (19.1) | (26.9) | (8.6) | (14.9) | (18.7) | |
aData shown is mean (Standard Deviation) at Month 3. bVisual analog scale: 0 = best, 100 = worst. cHealth Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. dThe recommended dose of Jakvinus is 5 mg twice daily. |
The percent of ACR20 responders by visit for Study IV is shown in Figure 5. Similar responses were observed for Jakvinus in Studies I, II, III, V, and VI.
Figure 5: Percentage of ACR20 Responders by Visit for Study IV
Radiographic Response
Two studies were conducted to evaluate the effect of Jakvinus on structural joint damage. In Study IV and Study VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.
In Study IV, Jakvinus 10 mg twice daily plus background MTX reduced the progression of structural damage compared to placebo plus MTX at Month 6. When given at a dose of 5 mg twice daily, Jakvinus exhibited similar effects on mean progression of structural damage (not statistically significant). These results are shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% and 79% of patients treated with Jakvinus plus MTX 5 or 10 mg twice daily.
In Study VI, Jakvinus monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% and 77% of patients treated with Jakvinus 5 or 10 mg twice daily.
Table 8: Radiographic Changes at Months 6 and 12
Study IV | |||||
Placebo N=139 Mean (SD)a | Jakvinus 5 mg Twice Daily N=277 Mean (SD) a | Jakvinus 5 mg Twice Daily Mean Difference from Placebob (CI) | Jakvinus 10 mg Twice Dailyd N=290 Mean (SD) a | Jakvinus 10 mg Twice Daily Mean Difference from Placebob (CI) | |
mTSSc | |||||
Baseline | 33 (42) | 31 (48) | - | 37 (54) | - |
Month 6 | 0.5 (2.0) | 0.1 (1.7) | -0.3 (-0.7, 0.0) | 0.1 (2.0) | -0.4 (-0.8, 0.0) |
Study VI | |||||
MTX N=166 Mean (SD)a | Jakvinus 5 mg Twice Daily N=346 Mean (SD) a | Jakvinus 5 mg Twice Daily Mean Difference from MTXb (CI) | Jakvinus 10 mg Twice Dailyd N=369 Mean (SD) a | Jakvinus 10 mg Twice Daily Mean Difference from MTXb (CI) | |
mTSSc | |||||
Baseline | 17 (29) | 20 (40) | - | 19 (39) | - |
Month 6 | 0.8 (2.7) | 0.2 (2.3) | -0.7 (-1.0, -0.3) | 0.0 (1.2) | -0.8 (-1.2, -0.4) |
Month 12 | 1.3 (3.7) | 0.4 (3.0) | -0.9 (-1.4, -0.4) | 0.0 (1.5) | -1.3 (-1.8, -0.8) |
aSD = Standard Deviation bDifference between least squares means Jakvinus minus placebo or MTX (95% CI = 95% confidence interval) c Month 6 and Month 12 data are mean change from baseline. d The recommended dose of Jakvinus is 5 mg twice daily. |
Physical Function Response
Improvement in physical functioning was measured by the HAQ-DI. Patients receiving Jakvinus 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.
The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg Jakvinus twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg Jakvinus twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in Jakvinus-treated patients were consistent at 6 and 12 months.
Other Health-Related Outcomes
General health status was assessed by the Short Form health survey (SF-36). In studies I, IV, and V, patients receiving Jakvinus 5 mg twice daily or Jakvinus 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.
Psoriatic Arthritis
The Jakvinus clinical development program to assess efficacy and safety included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA-II). Although other doses have been studied, the recommended dose of Jakvinus is 5 mg twice daily. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different psoriatic arthritis subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of psoriatic arthritis for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.
Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF-inhibitor (TNFi). Patients were randomized in a 2:2:2:1:1 ratio to receive Jakvinus 5 mg twice daily, Jakvinus 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to Jakvinus 5 mg twice daily treatment sequence, or placebo to Jakvinus 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a predetermined Jakvinus dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.
Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNFi (66%, 19%, and 15% were inadequate responders to 1 TNFi, 2 TNFi and ≥3 TNFi, respectively). Patients were randomized in a 2:2:1:1 ratio to receive Jakvinus 5 mg twice daily, Jakvinus 10 mg twice daily, placebo to Jakvinus 5 mg twice daily treatment sequence, or placebo to Jakvinus 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were advanced in a blinded fashion to a predetermined Jakvinus dose of 5 mg or 10 mg twice daily as in Study PsA-I.
Clinical Response
At Month 3, patients treated with either Jakvinus 5 mg or 10 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for both Jakvinus 5 mg or 10 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 9 and 10).
Table 9: Proportion of Patients with an ACR Response in Study PsA-I* [Nonbiologic DMARD Inadequate Responders (TNFi-Naïve)]
Treatment Group | Placebo | Jakvinus 5 mg Twice Daily | Jakvinus 10 mgb Twice Daily | ||
Na | 105 | 107 | 104 | ||
Response Rate | Response Rate | Difference (%) 95% CI from Placebo | Response Rate | Difference (%) 95% CI from Placebo | |
Month 3 | |||||
ACR20 | 33% | 50% | 17.1 (4.1, 30.2) | 61% | 27.2 (14.2, 40.3) |
ACR50 | 10% | 28% | 18.5 (8.3, 28.7) | 40% | 30.9 (19.9, 41.8) |
ACR70 | 5% | 17% | 12.1 (3.9, 20.2) | 14% | 9.7 (1.8, 17.6) |
Subjects with missing data were treated as non-responders. * Subjects received one concomitant nonbiologic DMARD. a N is number of randomized and treated patients. b The recommended dose of Jakvinus is 5 mg twice daily. |
Table 10: Proportion of Patients with an ACR Response in Study PsA-II* (TNFi Inadequate Responders)
Treatment Group | Placebo | Jakvinus 5 mg Twice Daily | Jakvinus 10 mgb Twice Daily | ||
Na | 131 | 131 | 132 | ||
Response Rate | Response Rate | Difference (%) 95% CI from Placebo | Response Rate | Difference (%) 95% CI from Placebo | |
Month 3 | |||||
ACR20 | 24% | 50% | 26.0 (14.7, 37.2) | 47% | 23.3 (12.1, 34.5) |
ACR50 | 15% | 30% | 15.3 (5.4, 25.2) | 28% | (3.8, 23.3) |
ACR70 | 10% | 17% | 6.9 (-1.3, 15.1) | 14% | 4.5 (-3.4, 12.4) |
Subjects with missing data were treated as non-responders. * Subjects received one concomitant nonbiologic DMARD. a N is number of randomized and treated patients. b The recommended dose of Jakvinus is 5 mg twice daily. |
Improvements from baseline in the ACR response criteria components for both studies are shown in Table11.
Table 11: Components of ACR Response at Baseline and Month 3 in Studies PsA-I and PsA-II
Nonbiologic DMARD Inadequate Responders (TNFi-Naïve) | TNFi Inadequate Responders | |||||
Study PsA-I* | Study PsA-II* | |||||
Treatment Group | Placebo | Jakvinus 5 mg Twice Daily | Jakvinus 10 mgd Twice Daily | Placebo | Jakvinus 5 mg Twice Daily | Jakvinus 10 mgd Twice Daily |
N at Baseline | 105 | 107 | 104 | 131 | 131 | 132 |
ACR Componenta | ||||||
Number of tender/painful joints (0-68) | ||||||
Baseline | 20.6 | 20.5 | 20.3 | 19.8 | 20.5 | 25.5 |
Month 3 | 14.6 | 12.2 | 9.9 | 15.1 | 11.5 | 14.5 |
Number of swollen joints (0-66) | ||||||
Baseline | 11.5 |
* Supplemental doses are not necessary in patients after dialysis. Reference values for weight, age, gender, and race comparisons are 70 kg, 55 years, male, and White, respectively; reference groups for renal and hepatic impairment data are subjects with normal renal and hepatic function. |
Drug Interactions
Potential For XELJANZ/XELJANZ XR To Influence The PK Of Other Drugs
In vitro studies indicate that tofacitinib does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 80 times the steady state Cmax of a 5 mg twice daily dose. These in vitro results were confirmed by a human drug interaction study showing no changes in the PK of midazolam, a highly sensitive CYP3A4 substrate, when coadministered with XELJANZ.
In vitro studies indicate that tofacitinib does not significantly inhibit the activity of the major human drug-metabolizing uridine 5'-diphospho-glucuronosyltransferases (UGTs) [UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7] at concentrations exceeding 250 times the steady state Cmax of a 5 mg twice daily dose.
In rheumatoid arthritis patients, the oral clearance of tofacitinib does not vary with time, indicating that tofacitinib does not normalize CYP enzyme activity in rheumatoid arthritis patients. Therefore, coadministration with XELJANZ/XELJANZ XR is not expected to result in clinically relevant increases in the metabolism of CYP substrates in rheumatoid arthritis patients.
In vitro data indicate that the potential for tofacitinib to inhibit transporters such as P-glycoprotein, organic anionic or cationic transporters at therapeutic concentrations is low.
Dosing recommendations for coadministered drugs following administration with XELJANZ/XELJANZ XR are shown in Figure 2.
Figure 2. Impact of Tofacitinib on PK of Other Drugs
Note: Reference group is administration of concomitant medication alone; OCT = Organic Cationic Transporter; MATE = Multidrug and Toxic Compound Extrusion |
Potential For Other Drugs To Influence The PK Of Tofacitinib
Since tofacitinib is metabolized by CYP3A4, interaction with drugs that inhibit or induce CYP3A4 is likely. Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to substantially alter the PK of tofacitinib. Dosing recommendations for XELJANZ/XELJANZ XR for administration with CYP inhibitors or inducers are shown in Figure 3.
Figure 3. Impact of Other Drugs on PK of Tofacitinib
Note: Reference group is administration of tofacitinib alone |
Clinical Studies
Rheumatoid Arthritis
The XELJANZ clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily.
Dose-Ranging Trials
Dose selection for XELJANZ was based on two pivotal dose-ranging trials.
Dose-Ranging Study 1 was a 6-month monotherapy trial in 384 patients with active rheumatoid arthritis who had an inadequate response to a DMARD. Patients who previously received adalimumab therapy were excluded. Patients were randomized to 1 of 7 monotherapy treatments: XELJANZ 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by XELJANZ 5 mg twice daily for 3 months, or placebo.
Dose-Ranging Study 2 was a 6-month trial in which 507 patients with active rheumatoid arthritis who had an inadequate response to MTX alone received one of 6 dose regimens of XELJANZ (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
The results of XELJANZ-treated patients achieving ACR20 responses in Studies 1 and 2 are shown in Figure 4. Although a dose-response relationship was observed in Study 1, the proportion of patients with an ACR20 response did not clearly differ between the 10 mg and 15 mg doses. In Study 2, a smaller proportion of patients achieved an ACR20 response in the placebo and XELJANZ 1 mg groups compared to patients treated with the other XELJANZ doses. However, there was no difference in the proportion of responders among patients treated with XELJANZ 3, 5, 10, 15 mg twice daily or 20 mg once daily doses.
Figure 4: Proportion of Patients with ACR20 Response at Month 3 in Dose-Ranging Studies 1 and 2
Study 1 was a dose-ranging monotherapy trial not designed to provide comparative effectiveness data and should not be interpreted as evidence of superiority to adalimumab.
Confirmatory Trials
Study I (NCT00814307) was a 6-month monotherapy trial in which 610 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a DMARD (nonbiologic or biologic) received XELJANZ 5 or 10 mg twice daily or placebo. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, changes in Health Assessment Questionnaire – Disability Index (HAQ-DI), and rates of Disease Activity Score DAS28-4(ESR) less than 2.6.
Study II (NCT00856544) was a 12-month trial in which 792 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to a nonbiologic DMARD received XELJANZ 5 or 10 mg twice daily or placebo added to background DMARD treatment (excluding potent immunosuppressive treatments such as azathioprine or cyclosporine). At the Month 3 visit, nonresponding patients were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. At the end of Month 6, all placebo patients were advanced to their second predetermined treatment in a blinded fashion. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, changes in HAQ-DI at Month 3, and rates of DAS28-4(ESR) less than 2.6 at Month 6.
Study III (NCT00853385) was a 12-month trial in 717 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX. Patients received XELJANZ 5 or 10 mg twice daily, adalimumab 40 mg subcutaneously every other week, or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, HAQ-DI at Month 3, and DAS28-4(ESR) less than 2.6 at Month 6.
Study IV (NCT00847613) was a 2-year trial with a planned analysis at 1 year in which 797 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to MTX received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. Placebo patients were advanced as in Study II. The primary endpoints were the proportion of patients who achieved an ACR20 response at Month 6, mean change from baseline in van der Heijde-modified total Sharp Score (mTSS) at Month 6, HAQ-DI at Month 3, and DAS284( ESR) less than 2.6 at Month 6.
Study V (NCT00960440) was a 6-month trial in which 399 patients with moderate to severe active rheumatoid arthritis who had an inadequate response to at least one approved TNF-inhibiting biologic agent received XELJANZ 5 or 10 mg twice daily or placebo added to background MTX. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a second predetermined treatment of XELJANZ 5 or 10 mg twice daily. The primary endpoints at Month 3 were the proportion of patients who achieved an ACR20 response, HAQ-DI, and DAS28-4(ESR) less than 2.6.
Study VI (NCT01039688) was a 2-year monotherapy trial with a planned analysis at 1 year in which 952 MTX-naïve patients with moderate to severe active rheumatoid arthritis received XELJANZ 5 or 10 mg twice daily or MTX dose-titrated over 8 weeks to 20 mg weekly. The primary endpoints were mean change from baseline in van der Heijde-modified Total Sharp Score (mTSS) at Month 6 and the proportion of patients who achieved an ACR70 response at Month 6.
Clinical Response
The percentages of XELJANZ-treated patients achieving ACR20, ACR50, and ACR70 responses in Studies I, IV, and V are shown in Table 5. Similar results were observed with Studies II and III. In trials I-V, patients treated with either 5 or 10 mg twice daily XELJANZ had higher ACR20, ACR50, and ACR70 response rates versus placebo, with or without background DMARD treatment, at Month 3 and Month 6. Higher ACR20 response rates were observed within 2 weeks compared to placebo. In the 12-month trials, ACR response rates in XELJANZ-treated patients were consistent at 6 and 12 months.
Table 5: Proportion of Patients with an ACR Response
Percent of Patients | |||||||||
Monotherapy in Nonbiologic or Biologic DMARD Inadequate Respondersc | MTX Inadequate Respondersd | TNF Inhibitor Inadequate Responderse | |||||||
Study I | Study IV | Study V | |||||||
Na | PBO | XELJANZ 5 mg Twice Daily | XELJANZ 10 mg Twice Dailyf | PBO + MTX | XELJANZ 5 mg Twice Daily + MTX | XELJANZ 10 mg Twice Daily + MTXf | PBO + MTX | XELJANZ 5 mg Twice Daily + MTX | XELJANZ 10 mg Twice Daily + MTXf |
122 | 243 | 245 | 160 | 321 | 316 | 132 | 133 | 134 | |
ACR20 | |||||||||
Month 3 | 26% | 59% | 65% | 27% | 55% | 67% | 24% | 41% | 48% |
Month 6 | NAb | 69% | 70% | 25% | 50% | 62% | NA | 51% | 54% |
ACR50 | |||||||||
Month 3 | 12% | 31% | 36% | 8% | 29% | 37% | 8% | 26% | 28% |
Month 6 | NA | 42% | 46% | 9% | 32% | 44% | NA | 37% | 30% |
ACR70 | |||||||||
Month 3 | 6% | 15% | 20% | 3% | 11% | 17% | 2% | 14% | 10% |
Month 6 | NA | 22% | 29% | 1% | 14% | 23% | NA | 16% | 16% |
a N is number of randomized and treated patients. b NA Not applicable, as data for placebo treatment is not available beyond 3 months in Studies I and V due to placebo advancement. c Inadequate response to at least one DMARD (biologic or nonbiologic) due to lack of efficacy or toxicity. d Inadequate response to MTX defined as the presence of sufficient residual disease activity to meet the entry criteria. e Inadequate response to a least one TNF inhibitor due to lack of efficacy and/or intolerance. f The recommended dose of XELJANZ is 5 mg twice daily. |
In Study IV, a greater proportion of patients treated with XELJANZ 5 mg or 10 mg twice daily plus MTX achieved a low level of disease activity as measured by a DAS28-4(ESR) less than 2.6 at 6 months compared to those treated with MTX alone (Table 6).
Table 6: Proportion of Patients with DAS28-4(ESR) Less Than 2.6 with Number of Residual Active Joints
Study IV | |||
DAS28-4(ESR) Less Than 2.6 | Placebo + MTX | XELJANZ 5 mg Twice Daily + MTX | XELJANZ 10 mg Twice Daily + MTX* |
160 | 321 | 316 | |
Proportion of responders at Month 6 (n) | 1% (2) | 6% (19) | 13% (42) |
Of responders, proportion with 0 active joints (n) | 50% (1) | 42% (8) | 36% (15) |
Of responders, proportion with 1 active joint (n) | 0 | 5% (1) | 17% (7) |
Of responders, proportion with 2 active joints (n) | 0 | 32% (6) | 7% (3) |
Of responders, proportion with 3 or more active joints (n) | 50% (1) | 21% (4) | 40% (17) |
*The recommended dose of XELJANZ is 5 mg twice daily. |
The results of the components of the ACR response criteria for Study IV are shown in Table 7. Similar results were observed for XELJANZ in Studies I, II, III, V, and VI.
Table 7: Components of ACR Response at Month 3
Study IV | ||||||
XELJANZ 5 mg Twice Daily + MTX | XELJANZ 10 mgd Twice Daily + MTX | Placebo + MTX | ||||
N=321 | N=316 | N=160 | ||||
Component(mean) a | Baseline | Month 3a | Baseline | Month 3a | Baseline | Month 3a |
Number of tender | ||||||
joints | 24 | 13 | 23 | 10 | 23 | 18 |
(0-68) | (14) | (14) | (15) | (12) | (13) | (14) |
Number of swollen | ||||||
joints | 14 | 6 | 14 | 6 | 14 | 10 |
(0-66) | (8) | (8) | (8) | (7) | (9) | (9) |
Painb | 58 | 34 | 58 | 29 | 55 | 47 |
(23) | (23) | (24) | (22) | (24) | (24) | |
Patient global | 58 | 35 | 57 | 29 | 54 | 47 |
assessmentb | (24) | (23) | (23) | (20) | (23) | (24) |
Disability index | 1.41 | 0.99 | 1.40 | 0.84 | 1.32 | 1.19 |
(HAQ-DI)c | (0.68) | (0.65) | (0.66) | (0.64) | (0.67) | (0.68) |
Physician global | 59 | 30 | 58 | 24 | 56 | 43 |
assessmentb | (16) | (19) | (17) | (17) | (18) | (22) |
CRP (mg/L) | 15.3 | 7.1 | 17.1 | 4.4 | 13.7 | 14.6 |
(19.0) | (19.1) | (26.9) | (8.6) | (14.9) | (18.7) | |
aData shown is mean (Standard Deviation) at Month 3. bVisual analog scale: 0 = best, 100 = worst. cHealth Assessment Questionnaire Disability Index: 0 = best, 3 = worst; 20 questions; categories: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. dThe recommended dose of XELJANZ is 5 mg twice daily. |
The percent of ACR20 responders by visit for Study IV is shown in Figure 5. Similar responses were observed for XELJANZ in Studies I, II, III, V, and VI.
Figure 5: Percentage of ACR20 Responders by Visit for Study IV
Radiographic Response
Two studies were conducted to evaluate the effect of XELJANZ on structural joint damage. In Study IV and Study VI, progression of structural joint damage was assessed radiographically and expressed as change from baseline in mTSS and its components, the erosion score and joint space narrowing score, at Months 6 and 12. The proportion of patients with no radiographic progression (mTSS change less than or equal to 0) was also assessed.
In Study IV, XELJANZ 10 mg twice daily plus background MTX reduced the progression of structural damage compared to placebo plus MTX at Month 6. When given at a dose of 5 mg twice daily, XELJANZ exhibited similar effects on mean progression of structural damage (not statistically significant). These results are shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the placebo plus MTX group, 74% of patients experienced no radiographic progression at Month 6 compared to 84% and 79% of patients treated with XELJANZ plus MTX 5 or 10 mg twice daily.
In Study VI, XELJANZ monotherapy inhibited the progression of structural damage compared to MTX at Months 6 and 12 as shown in Table 8. Analyses of erosion and joint space narrowing scores were consistent with the overall results.
In the MTX group, 55% of patients experienced no radiographic progression at Month 6 compared to 73% and 77% of patients treated with XELJANZ 5 or 10 mg twice daily.
Table 8: Radiographic Changes at Months 6 and 12
Study IV | |||||
Placebo N=139 Mean (SD)a | XELJANZ 5 mg Twice Daily N=277 Mean (SD) a | XELJANZ 5 mg Twice Daily Mean Difference from Placebob (CI) | XELJANZ 10 mg Twice Dailyd N=290 Mean (SD) a | XELJANZ 10 mg Twice Daily Mean Difference from Placebob (CI) | |
mTSSc | |||||
Baseline | 33 (42) | 31 (48) | - | 37 (54) | - |
Month 6 | 0.5 (2.0) | 0.1 (1.7) | -0.3 (-0.7, 0.0) | 0.1 (2.0) | -0.4 (-0.8, 0.0) |
Study VI | |||||
MTX N=166 Mean (SD)a | XELJANZ 5 mg Twice Daily N=346 Mean (SD) a | XELJANZ 5 mg Twice Daily Mean Difference from MTXb (CI) | XELJANZ 10 mg Twice Dailyd N=369 Mean (SD) a | XELJANZ 10 mg Twice Daily Mean Difference from MTXb (CI) | |
mTSSc | |||||
Baseline | 17 (29) | 20 (40) | - | 19 (39) | - |
Month 6 | 0.8 (2.7) | 0.2 (2.3) | -0.7 (-1.0, -0.3) | 0.0 (1.2) | -0.8 (-1.2, -0.4) |
Month 12 | 1.3 (3.7) | 0.4 (3.0) | -0.9 (-1.4, -0.4) | 0.0 (1.5) | -1.3 (-1.8, -0.8) |
aSD = Standard Deviation bDifference between least squares means XELJANZ minus placebo or MTX (95% CI = 95% confidence interval) c Month 6 and Month 12 data are mean change from baseline. d The recommended dose of XELJANZ is 5 mg twice daily. |
Physical Function Response
Improvement in physical functioning was measured by the HAQ-DI. Patients receiving XELJANZ 5 and 10 mg twice daily demonstrated greater improvement from baseline in physical functioning compared to placebo at Month 3.
The mean (95% CI) difference from placebo in HAQ-DI improvement from baseline at Month 3 in Study III was -0.22 (-0.35, -0.10) in patients receiving 5 mg XELJANZ twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg XELJANZ twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in XELJANZ-treated patients were consistent at 6 and 12 months.
Other Health-Related Outcomes
General health status was assessed by the Short Form health survey (SF-36). In studies I, IV, and V, patients receiving XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in physical component summary (PCS), mental component summary (MCS) scores and in all 8 domains of the SF-36 at Month 3.
Psoriatic Arthritis
The XELJANZ clinical development program to assess efficacy and safety included 2 multicenter, randomized, double-blind, placebo-controlled confirmatory trials in 816 patients 18 years of age and older (PsA-I and PsA-II). Although other doses have been studied, the recommended dose of XELJANZ is 5 mg twice daily. All patients had active psoriatic arthritis for at least 6 months based upon the Classification Criteria for Psoriatic Arthritis (CASPAR), at least 3 tender/painful joints and at least 3 swollen joints, and active plaque psoriasis. Patients randomized and treated across the 2 clinical trials represented different psoriatic arthritis subtypes at screening, including <5 joints or asymmetric involvement (21%), ≥5 joints involved (90%), distal interphalangeal (DIP) joint involvement (61%), arthritis mutilans (8%), and spondylitis (19%). Patients in these clinical trials had a diagnosis of psoriatic arthritis for a mean (SD) of 7.7 (7.2) years. At baseline, 80% and 53% of patients had enthesitis and dactylitis, respectively. At baseline, all patients were required to receive treatment with a stable dose of a nonbiologic DMARD (79% received methotrexate, 13% received sulfasalazine, 7% received leflunomide, 1% received other nonbiologic DMARDs). In both clinical trials, the primary endpoints were the ACR20 response and the change from baseline in HAQ-DI at Month 3.
Study PsA-I was a 12-month clinical trial in 422 patients who had an inadequate response to a nonbiologic DMARD (67% and 33% were inadequate responders to 1 nonbiologic DMARD and ≥2 nonbiologic DMARDs, respectively) and who were naïve to treatment with a TNF-inhibitor (TNFi). Patients were randomized in a 2:2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, all patients randomized to placebo treatment were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily. Study PsA-I was not designed to demonstrate noninferiority or superiority to adalimumab.
Study PsA-II was a 6-month clinical trial in 394 patients who had an inadequate response to at least 1 approved TNFi (66%, 19%, and 15% were inadequate responders to 1 TNFi, 2 TNFi and ≥3 TNFi, respectively). Patients were randomized in a 2:2:1:1 ratio to receive XELJANZ 5 mg twice daily, XELJANZ 10 mg twice daily, placebo to XELJANZ 5 mg twice daily treatment sequence, or placebo to XELJANZ 10 mg twice daily treatment sequence, respectively; study drug was added to background nonbiologic DMARD treatment. At the Month 3 visit, placebo patients were advanced in a blinded fashion to a predetermined XELJANZ dose of 5 mg or 10 mg twice daily as in Study PsA-I.
Clinical Response
At Month 3, patients treated with either XELJANZ 5 mg or 10 mg twice daily had higher (p≤0.05) response rates versus placebo for ACR20, ACR50, and ACR70 in Study PsA-I and for ACR20 and ACR50 in Study PsA-II; ACR70 response rates were also higher for both XELJANZ 5 mg or 10 mg twice daily versus placebo in Study PsA-II, although the differences versus placebo were not statistically significant (p>0.05) (Tables 9 and 10).
Table 9: Proportion of Patients with an ACR Response in Study PsA-I* [Nonbiologic DMARD Inadequate Responders (TNFi-Naïve)]
Treatment Group | Placebo | XELJANZ 5 mg Twice Daily | XELJANZ 10 mgb Twice Daily | ||
Na | 105 | 107 | 104 | ||
Response Rate | Response Rate | Difference (%) 95% CI from Placebo | Response Rate | ||
Mês 3 | |||||
ACR20 | 33% | 50% | 17.1 (4.1, 30.2) | 61% | 27,2 (14,2, 40,3) |
ACR50 | 10% | 28% | 18,5 (8,3, 28,7) | 40% | 30,9 (19,9, 41,8) |
ACR70 | 5% | 17% | 12.1 (3,9, 20,2) | 14% | 9.7 (1,8, 17,6) |
Os indivíduos com dados ausentes foram tratados como não respondedores. * Os sujeitos receberam um DMARD não biológico concomitante a N é o número de pacientes randomizados e tratados. b A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia. |
Tabela 10: Proporção de pacientes com resposta ao ACR no estudo PsA-II * (respondentes inadequados ao TNFi)
Grupo de Tratamento | Placebo | XELJANZ 5 mg Duas vezes por dia | XELJANZ 10 mgb Duas vezes por dia | ||
Na | 131 | 131 | 132 | ||
Taxa de resposta | Taxa de resposta | Diferença (%) IC 95% da Placebo | Taxa de resposta | Diferença (%) IC 95% da Placebo | |
Mês 3 | |||||
ACR20 | 24% | 50% | 26,0 (14,7, 37,2) | 47% | 23,3 (12,1, 34,5) |
ACR50 | 15% | 30% | 15,3 (5.4, 25.2) | 28% | 13,5 (3,8, 23,3) |
ACR70 | 10% | 17% | 6.9 (-1,3, 15,1) | 14% | 4.5 (-3,4, 12,4) |
Os indivíduos com dados ausentes foram tratados como não respondedores. * Os sujeitos receberam um DMARD não biológico concomitante a N é o número de pacientes randomizados e tratados. b A dose recomendada de XELJANZ é de 5 mg duas vezes ao dia. |
Melhorias da linha de base nos componentes dos critérios de resposta do ACR para ambos os estudos são mostradas na Tabela11.
Tabela 11: Componentes da resposta do ACR na linha de base e no mês 3 nos estudos PsA-I e PsA-II
Respondentes inadequados DMARD não biológicos (TNFi-Naé ̄ve) | Respondentes inadequados TNFi | |||||
Estudo PsA-I * | Estudo PsA-II * | |||||
Grupo de Tratamento | Placebo | XELJANZ 5 mg Duas vezes por dia | XELJANZ 10 mgd Duas vezes por dia | Placebo | XELJANZ 5 mg Duas vezes por dia | XELJANZ 10 mgd Duas vezes por dia |
N na linha de base | 105 | 107 | 104 | 131 | 131 | 132 |
Componente ACRa | ||||||
Número de articulações macias / dolorosas (0-68) | ||||||
Linha de base | 20,6 | 20,5 | 20,3 | 19,8 | 20,5 | 25,5 |
Mês 3 | 14,6 | 12.2 | 9.9 | 15.1 | 11,5 | 14,5 |
Número de juntas inchadas (0-66) | ||||||
Linha de base | 11,5 |