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Tedavide kullanılır:
Kovalenko Svetlana Olegovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 05.04.2022
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Aynı bileşenlere sahip en iyi 20 ilaç:
Romatoid Artrit
- Metotreksata yetersiz yanıt veya hoşgörüsüzlüğü olan orta ila şiddetli aktif romatoid artritli yetişkin hastaların tedavisi için Тофацитиниба / Тофацитиниба цитрат XR (tofacitinib) endikedir. Monoterapi olarak veya metotreksat veya diğer biyolojik olmayan hastalığı modifiye edici antiromatizmal ilaçlar (DMARD'lar) ile kombinasyon halinde kullanılabilir.
- Kullanım Sınırlamaları: Biyolojik DMARD'larla veya azatiyoprin ve siklosporin gibi güçlü immünosüpresanlarla birlikte Тофацитиниба цитрат XR kullanılması önerilmez.
Psoriatik Artrit
- Metotreksat veya diğer hastalığı modifiye edici antiromatizmal ilaçlara (DMARD) yetersiz yanıt veya intoleransı olan yetişkin psoriatik artritli yetişkin hastaların tedavisi için Тофацитиниба цит / Тофацитиниба цитрат XR (tofacitinib) endikedir.
- Kullanım Sınırlamaları: Biyolojik DMARD'larla veya azatiyoprin ve siklosporin gibi güçlü immünosüpresanlarla birlikte Тофацитиниба цитрат XR kullanılması önerilmez.
Romatoid Artrit
- XELJANZ / XELJANZ XR (tofasitinib), metotreksata yetersiz yanıt veya intoleransı olan orta ila şiddetli aktif romatoid artritli yetişkin hastaların tedavisi için endikedir. Monoterapi olarak veya metotreksat veya diğer biyolojik olmayan hastalığı modifiye edici antiromatizmal ilaçlar (DMARD'lar) ile kombinasyon halinde kullanılabilir.
- Kullanım Sınırlamaları: XELJANZ / XELJANZ XR'nin biyolojik DMARD'larla veya azatiyoprin ve siklosporin gibi güçlü immünosüpresanlarla birlikte kullanılması önerilmez.
Psoriatik Artrit
- XELJANZ / XELJANZ XR (tofasitinib), metotreksat veya diğer hastalığı modifiye edici antiromatizmal ilaçlara (DMARD) yetersiz yanıt veya intoleransı olan aktif psoriatik artritli yetişkin hastaların tedavisi için endikedir.
- Kullanım Sınırlamaları: XELJANZ / XELJANZ XR'nin biyolojik DMARD'larla veya azatiyoprin ve siklosporin gibi güçlü immünosüpresanlarla birlikte kullanılması önerilmez.
- Önerilen Тофацитиниба цитрат dozu günde iki kez 5 mg'dır ve önerilen Тофацитиниба цитрат XR dozu günde bir kez 11 mg'dır.
- XR, yiyecekle birlikte veya yemeksiz olarak oral olarak verilir.
- XR tabletleri bütün ve sağlam olarak yutun. Ezmeyin, bölmeyin veya çiğnemeyin.
Тофацитиниба цитрат Tabletlerden Тофацитиниба цитрат XR Tabletlere geçiş
Günde iki kez 5 mg Тофацитиниба цитрат ile tedavi edilen hastalar, 5 mg'lık son dozu takip eden günde bir kez Тофацитиниба цитрат XR 11 mg'a geçirilebilir.
Romatoid Artritte Dozaj
- XR, monoterapi olarak veya metotreksat veya diğer biyolojik olmayan hastalığı modifiye edici antiromatizmal ilaçlarla (DMARD'lar) birlikte kullanılabilir. Önerilen Тофацитиниба цитрат dozu günde iki kez 5 mg'dır ve önerilen Тофацитиниба цитрат XR dozu günde bir kez 11 mg'dır.
Psoriatik Artritte Dozaj
Önerilen Тофацитиниба цитрат dozu günde iki kez 5 mg'dır ve biyolojik olmayan DMARD'larla kombinasyon halinde kullanılır.
Önerilen Тофацитиниба цитрат XR dozu, biyolojik olmayan DMARD'larla kombinasyon halinde günde bir kez 11 mg'dır.
Тофацитиниба цитрат / Тофацитиниба цитрат XR'nin monoterapi olarak etkinliği psoriatik artritte araştırılmamıştır.
Ciddi Enfeksiyonlar ve Sitopeni Nedeniyle Dozaj Değişiklikleri (Aşağıdaki Tablo 1, 2 ve 3'e bakın)
- Mutlak lenfosit sayısı 500 hücre / mm'den az olan hastalarda Тофацитиниба цитрат XR'nin başlatılmaması önerilir3, 1000 hücre / mm'den daha az mutlak nötrofil sayısı (ANC)3 veya hemoglobin seviyeleri 9 g / dL'den az olan .
- Lenfopeni, nötropeni ve aneminin tedavisi için doz kesintisi önerilir.
- Bir hasta enfeksiyon kontrol edilene kadar ciddi bir enfeksiyon geliştirirse Тофацитиниба цитрат / Тофацитиниба цитрат XR kullanmaktan kaçının.
İlaç Etkileşimlerine Bağlı Dozaj Değişiklikleri
- Alan hastalarda:
- Sitokrom P450 3A4'ün (CYP3A4) güçlü inhibitörleri (ör., ketokonazol) veya
- hem CYP3A4'ün orta derecede inhibisyonu hem de güçlü CYP2C19 inhibisyonu ile sonuçlanan bir veya daha fazla eşlik eden ilaç (ör., flukonazol),
önerilen doz günde bir kez 5 mg'dır.
- CYP3A4'ün güçlü indükleyicilerinin birlikte uygulanması (ör., rifampin) ile Тофацитиниба цитрат / Тофацитиниба цитрат XR, Тофацитиниба цитрат / Тофацитиниба цитрат X'e klinik yanıtın kaybolmasına veya azalmasına neden olabilir
- CYP3A4'ün güçlü indükleyicilerinin Тофацитиниба цитрат / Тофацитиниба цитрат XR ile birlikte uygulanması önerilmez.
Böbrek veya Karaciğer yetmezliği olan hastalarda Dozaj Modifikasyonları
- Hastalarda:
- orta veya şiddetli böbrek yetmezliği veya
- orta şiddette karaciğer yetmezliği
önerilen doz günde bir kez 5 mg'dır.
- Şiddetli karaciğer yetmezliği olan hastalarda Тофацитиниба цитрат / Тофацитиниба цитрат XR kullanılması önerilmez.
Tablo 1: Lenfopeni için Doz Ayarlamaları
Düşük Lenfosit Sayısı | |
Laboratuvar Değeri (hücreler / mm3) | Öneri |
Lenfosit sayısı 500'den büyük veya ona eşittir | Dozu koruyun |
Lenfosit sayısı 500'den az (Tekrar test ile onaylanmıştır) | Тофацитиниба цитрат / Тофацитиниба цитрат XR'yi durdurun |
Tablo 2: Nötropeni için Doz Ayarlamaları
Düşük ANC | |
Laboratuvar Değeri (hücreler / mm3) | Öneri |
ANC 1000'den fazla | Dozu koruyun |
ANC 500-1000 | Bu aralıktaki kalıcı düşüşler için ANC 1000'den büyük olana kadar dozlamayı kesin
|
ANC 500'den az (Tekrar test ile onaylanmıştır) | Тофацитиниба цитрат / Тофацитиниба цитрат XR'yi durdurun |
Tablo 3: Anemi için Doz Ayarlamaları
Düşük Hemoglobin Değeri | |
Laboratuvar Değeri (G / dL) | Öneri |
2 g / dL'den az veya ona eşit ve 9.0 g / dL'ye eşit veya daha büyük | Dozu koruyun |
2 g / dL'den fazla azalma veya 8.0 g / dL'den az (Tekrar test ile onaylanmıştır) | Hemoglobin değerleri normalleşene kadar Тофацитиниба цитрат / Тофацитиниба цитрат XR yönetimini kesintiye uğratın |
- Önerilen XELJANZ dozu günde iki kez 5 mg'dır ve önerilen XELJANZ XR dozu günde bir kez 11 mg'dır.
- XELJANZ / XELJANZ XR, yiyecekle birlikte veya yemeksiz olarak oral olarak verilir.
- XELJANZ XR tabletleri tamamen ve sağlam olarak yutun. Ezmeyin, bölmeyin veya çiğnemeyin.
XELJANZ Tabletlerden XELJANZ XR Tabletlere geçiş
Günde iki kez 5 mg XELJANZ ile tedavi edilen hastalar, son XELJANZ 5 mg dozunu takip eden günde bir kez XELJANZ XR 11 mg'a geçirilebilir.
Romatoid Artritte Dozaj
- XELJANZ / XELJANZ XR, monoterapi olarak veya metotreksat veya diğer biyolojik olmayan hastalığı modifiye edici antiromatizmal ilaçlar (DMARD) ile kombinasyon halinde kullanılabilir. Önerilen XELJANZ dozu günde iki kez 5 mg'dır ve önerilen XELJANZ XR dozu günde bir kez 11 mg'dır.
Psoriatik Artritte Dozaj
Önerilen XELJANZ dozu günde iki kez 5 mg'dır, biyolojik olmayan DMARD'larla kombinasyon halinde kullanılır.
Önerilen XELJANZ XR dozu, biyolojik olmayan DMARD'larla kombinasyon halinde günde bir kez 11 mg'dır.
Psoriatik artritte XELJANZ / XELJANZ XR'nin bir monoterapi olarak etkinliği araştırılmamıştır.
Ciddi Enfeksiyonlar ve Sitopeni Nedeniyle Dozaj Değişiklikleri (Aşağıdaki Tablo 1, 2 ve 3'e bakın)
- Mutlak lenfosit sayısı 500 hücre / mm'den az olan hastalarda XELJANZ / XELJANZ XR'nin başlatılmaması önerilir3, 1000 hücre / mm'den daha az mutlak nötrofil sayısı (ANC)3 veya hemoglobin seviyeleri 9 g / dL'den az olan .
- Lenfopeni, nötropeni ve aneminin tedavisi için doz kesintisi önerilir.
- Bir hasta enfeksiyon kontrol edilene kadar ciddi bir enfeksiyon geliştirirse XELJANZ / XELJANZ XR kullanmaktan kaçının.
İlaç Etkileşimlerine Bağlı Dozaj Değişiklikleri
- Alan hastalarda:
- Sitokrom P450 3A4'ün (CYP3A4) güçlü inhibitörleri (ör., ketokonazol) veya
- hem CYP3A4'ün orta derecede inhibisyonu hem de güçlü CYP2C19 inhibisyonu ile sonuçlanan bir veya daha fazla eşlik eden ilaç (ör., flukonazol),
önerilen doz günde bir kez 5 mg XELJANZ'dır.
- CYP3A4'ün güçlü indükleyicilerinin birlikte uygulanması (ör., rifampin) ile XELJANZ / XELJANZ XR, XELJANZ / XELJANZ XR'ye klinik yanıtın kaybolmasına veya azalmasına neden olabilir
- CYP3A4'ün güçlü indükleyicilerinin XELJANZ / XELJANZ XR ile birlikte uygulanması önerilmez.
Böbrek veya Karaciğer yetmezliği olan hastalarda Dozaj Modifikasyonları
- Hastalarda:
- orta veya şiddetli böbrek yetmezliği veya
- orta şiddette karaciğer yetmezliği
önerilen doz günde bir kez 5 mg XELJANZ'dır.
- Şiddetli karaciğer yetmezliği olan hastalarda XELJANZ / XELJANZ XR kullanılması önerilmez.
Tablo 1: Lenfopeni için Doz Ayarlamaları
Düşük Lenfosit Sayısı | |
Laboratuvar Değeri (hücreler / mm3) | Öneri |
Lenfosit sayısı 500'den büyük veya ona eşittir | Dozu koruyun |
Lenfosit sayısı 500'den az (Tekrar test ile onaylanmıştır) | XELJANZ / XELJANZ XR'yi durdurun |
Tablo 2: Nötropeni için Doz Ayarlamaları
Düşük ANC | |
Laboratuvar Değeri (hücreler / mm3) | Öneri |
ANC 1000'den fazla | Dozu koruyun |
ANC 500-1000 | Bu aralıktaki kalıcı düşüşler için ANC 1000'den büyük olana kadar dozlamayı kesin
|
ANC 500'den az (Tekrar test ile onaylanmıştır) | XELJANZ / XELJANZ XR'yi durdurun |
Tablo 3: Anemi için Doz Ayarlamaları
Düşük Hemoglobin Değeri | |
Laboratuvar Değeri (G / dL) | Öneri |
2 g / dL'den az veya ona eşit ve 9.0 g / dL'ye eşit veya daha büyük | Dozu koruyun |
2 g / dL'den fazla azalma veya 8.0 g / dL'den az (Tekrar test ile onaylanmıştır) | Hemoglobin değerleri normalleşene kadar XELJANZ / XELJANZ XR uygulamasını kesin |
Yok
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 Тофацитиниба цитрат. The most common serious infections reported with Тофацитиниба цитрат 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 Тофацитиниба цитрат. 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR. Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат /Тофацитиниба цитрат XR.
Anti-tuberculosis therapy should also be considered prior to administration of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR.
Viral Reactivation
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with Тофацитиниба цитрат. The impact of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR. The risk of herpes zoster is increased in patients treated with Тофацитиниба цитрат/Тофацитиниба цитрат XR and appears to be higher in patients treated with Тофацитиниба цитрат in Japan and Korea.
Malignancy And Lymphoproliferative Disorders
Consider the risks and benefits of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR in patients who develop a malignancy. Malignancies were observed in clinical studies of Тофацитиниба цитрат.
In the seven controlled rheumatoid arthritis clinical studies, 11 solid cancers and one lymphoma were diagnosed in 3328 patients receiving Тофацитиниба цитрат 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 Тофацитиниба цитрат.
In the 2 controlled Phase 3 clinical trials in patients with active psoriatic arthritis, there were 3 malignancies (excluding NMSC) in 474 patients receiving Тофацитиниба цитрат 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 Тофацитиниба цитрат.
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 Тофацитиниба цитрат (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 Тофацитиниба цитрат. 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 Тофацитиниба цитрат, although the role of JAK inhibition in these events is not known.
Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR is not recommended.
Monitor lymphocyte counts at baseline and every 3 months thereafter. For recommended modifications based on lymphocyte counts.
Neutropenia
Treatment with Тофацитиниба цитрат was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.
Avoid initiation of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR treatment in patients with a low hemoglobin level (i.e. less than 9 g/dL). Treatment with Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR should be interrupted until this diagnosis has been excluded.
Lipid Elevations
Treatment with Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR therapy.
General
Specific To Тофацитиниба цитрат XR
As with any other non-deformable material, caution should be used when administering Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR.
Serious Infection
Inform patients that Тофацитиниба цитрат/Тофацитиниба цитрат XR may lower the ability of their immune system to fight infections. Advise patients not to start taking Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат.
Malignancies And Lymphoproliferative Disorders
Inform patients that Тофацитиниба цитрат/Тофацитиниба цитрат XR may increase their risk of certain cancers, and that lymphoma and other cancers have been observed in patients taking Тофацитиниба цитрат. Instruct patients to inform their healthcare provider if they have ever had any type of cancer.
Important Information On Laboratory Abnormalities
Inform patients that Тофацитиниба цитрат/Тофацитиниба цитрат XR may affect certain lab test results, and that blood tests are required before and during Тофацитиниба цитрат/Тофацитиниба цитрат XR treatment.
Pregnancy
Inform patients that Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR. Inform patients that Pfizer has a registry for pregnant women who have taken Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR and for at least 4 weeks after the last dose. Inform patients that they should not breastfeed while taking Тофацитиниба цитрат/Тофацитиниба цитрат XR.
Residual Tablet Shell
Patients receiving Тофацитиниба цитрат 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 Тофацитиниба цитрат and Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR during pregnancy. Patients should be encouraged to enroll in the Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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, Тофацитиниба цитрат/Тофацитиниба цитрат 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 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR. A decision should be made whether to discontinue breastfeeding or to discontinue Тофацитиниба цитрат/Тофацитиниба цитрат XR.
Data
Human Data
There are no adequate and well-controlled studies of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR.
Infertility
Females
Based on findings in rats, treatment with Тофацитиниба цитрат/Тофацитиниба цитрат XR may result in reduced fertility in females of reproductive potential.
Pediatric Use
The safety and effectiveness of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат-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
Тофацитиниба цитрат-treated patients with moderate hepatic impairment had greater tofacitinib levels than Тофацитиниба цитрат-treated patients with normal hepatic function. Higher blood levels may increase the risk of some adverse reactions, therefore, the recommended dose is Тофацитиниба цитрат 5 mg once daily in patients with moderate hepatic impairment. Тофацитиниба цитрат/Тофацитиниба цитрат XR has not been studied in patients with severe hepatic impairment; therefore, use of Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат XR have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
Renal Impairment
Тофацитиниба цитрат-treated patients with moderate and severe renal impairment had greater tofacitinib blood levels than Тофацитиниба цитрат-treated patients with normal renal function; therefore, the recommended dose is Тофацитиниба цитрат 5 mg once daily in patients with moderate and severe renal impairment. In clinical trials, Тофацитиниба цитрат/Тофацитиниба цитрат 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.
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.
Based on animal studies, XELJANZ/XELJANZ 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
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.
Klinik Araştırma Deneyimi
Klinik çalışmalar çok çeşitli koşullar altında yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve klinik uygulamada daha geniş bir hasta popülasyonunda gözlenen oranları tahmin etmeyebilir.
Romatoid Artrit
Aşağıdaki bölümlerde açıklanan klinik çalışmalar Тофацитиниба цитрат kullanılarak yapılmıştır. Diğer Тофацитиниба цитрат dozları incelenmiş olsa da, önerilen Тофацитиниба цитрат dozu günde iki kez 5 mg'dır.
Тофацитиниба цитрат XR için önerilen doz günde bir kez 11 mg'dır.
Aşağıdaki veriler iki Faz 2 ve beş Faz 3 çift kör, kontrollü, çok merkezli çalışmayı içermektedir. Bu denemelerde, hastalar günde iki kez 5 mg Тофацитиниба цитрат dozlarına randomize edildi (292 hasta) ve günde iki kez 10 mg (306 hasta) monoterapi, Günde iki kez 5 mg Тофацитиниба цитрат (1044 hasta) ve günde iki kez 10 mg (1043 hasta) DMARD'larla birlikte (metotreksat dahil) ve plasebo (809 hasta). Yedi protokolün tümü, plasebo alan hastaların 3. ayda veya 6. ayda hasta yanıtı (kontrolsüz hastalık aktivitesine dayanarak) veya tasarımla tedavi görmesi için hükümler içeriyordu, böylece advers olaylar her zaman açık bir şekilde belirli bir tedaviye atfedilemez. . Bu nedenle takip eden bazı analizler, belirli bir aralığın hem plasebo hem de Тофацитиниба цитрат grubuna tasarım veya hasta yanıtı ile tedaviyi değiştiren hastaları içerir. Plasebo ve Тофацитиниба цитрат arasındaki karşılaştırmalar, maruziyetin ilk 3 ayına dayanıyordu ve günde iki kez Тофацитиниба цитрат 5 mg ve günde iki kez Тофацитиниба цитрат arasındaki karşılaştırmalar ilk 12 aya dayanıyordu.
Uzun süreli güvenlik popülasyonu, çift kör, kontrollü bir çalışmaya (önceki geliştirme aşaması çalışmaları dahil) katılan ve daha sonra iki uzun süreli güvenlik çalışmasından birine katılan tüm hastaları içerir. Uzun süreli güvenlik çalışmalarının tasarımı, klinik karara göre Тофацитиниба цитрат dozlarının değiştirilmesine izin verdi. Bu, uzun vadeli güvenlik verilerinin doza göre yorumlanmasını sınırlar.
En yaygın ciddi advers reaksiyonlar ciddi enfeksiyonlardı.
Çift kör, plasebo kontrollü çalışmalarda 0 ila 3 aylık maruziyet sırasında herhangi bir advers reaksiyon nedeniyle tedaviyi bırakan hastaların oranı Тофацитиниба цитрат alan hastalar için% 4 ve plasebo ile tedavi edilen hastalar için% 3'tür.
Genel Enfeksiyonlar
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, genel enfeksiyon sıklığı günde iki kez 5 mg'da% 20 ve% 22 ve günde iki kez 10 mg ve plasebo grubunda% 18 idi.
Тофацитиниба цитрат ile en sık bildirilen enfeksiyonlar üst solunum yolu enfeksiyonları, nazofarenjit ve idrar yolu enfeksiyonlarıdır (hastaların sırasıyla% 4,% 3 ve% 2).
Ciddi Enfeksiyonlar
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan 1 hastada (100 hasta yılı başına 0.5 olay) ve Тофацитиниба 5 alan 11 hastada (100 hasta yılı başına 1.7 olay) ciddi enfeksiyonlar bildirilmiştir. mg veya günde iki kez 10 mg. Tedavi grupları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı), günde iki kez kombine 5 mg ve günde iki kez 10 mg için 100 hasta yılı başına 1.1 (-0.4, 2.5) olaydı.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 34 hastada ciddi enfeksiyonlar bildirilmiştir (100 hasta yılı başına 2.7 olay) günde iki kez 5 mg Тофацитиниба цитрат ve 33 hasta alan kişiler (100 hasta yılı başına 2.7 olay) günde iki kez 10 mg Тофацитиниба цитрат alan. Тофацитиниба цитрат dozları (ve karşılık gelen% 95 güven aralığı) arasındaki oran farkı, günde iki kez 10 mg için 100 hasta yılı başına -0.1 (-1.3, 1.2) olaydı. Günde iki kez Тофацитинцба цитрабит eksi 5 mg.
En yaygın ciddi enfeksiyonlar arasında pnömoni, selülit, herpes zoster ve idrar yolu enfeksiyonu vardı.
Tüberküloz
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan hastalarda, günde iki kez 5 mg Тофацитиниба цитрат veya günde iki kez 10 mg Тофацитиниба цитрат tüberküloz bildirilmemiştir.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, günde iki kez 5 mg Тофацитиниба цитрат alan 0 hastada ve günde iki kez 10 mg alan 6 hastada (100 hasta yılı başına 0.5 olay) tüberküloz bildirilmiştir. Тофацитиниба цитрат. Тофацитиниба цитрат dozları (ve karşılık gelen% 95 güven aralığı) arasındaki oran farkı, günde iki kez 10 mg için 100 hasta yılı başına 0.5 (0.1, 0.9) olaydı. Günde iki kez Тофацитиниба цитрат eksi 5 mg Тофаба.
Yaygın tüberküloz vakaları da bildirilmiştir. Tüberküloz tanısından önce medyan Тофацитиниба цитрат maruziyeti 10 aydı (152 ila 960 gün arasında).
Fırsatçı Enfeksiyonlar (Tüberküloz Hariç)
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan hastalarda, günde iki kez 5 mg Тофацитиниба цитрат veya günde iki kez 10 mg Тофацитиниба цитрат fırsatçı enfeksiyonlar bildirilmemiştir.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 4 hastada fırsatçı enfeksiyonlar bildirilmiştir (100 hasta yılı başına 0.3 olay) günde iki kez 5 mg Тофацитиниба цитрат ve 4 hasta alan kişiler (100 hasta yılı başına 0.3 olay) günde iki kez 10 mg Тофацитиниба цитрат alan. Тофацитиниба цитрат dozları (ve karşılık gelen% 95 güven aralığı) arasındaki oran farkı, günde iki kez 10 mg için 100 hasta yılı başına 0 (-0.5, 0.5) olaydı. Günde iki kez Тофацитинибацитрат eksi 5 mg Тофаци.
Fırsatçı bir enfeksiyon tanısından önce medyan Тофацитиниба цитрат maruziyeti 8 aydı (41 ila 698 gün arasında).
Malignancy
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan 0 hastada ve günde iki kez Тофацитиниба цитрат 5 mg veya 10 mg alan 2 hastada (100 hasta yılı başına 0.3 olay) NMSC hariç maligniteler bildirilmiştir. Tedavi grupları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı), kombine 5 mg için 100 hasta yılı başına 0.3 (-0.1, 0.7) olay ve günde iki kez Тофацитиниба цитрат grubu eksi plasebo idi.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 5 hastada NMSC hariç maligniteler bildirilmiştir (100 hasta yılı başına 0.4 olay) günde iki kez 5 mg Тофацитиниба цитрат ve 7 hasta alan kişiler (100 hasta yılı başına 0.6 olay) günde iki kez 10 mg Тофацитиниба цитрат alan. Тофацитиниба цитрат dozları (ve karşılık gelen% 95 güven aralığı) arasındaki oran farkı, günde iki kez 10 mg için 100 hasta yılı başına 0.2 (-0.4, 0.7) olaydı. Günde iki kez Тофацитинцба цитрат 5 mg Тоф. Bu malignitelerden biri, günde iki kez Тофацитиниба цитрат ile tedavi edilen bir hastada 0 ila 12 aylık dönemde meydana gelen bir lenfoma vakasıydı.
Uzun süreli uzatma sırasında gözlenen maligniteler dahil olmak üzere en yaygın malignite türleri akciğer ve meme kanseri, ardından mide, kolorektal, böbrek hücresi, prostat kanseri, lenfoma ve malign melanom idi.
Laboratuvar Anormallikleri
Lenfopeni
Kontrollü klinik çalışmalarda, mutlak lenfosit sayısında 500 hücre / mm'nin altında teyit edilen düşüşler3 maruziyetin ilk 3 ayında günde iki kez 5 mg ve günde iki kez 10 mg için hastaların% 0.04'ünde meydana geldi.
Onaylanmış lenfosit sayısı 500 hücre / mm'den azdır3 tedavi edilen ve ciddi enfeksiyon insidansında artış ile ilişkilendirilmiştir.
Nötropeni
Kontrollü klinik çalışmalarda, ANC'de 1000 hücre / mm'nin altında doğrulanmış düşüşler3 maruziyetin ilk 3 ayında günde iki kez 5 mg ve günde iki kez 10 mg için hastaların% 0.07'sinde meydana geldi.
ANC'de 500 hücre / mm'nin altında doğrulanmış bir azalma olmamıştır3 herhangi bir tedavi grubunda gözlenir.
Nötropeni ile ciddi enfeksiyonların ortaya çıkması arasında açık bir ilişki yoktu.
Uzun süreli güvenlik popülasyonunda, ANC'de teyit edilen düşüşlerin paterni ve insidansı, kontrollü klinik çalışmalarda görülenlerle tutarlı kalmıştır.
Karaciğer Enzim Yükseklikleri
Тофацитиниба цитрат ile tedavi edilen hastalarda karaciğer enzimlerinde normalin üst sınırının (3x ULN) 3 katından daha fazla doğrulanmış artışlar gözlenmiştir. Karaciğer enzimi yükselmesi yaşayan hastalarda, eşlik eden DMARD dozunda azalma, Тофацитиниба цитрат'in kesilmesi veya Тофацитиниба цитрат dozunda azalma gibi tedavi rejiminin modifikasyonu, karaciğer enzimlerinin azalmasına veya normalleşmesine neden oldu.
Kontrollü monoterapi çalışmalarında (0-3 ay), plasebo ile günde iki kez Тофацитиниба цитрат 5 mg ve 10 mg arasında ALT veya AST yükselme insidansında herhangi bir fark gözlenmemiştir.
Kontrollü arka plan DMARD çalışmalarında (0-3 ay), günde iki kez plasebo, 5 mg ve 10 mg alan hastaların% 1.0,% 1.3 ve% 1.2'sinde 3x ULN'den daha yüksek ALT yükselmeleri gözlenmiştir. Bu çalışmalarda, günde iki kez plasebo, 5 mg ve 10 mg alan hastaların% 0.6,% 0.5 ve% 0.4'ünde 3x ULN'den daha yüksek AST yükselmeleri gözlenmiştir.
Yaklaşık 2.5 ay boyunca günde iki kez 10 mg Тофацитиниба цитрат ile tedavi edilen bir hastada ilaca bağlı karaciğer hasarı vakası bildirilmiştir. Hastada 3x ULN'den daha yüksek AST ve ALT semptomatik yükselmeleri ve hastaneye yatış ve karaciğer biyopsisi gerektiren 2x ULN'den daha yüksek bilirubin yükselmeleri gelişti.
Lipid Yükseklikleri
Kontrollü klinik çalışmalarda, bir aylık maruziyette lipit parametrelerinde (toplam kolesterol, LDL kolesterol, HDL kolesterol, trigliseritler) doza bağlı yükselmeler gözlendi ve daha sonra stabil kaldı. Kontrollü klinik çalışmalarda maruziyetin ilk 3 ayında lipit parametrelerindeki değişiklikler aşağıda özetlenmiştir:
- Ortalama LDL kolesterol, günde iki kez Тофацитиниба цитрат 5 mg kolunda% 15 ve günde iki kez Тофацитиниба цитрат 10 mg kolunda% 19 arttı.
- Ortalama HDL kolesterol, günde iki kez Тофацитиниба цитрат 5 mg kolunda% 10 ve günde iki kez Тофацитиниба цитрат 10 mg kolunda% 12 arttı.
- Ortalama LDL / HDL oranları Тофацитиниба цитрат ile tedavi edilen hastalarda esasen değişmemiştir.
Kontrollü bir klinik çalışmada, statin tedavisine yanıt olarak LDL kolesterol ve ApoB'deki yükselmeler ön tedavi seviyelerine düşmüştür.
Uzun süreli güvenlik popülasyonunda, lipit parametrelerindeki yükselmeler, kontrollü klinik çalışmalarda görülenlerle tutarlı kalmıştır.
Serum Kreatinin Yükseklikleri
Kontrollü klinik çalışmalarda, Тофацитиниба цитрат tedavisi ile serum kreatinininde doza bağlı yükselmeler gözlenmiştir. 12 aylık havuzlanmış güvenlik analizinde serum kreatinininde ortalama artış <0.1 mg / dL idi; ancak uzun vadeli uzatmalarda artan maruz kalma süresi ile, kreatininde% 50'den fazla bir artış için protokolde belirtilen kesilme kriteri nedeniyle hastaların% 2'sine kadar Тофацитиниба цитрат tedavisinden kesildi. Gözlenen serum kreatinin yükselmelerinin klinik önemi bilinmemektedir.
Diğer Olumsuz Reaksiyonlar
Günde iki kez 5 mg veya günde iki kez 10 mg olan hastaların% 2 veya daha fazlasında meydana gelen advers reaksiyonlar Тофацитиниба цитрат ve DMARD olan veya olmayan plasebo hastalarında gözlemlenenden en az% 1 daha fazla Tablo 4'te özetlenmiştir.
Tablo 4: 5 veya 10 mg'da Hastaların En Az% 2 veya Daha Fazlasında meydana gelen Olumsuz Reaksiyonlar DMARD'lı veya DMARD'sız (0-3 ay) ve Plasebo'daki Romatoid Artrit Hastalarında Gözlemlenenden En Az% 1 Daha Fazlası Тофацитиниба цитрат
Тофацитиниба цитрат Günde 5 mg İki kez | Тофацитиниба цитрат 10 mg Günde İki Kez * | Plasebo | |
Tercih Edilen Terim | N = 1336 (%) | N = 1349 (%) | N = 809 (%) |
İshal | 4.0 | 2.9 | 2.3 |
Nazofarenjit | 3.8 | 2.8 | 2.8 |
Üst solunum yolu enfeksiyonu | 4.5 | 3.8 | 3.3 |
Baş ağrısı | 4.3 | 3.4 | 2.1 |
Hipertansiyon | 1.6 | 2.3 | 1.1 |
N, yedi klinik çalışmadan randomize ve tedavi edilen hastaları yansıtır * Önerilen Тофацитиниба цитрат dozu günde iki kez 5 mg'dır. |
Kontrollü ve açık etiketli uzatma çalışmalarında meydana gelen diğer advers reaksiyonlar şunları içermektedir:
Kan ve lenfatik sistem bozuklukları: Anemi
Enfeksiyonlar ve enfestasyonlar : Divertikülit
Metabolizma ve beslenme bozuklukları: Dehidrasyon
Psikiyatrik bozukluklar: Uykusuzluk
Sinir sistemi bozuklukları: Parestezi
Solunum, göğüs bozuklukları ve mediastinal hastalıklar: Dispne, öksürük, sinüs tıkanıklığı, interstisyel akciğer hastalığı (bazıları ölümcül)
Gastrointestinal hastalıklar: Karın ağrısı, hazımsızlık, kusma, gastrit, bulantı
Hepatobiliyer hastalıklar: Karaciğer steatozu
Deri ve deri altı doku hastalıkları: Döküntü, eritem, kaşıntı
Kas-iskelet sistemi, bağ dokusu ve kemik bozuklukları: Kas-iskelet ağrısı, artralji, tendinit, eklem şişmesi
İyi huylu, kötü huylu ve belirtilmemiş neoplazmalar (kistler ve polipler dahil): Melanom olmayan cilt kanserleri
Genel bozukluklar ve uygulama bölgesine ilişkin hastalıklar: Pireksi, yorgunluk, periferik ödem
Metotreksat-Naïve Hastalarında Klinik Deneyim
Çalışma VI, metotreksat naif hastalarda aktif kontrollü bir klinik çalışmadır. Bu hastalarda güvenlik deneyimi Çalışmalar I-V ile tutarlıydı
Psoriatik Artrit
Aktif psoriatik artritli (PsA) hastalarda yapılan 2 çift kör Faz 3 klinik çalışmada günde iki kez 5 mg ve günde iki kez 10 mg Тофацитиниба цитрат incelendi.
Çalışma PsA-I (NCT01877668) 12 aylık bir süreye sahipti ve biyolojik olmayan bir DMARD'a yetersiz yanıtı olan ve bir TNF inhibitörü (TNFi) ile tedaviye naif olan hastaları kaydetti. Çalışma PsA-I, 3 aylık plasebo kontrollü bir süre içerdi ve ayrıca 12 ay boyunca her 2 haftada bir subkütan olarak 40 mg adalimumab içeriyordu.
Çalışma PsA-II (NCT01882439) 6 aylık bir süreye sahipti ve en az bir onaylı TNFi'ye yetersiz yanıt veren hastaları kaydetti. Bu klinik çalışma 3 aylık plasebo kontrollü bir dönemi içermektedir.
Bu kombine Faz 3 klinik çalışmalarında 238 hasta randomize edildi ve günde iki kez 5 mg Тофацитиниба цитрат ile tedavi edildi ve 236 hasta randomize edildi ve günde iki kez Тофацитиниба цитрат 10 mg ile tedavi edildi. Klinik çalışmalardaki tüm hastaların stabil bir biyolojik olmayan DMARD dozu ile tedavi almaları gerekiyordu [çoğunluk (% 79) metotreksat aldı]. Тофацитиниба цитрат (474 hasta) ile randomize edilen ve tedavi edilen çalışma popülasyonu, 65 yaş ve üstü 45 (% 9.5) hasta ve başlangıçta diyabetli 66 (% 13.9) hastayı içermiştir.
Тофацитиниба цитрат ile tedavi edilen aktif psoriatik artritli hastalarda gözlenen güvenlik profili, romatoid artrit hastalarında gözlenen güvenlik profili ile tutarlıydı.
Klinik Araştırma Deneyimi
Klinik çalışmalar çok çeşitli koşullar altında yapıldığından, bir ilacın klinik çalışmalarında gözlenen advers reaksiyon oranları, başka bir ilacın klinik çalışmalarındaki oranlarla doğrudan karşılaştırılamaz ve klinik uygulamada daha geniş bir hasta popülasyonunda gözlenen oranları tahmin etmeyebilir.
Romatoid Artrit
Aşağıdaki bölümlerde açıklanan klinik çalışmalar XELJANZ kullanılarak yapılmıştır. Diğer XELJANZ dozları çalışılmış olmasına rağmen, önerilen XELJANZ dozu günde iki kez 5 mg'dır.
XELJANZ XR için önerilen doz günde bir kez 11 mg'dır.
Aşağıdaki veriler iki Faz 2 ve beş Faz 3 çift kör, kontrollü, çok merkezli çalışmayı içermektedir. Bu çalışmalarda, hastalar günde iki kez 5 mg XELJANZ (292 hasta) ve günde iki kez 10 mg (306 hasta) monoterapi, günde iki kez XELJANZ 5 mg (1044 hasta) ve günde iki kez 10 mg (1043 hasta) dozlarına randomize edildi. DMARD'lar (metotreksat dahil) ve plasebo (809 hasta ile. Yedi protokolün tümü, plasebo alan hastaların 3. ayda veya 6. ayda XELJANZ ile hasta yanıtı (kontrolsüz hastalık aktivitesine dayanarak) veya tasarım yoluyla tedavi görmesi için hükümler içermiştir, böylece advers olaylar her zaman belirli bir tedaviye açık bir şekilde atfedilemez. Bu nedenle, takip eden bazı analizler, belirli bir aralığın hem plasebo hem de XELJANZ grubunda tedaviyi tasarım veya plasebodan XELJANZ'a hasta yanıtı ile değiştiren hastaları içerir. Plasebo ve XELJANZ arasındaki karşılaştırmalar maruziyetin ilk 3 ayına dayanıyordu ve günde iki kez XELJANZ 5 mg ile günde iki kez XELJANZ 10 mg arasındaki karşılaştırmalar ilk 12 aylık maruziyete dayanıyordu.
Uzun süreli güvenlik popülasyonu, çift kör, kontrollü bir çalışmaya (önceki geliştirme aşaması çalışmaları dahil) katılan ve daha sonra iki uzun süreli güvenlik çalışmasından birine katılan tüm hastaları içerir. Uzun süreli güvenlik çalışmalarının tasarımı, klinik karara göre XELJANZ dozlarının değiştirilmesine izin verdi. Bu, uzun vadeli güvenlik verilerinin doza göre yorumlanmasını sınırlar.
En yaygın ciddi advers reaksiyonlar ciddi enfeksiyonlardı.
Çift kör, plasebo kontrollü çalışmalarda 0 ila 3 aylık maruziyet sırasında herhangi bir advers reaksiyon nedeniyle tedaviyi bırakan hastaların oranı XELJANZ alan hastalar için% 4 ve plasebo ile tedavi edilen hastalar için% 3'tür.
Genel Enfeksiyonlar
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, genel enfeksiyon sıklığı günde iki kez 5 mg'da% 20 ve% 22 ve günde iki kez 10 mg ve plasebo grubunda% 18 idi.
XELJANZ ile en sık bildirilen enfeksiyonlar üst solunum yolu enfeksiyonları, nazofarenjit ve idrar yolu enfeksiyonlarıdır (hastaların sırasıyla% 4,% 3 ve% 2'si).
Ciddi Enfeksiyonlar
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan 1 hastada (100 hasta yılı başına 0.5 olay) ve XELJANZ 5 mg alan 11 hastada (100 hasta yılı başına 1.7 olay) ciddi enfeksiyonlar bildirilmiştir. veya günde iki kez 10 mg. Tedavi grupları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı), günde iki kez kombine 5 mg ve günde iki kez 10 mg XELJANZ grubu eksi plasebo için 100 hasta yılı başına 1.1 (-0.4, 2.5) olaydı.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 34 hastada ciddi enfeksiyonlar bildirilmiştir (100 hasta yılı başına 2.7 olay) günde iki kez 5 mg XELJANZ ve 33 hasta aldı (100 hasta yılı başına 2.7 olay) günde iki kez 10 mg XELJANZ aldı. XELJANZ dozları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı) -0.1 idi (-1.3, 1.2) günde iki kez 10 mg XELJANZ eksi günde iki kez 5 mg XELJANZ için 100 hasta yılı başına olaylar .
En yaygın ciddi enfeksiyonlar arasında pnömoni, selülit, herpes zoster ve idrar yolu enfeksiyonu vardı.
Tüberküloz
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan hastalarda, günde iki kez 5 mg XELJANZ veya günde iki kez 10 mg XELJANZ olan hastalarda tüberküloz bildirilmemiştir
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, günde iki kez 5 mg XELJANZ alan 0 hastada ve 6 hastada tüberküloz bildirilmiştir (100 hasta yılı başına 0.5 olay) günde iki kez 10 mg XELJANZ aldı. XELJANZ dozları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı) 0.5 idi (0.1, 0.9) günde iki kez 10 mg XELJANZ eksi günde iki kez 5 mg XELJANZ için 100 hasta yılı başına olaylar .
Yaygın tüberküloz vakaları da bildirilmiştir. Tüberküloz tanısından önce medyan XELJANZ maruziyeti 10 aydı (152 ila 960 gün arasında).
Fırsatçı Enfeksiyonlar (Tüberküloz Hariç)
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan hastalarda, günde iki kez 5 mg XELJANZ veya günde iki kez 10 mg XELJANZ alan hastalarda fırsatçı enfeksiyonlar bildirilmemiştir
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 4 hastada fırsatçı enfeksiyonlar bildirilmiştir (100 hasta yılı başına 0.3 olay) günde iki kez 5 mg XELJANZ ve 4 hasta aldı (100 hasta yılı başına 0.3 olay) günde iki kez 10 mg XELJANZ aldı. XELJANZ dozları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı) 0 idi (-0.5, 0.5) günde iki kez 10 mg XELJANZ eksi günde iki kez 5 mg XELJANZ için 100 hasta yılı başına olaylar .
Fırsatçı bir enfeksiyon tanısı öncesinde medyan XELJANZ maruziyeti 8 aydı (41 ila 698 gün arasında).
Malignancy
Yedi kontrollü çalışmada, 0 ila 3 aylık maruziyet sırasında, plasebo alan 0 hastada ve günde iki kez XELJANZ 5 mg veya 10 mg alan 2 hastada (100 hasta yılı başına 0.3 olay) NMSC hariç maligniteler bildirilmiştir. Tedavi grupları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı), kombine 5 mg için 100 hasta yılı başına 0.3 (-0.1, 0.7) olay ve günde iki kez XELJANZ grubu eksi plasebo idi.
Yedi kontrollü çalışmada, 0 ila 12 aylık maruziyet sırasında, 5 hastada NMSC hariç maligniteler bildirilmiştir (100 hasta yılı başına 0.4 olay) günde iki kez 5 mg XELJANZ ve 7 hasta aldı (100 hasta yılı başına 0.6 olay) günde iki kez 10 mg XELJANZ aldı. XELJANZ dozları arasındaki oran farkı (ve karşılık gelen% 95 güven aralığı) 0.2 idi (-0.4, 0.7) günde iki kez 10 mg için 100 hasta yılı başına olaylar XELJANZ eksi günde iki kez 5 mg XELJANZ. Bu malignitelerden biri, günde iki kez 10 mg XELJANZ ile tedavi edilen bir hastada 0 ila 12 aylık dönemde meydana gelen bir lenfoma vakasıydı.
Uzun süreli uzatma sırasında gözlenen maligniteler dahil olmak üzere en yaygın malignite türleri akciğer ve meme kanseri, ardından mide, kolorektal, böbrek hücresi, prostat kanseri, lenfoma ve malign melanom idi.
Laboratuvar Anormallikleri
Lenfopeni
Kontrollü klinik çalışmalarda, mutlak lenfosit sayısında 500 hücre / mm'nin altında teyit edilen düşüşler3 maruziyetin ilk 3 ayında günde iki kez 5 mg ve günde iki kez 10 mg XELJANZ grupları için hastaların% 0.04'ünde meydana geldi.
Onaylanmış lenfosit sayısı 500 hücre / mm'den azdır3 tedavi edilen ve ciddi enfeksiyon insidansında artış ile ilişkilendirilmiştir.
Nötropeni
Kontrollü klinik çalışmalarda, ANC'de 1000 hücre / mm'nin altında doğrulanmış düşüşler3 maruziyetin ilk 3 ayında günde iki kez 5 mg ve günde iki kez 10 mg XELJANZ grupları için hastaların% 0.07'sinde meydana geldi.
ANC'de 500 hücre / mm'nin altında doğrulanmış bir azalma olmamıştır3 herhangi bir tedavi grubunda gözlenir.
Nötropeni ile ciddi enfeksiyonların ortaya çıkması arasında açık bir ilişki yoktu.
Uzun süreli güvenlik popülasyonunda, ANC'de teyit edilen düşüşlerin paterni ve insidansı, kontrollü klinik çalışmalarda görülenlerle tutarlı kalmıştır.
Karaciğer Enzim Yükseklikleri
Karaciğer enzimlerinde normalin üst sınırının 3 katından daha fazla teyit edilen artışlar (3x ULN) XELJANZ ile tedavi edilen hastalarda gözlendi. Karaciğer enzimi yükselmesi yaşayan hastalarda, tedavi rejiminin değiştirilmesi, eşlik eden DMARD dozunda azalma gibi, XELJANZ'ın kesintiye uğraması, veya XELJANZ dozunda azalma, karaciğer enzimlerinin azalması veya normalleşmesi ile sonuçlandı.
Kontrollü monoterapi çalışmalarında (0-3 ay), plasebo ile XELJANZ 5 mg ve günde iki kez 10 mg arasında ALT veya AST yükselme insidansında herhangi bir fark gözlenmemiştir.
Kontrollü arka plan DMARD çalışmalarında (0-3 ay), günde iki kez plasebo, 5 mg ve 10 mg alan hastaların% 1.0,% 1.3 ve% 1.2'sinde 3x ULN'den daha yüksek ALT yükselmeleri gözlenmiştir. Bu çalışmalarda, günde iki kez plasebo, 5 mg ve 10 mg alan hastaların% 0.6,% 0.5 ve% 0.4'ünde 3x ULN'den daha yüksek AST yükselmeleri gözlenmiştir.
Yaklaşık 2.5 ay boyunca günde iki kez XELJANZ 10 mg ile tedavi edilen bir hastada ilaca bağlı karaciğer hasarı vakası bildirilmiştir. Hastada 3x ULN'den daha yüksek AST ve ALT semptomatik yükselmeleri ve hastaneye yatış ve karaciğer biyopsisi gerektiren 2x ULN'den daha yüksek bilirubin yükselmeleri gelişti.
Lipid Yükseklikleri
Kontrollü klinik çalışmalarda, bir aylık maruziyette lipit parametrelerinde (toplam kolesterol, LDL kolesterol, HDL kolesterol, trigliseritler) doza bağlı yükselmeler gözlendi ve daha sonra stabil kaldı. Kontrollü klinik çalışmalarda maruziyetin ilk 3 ayında lipit parametrelerindeki değişiklikler aşağıda özetlenmiştir:
- Ortalama LDL kolesterol, günde iki kez XELJANZ 5 mg kolunda% 15 ve günde iki kez XELJANZ 10 mg kolunda% 19 arttı.
- Ortalama HDL kolesterol, günde iki kez XELJANZ 5 mg kolunda% 10 ve günde iki kez XELJANZ 10 mg kolunda% 12 arttı.
- XELJANZ ile tedavi edilen hastalarda ortalama LDL / HDL oranları esasen değişmemiştir.
Kontrollü bir klinik çalışmada, statin tedavisine yanıt olarak LDL kolesterol ve ApoB'deki yükselmeler ön tedavi seviyelerine düşmüştür.
Uzun süreli güvenlik popülasyonunda, lipit parametrelerindeki yükselmeler, kontrollü klinik çalışmalarda görülenlerle tutarlı kalmıştır.
Serum Kreatinin Yükseklikleri
Kontrollü klinik çalışmalarda, XELJANZ tedavisi ile serum kreatinininde doza bağlı yükselmeler gözlenmiştir. 12 aylık havuzlanmış güvenlik analizinde serum kreatinininde ortalama artış <0.1 mg / dL idi; ancak uzun vadeli uzatmalarda artan maruz kalma süresi ile, kreatininde% 50'den fazla bir artış için protokolde belirtilen kesilme kriteri nedeniyle hastaların% 2'sine kadar XELJANZ tedavisinden kesildi. Gözlenen serum kreatinin yükselmelerinin klinik önemi bilinmemektedir.
Diğer Olumsuz Reaksiyonlar
Günde iki kez 5 mg veya günde iki kez 10 mg XELJANZ ve DMARD olan veya olmayan plasebo alan hastalarda gözlenenden en az% 1 daha fazla olan hastaların% 2 veya daha fazlasında meydana gelen advers reaksiyonlar Tablo 4'te özetlenmiştir.
Tablo 4: 5 veya 10 mg'lık Hastaların En Az% 2 veya Daha Fazlasında DMARD'lı veya DMARD'sız (0-3 ay) ve Plasebo'daki Romatoid Artrit Hastalarında Gözlenenden En Az% 1 Daha Fazla Hastada Meydana Gelen Olumsuz Reaksiyonlar
XELJANZ Günde 5 mg İki kez | XELJANZ 10 mg Günde İki Kez * | Plasebo | |
Tercih Edilen Terim | N = 1336 (%) | N = 1349 (%) | N = 809 (%) |
İshal | 4.0 | 2.9 | 2.3 |
Nazofarenjit | 3.8 | 2.8 | 2.8 |
Üst solunum yolu enfeksiyonu | 4.5 | 3.8 | 3.3 |
Baş ağrısı | 4.3 | 3.4 | 2.1 |
Hipertansiyon | 1.6 | 2.3 | 1.1 |
N, yedi klinik çalışmadan randomize ve tedavi edilen hastaları yansıtır * Önerilen XELJANZ dozu günde iki kez 5 mg'dır. |
Kontrollü ve açık etiketli uzatma çalışmalarında meydana gelen diğer advers reaksiyonlar şunları içermektedir:
Kan ve lenfatik sistem bozuklukları: Anemi
Enfeksiyonlar ve enfestasyonlar : Divertikülit
Metabolizma ve beslenme bozuklukları: Dehidrasyon
Psikiyatrik bozukluklar: Uykusuzluk
Sinir sistemi bozuklukları: Parestezi
Solunum, göğüs bozuklukları ve mediastinal hastalıklar: Dispne, öksürük, sinüs tıkanıklığı, interstisyel akciğer hastalığı (bazıları ölümcül)
Gastrointestinal hastalıklar: Karın ağrısı, hazımsızlık, kusma, gastrit, bulantı
Hepatobiliyer hastalıklar: Karaciğer steatozu
Deri ve deri altı doku hastalıkları: Döküntü, eritem, kaşıntı
Kas-iskelet sistemi, bağ dokusu ve kemik bozuklukları: Kas-iskelet ağrısı, artralji, tendinit, eklem şişmesi
İyi huylu, kötü huylu ve belirtilmemiş neoplazmalar (kistler ve polipler dahil): Melanom olmayan cilt kanserleri
Genel bozukluklar ve uygulama bölgesine ilişkin hastalıklar: Pireksi, yorgunluk, periferik ödem
Metotreksat-Naïve Hastalarında Klinik Deneyim
Çalışma VI, metotreksat naif hastalarda aktif kontrollü bir klinik çalışmadır. Bu hastalarda güvenlik deneyimi Çalışmalar I-V ile tutarlıydı
Psoriatik Artrit
Aktif psoriatik artritli (PsA) hastalarda 2 çift kör Faz 3 klinik çalışmada günde iki kez 5 mg ve günde iki kez 10 mg XELJANZ incelenmiştir.
Çalışma PsA-I (NCT01877668) 12 aylık bir süreye sahipti ve biyolojik olmayan bir DMARD'a yetersiz yanıtı olan ve bir TNF inhibitörü (TNFi) ile tedaviye naif olan hastaları kaydetti. Çalışma PsA-I, 3 aylık plasebo kontrollü bir süre içerdi ve ayrıca 12 ay boyunca her 2 haftada bir subkütan olarak 40 mg adalimumab içeriyordu.
Çalışma PsA-II (NCT01882439) 6 aylık bir süreye sahipti ve en az bir onaylı TNFi'ye yetersiz yanıt veren hastaları kaydetti. Bu klinik çalışma 3 aylık plasebo kontrollü bir dönemi içermektedir.
Bu kombine Faz 3 klinik çalışmalarında 238 hasta randomize edildi ve günde iki kez 5 mg XELJANZ ile tedavi edildi ve 236 hasta randomize edildi ve günde iki kez 10 mg XELJANZ ile tedavi edildi. Klinik çalışmalardaki tüm hastaların stabil bir biyolojik olmayan DMARD dozu ile tedavi almaları gerekiyordu [çoğunluk (% 79) metotreksat aldı]. XELJANZ (474 hasta) ile randomize edilen ve tedavi edilen çalışma popülasyonu, başlangıçta diyabetli 45 (% 9.5) hasta ve başlangıçta diyabetli 66 (% 13.9) hastayı içermiştir.
XELJANZ ile tedavi edilen aktif psoriatik artritli hastalarda gözlenen güvenlik profili, romatoid artrit hastalarında gözlenen güvenlik profili ile tutarlıydı.
İnsanlarda Akut Aşırı Dozun İşaretleri, Belirtileri ve Laboratuvar Bulguları
Тофацитиниба цитрат / Тофацитиниба цитрат XR doz aşımı ile ilgili deneyim yoktur
Doz aşımı tedavisi veya yönetimi
Sağlıklı gönüllülerde 100 mg'lık tek bir doz içeren ve içeren farmakokinetik veriler, uygulanan dozun% 95'inden fazlasının 24 saat içinde ortadan kaldırılması beklendiğini göstermektedir.
Тофацитиниба цитрат / Тофацитиниба цитрат XR ile aşırı doz için spesifik bir antidot yoktur. Doz aşımı durumunda, hastanın advers reaksiyonların belirti ve semptomları açısından izlenmesi önerilir. Olumsuz reaksiyonlar geliştiren hastalara uygun tedavi uygulanmalıdır.
İnsanlarda Akut Aşırı Dozun İşaretleri, Belirtileri ve Laboratuvar Bulguları
XELJANZ / XELJANZ XR doz aşımı konusunda deneyim yoktur
Doz aşımı tedavisi veya yönetimi
Sağlıklı gönüllülerde 100 mg'lık tek bir doz içeren ve içeren farmakokinetik veriler, uygulanan dozun% 95'inden fazlasının 24 saat içinde ortadan kaldırılması beklendiğini göstermektedir.
XELJANZ / XELJANZ XR ile aşırı doz için spesifik bir antidot yoktur. Doz aşımı durumunda, hastanın advers reaksiyonların belirti ve semptomları açısından izlenmesi önerilir. Olumsuz reaksiyonlar geliştiren hastalara uygun tedavi uygulanmalıdır.
Тофацитиниба цитрат ile tedavi, dolaşımdaki CD16 / 56 + doğal katil hücrelerinin doza bağlı azalmaları ile ilişkiliydi ve tedavinin başlamasından yaklaşık 8-10 hafta sonra tahmini maksimum azalmalar meydana geldi. Bu değişiklikler genellikle tedavinin kesilmesinden sonraki 2-6 hafta içinde düzeldi. Тофацитиниба цитрат ile tedavi, B hücre sayısında doza bağlı artışlarla ilişkilendirilmiştir. Dolaşımdaki T-lenfosit sayılarındaki ve T-lenfosit alt kümelerindeki (CD3 +, CD4 + ve CD8 +) değişiklikler küçük ve tutarsızdı. Bu değişikliklerin klinik önemi bilinmemektedir.
Romatoid artritli hastalarda 6 aylık dozlamadan sonra toplam serum IgG, IgM ve IgA seviyeleri plasebodan daha düşüktü; ancak değişiklikler küçüktü ve doza bağlı değildi.
Romatoid artritli hastalarda Тофацитиниба цитрат ile tedaviden sonra, dozlama boyunca serum C-reaktif proteinde (CRP) hızlı düşüşler gözlendi ve korundu. Тофацитиниба цитрат tedavisi ile gözlenen CRP'deki değişiklikler, kesildikten sonraki 2 hafta içinde tam olarak tersine dönmez, bu da farmakokinetik yarılanma ömrüne kıyasla daha uzun bir farmakodinamik aktivite süresi olduğunu gösterir.
Tersinirlik değerlendirilmemesine rağmen, aktif psoriatik artritli hastalarda T hücreleri, B hücreleri ve serum CRP'de benzer değişiklikler gözlenmiştir. Aktif psoriatik artritli hastalarda toplam serum immünoglobulinleri değerlendirilmedi.
XELJANZ ile tedavi, dolaşımdaki CD16 / 56 + doğal öldürücü hücrelerin doza bağlı azalmaları ile ilişkiliydi ve tedavinin başlamasından yaklaşık 8-10 hafta sonra tahmini maksimum azalmalar meydana geldi. Bu değişiklikler genellikle tedavinin kesilmesinden sonraki 2-6 hafta içinde düzeldi. XELJANZ ile tedavi, B hücre sayısında doza bağlı artışlarla ilişkilendirildi. Dolaşımdaki T-lenfosit sayılarındaki ve T-lenfosit alt kümelerindeki (CD3 +, CD4 + ve CD8 +) değişiklikler küçük ve tutarsızdı. Bu değişikliklerin klinik önemi bilinmemektedir.
Romatoid artritli hastalarda 6 aylık dozlamadan sonra toplam serum IgG, IgM ve IgA seviyeleri plasebodan daha düşüktü; ancak değişiklikler küçüktü ve doza bağlı değildi.
Romatoid artritli hastalarda XELJANZ ile tedaviden sonra, dozlama boyunca serum C-reaktif proteinde (CRP) hızlı düşüşler gözlendi ve korundu. XELJANZ tedavisi ile gözlenen CRP'deki değişiklikler, kesildikten sonraki 2 hafta içinde tam olarak tersine dönmez, bu da farmakokinetik yarılanma ömrüne kıyasla daha uzun bir farmakodinamik aktivite süresi olduğunu gösterir.
Tersinirlik değerlendirilmemesine rağmen, aktif psoriatik artritli hastalarda T hücreleri, B hücreleri ve serum CRP'de benzer değişiklikler gözlenmiştir. Aktif psoriatik artritli hastalarda toplam serum immünoglobulinleri değerlendirilmedi.
* 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат.
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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат/Тофацитиниба цитрат 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 Тофацитиниба цитрат clinical development program included two dose-ranging trials and five confirmatory trials. Although other doses have been studied, the recommended dose of Тофацитиниба цитрат is 5 mg twice daily.
Dose-Ranging Trials
Dose selection for Тофацитиниба цитрат 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: Тофацитиниба цитрат 1, 3, 5, 10 or 15 mg twice daily, adalimumab 40 mg subcutaneously every other week for 10 weeks followed by Тофацитиниба цитрат 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 Тофацитиниба цитрат (20 mg once daily; 1, 3, 5, 10 or 15 mg twice daily), or placebo added to background MTX.
The results of Тофацитиниба цитрат-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 Тофацитиниба цитрат 1 mg groups compared to patients treated with the other Тофацитиниба цитрат doses. However, there was no difference in the proportion of responders among patients treated with Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат-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 Тофацитиниба цитрат 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 Тофацитиниба цитрат-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 | Тофацитиниба цитрат 5 mg Twice Daily | Тофацитиниба цитрат 10 mg Twice Dailyf | PBO + MTX | Тофацитиниба цитрат 5 mg Twice Daily + MTX | Тофацитиниба цитрат 10 mg Twice Daily + MTXf | PBO + MTX | Тофацитиниба цитрат 5 mg Twice Daily + MTX | Тофацитиниба цитрат 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 Тофацитиниба цитрат is 5 mg twice daily. |
In Study IV, a greater proportion of patients treated with Тофацитиниба цитрат 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 | Тофацитиниба цитрат 5 mg Twice Daily + MTX | Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат in Studies I, II, III, V, and VI.
Table 7: Components of ACR Response at Month 3
Study IV | ||||||
Тофацитиниба цитрат 5 mg Twice Daily + MTX | Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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, Тофацитиниба цитрат 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, Тофацитиниба цитрат 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 Тофацитиниба цитрат plus MTX 5 or 10 mg twice daily.
In Study VI, Тофацитиниба цитрат 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 Тофацитиниба цитрат 5 or 10 mg twice daily.
Table 8: Radiographic Changes at Months 6 and 12
Study IV | |||||
Placebo N=139 Mean (SD)a | Тофацитиниба цитрат 5 mg Twice Daily N=277 Mean (SD) a | Тофацитиниба цитрат 5 mg Twice Daily Mean Difference from Placebob (CI) | Тофацитиниба цитрат 10 mg Twice Dailyd N=290 Mean (SD) a | Тофацитиниба цитрат 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 | Тофацитиниба цитрат 5 mg Twice Daily N=346 Mean (SD) a | Тофацитиниба цитрат 5 mg Twice Daily Mean Difference from MTXb (CI) | Тофацитиниба цитрат 10 mg Twice Dailyd N=369 Mean (SD) a | Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат is 5 mg twice daily. |
Physical Function Response
Improvement in physical functioning was measured by the HAQ-DI. Patients receiving Тофацитиниба цитрат 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 Тофацитиниба цитрат twice daily and -0.32 (-0.44, -0.19) in patients receiving 10 mg Тофацитиниба цитрат twice daily. Similar results were obtained in Studies I, II, IV and V. In the 12-month trials, HAQ-DI results in Тофацитиниба цитрат-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 Тофацитиниба цитрат 5 mg twice daily or Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 5 mg twice daily, Тофацитиниба цитрат 10 mg twice daily, adalimumab 40 mg subcutaneously once every 2 weeks, placebo to Тофацитиниба цитрат 5 mg twice daily treatment sequence, or placebo to Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 Тофацитиниба цитрат 5 mg twice daily, Тофацитиниба цитрат 10 mg twice daily, placebo to Тофацитиниба цитрат 5 mg twice daily treatment sequence, or placebo to Тофацитиниба цитрат 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 Тофацитиниба цитрат dose of 5 mg or 10 mg twice daily as in Study PsA-I.
Clinical Response
At Month 3, patients treated with either Тофацитиниба цитрат 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 Тофацитиниба цитрат 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 | 5 mg Twice Daily | Тофацитиниба цитрат 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 Тофацитиниба цитрат is 5 mg twice daily. |
Table 10: Proportion of Patients with an ACR Response in Study PsA-II* (TNFi Inadequate Responders)
Treatment Group | Placebo | Тофацитиниба цитрат 5 mg Twice Daily | Тофацитиниба цитрат 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% | 13.5 (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 Тофацитиниба цитрат 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 | Тофацитиниба цитрат 5 mg Twice Daily | Тофацитиниба цитрат 10 mgd Twice Daily | Placebo | Тофацитиниба цитрат 5 mg Twice Daily | Тофацитиниба цитрат 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.
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 | 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 XELJANZ is 5 mg twice daily. |
Table 10: Proportion of Patients with an ACR Response in Study PsA-II* (TNFi Inadequate Responders)
Treatment Group | Placebo | XELJANZ 5 mg Twice Daily | XELJANZ 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% | 13.5 (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 XELJANZ 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 | XELJANZ 5 mg Twice Daily | XELJANZ 10 mgd Twice Daily | Placebo | XELJANZ 5 mg Twice Daily | XELJANZ 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 |