Tofacitinib for the Treatment of Rheumatoid Arthritis
December 14, 2012
Tofacitinib (Xeljanz ®) was approved by the FDA on November 6, 2012 for the treatment of adults with moderate to severe rheumatoid arthritis who have had an inadequate response to, or are intolerant of, methotrexate. It may be used as monotherapy or in combination with methotrexate (MTX) or other non-biologic DMARDs. The use of tofacitinib with biologic DMARDs has not been studied and it is not recommended.
Tofacitinib is the first of a new class of oral DMARDs that inhibit Janus Kinase (JAK). JAKs are a group of intracellular proteins that transmit signals delivered to the cell surface (e.g., through cytokine receptors) and ultimately can lead to the production of a variety of inflammatory mediators such as cytokines. The four JAK proteins (JAK 1/2/3 and Tyk 2) exist as homodimers or heterodimers with different pairs being associated with different cell surface receptors and producing different mediators. Tofacitinib exerts its effects primarily on the JAK1/JAK2, JAK1/JAK3 and JAK2/JAK2 pairs. Tofacitinib is metabolized primarily hepatically (70%), using the CYP3A4 and CYP2C19 enzymes; 30% is eliminated via the kidneys. It has a half-life of ~3 hours.
Tofacitinib has been studied in a number of Phase 2 dose ranging studies and five Phase 3 randomized controlled studies of at least 6 months duration. In all, about 5000 patients received tofacitinib in phase 2, 3 and long-term extension studies. Based on these studies, the FDA has approved a dose of 5mg administered orally, twice daily.
ACR 20, 50, and 70 response rates with tofacitinib 5 mg BID monotherapy or in combination with methotrexate in 3 representative studies:
Safety of Tofacitinib
Virtually all of the safety data have come from clinical trials and their long term extension studies.
Serious infections, some fatal, have been reported in clinical trials. The rates of these events are similar to those seen with biologic DMARDs (2.7/100 pt yr).
Opportunistic Infections, including TB (12 cases to date), fungal and pneumocystis infections, have been reported. TB screening should be performed prior to starting tofacitinib. Safety in patients with active Hepatitis B or Hepatitis C has not been studied; the use of tofacitinib in these patients should be avoided.
Herpes Zoster infections have been reported at a rate higher than current biologic therapies.4
Live vaccines should not be administered to patients taking tofacitinib.
In the clinical trials, 11 solid tumors and 1 lymphoma were diagnosed in 3328 RA patients on tofacitinib with or without background DMARD, compared to none in the placebo group (n=809), during the first 12 months of therapy.
In clinical trials of renal transplant patients (who received other immunosuppressives as well as higher doses of tofacitinib than the FDA approved dose for RA ), Epstein Barr Virus-associated post-transplant lymphoproliferative disease was reported in 2.3% of patients.5
Gastrointestinal perforations have been reported; caution should be used in patients at risk for this event (e.g., prior history of diverticulitis).
Because of its effect on the hematopoietic system, monitoring of absolute lymphocyte counts and absolute neutrophil counts is recommended. If a decrease occurs, tofacitinib should be reduced or stopped. Hemoglobin decreases below 9 g/dl have also been reported, and management should be similar to that with a WBC decrease.
Elevations in liver function tests, lipids and creatinine have all been reported during clinical trials. These tests should be monitored prior to initiation of therapy, and during treatment.
Use with immunosuppressants (other than MTX or non-biologic DMARDS) or in combination with biologics is not recommended. Specifically, tofacitinib should not be used with azathioprine or cyclosporine.
Additional information can be found online.
Administration and Cost
Tofacitinib is available as a 5 mg tablet to be administered, orally, twice daily. Higher doses have not been approved. In patients with moderate to severe renal impairment or moderate hepatic dysfunction, it has been recommended that the dose should be decreased to 5 mg daily. Dose reduction to 5 mg daily should also occur in patients taking inhibitors of CYP3A4/CYP2C19 (i.e., ketoconazole/fluconazole). In patients taking a CYP inducers (i.e., rifampin), no dose increase is available, but efficacy could be decreased. Based on reports from the manufacturer, the "Wholesale Acquisition Cost" will be $2055.13/30-day supply.
The Bottom Line
Tofacitinib is a first-in-class oral JAK inhibitor which has shown clinical efficacy in patients with moderate to severe rheumatoid arthritis. Tofacitinib is approved for patients with an inadequate response to both biologic and non-biologic DMARDS, as monotherapy or in combination with MTX or non-biologic DMARDs, but it should not be used in combination with biologic agents. Current labeling for tofacitinib does not include an indication for inhibition of structural damage. Data on safety suggests that infections, including severe "traditional" infections, as well as opportunistic infections and Herpes zoster, have occurred. Long-term safety studies and post-marketing safety data is being collected. Monitoring for hematologic abnormalities, liver enzyme abnormalities, lipid abnormalities and renal dysfunction is appropriate prior to initiation of therapy and throughout treatment.
Hotline Author: Martin J. Bergman, MD
Hotline Editors: Arthur Kavanaugh, MD, and Eric Ruderman, MD.
Disclosures: Dr. Bergman: Consultant - Pfizer. Dr. Ruderman: Consultant and research funding - Pfizer. Dr. Kavanaugh: Consultant and clinical research - Pfizer.
This Hotline has been reviewed by the editors, the ACR Executive Committee, the Drug Safety Subcommittee and the Communications & Marketing Committee.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the editors and does not represent a position statement of the American College of Rheumatology.
References
Fleischmann R, et al. NEJM 2012; 367(6): 495-507
Van der Heijde D, et al. ACR Annual Scientific Meeting, 2011, Abstract 2592
Burmester G, et al. ACR Annual Scientific Meeting, 2011, Abstract 718
Cohen S, et al. ACR Annual Scientific Meeting, 2012, Abstract 2485
Prescribing Information Revised: 11/2012
src: http://www.rheumatology.org/publications/hotline/2012_12_12_Tofacitinib.asp
Tofacitinib (Xeljanz ®) was approved by the FDA on November 6, 2012 for the treatment of adults with moderate to severe rheumatoid arthritis who have had an inadequate response to, or are intolerant of, methotrexate. It may be used as monotherapy or in combination with methotrexate (MTX) or other non-biologic DMARDs. The use of tofacitinib with biologic DMARDs has not been studied and it is not recommended.
Tofacitinib is the first of a new class of oral DMARDs that inhibit Janus Kinase (JAK). JAKs are a group of intracellular proteins that transmit signals delivered to the cell surface (e.g., through cytokine receptors) and ultimately can lead to the production of a variety of inflammatory mediators such as cytokines. The four JAK proteins (JAK 1/2/3 and Tyk 2) exist as homodimers or heterodimers with different pairs being associated with different cell surface receptors and producing different mediators. Tofacitinib exerts its effects primarily on the JAK1/JAK2, JAK1/JAK3 and JAK2/JAK2 pairs. Tofacitinib is metabolized primarily hepatically (70%), using the CYP3A4 and CYP2C19 enzymes; 30% is eliminated via the kidneys. It has a half-life of ~3 hours.
Tofacitinib has been studied in a number of Phase 2 dose ranging studies and five Phase 3 randomized controlled studies of at least 6 months duration. In all, about 5000 patients received tofacitinib in phase 2, 3 and long-term extension studies. Based on these studies, the FDA has approved a dose of 5mg administered orally, twice daily.
ACR 20, 50, and 70 response rates with tofacitinib 5 mg BID monotherapy or in combination with methotrexate in 3 representative studies:
Safety of Tofacitinib
Virtually all of the safety data have come from clinical trials and their long term extension studies.
Serious infections, some fatal, have been reported in clinical trials. The rates of these events are similar to those seen with biologic DMARDs (2.7/100 pt yr).
Opportunistic Infections, including TB (12 cases to date), fungal and pneumocystis infections, have been reported. TB screening should be performed prior to starting tofacitinib. Safety in patients with active Hepatitis B or Hepatitis C has not been studied; the use of tofacitinib in these patients should be avoided.
Herpes Zoster infections have been reported at a rate higher than current biologic therapies.4
Live vaccines should not be administered to patients taking tofacitinib.
In the clinical trials, 11 solid tumors and 1 lymphoma were diagnosed in 3328 RA patients on tofacitinib with or without background DMARD, compared to none in the placebo group (n=809), during the first 12 months of therapy.
In clinical trials of renal transplant patients (who received other immunosuppressives as well as higher doses of tofacitinib than the FDA approved dose for RA ), Epstein Barr Virus-associated post-transplant lymphoproliferative disease was reported in 2.3% of patients.5
Gastrointestinal perforations have been reported; caution should be used in patients at risk for this event (e.g., prior history of diverticulitis).
Because of its effect on the hematopoietic system, monitoring of absolute lymphocyte counts and absolute neutrophil counts is recommended. If a decrease occurs, tofacitinib should be reduced or stopped. Hemoglobin decreases below 9 g/dl have also been reported, and management should be similar to that with a WBC decrease.
Elevations in liver function tests, lipids and creatinine have all been reported during clinical trials. These tests should be monitored prior to initiation of therapy, and during treatment.
Use with immunosuppressants (other than MTX or non-biologic DMARDS) or in combination with biologics is not recommended. Specifically, tofacitinib should not be used with azathioprine or cyclosporine.
Additional information can be found online.
Administration and Cost
Tofacitinib is available as a 5 mg tablet to be administered, orally, twice daily. Higher doses have not been approved. In patients with moderate to severe renal impairment or moderate hepatic dysfunction, it has been recommended that the dose should be decreased to 5 mg daily. Dose reduction to 5 mg daily should also occur in patients taking inhibitors of CYP3A4/CYP2C19 (i.e., ketoconazole/fluconazole). In patients taking a CYP inducers (i.e., rifampin), no dose increase is available, but efficacy could be decreased. Based on reports from the manufacturer, the "Wholesale Acquisition Cost" will be $2055.13/30-day supply.
The Bottom Line
Tofacitinib is a first-in-class oral JAK inhibitor which has shown clinical efficacy in patients with moderate to severe rheumatoid arthritis. Tofacitinib is approved for patients with an inadequate response to both biologic and non-biologic DMARDS, as monotherapy or in combination with MTX or non-biologic DMARDs, but it should not be used in combination with biologic agents. Current labeling for tofacitinib does not include an indication for inhibition of structural damage. Data on safety suggests that infections, including severe "traditional" infections, as well as opportunistic infections and Herpes zoster, have occurred. Long-term safety studies and post-marketing safety data is being collected. Monitoring for hematologic abnormalities, liver enzyme abnormalities, lipid abnormalities and renal dysfunction is appropriate prior to initiation of therapy and throughout treatment.
Hotline Author: Martin J. Bergman, MD
Hotline Editors: Arthur Kavanaugh, MD, and Eric Ruderman, MD.
Disclosures: Dr. Bergman: Consultant - Pfizer. Dr. Ruderman: Consultant and research funding - Pfizer. Dr. Kavanaugh: Consultant and clinical research - Pfizer.
This Hotline has been reviewed by the editors, the ACR Executive Committee, the Drug Safety Subcommittee and the Communications & Marketing Committee.
The ACR Hotline is provided by the ACR Communications and Marketing Committee as a service to members. This Hotline reflects the views of the editors and does not represent a position statement of the American College of Rheumatology.
References
Fleischmann R, et al. NEJM 2012; 367(6): 495-507
Van der Heijde D, et al. ACR Annual Scientific Meeting, 2011, Abstract 2592
Burmester G, et al. ACR Annual Scientific Meeting, 2011, Abstract 718
Cohen S, et al. ACR Annual Scientific Meeting, 2012, Abstract 2485
Prescribing Information Revised: 11/2012
src: http://www.rheumatology.org/publications/hotline/2012_12_12_Tofacitinib.asp