New Oral Option Available for Rheumatoid Arthritis Treatment

The approval of tofacitinib (Xeljanz) brings a new therapy to the market that could have a big impact on the rheumatoid arthritis treatment paradigm.

The treatment of rheumatoid arthritis (RA) entered a new era on November 6, 2012, when the FDA approved tofacitinib (Xeljanz, Pfizer) for the treatment of adult patients with moderately to severely active RA who cannot tolerate or did not respond adequately to methotrexate. Tofacitinib is an orally administered Janus kinase (JAK) inhibitor, the first of its kind to be approved for RA.¹

JAKs are intracellular enzymes that transmit signals resulting from the binding of extracelluar cytokines or growth factors to cell membrane receptors. JAK-dependent cytokines have been implicated in various anti-inflammatory and autoimmune diseases. As a JAK inhibitor, tofacitinib specifically acts to prevent the phosphorylation and activation of signal transducers and assists in downregulating the immune response. Slowing the immune response is crucial to preventing the inflammation that occurs with RA.²

Tofacitinib received approval at a dose of 5 mg twice daily with or without food based on the results of 2 doseranging trials and 5 confirmatory trials, which ranged from 6 to 24 months in duration and evaluated both tofacitinib therapy alone and tofacitinib therapy in combination with methotrexate. One of the tofacitinib trials had not been completed at the time of approval and was designed as a 2-year trial with scheduled analysis at 1 year.

In all of the phase 3 clinical trials, patients treated with tofacitinib had a greater improvement in their RA symptoms versus patients receiving placebo. Specifically, more patients treated with tofacitinib achieved ACR20, ACR50, and ACR70 response rates at 3 and 6 months, regardless of background disease-modifying antirheumatic drug treatment. In the 12-month trial, response rates in patients treated with tofacitinib were consistent at 6 and 12 months.

Tofacitinib-treated patients also experienced greater improvements in physical functioning as measured by the Health Assessment QuestionnaireDisability Index and were more likely to achieve a low level of disease activity as measured by the Disease Activity Score DAS28-4(ESR).² Despite being studied in the pivotal clinical trials, a dose of 10 mg twice daily did not obtain approval by the FDA.³

Prescribing Information

The tofacitinib prescribing information contains a boxed warning discussing the risk of serious infections and malignancy. Patients should be screened for latent tuberculosis prior to starting therapy and tofacitinib therapy should be interrupted if a serious infection develops while taking the drug. Lymphoma and other malignancies have been reported in patients taking tofacitinib. Tofacitinib should be used with caution in patients at risk for gastrointestinal (GI) perforations, such as patients with a history of diverticulitis, as GI perforations were reported in clinical trials.²

The most common side effects reported with tofacitinib in the first 3 months of clinical trials included diarrhea, nasopharyngitis, upper respiratory tract infection, headache, and hypertension. Increases in lipid parameters such as total cholesterol, low-density lipoprotein, high-density lipoprotein, and triglycerides were also observed in clinical trials. Maximum effect of the lipid increase was generally seen within 6 weeks of initiating tofacitinib therapy.²

Tofacitinib is primarily metabolized by cytochrome P450 (CYP) 3A4, with a minor contribution from CYP2C19. Prescribing information recommends a dosage adjustment to 5 mg once daily when tofacitinib is concomitantly administered with strong CYP3A4 inhibitors (such as ketoconazole) or with a combination of a moderate CYP3A4 inhibitor and a potent CYP2C19 inhibitor (such as fluconazole). Coadministration with potent CYP3A4 inducers (such as rifampin) may result in loss of or reduced clinical response to tofacitinib. The tofacitinib dose should also be reduced to 5 mg once daily in patients with moderate to severe renal impairment and in patients with hepatic impairment.²

Risk Evaluation and Mitigation Strategy

The FDA approved tofacitinib with a Risk Evaluation and Mitigation Strategy (REMS) designed to inform health care providers and patients about the risks of tofacitinib treatment. The REMS includes a medication guide for patients, a communication plan for health care providers and pharmacists, and periodic submissions of assessments of the REMS program to the FDA. In addition, the FDA has requested that Pfizer conduct a clinical trial to assess long-term safety of tofacitinib, and the manufacturer will also be working with the FDA to understand what additional data may be required to reassess the risk to benefit profile of the 10-mg twice-daily dose. ⁴

Analysts anticipate that the new oral agent could reach $2.5 billion to $3 billion in sales out of the estimated total $20 billion in drug sales generated by treatments in the RA therapeutic category. That number could grow if additional indications are approved. Clinical trials evaluating tofacitinib for the treatment of juvenile idiopathic arthritis, ulcerative colitis, and plaque psoriasis are all ongoing, according to clinicaltrials.gov.^3,5

Specialty Pharmacy Considerations for Tofacitinib Therapy ^2,6,7

• Counsel patients on potential side effects, therapy considerations, and potential drug—drug interactions of medications used in RA.
• Ensure that hemoglobin/hematocrit, liver function tests, serum lipids, and white blood cell counts are being monitored by the physician. Lymphocytes should be monitored at baseline and every 3 months thereafter. Neutrophils should be monitored at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Hemoglobin should be monitored at baseline, after 4 to 8 weeks of treatment, and every 3 months thereafter. Routine liver function tests should be given to a patient on tofacitinib therapy. Lipid monitoring should be performed approximately 4 to 8 weeks after initiation of therapy.
• It is recommended that tofacitinib not be initiated in patients with a lymphocyte count less than 500 cells/mm3 , an absolute neutrophil count less than 1000 cells/mm3 , or a hemoglobin level less than 9 g/dL.
• Dose modifications for tofacitinib therapy are listed in the prescribing information for patients experiencing lymphopenia, neutropenia, or anemia.
• Assess barriers in adherence and persistency of RA therapy and provide tools to remove the identified barriers. Examples may include copayment assistance resources, refill management, and reminder strategies for the patient.
• Become familiar with the process and required elements for prior authorizations, if necessary. Manufacturer reimbursement resources may be of assistance and can be found on the respective product websites.
• Consider vaccination status and administration of necessary vaccines prior to tofacitinib initiation, as concurrent live vaccines are not recommended with tofacitinib therapy.
• Use caution when dispensing tofacitinib to women of child-bearing age. Tofacitinib is a pregnancy category C drug and use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus. Tofacitinib should not be taken while breastfeeding.
• Be aware that the frequency of serious infection was higher in those patients 65 years and older than in patients younger than 65 years. Caution should be used in geriatric patients.
• Assess patients for any history of cancer. Tofacitinib may be inappropriate for patients with a current or past malignancy as treatment with tofacitinib may precipitate a secondary malignancy.
• Educate patients to report new-onset abdominal symptoms or pain, as they could be signs of GI perforation.
• Monitoring parameters for RA may include pain, number of tender joints, health assessment questionnaire score, and erythrocyte sedimentation rate.

References:

• FDA approves Xeljanz for rheumatoid arthritis [press release]. Silver Springs, MD: US Food and Drug Administration; November 6, 2012. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm327152.htm. Accessed December 19, 2012.
• Xeljanz Prescribing Information. Pfizer, November 2012. http://labeling.pfizer.com/ShowLabeling.aspx?id=959. Accessed December 19, 2012.
• Pfizer’s blockbuster hopeful Xeljanz sets up Humira challenge. Fierce Pharma, November 6, 2012. www.fiercepharma.com/story/pfizer-nabs-fda-blessing-blockbuster-hopeful-xeljanz/2012-11-06. Accessed December 19, 2012.
• US Food and Drug Administration approves Pfizer’s Xeljanz (tofacitinib citrate) for Adults with Moderately to Severely Active Rheumatoid Arthritis (RA) who have had an inadequate response or intolerance to methotrexate. Pfizer; November 7, 2012. http://press.pfizer.com/press-release/multimedia-us-food-and-drug-administration-approves-pfizers-xeljanz-tofacitinib-citrat. Accessed December 20, 2012.
• Clinicaltrials.gov. US National Institutes of Health. Search for tofacitinib. Accessed December 19, 2012.
• Clinical Pharmacology. Tofacitinib. Elsevier, 2012. Accessed December 19, 2012.
• Chandrashekara S, Syed M, Swapna R. Is three selected parameters adequate to monitor rheumatoid arthritis? Clinical Rheumatology. 2007;26(6):911-914. http://link.springer.com/article/10.1007%2Fs10067-006-0431-y?LI=true. Accessed December 19, 2012.

About the Author

Stacey Ness, PharmD, RPh, MSCS, AAHIVP, has worked in both national specialty pharmacy and payer organizations and has experience in clinical management, adherence, and persistency programs, as well as chronic disease cost optimization strategies. Dr. Ness is active in the Consortium of Multiple Sclerosis Centers, Academy of Managed Care Pharmacy, National Home Infusion Association, National Association of Specialty Pharmacy, and Hematology and Oncology Pharmacy Association, and has served on the Minnesota Medicaid Drug Formulary Committee since 2008. She is a multiple sclerosis certified specialist, a credentialed HIV pharmacist, and currently serves as the director of specialty clinical services at Managed Health Care Associates, Inc, a health care services organization based in Florham Park, New Jersey.