Pharmacologic treatments for ulcerative colitis mainly include anti-inflammatory drugs (ie, corticosteroids, 5-aminosalicylates) and immunosuppressant drugs (ie, azathioprine, mercaptopurine, cyclosporine, the tumor necrosis factor [TNF] inhibitors, and an integrin receptor antagonist).2 The TNF inhibitors and the integrin receptor antagonist are biologic agents.
Xeljanz Approved for Moderate-to-Severe Ulcerative Colitis
On May 30, 2018, the US Food and Drug Administration (FDA) expanded the indication of tofacitinib (Xeljanz; Pfizer), an oral Janus kinase (JAK) inhibitor, for the treatment of adults with moderately to severely active ulcerative colitis.4,5 Tofacitinib is the first oral medication approved for long-term use in this setting. Other FDA-approved agents for moderately to severely active ulcerative colitis are administered intravenously or subcutaneously.4
“New treatments are needed for patients with moderately to severely active ulcerative colitis,” said Julie Beitz, MD, Director, Office of Drug Evaluation III, FDA’s Center for Drug Evaluation and Research. “Today’s approval provides an alternative therapy for a debilitating disease with limited treatment options,” she added.4
Tofacitinib was initially approved in 2012 for moderately to severely active rheumatoid arthritis, and tofacitinib extended-release tablets were approved in 2016 for moderately to severely active rheumatoid arthritis.6 In December 2017, both agents were granted FDA approval for the treatment of active psoriatic arthritis.6
Mechanism of Action
Tofacitinib inhibits the activity of JAKs, which are intracellular enzymes that transmit signals from cytokines or growth factor–receptor interactions involved in the pathogenesis of ulcerative colitis. These signals are implicated in immune-cell function and hematopoiesis. JAKs activate and phosphorylate the signal transducers and activators of transcription, a process that affects intracellular activity, including gene expression.5
Dosing and Administration
Tofacitinib is available as 5-mg or 10-mg tablets.5 For the treatment of ulcerative colitis, the recommended dosage of tofacitinib is 10 mg twice daily for at least 8 weeks, followed by 5 mg or 10 mg twice daily. If adequate therapeutic benefit is not achieved after 16 weeks, treatment should be discontinued. The lowest effective dose required to maintain response should be used. Tofacitinib can be taken with or without food.5
Pivotal Clinical Trials: The OCTAVE Studies
The FDA approval of tofacitinib was based on 3 randomized, double-blind, placebo-controlled phase 3 studies in patients with moderately to severely active ulcerative colitis: OCTAVE 1 and OCTAVE 2 were 2 identical induction trials with 1139 patients; and OCTAVE Sustain was a maintenance trial with 593 patients.5,7
In OCTAVE 1 and OCTAVE 2, a significantly greater proportion of patients who received tofacitinib 10 mg twice daily were in remission at week 8 (18% and 17%, respectively) compared with patients who received placebo (8% and 4%, respectively; Table 1).5,7
In the OCTAVE Sustain clinical trial, a significantly greater proportion of patients who received tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily were in remission at week 52 (34% and 41%, respectively) compared with those who received placebo (11%; Table 2). Clinical response was sustained in 52% of patients in the tofacitinib 5-mg twice-daily arm and in 62% of patients in the tofacitinib 10-mg twice-daily arm versus 20% of patients who received placebo.5,7
The most common (≥5%) adverse reactions in patients who received tofacitinib 5 mg or 10 mg twice daily and ≥1% greater than in patients who received placebo were nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase levels, rash, diarrhea, and herpes zoster.5
In the long-term extension clinical trial, malignancies, including lymphomas and solid cancers, occurred more often with tofacitinib 10 mg twice daily than with tofacitinib 5 mg or with placebo; 4 cases of pulmonary embolism and 1 fatality were reported with tofacitinib 10 mg twice daily.5
Dose-dependent adverse events reported with tofacitinib 10 mg twice daily versus 5 mg twice daily included herpes zoster infections, serious infections, and nonmelanoma skin cancers.5
Tofacitinib has no contraindications.5
The coadministration of strong cytochrome (CY) P3A4 inhibitors (eg, ketoconazole) with tofacitinib can increase exposure to tofacitinib.5 The coadministration of moderate CYP3A4 inhibitors with strong CYP2C19 inhibitors (eg, fluconazole) can increase exposure to tofacitinib. For patients using strong CYP3A4 inhibitors or a moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor, the recommended dosage of tofacitinib is 5 mg once daily.5
Concomitant use of strong CYP3A4 inducers with tofacitinib is not recommended, because it can decrease the exposure to tofacitinib and may negatively affect the response to tofacitinib.5
Coadministration of immunosuppressive drugs (eg, azathioprine, tacrolimus, cyclosporine) with tofacitinib is not recommended, because of the risk for added immunosuppression.5
Use in Specific Populations
Women of reproductive potential should be cautioned about the potential risk of tofacitinib to the fetus and should be advised to consider contraception. Nursing women should not breastfeed during tofacitinib treatment and for ≥18 hours after the last dose.5
In clinical trials, a higher incidence of serious infections occurred in patients aged ≥65 years than in younger patients.5
Caution is needed when treating patients with diabetes, who have an increased incidence of infection.5
Tofacitinib therapy is not recommended in patients with severe hepatic impairment; for moderate hepatic impairment, the recommended dosage is 5 mg once daily, and for mild hepatic impairment, no dosage adjustment is needed.5
For patients with moderate or severe renal impairment, the recommended tofacitinib dosage is 5 mg once daily; no dosage adjustment is needed for mild renal impairment.5
Warnings and Precautions
Tofacitinib was approved with a boxed warning about the risk for serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections. In patients with a serious infection, tofacitinib should be discontinued until the infection is controlled. Patients should be tested for tuberculosis before starting tofacitinib therapy; if the test result is positive, patients should receive treatment for tuberculosis before starting tofacitinib therapy. All patients who receive tofacitinib should be monitored for active tuberculosis, regardless of the initial test results.5
The boxed warning also states that lymphoma and other malignancies have been reported in patients receiving tofacitinib. In addition, an increased rate of Epstein Barr virus–associated posttransplant lymphoproliferative disorder has been reported in patients who underwent renal transplantation and received tofacitinib and concomitant immunosuppressive drugs.5
Tofacitinib should be avoided if the patient has an active serious infection, including localized infections. Tofacitinib should be used with caution in patients who are at an increased risk for gastrointestinal perforations, including patients with diverticulitis or those taking nonsteroidal anti-inflammatory drugs.5
Because of the potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids associated with tofacitinib therapy, laboratory monitoring is recommended at specific intervals, as outlined in the full prescribing information.5
Before the initial treatment with tofacitinib, immunizations should be updated, according to current immunization guidelines. Live vaccines should not be used concurrently with tofacitinib.5
Tofacitinib, the first oral JAK inhibitor to receive FDA approval for patients with moderately to severely active ulcerative colitis, may provide certain patients with an oral, nonbiologic treatment option.
In 3 clinical trials, a significantly greater proportion of patients who received tofacitinib achieved remission than patients who received placebo.
- Crohn’s & Colitis Foundation. What is ulcerative colitis? www.crohnscolit isfoundation.org/what-are-crohns-and-colitis/what-is-ulcerative-colitis/. Accessed July 24, 2018.
- Mayo Clinic. Ulcerative colitis. March 8, 2018. www.mayoclinic.org/diseases-conditions/ulcerative-colitis/symptoms-causes/syc-20353326. Accessed July 24, 2018.
- Kappelman MD, Rifas-Shiman SL, Porter CQ, et al. Direct health care costs of Crohn’s disease and ulcerative colitis in US children and adults. Gastroenterology. 2008;135:1907-1913.
- US Food and Drug Administration. FDA approves new treatment for moderately to severely active ulcerative colitis. May 30, 2018. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm609225.htm. Accessed July 23, 2018.
- Xeljanz/Xeljanz XR (tofacitinib) tablets/extended-release tablets, for oral use [prescribing information]. New York, NY: Pfizer; August 2018.
- Drugs.com. Xeljanz approval history. www.drugs.com/history/xeljanz.html. Accessed July 26, 2018.
- Sandborn WJ, Su C, Sands BE, et al; for the OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain investigators. Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2017;376:1723-1736.