Safety in UC, including ORAL Surveillance summaryThe safety profile for Tofacitinib Pfizer was studied across 3 large placebo-controlled phase 3 clinical trials (2 induction and 1 maintenance) that included 1139 patients with moderate to severe UC, and an open-label safety and tolerability study1,2
Tofacitinib Pfizer offers up to 7.8 years of safety data in UC; 315 patients had >4 years of follow-up.Adverse reactions
- In the induction and maintenance studies across all treatment groups, the most common types of serious adverse reactions were gastrointestinal disorders and infections, and the most common serious adverse reaction was worsening of UC2
- <5% of patients in any of the Tofacitinib Pfizer or placebo treatment groups in the induction and maintenance studies discontinued because of adverse events (excluding patients with worsening UC)2
Use in patients over 65 years of age
- Considering the increased risk of serious infections, myocardial infarction, and malignancies with Tofacitinib Pfizer in patients over 65 years of age, Tofacitinib Pfizer should only be used in these patients if no suitable treatment alternatives are available4
The rates of the 4 most frequent adverse events occurring in the maintenance trial are listed for the 3 placebo-controlled trials, and the rates of the most frequently reported treatment related adverse events are reported for the open-label extension study.1,5Pooled UC studies (phases 2-3 and OLE)Predominant dose in the overall cohort (including patients in Phase II, III, and OLE studies) as of May 2019.6Limitations of overall cohort and open-label extension (OLE) data
- Pooled, post hoc analysis of studies from the UC clinical trial program are subject to certain limitations. First, unlike ORAL Surveillance, the patient population is not limited to a high-risk population but includes all enrolled patients. Second, endpoints of interest (such as MACE and malignancy for ORAL Surveillance) were not specifically defined and adjudicated. Additionally, ORAL Surveillance was a long-term safety study (vs. shorter term and designed to test efficacy). Resultant incidence rates in ORAL Surveillance differed from rates seen from pooled study data, suggesting the pooled data may be obscuring information about predictors of events given adverse rates may differ from one patient population to another and may change over time
- OLE studies may provide useful data, however, conduct of OLE studies where both treatment and dose are known to both investigator and patient is subject to certain biases and limitations
- Biases include, but are not limited to, patient selection (patient willingness or ineligibility to enroll, which may be due to a prior serious AE), prior treatment, volunteer, observer, initial dose or study drug, investigator/patient expectation and study duration. Limitations include, but are not limited to, AE frequencies and incidence rates subject to change over time due to patient entry/exit, dose changes influenced by both investigator and patient, dose restrictions in certain countries, the number of patients and exposure for a specific safety event possibly differing depending on the timing of censored events, and the number of observed patients with longer exposure times becoming lower
AEs of Special Interest in the Tofacitinib Pfizer UC Trials
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In the long-term extension study, malignancies (including solid cancers, lymphomas, and NMSC) were observed more often in patients treated with Tofacitinib Pfizer 10 mg BID5
Data as of August 2020.Data as of May 2019.Hepatic impairment
Use in pregnancy
- There are no adequate and well-controlled studies on the use of Tofacitinib Pfizer in pregnant women. As a precautionary measure, the use of Tofacitinib Pfizer in pregnant women is contraindicated4
- Women of childbearing potential should be advised to use effective contraception during treatment with Tofacitinib Pfizer and for at least 4 weeks after the last dose4
Venous thromboembolism (VTE)
- Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein thrombosis (DVT), have been observed in patients taking Tofacitinib Pfizer. In a randomised post-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed with Tofacitinib Pfizer compared to TNF inhibitors. The majority of these events were serious and some resulted in death4
- Tofacitinib Pfizer 10 mg BID for maintenance treatment is not recommended in patients with UC who have known VTE risk factors, unless there is no suitable alternative treatment available4
Major adverse cardiovascular events (MACE)
- Major adverse cardiovascular events (MACE) have been observed in patients taking Tofacitinib Pfizer . In patients over 65 years of age, patients who are current or past smokers, and patients with other cardiovascular risk factors, Tofacitinib Pfizer should only be used if no suitable treatment alternatives are available4
- Tofacitinib Pfizer may affect host defences against malignancies. In patients over 65 years of age, patients who are current or past smokers, and patients with other malignancy risk factors (eg, current malignancy or history of malignancy other than a successfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitable treatment alternatives are available4
ORAL Surveillance (Study A3921133)4,10In a Phase IIIb/IV randomized, open-label, non-inferiority, postauthorization safety, endpoint-driven study among patients 50 years of age or older with moderate to severe RA, with at least one additional CV risk factor and taking MTX without adequate control of symptoms:
- The coprimary endpoints were adjudicated MACEa and adjudicated malignancies (excluding NMSC)4
- For adjudicated MACE and adjudicated malignancies (excluding NMSC), the prespecified noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNFi4,b
For more information on the ORAL Surveillance study, click here.Example TextMACE defined as cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke.The noninferiority criterion was not met for the primary comparison of the combined tofacitinib doses to TNF-alpha inhibitors since the upper limit of the 95% CI exceeded the prescribed noninferiority criterion of 1.8 (ie, for MACE: 1.94>1.8, for malignancy: 2.09>1.8).10Explore moreDosing and administration in UC See recommended dosing
BID=twice daily; BMI=body mass index; CI=confidence interval; CV=cardiovascular; DVT=deep vein thrombosis; GI=gastrointestinal; JAKi=Janus kinase inhibitor; MACE=major adverse cardiovascular event; MTX=methotrexate; NMSC=non-melanoma skin cancer; OLE=open-label extension; PD=predominant dose; PE=pulmonary embolism;
pt-yr=patient years; QD=once a day; RA=rheumatoid arthritis; SD=standard deviation; TNFi=tumor necrosis factor inhibitor; UC=ulcerative colitis; VTE=venous thromboembolism.References: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(18):1723-1736.Data on file. PfizerSandborn WJ, D'Haens GR, Sands BE, et al. Tofacitinib for the treatment of ulcerative colitis: up to 7.8 years of safety data from global clinical trials. Poster presented at: American College of Gasteroenterology Annual Scientific Meeting; October 22-17, 2021; Las Vegas, NV, USA.Tofacitinib Pfizer Summary of Product Characteristics. PfizerSandborn WJ, Lawendy N, Danese S, et al. Safety and efficacy of tofacitinib for treatment of ulcerative colitis: final analysis of OCTAVE Open, an open-label, long-term extension study with up to 7.0 years of treatment. Aliment Pharmacol Ther. 2021;00:1–15. Suppl:1-36.Winthrop KL, Loftus EV, Baumgart DC, et al. Tofacitinib for the Treatment of Ulcerative Colitis: Analysis of Infection Rates from the Ulcerative Colitis Clinical Programme. J Crohns Colitis. 2020;15(6):914-929. Suppl:1-20.Vermeire S, Armuzzi A, Kwok KK, et al. The effect of tofacitinib on serum lipids and cardiovascular safety in patients with ulcerative colitis: results from the tofacitinib OCTAVE ulcerative colitis clinical program. Field report 538 presented at: Digestive Disease Week Virtual (DDW); May 21-23, 2021.Lichtenstein GR, Rogler G, Ciorba MA, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancy (excluding nonmelanoma skin cancer) events across the ulcerative colitis clinical program. Inflamm Bowel Dis. 2021.27;(6):816-825.Sandborn WJ, Panés J, Sands BE, et al. Incidence of venous thromboembolic events in patients with ulcerative colitis treated with tofacitinib in the ulcerative colitis clinical programme: an update as of May 2019. Poster P598 presented at: Congress of the European Crohn’s and Colitis Organisation (ECCO); 12-15 February 2020; Vienna, Austria.Ytterberg SR, Bhatt DL, Mikuls TR, et al; for the ORAL Surveillance Investigators. Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis. N Engl J Med. 2022;386(4):316-326.