Common side effects include diarrhea, headache, and high blood pressure.[9] Serious side effects may include infections,
cancer, and
pulmonary embolism.[9][10] In 2019, the safety committee of the
European Medicines Agency began a review of tofacitinib and recommended that doctors temporarily not prescribe the 10 mg twice-daily dose to people at high risk for pulmonary embolism.[11] The U.S.
Food and Drug Administration (FDA) also released warnings about the risk of blood clots.[12][13][14] An important side effect of Jakinibs is serious bacterial, mycobacterial, fungal and viral infections. In the phase III trials of tofacitinib among opportunistic infections, pulmonary tuberculosis (TB) was reported in 3 cases all of which were initially negative upon screening for TB.[15]
It was approved for medical use in the United States in November 2012.[16] The extended release version was approved in February 2016.[17] It is available as a
generic medication.[18]
Medical uses
Rheumatoid arthritis
Tofacitinib citrate is approved for medical use in the United States with an indication "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate."[19][7]
In the European Union, in combination with
methotrexate, tofacitinib citrate is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs.[8] It can be given as monotherapy in case of intolerance to methotrexate or when treatment with MTX is inappropriate.[8]
Ulcerative colitis
In May 2018, the FDA approved tofacitinib citrate "for the treatment of adult patients in the U.S. with moderately to severely active ulcerative colitis."[20] Tofacitinib citrate is the first oral JAK inhibitor approved for use in chronic ulcerative colitis.
Adverse effects
Tofacitinib was initially not approved by European regulatory agencies because of concerns over
efficacy and safety,[21] although by 2018, the European Commission had approved it.[22] Animal studies with tofacitinib conducted prior to human trials showed some
carcinogenesis,
mutagenesis, and impairment of
fertility.[7]
Tofacitinib is required by the FDA to have a
boxed warning on its label about possible
injury and
death due to problems such as infections,
lymphoma, and other
malignancies, which can arise from use of this drug.[19] Serious
infections leading to
hospitalization or death, including
tuberculosis and bacterial, invasive fungal, viral, and other
opportunistic infections, have occurred in patients receiving tofacitinib.
Epstein Barr virus-associated post-
transplantlymphoproliferative disorder has been observed at an increased rate in
renal transplant patients treated with tofacitinib while on immunosuppressive medications. Patients are warned to avoid use of tofacitinib citrate during an "active serious infection, including localized infections." Doctors are advised to use it with caution in patients who may be at increased risk of gastrointestinal perforations. Laboratory monitoring is recommended due to potential changes in
lymphocytes,
neutrophils,
hemoglobin,
liver enzymes, and
lipids. Tofacitinib claims to have no
contraindications, but doctors are advised to reduce the patient's dosage when combined with "potent inhibitors of
cytochrome P450 3A4 (CYP3A4)," such as
ketoconazole, or one or more combined
medications that result in both moderate inhibition of CYP3A4 and potent inhibition of
CYP2C19 such as
fluconazole. Furthermore,
immunizations with live
vaccines should be avoided by tofacitinib users.[7]
According to postmarketing research, tofacitinib may also increase the risk for pulmonary embolism. Prescribers should consider risk factors for pulmonary embolism, including age, obesity, smoking, and immobilization before prescribing this medication. Patients taking this medication, irrespective of indication or risk factors, should be monitored for signs and symptoms of pulmonary embolism.[23]
In a mouse model of established arthritis, tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing
STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to
inhibition of JAK3.[25]
History
The potential significance of JAK3 inhibition was first discovered in the laboratory of
John O'Shea, an
immunologist at the
National Institute of Arthritis and Musculoskeletal and Skin Diseases of the
National Institutes of Health (NIH).[26] In 1994, Pfizer was approached by the NIH to form a public-private partnership to evaluate and bring to market experimental compounds based on this research.[26] Pfizer initially declined the partnership, but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the "health and safety needs of the public."[26] Pfizer worked with O'Shea's laboratory to define the structure and function of JAK3 and its receptors, and then handled the drug discovery,
preclinical development, and
clinical development of tofacitinib in-house.[27]
The drug was coded as
CP-690,550[28] during development. Its original recommended
International nonproprietary name (rINN) was tasocitinib,[29] but that was overruled during the INN approval process as being not optimally differentiable from other existing INNs, so the name "tofacitinib" was proposed and became the INN.
In November 2012, the FDA approved tofacitinib for treatment of rheumatoid arthritis.[7][16]
A 2014 study showed that tofacitinib treatment was able to convert
white fat tissues into more metabolically active
brown fat, suggesting it may have potential applications in the treatment of
obesity.[30]
In November 2012, the FDA approved tofacitinib to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of,
methotrexate.[19] The FDA approved only the five-mg, twice-daily dose on the grounds that a higher dose was not considered to have an adequate risk-to-benefit ratio.[31]
In September 2020, the FDA approved tofacitinib for the treatment of children and adolescents two years of age and older with active polyarticular course juvenile idiopathic arthritis.[32]
In December 2021, the FDA approved tofacitinib for the treatment of adults with active ankylosing spondylitis.[33]
Tofacitinib is marketed as Xeljanz except for Russia, where it is marketed as Jaquinus.[36]
Research
This section needs to be updated. Please help update this article to reflect recent events or newly available information.(November 2020)
It has demonstrated effectiveness in the treatment of
psoriasis in phase III studies. As of November 2013 it was studied in immunological diseases, as well as for the prevention of
organ transplant rejection.[37][38][39][40]
Psoriasis
Tofacitinib is an investigational drug in psoriasis. As of October 2015, it demonstrated its effectiveness for plaque psoriasis in phase III, randomized, controlled trials in comparison to placebo and to
etanercept.[31][41][42][43] In particular, a ten-mg, twice-daily dose of tofacitinib was shown to be not inferior to etanercept 50 mg, subcutaneously, twice weekly.[42]
In October 2015, the FDA rejected approval of tofacitinib for the treatment of psoriasis due to safety concerns.[44]
Alopecia areata
Based on preclinical studies in a mouse model of the disease,[45] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports[46][47] suggested potential efficacy, as did a phase II open-label clinical trial,[48] published in tandem with a phase II clinical trial showing the same for ruxolitinib.[49]
Vitiligo
In a June 2015 case report, a 53-year-old woman with
vitiligo showed noticeable improvement after taking tofacitinib for five months.[50]
Atopic dermatitis
The results of using tofacitinib in six patients with recalcitrant
atopic dermatitis was published in September 2015. All saw improvement in their atopic dermatitis without any adverse events.[51]
Ankylosing spondylitis
In 2021 and 2022, results of a phase III randomised, double-blind, placebo-controlled trial were reported, that showed significant improvements for patients with active
ankylosing spondylitis compared to placebo.[52][53]
^Garber K (January 2013). "Pfizer's first-in-class JAK inhibitor pricey for rheumatoid arthritis market". Nature Biotechnology. 31 (1): 3–4.
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^Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, et al. (July 2009). "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo". Arthritis and Rheumatism. 60 (7): 1895–1905.
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^
abBachelez H, van de Kerkhof PC, Strohal R, Kubanov A, Valenzuela F, Lee JH, et al. (August 2015). "Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial". Lancet. 386 (9993): 552–561.
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^Vuitton L, Koch S, Peyrin-Biroulet L (November 2013). "Janus kinase inhibition with tofacitinib: changing the face of inflammatory bowel disease treatment". Current Drug Targets. 14 (12): 1385–1391.
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