Tofacitinib

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Tofacitinib
Clinical data
Trade namesXeljanz, Jaquinus, Tofacinix, Others
Other namesCP-690550
AHFS/Drugs.comMonograph
MedlinePlusa613025
License data
Pregnancy
category
Routes of
administration		By mouth
Drug classJanus kinase (JAK) inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability74%
Protein binding40%
MetabolismLiver (via CYP3A4 and CYP2C19)
Elimination half-life3 hours
ExcretionUrine
Identifiers
  • 3-[(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
JSmol)
  • CC1CCN(C(=O)CC#N)CC1N(C)c1ncnc2[nH]ccc12
  • InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1
  • Key:UJLAWZDWDVHWOW-YPMHNXCESA-N

Tofacitinib, sold under the brand Xeljanz among others, is a medication used to treat rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, polyarticular course juvenile idiopathic arthritis, and ulcerative colitis.[7][8][9] It is a janus kinase (JAK) inhibitor,[7][8] discovered and developed by the National Institutes of Health and Pfizer.

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.

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]

The most commonly reported

nasopharyngitis (the "common cold").[7]

Tofacitinib is required by the FDA to have a

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]

Mechanism

It is an

DNA transcription.[24]

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

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

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]

As of June 2021, tofacitinib is available as a

generic medicine in the US.[34][35]

Society and culture

Names

Tofacitinib is marketed as Xeljanz except for Russia, where it is marketed as Jaquinus.[36]

Research

It has demonstrated effectiveness in the treatment 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]

Ulcerative colitis

As of November 2013 it was studied for treatment of inflammatory bowel disease.[54][43]The FDA approved tofacitinib in May 2018 for treatment of ulcerative colitis.[20]

References

  1. ^ "Tofacitinib Use During Pregnancy". Drugs.com. 15 April 2020. Retrieved 23 October 2020.
  2. FDA
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  3. ^ "Xeljanz/Xeljanz XR (Pfizer Australia Pty Ltd)". Therapeutic Goods Administration (TGA). 16 February 2023. Retrieved 10 April 2023.
  4. ^ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  5. ^ "10 mg film-coated tablets - Summary of Product Characteristics (SmPC)". (emc). 13 October 2020. Retrieved 3 November 2020.
  6. ^ "Xeljanz 11 mg prolonged release tablets - Summary of Product Characteristics (SmPC)". (emc). Retrieved 3 November 2020.
  7. ^ a b c d e f g h "Xeljanz- tofacitinib tablet, film coated Xeljanz XR- tofacitinib tablet, film coated, extended release Xeljanz- tofacitinib solution". DailyMed. 2 October 2020. Retrieved 3 November 2020.
  8. ^ a b c d e "Xeljanz EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 3 November 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  9. ^ a b c "Tofacitinib Citrate". The American Society of Health-System Pharmacists. Retrieved 1 June 2018.
  10. ^ "Safety Alerts for Human Medical Products - Xeljanz, Xeljanz XR (tofacitinib): Safety Communication - Safety Trial Finds Increased Risk of Blood Clots in the Lungs and Death with Higher Dose in Rheumatoid Arthritis Patients". U.S. Food and Drug Administration (FDA). Retrieved 2 March 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  11. ^ "Meeting highlights from the Pharmacovigilance Risk Assessment Committee (PRAC) 13-16 May 2019, May 17, 2019". European Medicines Agency. 17 May 2019. Retrieved 17 May 2019.
  12. ^ "Xeljanz, Xeljanz XR (tofacitinib): Drug Safety Communication - Due to an Increased Risk of Blood Clots and Death with Higher Dose". U.S. Food and Drug Administration (FDA). 26 July 2019. Archived from the original on 15 December 2019. Retrieved 10 August 2019. Public Domain This article incorporates text from this source, which is in the public domain.
  13. ^ FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR). U.S. Food and Drug Administration (FDA) (Podcast). 5 August 2019. Retrieved 15 December 2019.
  14. ^ "FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR)". U.S. Food and Drug Administration. 15 December 2019. Archived from the original on 15 December 2019. Retrieved 15 December 2019.
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  16. ^ a b "Drug Approval Package: Xeljanz (tofacitinib) Tablets NDA #203214". U.S. Food and Drug Administration (FDA). 28 December 2012. Retrieved 30 June 2023.
  17. ^ "Drug Approval Package: Xeljanz (tofacitinib) Extended Release (XR) Tablets NDA #208246". U.S. Food and Drug Administration (FDA). 26 June 2017. Retrieved 30 June 2023.
  18. ^ "First Generic Drug Approvals 2023". U.S. Food and Drug Administration (FDA). 30 May 2023. Archived from the original on 30 June 2023. Retrieved 30 June 2023.
  19. ^ a b c "FDA approves Xeljanz for rheumatoid arthritis". U.S. Food and Drug Administration (FDA) (Press release). 6 November 2012. Archived from the original on 2 April 2014. Public Domain This article incorporates text from this source, which is in the public domain.
  20. ^ a b "FDA approves new treatment for moderately to severely active ulcerative colitis". U.S. Food and Drug Administration (FDA) (Press release). 30 May 2018. Archived from the original on 15 December 2019. Retrieved 1 June 2018. Public Domain This article incorporates text from this source, which is in the public domain.
  21. ^ Nordqvist C (27 April 2013). "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. Retrieved 2 August 2013.
  22. ^ McKee S (29 June 2018). "EU approves Pfizer's Xeljanz for psoriatic arthritis". PharmaTimes. Retrieved 3 June 2019.
  23. ^ FDA Warns of Risk for PE, Death With Higher Dose Tofacitinib (Xeljanz) for RA - Medscape - 25 February 2019.
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  32. ^ "U.S. FDA Approves Pfizer's Xeljanz (tofacitinib) for the Treatment of Active Polyarticular Course Juvenile Idiopathic Arthritis". Pfizer (Press release). Retrieved 21 August 2023.
  33. ^ "U.S. FDA Approves Pfizer's Xeljanz (tofacitinib) for the Treatment of Active Ankylosing Spondylitis". Pfizer (Press release). Retrieved 21 August 2023.
  34. ^ "Tofacitinib citrate: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 24 September 2021.
  35. ^ "Tofacitinib: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 24 September 2021.
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External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Tofacitinib&oldid=1204840789"