Tofacitinib (tofacitinib)

Overview

Tofacitinib is an oral Janus kinase (JAK) inhibitor developed by Pfizer and first approved in the United States in 2012 as Xeljanz. Unlike the biologics that must be injected or infused, it is a small molecule taken by mouth, which made it the first oral option of its class for rheumatoid arthritis. It blocks JAK1 and JAK3 inside immune cells and interrupts the JAK-STAT signalling that keeps inflammatory cytokines such as IL-2, IL-6, IL-15 and the interferons switched on. Tofacitinib is approved for moderately to severely active rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and ulcerative colitis in adults who have had an inadequate response or intolerance to one or more TNF blockers, and for polyarticular course juvenile idiopathic arthritis in patients 2 years of age and older. Tofacitinib carries one of the most serious boxed warnings in rheumatology. A large safety trial (ORAL Surveillance) in RA patients with cardiovascular risk factors found higher rates of major adverse cardiovascular events, venous and arterial thrombosis, all-cause mortality, lymphomas and lung cancers compared with TNF blockers, and the warning was expanded in December 2021. The label also warns of serious infections including tuberculosis and herpes zoster, gastrointestinal perforation, and laboratory abnormalities such as cytopenias, raised liver enzymes and elevated lipids. Blood counts, liver enzymes, lipids, and renal and hepatic function are checked before and during treatment, and live vaccines must be avoided. Tofacitinib is a small molecule, so ordinary generics are possible. Cipla (Tofajak) and Natco (Jaknat) sell generics in India, and at least twelve brands are registered in Bangladesh. Every generic carries the same JAK-inhibitor boxed warning, and the immediate-release tablet, the extended-release tablet and the oral solution are not interchangeable with one another.

How it works

Tofacitinib is an oral tablet that blocks Janus kinase (JAK) enzymes inside immune cells, interrupting the signals that keep inflammation switched on. This reduces inflammation and joint damage, but it also dampens the immune system's ability to fight infection.

Tofacitinib is a potent inhibitor of the JAK family of kinases with functional selectivity for JAK1 and JAK3 over JAK2 (and TYK2). It is an ATP-competitive, reversible inhibitor and is metabolized mainly by CYP3A4 with a minor contribution from CYP2C19. Inhibition of JAK1/JAK3 blocks cytokine receptor signalling through the JAK-STAT pathway, reducing phosphorylation and activation of STAT transcription factors and thereby transcription of inflammatory cytokines such as IL-2, IL-6, IL-15 and interferons.

Approved indications

• Rheumatoid arthritis: moderately to severely active RA in adults who have had an inadequate response or intolerance to one or more TNF blockers
• Psoriatic arthritis: active PsA in adults who have had an inadequate response or intolerance to one or more TNF blockers
• Ankylosing spondylitis: active AS in adults who have had an inadequate response or intolerance to one or more TNF blockers
• Ulcerative colitis: moderately to severely active UC in adults who have had an inadequate response or intolerance to one or more TNF blockers
• Polyarticular course juvenile idiopathic arthritis: active pcJIA in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers (Xeljanz Oral Solution)

Dosage & administration

Rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis: 5 mg twice daily (immediate release) or Xeljanz XR 11 mg once daily. Ulcerative colitis induction: 10 mg twice daily or XR 22 mg once daily for 8 weeks; may continue for a maximum of 16 weeks, then discontinue if an adequate response is not achieved. UC maintenance: 5 mg twice daily or XR 11 mg once daily. Xeljanz XR is not interchangeable or substitutable with Xeljanz Oral Solution, and changes between formulations should be made by the healthcare provider.

Dose adjustment

Recommended dosage in patients with moderate to severe renal impairment or moderate hepatic impairment is 5 mg once daily (instead of twice daily). Do not initiate treatment if absolute lymphocyte count <500 cells/mm3, absolute neutrophil count <1000 cells/mm3, or hemoglobin <9 g/dL. Dose is interrupted or reduced for cytopenias and laboratory abnormalities per label.

Side effects

Upper respiratory tract infection · Nasopharyngitis · Headache · Diarrhea · Hypertension · Herpes zoster (shingles) · Increases in liver enzymes · Elevated lipids · Anemia, lymphopenia, neutropenia · Pneumonia, cellulitis, diverticulitis · Major adverse cardiovascular events (myocardial infarction, stroke)

Monitoring

• Test for latent tuberculosis before and during therapy; treat latent TB prior to use; monitor all patients for active TB
• Monitor for serious infections during and after treatment
• Baseline and periodic blood counts — lymphocyte count, neutrophil count, hemoglobin (do not initiate outside label thresholds)
• Baseline and periodic liver enzymes (hepatotoxicity)
• Lipid panel after initiation (elevated lipids)
• Monitor for thrombosis and for symptoms of MACE
• Monitor for malignancy including skin cancer
• Renal and hepatic function to guide dose reduction
• Avoid live vaccines during treatment

Generic and biosimilar landscape

Tofacitinib is a small-molecule drug, so conventional generics are possible and have been approved via the ANDA route (demonstrating pharmaceutical equivalence and bioequivalence to Xeljanz, not biosimilarity to a biologic). Generic tofacitinib tablets are now available in the US, with reported the data as low as -150 per month in some discount programs. Cipla (Tofajak) and Natco (Jaknat) market generic tofacitinib in India, and multiple local manufacturers sell it in Bangladesh. Generic products are bioequivalent to the reference product but are not identical in excipients and are not interchangeable between the immediate-release tablet and the extended-release tablet or oral solution. The same JAK-inhibitor boxed warning and monitoring apply to every tofacitinib product, branded or generic.

Who makes it

Availability in Southeast Asia

Frequently asked questions

Sources

1. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203214s028,208246s013,213082s003lbl.pdf
2. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203214s018lbl.Pdf
3. https://medex.com.bd/generics/1392/tofacitinib/brand-names
4. https://www.1mg.com/drugs/jaknat-tablet-636900
5. https://www.1mg.com/drugs/tofajak-5mg-tablet-672538
6. https://www.npra.gov.my/index.php/en/component/content/article/426-english/safety-alerts-main/safety-alerts-2021/1527288-janus-kinase-jak-inhibitors-in-rheumatoid-arthritis-patients-risk-of-major-adverse-cardiovascular-events-mace-and-malignancies-excluding-non-melanoma-skin-cancer-nmsc-2.html
7. https://ndi.fda.moph.go.th/uploads/drug_detail_corporation/doc/word/1302/40ec49d1c0cbdb29fe51e9d2b796d619-a2.pdf
8. https://www.naaf.org/news/generic-tofacitinib-alopecia-areata
9. https://www.prnewswire.com/news-releases/breckenridge-announces-launch-of-tofacitinib-tablets-generic-equivalent-of-xeljanz-by-pfizer-302791702.html
10. https://www.hikma.com/news/hikma-launches-tofacitinib-oral-solution-in-the-us