Tofacitinib

What is Tofacitinib

Tofacitinib is an oral Janus kinase (JAK) inhibitor, and is considered a targeted synthetic disease-modifying antirheumatic drug (tsDMARD).

Janus kinases are intracellular enzymes that transmit signals arising from cytokine interactions on the cellular membrane to influence cellular processes of immune cell function.

Tofacitinib has been shown useful for a variety of inflammatory conditions.

It is indicated for adults with moderately to severely active rheumatoid arthritis (RA) and psoriatic arthritis (PsA) who have had an inadequate response or intolerance to methotrexate.

Tofacitinib acts on JAK1/JAK2 (important for IL-6 and IFN signaling), JAK1/JAK3 (important for T-cell and B-cell signaling), and JAK2/JAK2 (growth factor signaling) dimer pairs. As a result of JAK 3 inhibition, the production of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, which are important in T-cell and B-cell activation and function, is decreased. Additionally, with JAK1 inhibition, IL-6 and IFN-γ production are attenuated. Finally IL-2-dependent differentiation of Th2 and Th17 cells is decreased. It is metabolized and eliminated primarily by the liver (70%) with the remainder excreted by the kidneys (30%). Half-life is 3 hours for 5-mg tablet and 6 hours for extended-release (XR) tablet.

  • • FDA-approved indication: RA and PsA with inadequate response to MTX. Also approved for ulcerative colitis. Case reports show effectiveness in dermatomyositis rash and uveitis.
  • • Available formulation: 5-mg tablet, 11-mg XR tablet. There is a 10-mg tablet for use in ulcerative colitis.
  • • Dosage (RA and PsA): 5-mg tablet BID or 11-mg XR tablet QD. Not affected by food. Dose should be decreased to 5 mg daily if severe liver or renal disease. Can be used alone or in combination with MTX. Avoid use with AZA, cyclosporine, or biologic disease-modifying antirheumatic drugs (DMARDs).
  • • Cost (5-mg BID): $4300/month.
  • • Follow-up: CBC (with differential), creatinine, and hepatic enzymes monthly for 3 months, then every 3 months. Maximum effect on lipids occurs by 6 to 8 weeks, thus lipid panel should be done by 12 weeks.
  • • Adverse reactions: common symptoms (4%–5%) include nasopharyngitis, diarrhea, and headache.
  • • Infections: any (20%), serious (2.7 events/100 patient years), opportunistic (0.3 events/100 patient years). Herpes zoster may be increased more than with other biologics and DMARDs.
  • • Hematologic: lymphopenia <500/mm (0.3%), absolute neutrophil count <1000/mm (0.07%), or hemoglobin drop >2 g/dL. Stop tofacitinib until counts recover, and then restart at lower dose. Lymphopenia associated with higher infection rate.
  • • Hepatic enzyme elevations >3 × upper limit of normal (ULN; 1.3%). Stop tofacitinib until enzymes improve, restart at lower dose.
  • • Lipid abnormalities: low-density and high-density lipoprotein increases 15% and 10%, respectively.
  • • Creatinine increase >50% of baseline (2% of patients): etiology unknown. Reversible if stop tofacitinib.
  • • Malignancy: solid tumors (0.6 events/100 patient years) and lymphoma reported in tofacitinib group but not placebo-treated group.
  • • GI perforations: have been reported.
  • • Immunizations: decreases response to inactivated vaccines.
  • • Precautions: do not use in patients with active infection. Patients with hepatitis B and C excluded from trials. Drug interactions include decreased effectiveness if used with rifampin. The tofacitinib dose needs to be decreased by half if the patient is put on ketoconazole/fluconazole. Do not use during pregnancy or breast feeding.

Brand Name

  • Xeljanz
  • Xeljanz XR

Indications

  1. coronavirus disease 2019 (COVID-19)
  2. psoriatic arthritis
  3. rheumatoid arthritis
  4. severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection
  5. ulcerative colitis

For the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to or intolerance to methotrexate

Side Effects

  1. abdominal pain
  2. acne vulgaris
  3. anemia
  4. angioedema
  5. arthralgia
  6. candidiasis
  7. cardiac arrest
  8. cough
  9. dehydration
  10. diarrhea
  11. dyspepsia
  12. elevated hepatic enzymes
  13. erythema
  14. fatigue
  15. fever
  16. gastritis
  17. GI perforation
  18. headache
  19. hepatitis B exacerbation
  20. hepatotoxicity
  21. hypercholesterolemia
  22. hyperlipidemia
  23. hypertension
  24. hypertriglyceridemia
  25. infection
  26. insomnia
  27. interstitial lung disease
  28. lymphocytosis
  29. lymphoma
  30. lymphopenia
  31. musculoskeletal pain
  32. nasal congestion
  33. nausea
  34. neutropenia
  35. new primary malignancy
  36. paresthesias
  37. peripheral edema
  38. pharyngitis
  39. post-transplant lymphoproliferative disorder (PTLD)
  40. pruritus
  41. pulmonary embolism
  42. rash
  43. skin cancer
  44. steatosis
  45. thromboembolism
  46. thrombosis
  47. urticaria
  48. vomiting

Monitoring Parameters

  • CBC with differential
  • hemoglobin/hematocrit
  • LFTs
  • platelet count
  • serum cholesterol profile
  • serum creatinine/BUN
  • skin cancer screening exam
  • tuberculin skin test

Contraindications

  • acquired immunodeficiency syndrome (AIDS)
  • anemia
  • Asian patients
  • breast-feeding
  • cardiac disease
  • children
  • contraception requirements
  • corticosteroid therapy
  • diabetes mellitus
  • diverticulitis
  • fungal infection
  • geriatric
  • GI obstruction
  • GI perforation
  • hepatic disease
  • hepatitis
  • hepatitis B exacerbation
  • herpes infection
  • human immunodeficiency virus (HIV) infection
  • hypercholesterolemia
  • hyperlipidemia
  • hypertension
  • immunosuppression
  • infants
  • infection
  • infertility
  • interstitial lung disease
  • kidney transplant
  • lymphoma
  • mortality
  • myocardial infarction
  • neutropenia
  • new primary malignancy
  • post-transplant lymphoproliferative disorder (PTLD)
  • pregnancy
  • pulmonary disease
  • renal failure
  • renal impairment
  • reproductive risk
  • skin cancer
  • thromboembolism
  • thrombosis
  • tuberculosis
  • vaccination
  • viral infection

Interactions

  • Abatacept
  • Amoxicillin; Clarithromycin; Lansoprazole
  • Amoxicillin; Clarithromycin; Omeprazole
  • Anakinra
  • Apalutamide
  • Atazanavir
  • Atazanavir; Cobicistat
  • Atropine; Hyoscyamine; Phenobarbital; Scopolamine
  • Azathioprine
  • Bacillus Calmette-Guerin Vaccine, BCG
  • Baricitinib
  • Belladonna Alkaloids; Ergotamine; Phenobarbital
  • Canakinumab
  • Carbamazepine
  • Ceritinib
  • Chloramphenicol
  • Clarithromycin
  • Cobicistat
  • Conivaptan
  • Cyclosporine
  • Darunavir
  • Darunavir; Cobicistat
  • Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide
  • Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir
  • Delavirdine
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide
  • Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate
  • Enzalutamide
  • Everolimus
  • Fluconazole
  • Fluoxetine
  • Fluoxetine; Olanzapine
  • Fluvoxamine
  • Fosamprenavir
  • Fosphenytoin
  • grapefruit juice
  • Idelalisib
  • Indinavir
  • Influenza Virus Vaccine
  • Intranasal Influenza Vaccine
  • Isoniazid, INH; Pyrazinamide, PZA; Rifampin
  • Isoniazid, INH; Rifampin
  • Itraconazole
  • Ixekizumab
  • Ketoconazole
  • Letermovir
  • Live Vaccines
  • Lopinavir; Ritonavir
  • Lumacaftor; Ivacaftor
  • Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live
  • Measles/Mumps/Rubella Vaccines, MMR
  • Mercaptopurine, 6-MP
  • Mifepristone
  • Mitotane
  • Nefazodone
  • Nelfinavir
  • Ombitasvir; Paritaprevir; Ritonavir
  • Phenobarbital
  • Phenytoin
  • Posaconazole
  • Primidone
  • Ribociclib
  • Ribociclib; Letrozole
  • Rifampin
  • Ritonavir
  • Rituximab
  • Rituximab; Hyaluronidase
  • Rotavirus Vaccine
  • Rubella Virus Vaccine Live
  • Saquinavir
  • Sarilumab
  • Secukinumab
  • Sirolimus
  • Smallpox and Monkeypox Vaccine, Live, Nonreplicating
  • Smallpox Vaccine, Vaccinia Vaccine
  • St. John’s Wort, Hypericum perforatum
  • Tacrolimus
  • Telithromycin
  • Ticlopidine
  • Tipranavir
  • Tocilizumab
  • Tucatinib
  • Tumor Necrosis Factor modifiers
  • Typhoid Vaccine
  • Upadacitinib
  • Ustekinumab
  • Varicella-Zoster Virus Vaccine, Live
  • Voriconazole
  • Yellow Fever Vaccine, Live
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