tofacitinib

General

Genetic Implications:

Pronunciation:
toe-fa-sye-ti-nib

Trade Name(s)

• Xeljanz
• Xeljanz XR

Ther. Class.

antirheumatics

Pharm. Class.

kinase inhibitors

Indications

• Moderately to severely active rheumatoid arthritis in patients who have had an inadequate response/intolerance to ≥1 tumor necrosis factor (TNF) blocker (as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs [DMARDs]) (not to be used with biologic DMARDs or potent immunosuppressants, including azathioprine and cyclosporine) (immediate-release and extended-release tablets only).
• Active psoriatic arthritis in patients who have had an inadequate response/intolerance to ≥1 TNF blocker (in combination with other nonbiologic DMARDs) (not to be used with biologic DMARDs or potent immunosuppressants, including azathioprine and cyclosporine) (immediate-release and extended-release tablets only).
• Active ankylosing spondylitis in patients who have had an inadequate response/intolerance to ≥1 TNF blocker (not to be used with biologic DMARDs or potent immunosuppressants, including azathioprine and cyclosporine) (immediate-release and extended-release tablets only).
• Moderately to severely active ulcerative colitis in patients who have had an inadequate response/intolerance to ≥1 TNF blocker (not to be used with biologic therapies or potent immunosuppressants, including azathioprine and cyclosporine) (immediate-release and extended-release tablets only).
• Active polyarticular course juvenile idiopathic arthritis in patients who have had an inadequate response/intolerance to ≥1 TNF blocker (not to be used with biologic DMARDs or potent immunosuppressants, including azathioprine and cyclosporine) (immediate-release tablets and oral solution only).

Action

Acts as a Janus kinase inhibitor. Some results of inhibition include decreased hematopoiesis and immune cell function. Decreases circulating killer cells, increases B cell count, and decreases serum C-reactive protein.

Therapeutic Effect(s):

Improvement in clinical and symptomatic parameters of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis.

Pharmacokinetics

Absorption: 74% absorbed following oral administration.

Distribution: Well distributed to tissues.

Metabolism and Excretion: Primarily metabolized by the liver via the CYP3A4 isoenzyme, with some contribution from the CYP2C19 isoenzyme. 30% renal excretion of the parent drug.

Half-life: 3 hr.

TIME/ACTION PROFILE (clinical improvement)

Contraindication/Precautions

Contraindicated in:

• Active infection;
• Administration of live vaccines;
• Severe hepatic impairment;
• ↑ risk for thrombosis;
• History of MI or stroke;
• Lymphocyte count <500 cells/mm³ , ANC <1000 cells/mm³ , or Hgb <9 g/dL;
• Lactation: Lactation.

Use Cautiously in:

• Patients with rheumatoid arthritis who are >50 yr old and have ≥1 cardiovascular risk factor (↑ risk of all-cause mortality, cardiovascular death, MI, stroke, and thrombosis);
• Current or past history of smoking (↑ risk of malignancy, cardiovascular death, MI, or stroke);
• Known malignancy;
• Risk of GI perforation;
• Chronic lung disease (↑ risk of infection);
•  Japanese patients (↑ risk of herpes zoster);
• OB:  Use during pregnancy only if potential maternal benefit justifies potential fetal risk;
• Pedi:  Safety and effectiveness not established in children <18 yr (rheumatoid arthritis, psoriatic arthritis, ulcerative colitis) or <2 yr (active polyarticular course juvenile idiopathic arthritis);
• Geri:  Infection risk may be ↑ in older adults.

Adverse Reactions/Side Effects

CV: ARTERIAL THROMBOSIS, CARDIOVASCULAR DEATH, DEEP VEIN THROMBOSIS (DVT), MI, peripheral edema

Derm: erythema, pruritus, rash

F and E: dehydration

GI: ↑ liver enzymes, abdominal pain, diarrhea, dyspepsia, gastritis, GI PERFORATION, vomiting

GU: ↑ serum creatinine

Hemat: anemia, neutropenia

Metabolic: hyperlipidemia

MS: arthralgia, joint swelling, musculoskeletal pain, tendonitis

Neuro: fatigue, headache, insomnia, paresthesia, STROKE

Resp: PULMONARY EMBOLISM (PE)

Misc: DEATH, fever, HYPERSENSITIVITY REACTIONS (including angioedema and urticaria), INFECTION (including tuberculosis [TB], bacterial, invasive fungal infections, viral, and other infections due to opportunistic pathogens), MALIGNANCY

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• May ↑ risk of adverse reactions and ↓ antibody response to  live vaccines ; avoid concurrent use.
•  Strong CYP3A4 inhibitors, including  ketoconazole, or  moderate CYP3A4 inhibitors/strong CYP2C19 inhibitors, including  fluconazole, may ↑ levels and risk of toxicity; dose ↓ recommended.
•  Strong CYP3A4 inducers, including  rifampin, may ↓ levels and effectiveness; avoid concurrent use.
• ↑ risk of immunosuppression when used concurrently with other potent  immunosuppressants, including  azathioprine,  cyclosporine,  tacrolimus,  antineoplastics, or  radiation therapy.

Route/Dosage

Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis

PO (Adults): Immediate-release tablets:  5 mg twice daily;  Extended-release tablets:  11 mg once daily;  Concurrent use of strong CYP3A4 inhibitors or concurrent use of moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor:  5 mg once daily (immediate-release tablets); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release tablets).

Renal Impairment 
PO (Adults): Moderate or severe renal impairment:  5 mg once daily (immediate-release); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release tablets). For patients undergoing hemodialysis, administer dose after dialysis session.

Hepatic Impairment 
PO (Adults):  Moderate hepatic impairment:  5 mg once daily (immediate-release tablets); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release tablets).

Ulcerative Colitis

PO (Adults): Immediate-release tablets:  Induction: 10 mg twice daily for ≥8 wk; based on therapeutic response, may transition to maintenance dose or continue 10 mg twice daily for an additional 8 wk. Discontinue therapy if inadequate response achieved after 16 wk using 10 mg twice daily. Maintenance: 5 mg twice daily; if patient experiences loss of response on 5 mg twice daily, then use 10 mg twice daily after assessing the benefits and risks and use for the shortest duration; use lowest effective dose to maintain response;  Extended-release tablets:  Induction: 22 mg once daily for ≥8 wk; based on therapeutic response, may transition to maintenance dose or continue 22 mg once daily for an additional 8 wk. Discontinue therapy if inadequate response achieved after 16 wk using 22 mg once daily. Maintenance: 11 mg once daily; if patient experiences loss of response on 11 mg once daily, then use 22 mg once daily after assessing the benefits and risks and use for the shortest duration; use lowest effective dose to maintain response;  Concurrent use of strong CYP3A4 inhibitors or concurrent use of moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor:  If taking 10 mg twice daily (immediate-release tablets), ↓ to 5 mg twice daily (immediate-release tablets); if taking 5 mg twice daily (immediate-release tablets), ↓ to 5 mg once daily (immediate-release tablets). If taking 22 mg once daily (extended-release tablets), then ↓ to 11 mg once daily (extended-release tablets); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release tablets).

Renal Impairment 
PO (Adults): Moderate or severe renal impairment:  If taking 10 mg twice daily (immediate-release tablets), ↓ to 5 mg twice daily (immediate-release tablets); if taking 5 mg twice daily (immediate-release tablets), ↓ to 5 mg once daily (immediate-release tablets). If taking 22 mg once daily (extended-release tablets), then ↓ to 11 mg once daily (extended-release tablets); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release tablets). For patients undergoing hemodialysis, administer dose after dialysis session.

Hepatic Impairment 
PO (Adults):  Moderate hepatic impairment:  If taking 10 mg twice daily (immediate-release tablets), ↓ to 5 mg twice daily (immediate-release tablets); if taking 5 mg twice daily (immediate-release tablets), ↓ to 5 mg once daily (immediate-release tablets). If taking 22 mg once daily (extended-release tablets), then ↓ to 11 mg once daily (extended-release tablets); if taking 11 mg once daily (extended-release tablets), then switch to 5 mg once daily (immediate-release).

Active Polyarticular Course Juvenile Idiopathic Arthritis

PO (Children  ≥2 yr and ≥40 kg): Immediate-release tablets or oral solution:  5 mg twice daily.  Concurrent use of strong CYP3A4 inhibitors or concurrent use of moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor:  5 mg once daily (immediate-release tablets or oral solution).

PO (Children  ≥2 yr and 20–<40 kg): Oral solution:  4 mg twice daily.  Concurrent use of strong CYP3A4 inhibitors or concurrent use of moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor:  4 mg once daily (oral solution).

PO (Children  ≥2 yr and 10–<20 kg): Oral solution:  3.2 mg twice daily.  Concurrent use of strong CYP3A4 inhibitors or concurrent use of moderate CYP3A4 inhibitor with a strong CYP2C19 inhibitor:  3.2 mg once daily (oral solution).

Renal Impairment 
PO (Children  ≥2 yr and ≥40 kg): Moderate or severe renal impairment:  Immediate-release tablets or oral solution: 5 mg once daily. For patients undergoing hemodialysis, administer dose after dialysis session.

Renal Impairment 
PO (Children  ≥2 yr and 20–<40 kg): Moderate or severe renal impairment:  Oral solution: 4 mg once daily. For patients undergoing hemodialysis, administer dose after dialysis session.

Renal Impairment 
PO (Children  ≥2 yr and 10–<20 kg): Moderate or severe renal impairment:  Oral solution: 3.2 mg once daily. For patients undergoing hemodialysis, administer dose after dialysis session.

Hepatic Impairment 
PO (Children  ≥2 yr and ≥40 kg): Moderate hepatic impairment:  Immediate-release tablets or oral solution: 5 mg once daily.

Hepatic Impairment 
PO (Children  ≥2 yr and 20–<40 kg): Moderate hepatic impairment:  Oral solution: 4 mg once daily.

Hepatic Impairment 
PO (Children  ≥2 yr and 10–<20 kg): Moderate hepatic impairment:  Oral solution: 3.2 mg once daily.

Availability (generic available)

Immediate-release tablets: 5 mg, 10 mg

Extended-release tablets: 11 mg, 22 mg

Oral solution (grape flavor): 1 mg/mL

Assessment

• Assess pain and range of motion before and periodically during therapy.
• Assess for signs and symptoms of infection, including opportunistic infections and TB, prior to and periodically during therapy.  If sepsis or serious infection occurs,  interrupt therapy and provide appropriate diagnostic testing, antimicrobial therapy, and close monitoring. Most common are pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Infections may be fatal, especially in patients taking immunosuppressive therapy.
• Assess for signs and symptoms of systemic fungal infections (fever, malaise, weight loss, sweats, cough, dypsnea, pulmonary infiltrates, serious systemic illness with or without concomitant shock). Ascertain if patient lives in or has traveled to areas of endemic mycoses. Consider empiric antifungal treatment for patients at risk of histoplasmosis and other invasive fungal infections until pathogen identified. Consult with infectious diseases specialist. Consider stopping tofacitinib until the infection has been diagnosed and adequately treated.
• Monitor for thrombosis, including PE, DVT, and arterial thrombi.  If symptoms of thrombosis occur,  permanently discontinue tofacitinib.

Lab Test Considerations:

• Monitor CBC with differential prior to and periodically during therapy. Do not initiate tofacitinib in patients with lymphocyte count <500 cells/mm³ , ANC <1000 cells/mm³ , or Hgb <9 g/dL.

  • Monitor lymphocyte count at baseline and every 3 mo thereafter.  If lymphocyte count ≥500 cells/mm³ ,  maintain dose.  If lymphocyte count <500 cells/mm³  and confirmed by repeat testing,  permanently discontinue tofacitinib.
  • Monitor neutrophil count at baseline, after 4–8 wk of therapy, and every 3 mo thereafter.  If ANC >1000 cells/mm³ ,  maintain dose.  If ANC 500–1000 cells/mm³ ,  interrupt dosing until ANC >1000 cells/mm³ .  If ANC <500 cells/mm³  and confirmed by repeat testing,  permanently discontinue tofacitinib.
  • Monitor Hgb at baseline, after 4–8 wk of therapy, and every 3 mo thereafter.  If ↓ in Hgb ≤2 g/dL and Hgb ≥9.0 g/dL and confirmed by repeat testing,  maintain dose.  If ↓ in Hgb >2 dL and Hgb <8.0 g/dL,  interrupt administration of tofacitinib until Hgb values have normalized.
  • Monitor liver enzymes prior to and periodically during therapy.
  • Monitor total cholesterol, LDL-C, and HDL-C for 4–8 wk following initiation of therapy.
• Complete tuberculin skin test prior to initiation of therapy. Treatment of latent TB should be started before therapy with tofacitinib.

Implementation

• Immunizations should be current prior to initiating therapy. Patients on tofacitinib should not receive live vaccines.
• Screen patient for viral hepatitis before starting therapy.
• Extended-release tablets are not interchangeable with oral solution.
• To switch from immediate release to extended release,  patients treated with  Xeljanz  5 mg twice daily may be switched to  Xeljanz XR  11 mg once daily the day following the last dose of  Xeljanz  5 mg.
• PO Administer twice daily without regard to food.  DNC: Swallow extended-release tablets whole; do not crush, break, or chew. 
  • Oral solution is clear and colorless. Administer oral solution using the included press-in bottle adapter and oral dosing syringe.

Patient/Family Teaching

• Instruct patient to take tofacitinib as directed. Advise patient to read  Medication Guide  before starting and with each Rx refill in case of changes.
• Caution patient to notify health care professional immediately if signs of infection (fever; sweating; chills; muscle aches; cough; shortness of breath; blood in phlegm; weight loss; warm, red, or painful skin or sores; diarrhea or stomach pain; burning on urination or urinating more often than normal; feeling very tired), hypersensitivity (facial swelling, hives), or stomach or intestinal perforation (fever, stomach-area pain that does not go away, change in bowel habits) occur.
• Inform patient ≥50 yr of age with ≥1 cardiovascular risk factor that risk of death from all causes is ↑ with tofacitinib use. They should discontinue therapy if they experience heart attack or stroke.
• Inform patient that risk of malignancy and lymphoproliferative disorders is ↑ with tofacitinib use and periodic cancer screens, including skin assessments, are recommended.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
• Instruct patient to notify health care professional of medication regimen prior to treatment or surgery.
• Rep:  Advise women of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy and for ≥18 hr after the last dose of oral solution or 36 hr after the last dose of extended-release tablets. May impair female fertility.
• Emphasize importance of follow-up lab tests to monitor for adverse reactions.

Evaluation/Desired Outcomes

• Decreased pain and swelling with improved physical functioning and ↓ rate of joint destruction in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and polyarticular course juvenile idiopathic arthritis.
• Decrease in diarrhea and abdominal pain in patients with ulcerative colitis.