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 (RA) in patients who have had an inadequate response/intolerance to methotrexate (as monotherapy or in combination with methotrexate or other 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 methotrexate or other DMARDs (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).
• Moderately-to-severely active ulcerative colitis in patients who have had an inadequate response/intolerance to tumor necrosis factor inhibitors (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 (immediate-release tablets and oral solution only).

Action

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

Therapeutic Effect(s):

Improvement in clinical and symptomatic parameters of RA, psoriatic arthritis, and ulcerative colitis.

Pharmacokinetics

Absorption: Well absorbed following oral administration (74%).

Distribution: Distributes equally between red blood cells and plasma.

Metabolism and Excretion: 70% metabolized by the liver (primarily CYP3A4 with some contribution from CYP2C19). 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;
• Increased risk for thrombosis;
• Lymphocyte count <500 cells/mm³ , absolute neutrophil count (ANC) <1000 cells/mm³ , or hemoglobin levels <9 g/dL;
•  Lactation .

Use Cautiously in:

• Patients with RA who are >50 yr old and have ≥1 cardiovascular risk factor (↑ risk of mortality and thrombosis with use of higher than recommended doses for RA);
• 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 (RA, psoriatic arthritis, and 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, DEEP VEIN THROMBOSIS, peripheral edema

Derm: erythema, pruritus, rash

F and E: dehydration

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

GU: ↑ serum creatinine

Hemat: anemia, neutropenia

Metabolic: ↑ lipids

MS: arthralgia, joint swelling, musculoskeletal pain, tendonitis

Neuro: paresthesia, fatigue, headache, insomnia

Resp: PULMONARY EMBOLISM

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

* 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.
• Blood levels and effects may be ↑ by  strong CYP3A4 inhibitors  including  ketoconazole  or  moderate CYP3A4 inhibitors/strong CYP2C19 inhibitors  including  fluconazole ; dose ↓ recommended.
• Blood levels and effectiveness may be ↓  strong CYP3A4 inducers  including  rifampin ; avoid concurrent use.
• ↑ risk of immunosuppression when used concurrently with other potent  immunosuppressants  including  azathioprine,  cyclosporine,  tacrolimus,  antineoplastics, or  radiation therapy.

Route/Dosage

RA and Psoriatic Arthritis

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 (immedate-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): Moderate or severe renal impairment– ≥40 kg: 5 mg once daily (immediate-release tablets or oral solution); 20–<40 kg: 4 mg once daily (oral solution). 10–<20 kg: 3.2 mg once daily (oral solution). For patients undergoing hemodialysis, administer dose after dialysis session.

Hepatic Impairment 
PO (Children ≥2 yr): Moderate hepatic impairment– ≥40 kg: 5 mg once daily (immediate-release tablets or oral solution); 20–<40 kg: 4 mg once daily (oral solution). 10–<20 kg: 3.2 mg once daily (oral solution).

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 of infection (fever, dyspnea, flu-like symptoms, frequent or painful urination, redness or swelling at the site of a wound), including tuberculosis, prior to and periodically during therapy. Interrupt therapy if patient develops an active infection. Monitor new infections closely; 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 the pathogens are identified. Consult with an infectious diseases specialist. Consider stopping tofacitinib until the infection has been diagnosed and adequately treated.
• Assess patient for latent tuberculosis with a tuberculin skin test prior to initiation of therapy. Treatment of latent tuberculosis should be started before therapy with tofacitinib.

Lab Test Considerations:

Monitor CBC prior to and periodically during therapy. Do not initiate tofacitinib in patients with lymphocyte count <500 cells/mm³ , an ANC <1000 cells/mm³ , or who have hemoglobin level <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,  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 , for persistent decreases in this range, interrupt dosing until ANC is >1000 cells/mm³ .  If ANC <500 cells/mm³  and confirmed by repeat testing , discontinue tofacitinib.
• Monitor hemoglobin at baseline, after 4–8 wk of therapy, and every 3 mo thereafter.  If hemoglobin ≤2 g/dL decrease and ≥9.0 g/dL and confirmed by repeat testing , maintain dose.  If hemoglobin >2 dL decrease and <8.0 g/dL , interrupt administration of tofacitinib until hemoglobin values have normalized.
• Monitor liver enzymes prior to and periodically during therapy.
• Monitor total cholesterol, LDL cholesterol, HDL cholesterol 4–8 wk following initiation of therapy.

Implementation

• Administer a tuberculin skin test prior to administration of tofacitinib. Patients with active latent TB should be treated for TB prior to therapy.

  • 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. 

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) or stomach or intestinal perforation (fever, stomach-area pain that does not go away, change in bowel habits) occur.
• 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.
• Inform patient of increased risk of lymphoma and other cancers. Advise patient to have periodic skin exams for new lesions of skin cancer.
• Rep:  Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breast feeding during therapy. Inform patient of pregnancy exposure registry that monitors pregnancy outcomes in women exposed to tofacitinib during pregnancy. Encourage patients who become pregnant during therapy to enroll in the pregnancy registry by calling 1-877-311-8972. May impair female fertility.
• Emphasize the importance of follow-up lab tests to monitor for adverse reactions.

Evaluation/Desired Outcomes

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