Dosing and uses of Xeljanz, Xeljanz XR (tofacitinib)
Adult dosage forms and strengths
tablet (Xeljanz)
- 5mg
tablet, extended-release (Xeljanz XR)
- 11mg
Rheumatoid Arthritis
Indicated as second-line treatment for moderate-to-severe active rheumatoid arthritis in patients with an inadequate response or intolerance to methotrexate; may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs
5 mg PO BID or 11 mg PO qDay
Dosage modifications
Coadministration with strong CYP3A4 inhibitors: Not to exceed 5 mg qDay
Coadministration with 1 or more drugs that result in both moderate CYP3A4 inhibition and strong CYP2C19 inhibition (eg, fluconazole): Not to exceed 5 mg qDay
Coadministration with strong CYP3A4 inducers: May result in loss of or reduced clinical response; coadministration is not recommended
Coadministration with methotrexate: No dosage adjustment required
Coadministration with P-gp inhibitors: No dosage adjustment required
Renal impairment
- Mild: No dosage adjustment required
- Moderate-to-severe: Not to exceed 5 mg qDay
Hepatic impairment
- Mild: No dosage adjustment required
- Moderate: Not to exceed 5 mg qDay
- Severe: Not recommended
Serious infection
- Interrupt treatment if serious infection develops until infection is controlled
- Lymphocytes ≥500/mm³: Maintain dose
- Lymphocytes <500/mm³: Discontinue until infection controlled
Neutropenia
- ANC >1000/mm³: Maintain dose
- ANC 500-1000/mm³: Interrupt dosing for persistent decreases; when ANC >1000/mm³, resume dose at 5 mg BID
- ANC <500/mm³: Discontinue
Anemia
- Hgb ≤2 g/dL decrease and level ≥9.0 g/dL: Maintain dose
- Hgb >2g/dL decrease or level <8.0 g/dL: Interrupt treatment until Hgb levels have normalized
Dosing Considerations
Should not be used in combination with biologic DMARDs or potent immunosuppressive agents (eg, azathioprine, cyclosporine)
Structural joint damage progression
- Radiographic response data from the ORAL Scan and ORAL Start studies evaluated the efficacy of tofacitinib on structural joint damage progression as measured by mean change from baseline in van der Heijde modified Total Sharp Score (mTSS) and its components, erosion score, and joint space narrowing (JSN) score
- In ORAL Scan, 74% of patients in the placebo/methotrexate group experienced no radiographic progression at Month 6 compared to 84% of patients treated with tofacitinib 5mg BID plus methotrexate
- In ORAL Start, 55% of patients in the methotrexate group experienced no radiographic progression at Month 6 compared to 73% of patients treated with tofactinib 5mg BID
Pediatric dosage forms and strengths
Safety and efficacy not established
Xeljanz, Xeljanz XR (tofacitinib) adverse (side) effects
>10%
Overall infections (20-22%)
1-10%
URTI (4.5%)
Headache (4.3%)
Diarrhea (4%)
Nasopharyngitis (3.8%)
UTI (2%)
Hypertension (1.6%)
<1%
ANC <500/mm³ (0.07%)
Lymphocytes <500/mm³ (0.04%)
Frequency not defined
Serious infections: 1.7 events per 100 patient-years
Malignancies: 0.3 events per 100 patient-years
Postmarketing reports
Diverticulitis
Warnings
Black box warnings
Serious infections
- Increased risk for developing serious infections that may lead to hospitalization or death; most patients who developed these infections were taking concomitant immunosuppressants (eg, methotrexate, corticosteroid)
- If serious infection develops, interrupt until infection controlled
- Reported infections include active TB, invasive fungal infections, and bacterial, viral, or other opportunistic pathogens
- Test patients for latent TB before and during tofacitinib treatment; treatment for latent TB infection should be initiated prior to tofacitinib treatment
Malignancies
- Lymphoma and other malignancies reported
- Epstein Barr virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications
Contraindications
None
Cautions
Serious and sometimes fatal infections reported due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens (see Black box warnings)
Malignancy and lymphoproliferative disorders reported (see Black box warnings)
GI perforation reported, although role of JAK inhibition in these events is unknown; caution in patients at increased risk for gastrointestinal perforation (eg, diverticulitis)
Associated with gradual decrease in lymphocyte and neutrophils counts, and hemoglobin levels that may require treatment interruption (see Dosage modifications)
Associated with increased LFTs
Associated with increase lipid parameters including total cholesterol, LDL, and HDL
Avoid coadministration with live virus vaccines
Not recommended with severe hepatic impairment
Strong CYP3A4 inducers may decrease clinical response
Decreased dose required if coadministered with strong CYP3A4 inhibitors, or moderate CYP3A4 inhibitors plus CYP2C19 inhibitors (see Dosage modifications)
Avoid use in patients with active, serious infection, including localized infections
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), reported; impact on chronic viral hepatitis reactivation unknown; perform screening for viral hepatitis in accordance with clinical guidelines before starting therapy
Non-melanoma skin cancers (NMSCs) reported; periodic skin examination recommended for patients at increased risk for skin cancer
Decreased dose required with moderate hepatic impairment or moderate-to-severe renal impairment (see Dosage modifications)
Use caution when treating patients with diabetes; higher incidence of infection in diabetic population in general reported
Diverticulitis reported
Extended-release tablet
- Patients may notice an inert tablet shell passing in the stool or via colostomy
- Caution when administering the extended-release tablet to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic); rare reports of obstructive symptoms with strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation
Pregnancy and lactation
Pregnancy category: C
Lactation: Unknown whether distributed in human breast milk; decision should be made whether to discontinue nursing or the drug, taking into account the importance of therapy to the mother
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Xeljanz, Xeljanz XR (tofacitinib)
Mechanism of action
Janus kinases (JAKs) pathways inhibitor; JAK consists of a group of intracellular tyrosine kinases that transmit signals from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoieses and immune cell function
Within the signaling pathway, JAKs phosphorylate and activate signal transducers and activators of transcription (STATs) which modulate intracellular activity including gene expression; tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs
These signals are essential in maintaining the inflammatory condition in rheumatoid arthritis (RA); inhibition of JAKs reduces production of and modulates proinflammatory cytokines central to RA
Absorption
Bioavailability: 74%
Peak Plasma Time: 0.5-1 hr
Distribution
Protein Bound: ~40% (predominately to albumin)
Vd: 87 L (following IV administration)
Distributes equally between RBCs and plasma
Metabolism
Clearance mechanisms: ~70% hepatic metabolism and 30% renal excretion
Primarily metabolized by CYP3A4 (accounting for ~53% of total clearance) and by CYP2C19 (accounting for ~17% of total clearance)
Metabolites: Potency <10% of parent compound
Elimination
Half-life: 3 hr
Renal clearance: 30%
Excretion: 30% urine
Administration
Oral Administration
May take with or without food
Extended-release tablets: Swallow whole; do not crush, split, or chew
Switching from regular tablets to extended-release
- 5 mg BID may be switched to extended-release 11 mg once daily the day following the last dose of 5 mg BID
