Dosing & Uses
Dosage Forms & Strengths
tablet (Xeljanz)
- 5mg
- 10mg
tablet, extended-release (Xeljanz XR)
- 11mg
Rheumatoid Arthritis
Xeljanz or Xeljanz XR
Indicated for moderate-to-severe active rheumatoid arthritis (RA) in adults with an inadequate response or intolerance to methotrexate; may be used as monotherapy or in combination with methotrexate or other nonbiologic DMARDs
Xeljanz: 5 mg PO BID
Xeljanz XR: 11 mg PO qDay
Psoriatic Arthritis
Xeljanz or Xeljanz XR
Indicated for active psoriatic arthritis who have had an inadequate response or intolerance to methotrexate or other DMARDs
Recommended dose in combination with nonbiologic DMARDs
- Xeljanz: 5 mg PO BID
- Xeljanz XR: 11 mg PO qDay
Ulcerative Colitis
Xeljanz only
Indicated for adults with moderately to severely active ulcerative colitis (UC)
10 mg PO BID for at least 8 weeks; followed by 5-10 mg BID, depending on therapeutic response
Use lowest effective dose that maintains response
Discontinue after 16 weeks with 10 mg BID if adequate therapeutic benefit not achieved
Dosage Modifications
Strong CYP3A4 inhibitors OR moderate CYP3A4 inhibitors with strong CYP2C19 inhibitors
- RA or PsA
- Xeljanz: Not to exceed 5 mg qDay
- Xeljanz XR: Switch to Xeljanz 5 mg qDay
- UC
- If taking 10 mg BID, reduce to 5 mg BID
- If taking 5 mg BID, reduce to 5 mg qDay
Renal impairment
- RA or PsA
- Mild: No dosage adjustment required
- Moderate-to-severe (Xeljanz): Not to exceed 5 mg qDay
- Moderate-to-severe (Xeljanz XR): Switch to Xeljanz 5 mg qDay
- UC
- Xeljanz only
- Mild: No dosage adjustment required
- Moderate-to-severe: If taking 10 mg BID, reduce to 5 mg BID; if taking 5 mg BID, reduce to 5 mg qDay
Hepatic impairment
- RA or PsA
- Mild: No dosage adjustment required
- Moderate-to-severe (Xeljanz): Not to exceed 5 mg qDay
- Moderate-to-severe (Xeljanz XR): Switch to Xeljanz 5 mg qDay
- Severe: Not recommended
- UC
- Xeljanz only
- Mild: No dosage adjustment required
- Moderate-to-severe: If taking 10 mg BID, reduce to 5 mg BID; if taking 5 mg BID, reduce to 5 mg qDay
- Severe: Not recommended
Lymphopenia
- RA, PsA, or UC
- Lymphocytes ≥500 cells/mm³: Maintain dose
- Lymphocytes <500 cells/mm³: Confirmed by repeat testing; discontinue until infection controlled
ANC 500-1000cells/mm³
- RA or PsA
- Interrupt dosing for persistent decreases; when ANC >1000/mm³, resume dose at Xeljanz 5 mg BID or Xeljanz XR 11 mg qDay
- ANC <500 cells/mm³: Confirmed by repeat testing; discontinue
- UC
- Xeljanz only
- If taking 10 mg BID, reduce to 5 mg BID; when ANC >1000, increase to 10 mg BID based on clinical response
- If taking 5 mg BID, interrupt dosing; when ANC >1000, resume 5 mg BID
- ANC <500 cells/mm³: Confirmed by repeat testing; discontinue
Anemia
- RA, PsA, or UC
- Hgb ≤2 g/dL decrease and level ≥9.0 g/dL: Maintain dose
- Hgb >2 g/dL decrease or level <8.0 g/dL: Confirmed by repeat testing; 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)
Interrupt dose for management of lymphopenia, neutropenia, and anemia
Interrupt use if patient develops a serious infection until the infection is controlled
There is a higher incidence of infections in geriatric patients; use with caution
Do not initiate if
- Absolute lymphocyte count <500 cells/mm³ OR
- ANC <1000 cells/mm³ OR
- Hgb <9 g/dL
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse 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
Blood and lymphatic system disorders: Anemia
Infections and infestations: Diverticulitis
Metabolism and nutrition disorders: Dehydration
Psychiatric disorders: Insomnia
Nervous system disorders: Paresthesia
Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (some fatal)
Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea
Hepatobiliary disorders: Hepatic steatosis
Skin and subcutaneous tissue disorders: Rash, erythema, pruritus
Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling
Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers
General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema
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
Malignancy and lymphoproliferative disorders reported (see Black Box Warnings); malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer
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
Not recommended with severe hepatic impairment
Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), reported; hepatitis B reactivation 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; dosage adjustment recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis; see Dosage Modifications)
Use caution when treating patients with diabetes; higher incidence of infection in diabetic population in general reported
Diverticulitis reported
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
Serious infections
- Serious and sometimes fatal infections reported due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens; the most common serious infections reported have included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis; among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis reported
- In the UC population, treatment with 10 mg BID was associated with greater risk of serious infections compared with 5 mg BID; additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with 10 mg twice daily
- Caution is recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections
- Risk of infection may be higher with increasing degrees of lymphopenia; consideration should be given to lymphocyte counts when assessing individual patient risk of infection
- Reactions such as angioedema and urticaria that may reflect drug hypersensitivity observed; if serious hypersensitivity reaction occurs, promptly discontinue therapy while evaluating potential cause or causes of reaction
- Avoid use in patients with an active, serious infection, including localized infections
- Consider the risks and benefits of tofacitinib prior to initiating treatment
- Patients with chronic or recurrent infection
- Patients who have been exposed to tuberculosis
- Patients with a history of a serious or an opportunistic infection
- Patients who have resided or traveled in areas of endemic tuberculosis or endemic mycoses
- Patients with underlying conditions that may predispose them to infection
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
Drug interactions overview
- 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 coadministration with live virus vaccines
- Risk of added immunosuppression when tofacitinib is concomitantly used with potent immunosuppressive drugs (eg, azathioprine, tacrolimus, cyclosporine); combined use of multiple dose tofacitinib with potent immunosuppressants has not been studied in rheumatoid arthritis and psoriatic arthritis
Pregnancy & Lactation
Pregnancy
There is a pregnancy exposure registry that monitors pregnancy outcomes in women during pregnancy; patients can call the toll free number 1-877-311-8972
There are no adequate and well-controlled studies therapy in pregnant women
In the tofacitinib clinical development programs, birth defects and miscarriages were reported
Animal data
- Based on animal studies, tofacitinib has the potential to affect a developing fetus
- Feticidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 146 times and 13 times the human dose of 5 mg BID, respectively
- In a peri and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73 times the human dose of 5 mg BID
- Based on findings in rats, females of reproductive potential taking tofacitinib may result in reduced fertility
Contraception
- Advise females of reproductive potential to use effective contraception during treatment and for >4 weeks after the last dose
- Advise females to inform their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment
Lactation
It is not known whether the drug is excreted in human milk
There are no data to assess effects of drug on breastfed child; drug is excreted in rat milk at concentrations higher than in maternal serum
Women should not breastfeed while treated; a decision should be made whether to discontinue breastfeeding or to discontinue therapy
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
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
Tablet
- Bioavailability: 74%
- Peak Plasma Time: 0.5-1 hr
- Coadministration with high-fat meal resulted in no changes in AUC while peak plasma concentration was reduced by 32%
Extended-release tablet
- Coadministration of with a high-fat meal resulted in no changes in AUC while peak plasma concentration was increased by 27% and peak plasma time was extended by ~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 tablets
- Patients treated with tofacitinib 5 mg PO BID may be switched to tofacitinib extended-release 11 mg PO qDay the day following the last dose of tofacitinib 5 mg
Storage
Xeljanz or Xeljanz ER: Store at 20-25°C (68-77°F)
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Patient Handout
Formulary
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