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Tofacitinib

Class: Disease-modifying Antirheumatic Drugs
- JAK Inhibitor
- Janus Kinase Inhibitor
Chemical Name: (3R,4R)-4-Methyl-3-(methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-β-oxo-1-piperidinepropanenitrile 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
Molecular Formula: C16H20N6O•C6H8O7
CAS Number: 540737-29-9
Brands: Xeljanz

Medically reviewed by Drugs.com. Last updated on Nov 18, 2019.

Warning

    Serious Infections
  • Serious, sometimes fatal infections including tuberculosis (pulmonary or extrapulmonary disease), bacterial and viral infections, invasive fungal infections (may be disseminated), and other opportunistic infections reported.1 3 4 5 (See Infectious Complications under Cautions.)

  • Carefully consider risks and benefits prior to initiating tofacitinib therapy in patients with chronic or recurring infections.1

  • Evaluate patients for latent tuberculosis infection prior to and periodically during tofacitinib therapy; if indicated, initiate appropriate antimycobacterial regimen prior to initiating tofacitinib therapy.1

  • Closely monitor patients for infection, including active tuberculosis in those with a negative test for latent tuberculosis, during and after treatment.1 If serious infection develops, discontinue tofacitinib until infection is controlled.1

    Mortality
  • Higher overall mortality rate, including sudden cardiovascular death, reported with tofacitinib 10 mg twice daily compared with either tofacitinib 5 mg twice daily or a TNF blocking agent in an ongoing postmarketing safety study in rheumatoid arthritis patients ≥50 years of age with ≥1 cardiovascular risk factor.1 27 (See Mortality under Cautions.)

    Malignancies
  • Lymphoma and other malignancies reported.1 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

  • Increased incidence of Epstein Barr virus-associated lymphoproliferative disorder observed in renal allograft recipients receiving tofacitinib and concomitant immunosuppressive agents.1

    Thrombosis
  • Higher incidences of thromboembolic events, including PE, DVT, and arterial thrombosis, reported with tofacitinib 10 mg twice daily compared with either tofacitinib 5 mg twice daily or a TNF blocking agent in an ongoing postmarketing safety study in rheumatoid arthritis patients ≥50 years of age with ≥1 cardiovascular risk factor.1 27 (See Thromboembolic Complications under Cautions.)

  • Discontinue tofacitinib and promptly evaluate patient if symptoms of thrombosis occur.1 27

  • In patients with ulcerative colitis, use tofacitinib at lowest effective dosage and for shortest duration needed to achieve and maintain response.1 27 (See Dosage under Dosage and Administration.)

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD); Janus kinase (JAK) inhibitor.1 3 4 5 6 7 11

Uses for Tofacitinib

Rheumatoid Arthritis in Adults

Management of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response or intolerance to methotrexate;1 3 4 5 11 can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, minocycline, sulfasalazine).1

Concomitant use with biologic DMARDs, such as tumor necrosis factor (TNF) blocking agents (e.g., adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), interleukin-1 (IL-1) receptor antagonists (e.g., anakinra), anti-CD20 monoclonal antibodies (e.g., rituximab), selective costimulation modulators (e.g., abatacept), and anti-interleukin-6-receptor monoclonal antibodies (e.g., sarilumab, tocilizumab), not recommended.1

Concomitant use with potent immunosuppressive agents (e.g., azathioprine, cyclosporine) also not recommended.1

Psoriatic Arthritis

Management of active psoriatic arthritis in adults who have had an inadequate response or intolerance to methotrexate or other DMARDs.1 18 19

Concomitant use with biologic DMARDs (see Rheumatoid Arthritis in Adults under Uses) or potent immunosuppressive agents (e.g., azathioprine, cyclosporine) not recommended.1

Ulcerative Colitis

Management of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to TNF blocking agents.1 20 27

Concomitant use with biologic therapies for ulcerative colitis or potent immunosuppressive agents (e.g., azathioprine, cyclosporine) not recommended.1

Tofacitinib Dosage and Administration

General

  • Do not initiate tofacitinib therapy in patients with lymphocyte count <500/mm3, ANC <1000/mm3, or hemoglobin concentration <9 g/dL.1

Concomitant Therapy

  • Do not use concomitantly with biologic DMARDs or potent immunosuppressive agents.1 (See Rheumatoid Arthritis in Adults under Uses.)

  • Concomitant use of potent CYP3A4 inducers may result in loss of or reduced clinical response to tofacitinib.1

Administration

Oral Administration

Administer conventional or extended-release tablets orally without regard to meals.1

Swallow extended-release tablets intact; do not crush, split, or chew.1

Dosage

Available as tofacitinib citrate; dosage expressed in terms of tofacitinib.1

Follow dosage recommendations specific to the condition being treated.1 25 27 (See Warnings under Cautions.)

Dosage reduction required when used concomitantly with a potent CYP3A4 inhibitor or with 1 or more drugs that result in both moderate CYP3A4 inhibition and potent CYP2C19 inhibition.1 (See Interactions.)

Adults

Rheumatoid Arthritis
Oral

5 mg twice daily (as conventional tablets) or 11 mg once daily (as extended-release tablets).1

May switch from dosage of 5 mg twice daily (as conventional tablets) to dosage of 11 mg once daily (as extended-release tablets) the day following the last dose of the conventional tablets.1

Psoriatic Arthritis
Oral

5 mg twice daily (as conventional tablets) or 11 mg once daily (as extended-release tablets).1

May switch from dosage of 5 mg twice daily (as conventional tablets) to dosage of 11 mg once daily (as extended-release tablets) the day following the last dose of the conventional tablets.1

Ulcerative Colitis
Oral

Induction: 10 mg twice daily (as conventional tablets) for 8 weeks, then evaluate patient and, depending on therapeutic response, begin maintenance therapy.1 If necessary, may administer 10 mg twice daily for maximum of 16 weeks.1 If adequate therapeutic benefit not achieved after 16 weeks of treatment with tofacitinib 10 mg twice daily, discontinue dosage.1

Maintenance: Recommended dosage is 5 mg twice daily.1 Reserve use of 10 mg twice daily beyond the induction period for patients with loss of response and limit to shortest duration, with careful consideration of potential benefits and risks for the individual patient.1 Use lowest effective dosage that maintains response.1

Treatment Interruptions for Toxicity
Treatment Interruptions for Infection

If a serious infection develops, discontinue tofacitinib until the infection is controlled.1

Treatment Interruptions for Lymphopenia
Table 1. Treatment Interruptions Based on Lymphocyte Count1

Lymphocyte Count

Recommendation

<500/mm3 (confirmed by repeat testing)

Discontinue tofacitinib

Treatment Interruptions and Dosage Modifications for Neutropenia
Table 2. Treatment Interruptions and Dosage Modifications Based on ANC1

ANC

Recommendation

500–1000/mm3 (persistently within this range)

Rheumatoid arthritis or psoriatic arthritis: Interrupt tofacitinib until ANC >1000/mm3, then resume tofacitinib 5 mg twice daily (as conventional tablets) or 11 mg once daily (as extended-release tablets)

Ulcerative colitis, if dosage is 10 mg twice daily: Reduce dosage to 5 mg twice daily until ANC >1000/mm3, then may return dosage to 10 mg twice daily based on clinical response

Ulcerative colitis, if dosage is 5 mg twice daily: Interrupt tofacitinib until ANC >1000/mm3, then resume tofacitinib 5 mg twice daily

<500/mm3

Discontinue tofacitinib

Treatment Interruptions for Anemia
Table 3. Treatment Interruptions Based on Hemoglobin Concentration1

Hemoglobin Concentration

Recommendation

Decrease of >2 g/dL or concentration of <8 g/dL

Interrupt tofacitinib until hemoglobin concentration has normalized

Prescribing Limits

Adults

Rheumatoid Arthritis
Oral

10 mg twice daily (as conventional tablets) not recommended.1 (See Warnings under Cautions.)

Psoriatic Arthritis
Oral

10 mg twice daily (as conventional tablets) not recommended.1 (See Warnings under Cautions.)

Ulcerative Colitis
Oral

Induction: Maximum duration of use at dosage of 10 mg twice daily (as conventional tablets) is 16 weeks.1 (See Warnings under Cautions.)

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment needed.1

Moderate hepatic impairment: 5 mg once daily (as conventional tablets) in patients with rheumatoid arthritis or psoriatic arthritis; for those receiving tofacitinib extended-release tablets, switch to conventional tablets.1 In patients with ulcerative colitis, reduce dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily.1

Severe hepatic impairment: Use not recommended.1

Renal Impairment

Mild renal impairment: No dosage adjustment needed.1

Moderate to severe renal impairment (including renal impairment requiring hemodialysis): 5 mg once daily (as conventional tablets) in patients with rheumatoid arthritis or psoriatic arthritis; for those receiving tofacitinib extended-release tablets, switch to conventional tablets.1 In patients with ulcerative colitis, reduce dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily.1

On dialysis days, administer dose after the hemodialysis session; if a dose is given before dialysis, supplemental dose following dialysis is not necessary.1

Geriatric Patients

No special dosage recommendations at this time.1

Other Special Populations

Dosage adjustment based on body weight, ethnicity, or gender not required.1

Cautions for Tofacitinib

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Infectious Complications

Serious, sometimes fatal infections (including cryptococcosis, pneumocystosis, histoplasmosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, listeriosis, BK virus infection) reported, particularly in patients receiving concomitant therapy with immunosuppressive agents (e.g., methotrexate, corticosteroids).1 3 4 5 Infections may be disseminated.1

In patients with ulcerative colitis, risk of serious infections and herpes zoster (including meningoencephalitis and ophthalmologic and disseminated cutaneous infections) was dose dependent (more common at dosage of 10 mg twice daily compared with 5 mg twice daily).1

Risk of infection may be higher with increasing degrees of lymphopenia.1 (See Hematologic Effects under Cautions.) Consider lymphocyte counts when assessing patient’s risk of infection.1

Use with caution in patients with diabetes mellitus; incidence of infections generally is increased in this population.1

Patients with a history of chronic lung disease and those who develop interstitial lung disease may be more susceptible to infections; caution advised.1

Do not initiate tofacitinib in patients with serious active infections, including localized infections.1 Consider potential risks and benefits of the drug prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who have resided or traveled in regions where tuberculosis or mycoses are endemic.1

Closely monitor patients during and after treatment with tofacitinib for the development of signs or symptoms of infection.1 If new infection occurs during therapy, perform thorough diagnostic evaluation (appropriate for immunocompromised patient), initiate appropriate anti-infective therapy, and closely monitor patient.1 If serious infection, opportunistic infection, or sepsis develops, discontinue tofacitinib until the infection is controlled.1

Evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy.1 When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to tofacitinib therapy.1 Consider initiation of antimycobacterial therapy prior to initiation of tofacitinib in individuals with a history of latent or active tuberculosis in whom an adequate course of antimycobacterial treatment cannot be confirmed and in individuals with a negative test for latent tuberculosis who have risk factors for tuberculosis.1 Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.1

Monitor all patients, including those with a negative test for latent tuberculosis, for active tuberculosis.1

Viral reactivation, including herpes zoster reactivation, reported.1 Risk of herpes zoster is increased in patients receiving tofacitinib and appears to be increased in patients treated in Japan or Korea.1

Reactivation of HBV infection reported during postmarketing experience.1 Effect on risk of reactivation of chronic viral hepatitis not known.1 Patients with serologic evidence of HBV or HCV infection were excluded from clinical trials.1 Screen all patients for viral hepatitis in accordance with clinical guidelines before initiation of tofacitinib therapy.1

Mortality

Higher overall mortality rate, including sudden cardiovascular death, reported in an ongoing postmarketing safety study in rheumatoid arthritis patients receiving tofacitinib 10 mg twice daily compared with those receiving either tofacitinib 5 mg twice daily or a TNF blocking agent, each given in combination with methotrexate.1 27 All study patients were ≥50 years of age and had ≥1 cardiovascular risk factor.25 26 27 FDA will reassess when final study results are available.27 (See Thromboembolic Complications under Cautions.)

The 10-mg twice-daily dosage is FDA-labeled only for the management of ulcerative colitis for use as induction therapy and in limited situations during maintenance therapy.1 27 (See Dosage under Dosage and Administration.) Tofacitinib 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) is not recommended for management of rheumatoid arthritis or psoriatic arthritis.1

In patients with ulcerative colitis, use tofacitinib at lowest effective dosage and for shortest duration needed to achieve and maintain response.1 27

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies (e.g., lung cancer, breast cancer, melanoma, prostate cancer, pancreatic cancer) observed.1 4 5

In long-term extension study in patients with ulcerative colitis, malignancies (including solid tumors and lymphoma) observed more frequently in patients receiving tofacitinib 10 mg twice daily.1 In patients with ulcerative colitis, tofacitinib 10 mg twice daily also associated with increased risk of nonmelanoma skin cancer.1

Increased incidence of Epstein Barr virus-associated posttransplant lymphoproliferative disorder observed in renal allograft recipients receiving tofacitinib and immunosuppressive agents concomitantly.1

Consider risks and benefits of tofacitinib prior to initiating therapy in patients with a known malignancy (other than a successfully treated nonmelanoma skin cancer) or when considering whether to continue tofacitinib in patients who develop a malignancy.1

Periodic dermatologic examinations recommended for patients at increased risk for skin cancer.1

Thromboembolic Complications

Higher incidences of thromboembolic events, including PE, DVT, and arterial thrombosis, reported in an ongoing safety study in rheumatoid arthritis patients receiving tofacitinib 10 mg twice daily compared with those receiving either tofacitinib 5 mg twice daily or a TNF blocking agent, each given in combination with methotrexate.1 25 26 27 Many of the events were serious; some were fatal.1 (See Mortality under Cautions.) All study patients were ≥50 years of age and had ≥1 cardiovascular risk factor.25 26 27 FDA will reassess when final study results are available.27

In a long-term extension study in patients with ulcerative colitis, 4 cases of PE reported in patients receiving tofacitinib 10 mg twice daily, including one death in a patient with advanced cancer.1

The 10-mg twice-daily dosage is FDA-labeled only for the management of ulcerative colitis for use as induction therapy and in limited situations during maintenance therapy.1 27 (See Dosage under Dosage and Administration.) Tofacitinib 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) is not recommended for management of rheumatoid arthritis or psoriatic arthritis.1

In patients with ulcerative colitis, use tofacitinib at lowest effective dosage and for shortest duration needed to achieve and maintain response.1 27

If symptoms of thrombosis develop, discontinue tofacitinib and promptly evaluate the patient.1 27 (See Advice to Patients.)

Avoid use in patients who may be at increased risk of thrombosis.1 27

Sensitivity Reactions

Serious hypersensitivity reactions (e.g., angioedema, urticaria) reported.1 If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while investigating the potential cause.1

Other Warnings/Precautions

GI Perforation

GI perforation reported.1 4 In rheumatoid arthritis studies, many patients received NSAIAs concomitantly.1 In ulcerative colitis studies, GI perforation appeared to occur at similar frequencies in patients receiving tofacitinib and those receiving placebo; many patients in these studies received corticosteroids concomitantly.1 Role of JAK inhibition by tofacitinib not known.1

Use with caution in patients at increased risk for GI perforation (e.g., patients with history of diverticulitis or receiving NSAIAs).1 Promptly evaluate patients with new-onset abdominal symptoms for early identification of GI perforation.1

Hematologic Effects

Possible lymphopenia, neutropenia, and anemia.1 3 5 6 May require interruption or discontinuance of tofacitinib therapy (see Treatment Interruptions for Toxicity under Dosage and Administration).1

Do not initiate tofacitinib therapy in patients with lymphocyte count <500/mm3, ANC <1000/mm3, or hemoglobin concentration <9 g/dL.1

Lymphocyte counts <500/mm3 associated with increased incidence of treated and serious infections.1

Monitor lymphocyte count at baseline and every 3 months during therapy.1 Monitor neutrophil count and hemoglobin concentration at baseline, 4–8 weeks after initiation of therapy, and every 3 months thereafter.1

Hepatic Effects

Elevated hepatic aminotransferases reported, mainly in patients receiving other DMARDs (primarily methotrexate) concomitantly.1 4 5 Reversible upon modification of the treatment regimen (e.g., dosage reduction of concomitant DMARD or tofacitinib or interruption of tofacitinib therapy).1

Routinely monitor hepatic aminotransferase concentrations.1 In case of elevations, promptly evaluate patient for drug-induced hepatotoxicity.1 If drug-induced hepatic injury is suspected, interrupt tofacitinib therapy until such diagnosis excluded.1

Effects on Serum Lipids

Dose-related increases in total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglyceride concentrations reported.1 3 4 5 6 Increases observed at 1 month of therapy and remain stable thereafter; maximum increases generally occur within 6 weeks.1 No clinically relevant changes in the ratio of LDL-cholesterol to HDL-cholesterol observed.1 Effect on cardiovascular morbidity and mortality not known.1 3 4 6

Measure lipid concentrations approximately 4–8 weeks after initiation of therapy.1 Manage hyperlipidemia according to current standards of care.1

Immunizations

Avoid live vaccines during therapy with tofacitinib.1 (See Vaccines under Interactions.) Update immunizations according to current administration guidelines prior to initiation of tofacitinib therapy.1

GI Obstruction

GI obstruction reported rarely following administration of nondeformable extended-release drug formulations in patients with known GI strictures; use tofacitinib extended-release tablets with caution in patients with preexisting, severe, pathologic or iatrogenic narrowing of the GI tract.1

Effects on Fertility

Animal studies suggest tofacitinib may reduce fertility in females; not known whether this effect is reversible.1

Specific Populations

Pregnancy

Adequate data not available regarding use in pregnant women.1 Fetocidal and teratogenic effects observed in animals; applicability of these findings to women receiving recommended tofacitinib dosages is uncertain.1 Consider pregnancy planning and prevention in females with reproductive potential.1

Data suggest increased disease activity in women with rheumatoid arthritis or ulcerative colitis is associated with increased risk of adverse pregnancy outcomes (e.g., preterm delivery, low birthweight, small for gestational age at birth).1

Pregnancy registry at 877-311-8972.1

Lactation

Distributed into milk in rats; not known whether tofacitinib distributes into human milk, affects milk production, or affects nursing infants.1 Breast-feeding not recommended during tofacitinib therapy or within 18 hours after the last dose of tofacitinib conventional tablets or 36 hours after the last dose of tofacitinib extended-release tablets.1

Pediatric Use

Safety and efficacy not established.1

Geriatric Use

Increased incidence of serious infections in patients ≥65 years of age compared with younger patients.1 Use with caution.1

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment.1

Increased drug exposure in patients with moderate hepatic impairment (see Special Populations under Pharmacokinetics) may increase risk of adverse effects.1 Adjust dosage for moderate hepatic impairment.1 Tofacitinib extended-release tablets not recommended in those with moderate hepatic impairment; switch to reduced dosage of conventional tablets.1 (See Hepatic Impairment under Dosage and Administration.)

Safety and efficacy not evaluated in patients with serologic evidence of HBV or HCV infection.1

Renal Impairment

Renal impairment increases tofacitinib systemic exposure.1 13 (See Special Populations under Pharmacokinetics.) Adjust dosage for moderate to severe renal impairment.1 Tofacitinib extended-release tablets not recommended in those with moderate or severe renal impairment; switch to reduced dosage of conventional tablets.1 (See Renal Impairment under Dosage and Administration)

Common Adverse Effects

Rheumatoid arthritis: Diarrhea,1 3 4 6 nasopharyngitis,1 3 4 6 upper respiratory tract infection,1 3 4 6 headache,1 3 4 6 hypertension1 3 4

Psoriatic arthritis: Adverse effects similar to those observed in patients with rheumatoid arthritis.1

Ulcerative colitis: Nasopharyngitis,1 20 elevated cholesterol concentrations, 1 20 headache,1 20 upper respiratory tract infection,1 increased blood creatine kinase (CK, creatine phosphokinase, CPK) concentrations,1 20 rash,1 diarrhea,1 herpes zoster.1 20

Interactions for Tofacitinib

Metabolized mainly by CYP3A4, with minor contribution from CYP2C19.1 Does not substantially inhibit or induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4 in vitro at clinically relevant concentrations.1 10

Does not appear to normalize CYP enzyme activity over time in patients with rheumatoid arthritis.1

Unlikely to inhibit P-glycoprotein or organic anion or cation transport proteins at clinically relevant concentrations.1

Does not substantially inhibit uridine diphosphate-glucuronosyltransferase (UGT) isoenzymes 1A1, 1A4, 1A6, 1A9, or 2B7 in vitro.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased tofacitinib concentrations).1 In patients with rheumatoid arthritis or psoriatic arthritis, reduce tofacitinib dosage to 5 mg once daily (as conventional tablets); switch those receiving tofacitinib extended-release tablets to conventional tablets at this reduced dosage.1 In patients with ulcerative colitis, reduce dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily.1

Drugs (or drug combinations) that result in both moderate CYP3A4 inhibition and potent CYP2C19 inhibition: Pharmacokinetic interaction (increased tofacitinib concentrations).1 In patients with rheumatoid arthritis or psoriatic arthritis, reduce tofacitinib dosage to 5 mg once daily (as conventional tablets); switch those receiving tofacitinib extended-release tablets to conventional tablets at this reduced dosage.1 In patients with ulcerative colitis, reduce dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily.1

Drugs that inhibit only CYP2C19: Pharmacokinetic interaction unlikely.1

Potent CYP3A4 inducers: Pharmacokinetic interaction (decreased tofacitinib concentrations); possible decreased tofacitinib efficacy or loss of efficacy.1

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.1 13

Drugs Affecting P-Glycoprotein Transport

P-glycoprotein inhibitors: Pharmacokinetic interaction unlikely.1

Biologic Antirheumatic Agents

Concomitant use with biologic agents used in the management of rheumatoid arthritis, psoriatic arthritis, or ulcerative colitis not recommended.1

Immunosuppressive Agents

Pharmacologic interaction (increased risk of immunosuppression).1 Concomitant use with potent immunosuppressive agents not recommended.1

Vaccines

Avoid live vaccines.1 Interval between administration of live vaccines and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines for patients receiving immunosuppressive agents.1

Specific Drugs

Drug

Interaction

Comments

Azathioprine

Increased risk of immunosuppression1

Concomitant use not studied to date1

Concomitant use not recommended1

Cyclosporine

Increased risk of immunosuppression1

Decreased clearance and increased AUC of cyclosporine1 13

Concomitant use not studied to date1

Concomitant use not recommended1

Fluconazole

Increased tofacitinib concentrations1 13

Rheumatoid arthritis or psoriatic arthritis: Reduce tofacitinib dosage to 5 mg once daily (as conventional tablets); switch those receiving tofacitinib extended-release tablets to conventional tablets at this reduced dosage1

Ulcerative colitis: Reduce tofacitinib dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily1

Ketoconazole

Increased tofacitinib concentrations1 13

Rheumatoid arthritis or psoriatic arthritis: Reduce tofacitinib dosage to 5 mg once daily (as conventional tablets); switch those receiving tofacitinib extended-release tablets to conventional tablets at this reduced dosage1

Ulcerative colitis: Reduce tofacitinib dosage (as conventional tablets) from 10 mg twice daily to 5 mg twice daily or from 5 mg twice daily to 5 mg once daily1

Metformin

No substantial effect on tofacitinib concentrations1

No dosage adjustment required1

Methotrexate

No clinically important effect on pharmacokinetics of either drug1 9

No dosage adjustment required1 9

Midazolam

No substantial effect on midazolam pharmacokinetics1 10

No dosage adjustment required1

Oral contraceptives

No substantial effect on ethinyl estradiol or levonorgestrel concentrations1 13

No dosage adjustment required1

Rifampin

Decreased tofacitinib concentrations;1 13 possible reduced tofacitinib efficacy or loss of efficacy

Tacrolimus

Increased risk of immunosuppression1

Slight decrease in clearance and increase in AUC of tacrolimus1 13

Concomitant use not studied to date1

Concomitant use not recommended1

Zoster vaccine live

Dissemination of vaccine virus strain reported (16 days after vaccine administration and 2 days after initiation of tofacitinib); patient recovered following tofacitinib discontinuance and standard antiviral therapy1

Tofacitinib Pharmacokinetics

Absorption

Bioavailability

Conventional tablets: Peak plasma concentrations attained within 0.5–1 hour following oral administration.1 9 Absolute oral bioavailability is 74%.1 8

Extended-release tablets: Peak plasma concentrations attained 4 hours following oral administration.1

Peak concentrations and AUC are equivalent following oral administration of 5 mg twice daily as conventional tablets or 11 mg once daily as extended-release tablets.1

Food

Conventional tablets: High-fat meal reduces peak plasma concentration by 32% but does not affect extent of absorption.1

Extended-release tablets: High-fat meal increases peak plasma concentration by 27% and delays time to peak concentration by approximately 1 hour, but does not alter AUC.1

Special Populations

In patients with mild or moderate hepatic impairment, exposure increased by 3 or 65%, respectively.1 8 13

In patients with mild, moderate, or severe renal impairment, exposure increased by 41, 71, or 156%, respectively.1 13 In those with end-stage renal disease receiving hemodialysis, exposure increased by approximately 40%.1

Age, weight, gender, or ethnicity does not substantially alter pharmacokinetics.1

Distribution

Extent

Distributes equally between RBCs and plasma.1

Distributed into milk in rats; not known whether distributed into human milk.1

Plasma Protein Binding

Approximately 40% (primarily albumin).1

Elimination

Metabolism

Hepatic metabolism accounts for approximately 70% of total clearance.1 Metabolized to inactive metabolites mainly by CYP3A4, with minor contribution from CYP2C19.1

Elimination Route

Renal excretion of unchanged drug accounts for approximately 30% of total clearance.1

Half-life

Conventional tablets: Approximately 3 hours.1

Extended-release tablets: Approximately 6 hours.1

Stability

Storage

Oral

Tablets (Conventional or Extended-release)

20–25°C.1 Store in original container; do not repackage.1

Actions

  • Inhibits JAK1 and JAK3 and, to a lesser extent, JAK2.3 4 5 7 8 12 JAKs mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.1 4 7 8 11 12

  • Binding of cytokines to receptors on the cell surface activates pairing of JAKs (e.g., JAK1/JAK2, JAK1/JAK3, JAK1/tyrosine kinase 2 [TYK2], JAK2/JAK2, JAK2/TYK2), which leads to phosphorylation and subsequent localization of signal transducer and activator of transcription (STAT) proteins to the nucleus and modulation of gene expression.1 3 8 12 23 24 Tofacitinib prevents phosphorylation and activation of STATs.1 7 8 11

  • Inhibited activity of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations in vitro.1 Relevance of inhibition of specific JAK combinations to therapeutic efficacy not known.1

  • Causes dose-dependent decreases in circulating CD16/56+ natural killer cells and increases in B cells; changes in circulating T-lymphocyte counts and T-lymphocyte subsets (CD3+, CD4+, and CD8+) are small and inconsistent.1 Decreases CRP concentrations in patients with rheumatoid arthritis or active psoriatic arthritis.1

Advice to Patients

  • Importance of discussing potential risks and benefits of therapy with the patient; importance of the patient reading the medication guide prior to initiation of therapy and each time the prescription is refilled.1

  • Importance of storing tofacitinib conventional or extended-release tablets in the original container.1

  • Increased susceptibility to infection.1 Risk of herpes zoster, which may be serious.1 Importance of not initiating tofacitinib therapy if active infection is present.1 Importance of promptly informing clinicians if any signs or symptoms of infection (e.g., persistent fever, sweating, chills, myalgia, cough, dyspnea, fatigue, diarrhea, dysuria, erythema) develop.1

  • Risk of lymphoma and other malignancies.1 Risk of lymphoproliferative disorder in patients receiving tofacitinib in combination with drugs for prevention of renal allograft rejection.1

  • Importance of discontinuing tofacitinib and seeking immediate medical attention if signs or symptoms suggestive of thrombosis (e.g., sudden shortness of breath; chest pain exacerbated by breathing; leg pain or tenderness; redness, swelling, or discoloration of a leg or arm) occur.1 25 27

  • Importance of discontinuing tofacitinib and promptly notifying clinician if manifestations of a hypersensitivity reaction (e.g., swelling of the lips, tongue, or throat; urticaria) occur.1

  • Risk of GI perforation.1 Importance of promptly notifying clinicians of persistent fever and abdominal pain or changes in bowel function.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses or any history of cancer, tuberculosis, HBV or HCV infection, other chronic or recurring infection, or thrombotic or cardiac disease.1

  • Importance of periodic laboratory monitoring.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Advise women with reproductive potential of potential fetal risk; advise those who become pregnant that a pregnancy registry is available.1 Advise women to avoid breast-feeding during tofacitinib therapy and for ≥18 hours after the last dose of tofacitinib conventional tablets or ≥36 hours after the last dose of tofacitinib extended-release tablets.1

  • Potential for tofacitinib to impair fertility in females.1 Not known whether effect is reversible.1

  • Potential for the inert shell of the extended-release tablets to be eliminated in the stool or via colostomy after the drug has been absorbed.1

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Tofacitinib Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, extended-release, film-coated

11 mg (of tofacitinib)

Xeljanz XR

Pfizer

Tablets, film-coated

5 mg (of tofacitinib)

Xeljanz

Pfizer

10 mg (of tofacitinib)

Xeljanz

Pfizer

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 18, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pfizer Labs. Xeljanz (tofacitinib citrate) tablets and Xeljanz XR (tofacitinib citrate) extended-release tablets prescribing information. New York, NY; 2019 Jul. http://labeling.pfizer.com/ShowLabeling.aspx?id=959

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