Tofacitinib (Monograph)

Brand name: Xeljanz
Drug 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

Medically reviewed by Drugs.com on Apr 17, 2024. Written by ASHP.

Introduction

Immunomodulating agent and disease-modifying antirheumatic drug (DMARD); Janus kinase (JAK) inhibitor.

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 one or more tumor necrosis factor (TNF) blocking agents; can be used alone or in combination with methotrexate or other nonbiologic DMARDs (e.g., hydroxychloroquine, leflunomide, sulfasalazine). Guidelines generally support use of Janus kinase (JAK) inhibitors, including tofacitinib, as add on therapy to methotrexate in patients who do not meet treatment goals with methotrexate alone.

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.

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

Juvenile Idiopathic Arthritis (JIA)

Management of active polyarticular-course JIA in pediatric patients ≥2 years of age who have had an inadequate response or intolerance to one or more TNF blocking agents.

Concomitant use with biologic DMARDs or potent immunosuppressive agents (e.g., azathioprine, cyclosporine) not recommended.

Psoriatic Arthritis

Management of active psoriatic arthritis in adults who have had an inadequate response or intolerance to one or more TNF blocking agents. Guidelines for the treatment of psoriatic arthritis generally recommend that patients with active disease despite treatment with an nonbiologic DMARD or with a TNF blocking agent be switched to a TNF blocking agent, an IL-17 inhibitor, or an IL-12/23 inhibitor instead of switching to tofacitinib. Tofacitinib may also be used if oral administration is preferred by the patient or if the patient has a history of recurrent or severe Candida infection.

Concomitant use with biologic DMARDs or potent immunosuppressive agents (e.g., azathioprine, cyclosporine) not recommended.

Ankylosing Spondylitis

Treatment of adults with active ankylosing spondylitis who have had an inadequate response or intolerance to one or more TNF blocking agents. Guidelines for the treatment of ankylosing spondylitis generally recommend other agents, including nonbiologic DMARDs, TNF blocking agents, secukinumab, and ixekizumab, over treatment with tofacitinib in patients with active disease.

Concomitant use of tofacitinib with biologic DMARDs or with potent immunosuppressive agents (e.g., azathioprine, cyclosporine) not recommended.

Ulcerative Colitis

Management of moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to one or more TNF blocking agents. Guidelines generally support the use of tofacitinib as an option for induction of remission in patients with moderate to severe ulcerative colitis; continuation of tofacitinib is recommended in patients with previously moderate to severe active disease who are in remission after induction with tofacitinib.

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

Other Uses

Has been used for the treatment of psoriasis^{† [off-label]}.

Tofacitinib Dosage and Administration

General

Pretreatment Screening

• Evaluate for latent or active tuberculosis infection prior to initiation of therapy; initiate antimycobacterial therapy if indicated.

• Evaluate for risk of thrombosis prior to initiation of therapy.

• Measure absolute lymphocyte count, absolute neutrophil count (ANC), and hemoglobin prior to initiation of therapy. Do not initiate therapy in patients with an absolute lymphocyte count of <500/mm³, ANC <1000/mm³, or hemoglobin concentration <9 g/dL.

• Screen for viral hepatitis infection before initiating therapy.

Patient Monitoring

• Evaluate for latent or active tuberculosis infection during therapy according to applicable guidelines.

• Monitor closely for signs or symptoms of infection, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis prior to initiating therapy, during and after treatment with tofacitinib.

• Monitor lymphocyte count every 3 months during therapy.

• Monitor ANC and hemoglobin concentrations 4–8 weeks after initial of therapy and then every 3 months.

• Monitor liver enzymes periodically during therapy.

• Perform dermatologic examinations periodically throughout therapy in patients at increased risk for skin cancer.

• Monitor lipids 4–8 weeks after therapy initiation.

Other General Considerations

• Do not use concomitantly with biologic disease-modifying antirheumatic drugs (DMARDs), or potent immunosuppressive agents.

• Concomitant use with potent inducers of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., rifampin) may result in loss of or reduced clinical response to tofacitinib.

• Update immunizations according to current immunization guidelines prior to initiating therapy.

Administration

Oral Administration

Administer conventional tablets, oral solution, or extended-release tablets orally without regard to meals.

Changes between conventional and extended-release tablets should be made by a clinician.

Pediatric patients receiving 5 mg as oral solution may be switched to the equivalent dose as conventional tablets. Extended-release tablets and oral solution are not interchangeable and should not be substituted for each other.

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

Administer oral solution using the press-in bottle adapter and oral dosing syringe provided by the manufacturer.

Dosage

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

Follow dosage recommendations specific to the condition being treated.

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. (See Interactions.)

Pediatric Patients

Juvenile Idiopathic Arthritis

Oral

Pediatric patients ≥2 years of age weighing 10 to <20 kg: 3.2 mg twice daily (as oral solution).

Pediatric patients ≥2 years of age weighing 20 to <40 kg: 4 mg twice daily (as oral solution).

Pediatric patients ≥2 years of age weighing ≥40 kg: 5 mg twice daily (as conventional tablets or oral solution).

Treatment Interruption for Toxicity

Infection

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

Lymphopenia

For lymphocyte count <500/mm³ (confirmed by repeat testing), discontinue tofacitinib.

Neutropenia

For persistent ANC of 500–1000/mm³, interrupt tofacitinib until ANC >1000/mm³.

For ANC <500/mm³, discontinue tofacitinib.

Anemia

For hemoglobin concentration <8 g/dL or a decrease of >2 g/dL, interrupt tofacitinib until hemoglobin concentration has normalized.

Adults

Rheumatoid Arthritis

Oral

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

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.

Psoriatic Arthritis

Oral

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

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.

Ankylosing Spondylitis

Oral

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

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.

Ulcerative Colitis

Oral

Induction: 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) for at least 8 weeks, then evaluate patient and, depending on therapeutic response, begin maintenance therapy. If necessary, may administer 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) for maximum of 16 weeks. If adequate therapeutic benefit not achieved after 16 weeks at this dosage, discontinue dosage.

Maintenance: Recommended dosage is 5 mg twice daily (as conventional tablets) or 11 mg once daily (as extended-release tablets). May consider 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) for patients with loss of response during maintenance therapy, but limit to shortest duration, with careful consideration of potential benefits and risks for the individual patient. Use lowest effective dosage that maintains response.

May switch from conventional tablets to extended-release tablets (i.e., from 5 mg twice daily [as conventional tablets] to 11 mg once daily [as extended-release tablets] or from 10 mg twice daily [as conventional tablets] to 22 mg once daily [as extended-release tablets]) the day following the last dose of conventional tablets.

Use at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Plaque Psoriasis† [off-label]

Oral

Has been administered at dosages of 5 or 10 mg twice daily (as conventional tablets).

Treatment Interruptions and Dosage Modifications for Toxicity

Infection

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

Lymphopenia

For lymphocyte count <500/mm³ (confirmed by repeat testing), discontinue tofacitinib.

Neutropenia

Anemia

For hemoglobin concentration <8 g/dL or a decrease of >2 g/dL, interrupt tofacitinib until hemoglobin concentration has normalized.

Prescribing Limits

Adults

Rheumatoid Arthritis

Oral

10 mg twice daily (as conventional tablets or oral solution) or 22 mg once daily (as extended-release tablets) not recommended.

Psoriatic Arthritis

Oral

10 mg twice daily (as conventional tablets or oral solution) or 22 mg once daily (as extended-release tablets) not recommended.

Ankylosing Spondylitis

Oral

10 mg twice daily (as conventional tablets or oral solution) or 22 mg once daily (as extended-release tablets) not recommended.

Ulcerative Colitis

Oral

Induction: Maximum duration of use at dosage of 10 mg twice daily (as conventional tablets) or 22 mg once daily (as extended-release tablets) is 16 weeks.

Special Populations

Hepatic Impairment

Dosage reduction may be necessary in patients with hepatic impairment (see Table 2).

Renal Impairment

Dosage reduction may be necessary in patients with renal impairment (see Table 3).

Geriatric Patients

No special dosage recommendations at this time.

Cautions for Tofacitinib

Contraindications

• No known contraindications.

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). Infections may be disseminated.

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).

Risk of infection may be higher with increasing degrees of lymphopenia. Consider lymphocyte counts when assessing patient’s risk of infection.

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

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

Do not initiate tofacitinib in patients with serious active infections, including localized infections. 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.

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

Evaluate all patients for active or latent tuberculosis and for risk factors for tuberculosis prior to and periodically during therapy. When indicated, initiate appropriate antimycobacterial regimen for treatment of latent tuberculosis infection prior to tofacitinib therapy. 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. Consultation with a tuberculosis specialist is recommended when deciding whether to initiate antimycobacterial therapy.

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

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

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

Mortality

Higher overall mortality rate, including sudden cardiovascular death, reported in a postmarketing safety study (NCT02092467) 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. All study patients were ≥50 years of age and had ≥1 cardiovascular risk factor.

The 10-mg twice-daily (as conventional tablets) or 22-mg once-daily (as extended-release tablets) dosage is FDA-labeled only for the management of ulcerative colitis for use as induction therapy and in limited situations during maintenance therapy. Tofacitinib 10 mg twice daily or an equivalent weight-based, twice-daily dosage (as conventional tablets or oral solution) or 22 mg once daily (as extended-release tablets) is not recommended for management of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or polyarticular-course JIA.

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

Malignancies and Lymphoproliferative Disorders

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

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. In patients with ulcerative colitis, tofacitinib 10 mg twice daily also associated with increased risk of nonmelanoma skin cancer.

Initial results from a postmarketing safety study (NCT02092467) in patients with rheumatoid arthritis suggest higher incidence of malignancies (excluding nonmelanoma skin cancer) in patients receiving tofacitinib (either 5 or 10 mg twice daily) compared with those receiving a TNF blocking agent. FDA is awaiting additional results from the study.

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

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

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

Major Adverse Cardiovascular Events

Major adverse cardiovascular events (i.e., cardiovascular death, nonfatal MI, nonfatal stroke) reported in patients receiving tofacitinib. Patients who are current or past smokers are at additional risk.

Consider risks and benefits of tofacitinib prior to initiating therapy or when considering whether to continue tofacitinib, particularly in patients who are current or past smokers and in those with other cardiovascular risk factors.

Patients should be advised to seek immediate medical attention if symptoms of serious cardiovascular events occur. In patients who experience MI or stroke, discontinue tofacitinib. Tofacitinib dosages of 10 mg twice daily (as conventional tablets or oral solution) or 22 mg once daily of tofacitinib extended-release tablets are not recommended for the treatment of rheumatoid arthritis or psoriatic arthritis, ankylosing spondylitis, or polyarticular-course JIA.

Thromboembolic Events

Higher incidences of thromboembolic events, including PE, DVT, and arterial thrombosis, reported in a safety study (NCT02092467) 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. Many of the events were serious; some were fatal. All study patients were ≥50 years of age and had ≥1 cardiovascular risk factor.

In a long-term extension study in patients with ulcerative colitis, 5 cases of PE reported in patients receiving tofacitinib 10 mg twice daily, including one death in a patient with advanced cancer.

The 10-mg twice-daily (as conventional tablets) or 22-mg once-daily (as extended-release tablets) dosage is FDA-labeled only for the management of ulcerative colitis for use as induction therapy and in limited situations during maintenance therapy. Tofacitinib 10 mg twice daily (as conventional tablets or oral solution) or 22 mg once daily (as extended-release tablets) is not recommended for management of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, or polyarticular-course JIA.

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

If symptoms of thrombosis develop, discontinue tofacitinib and promptly evaluate the patient.

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

Other Warnings/Precautions

Sensitivity Reactions

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

GI Perforation

GI perforation reported. In rheumatoid arthritis studies, many patients received NSAIAs concomitantly. 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. Role of JAK inhibition by tofacitinib not known.

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

Hematologic Effects

Possible lymphopenia, neutropenia, and anemia. May require interruption or discontinuance of tofacitinib therapy.

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

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

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

Hepatic Effects

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

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

Metabolic Effects

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

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

Immunizations

Avoid live vaccines during therapy with tofacitinib. Update immunizations according to current administration guidelines prior to initiation of tofacitinib therapy.

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.

Specific Populations

Pregnancy

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

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).

Pregnancy registry at 877-311-8972.

Lactation

Distributed into milk in rats; not known whether tofacitinib distributes into human milk, affects milk production, or affects nursing infants. 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.

Females or Males of Reproductive Potential

Consider pregnancy planning and prevention in females with reproductive potential.

Animal studies suggest tofacitinib may reduce fertility in females; this effect may be irreversible.

Pediatric Use

Conventional tablets and oral solution: Safety and efficacy for management of active polyarticular-course JIA established in pediatric patients 2–17 years of age based on evidence from adequate and well-controlled studies of tofacitinib (as conventional tablets) in adults with rheumatoid arthritis and data from a clinical trial of tofacitinib (as conventional tablets or oral solution) in pediatric patients with active polyarthritis. Adverse reactions observed in pediatric patients generally consistent with those reported in adults with rheumatoid arthritis. Safety and efficacy not established for management of active polyarticular-course JIA in patients <2 years of age or for uses other than polyarticular-course JIA in pediatric patients.

Extended-release tablets: Safety and efficacy not established in pediatric patients.

Geriatric Use

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

Hepatic Impairment

Use not recommended in patients with severe hepatic impairment.

Increased drug exposure in patients with moderate hepatic impairment may increase risk of adverse effects. Adjust dosage for moderate hepatic impairment.

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

Renal Impairment

Renal impairment increases tofacitinib systemic exposure. Adjust dosage for moderate to severe renal impairment.

Common Adverse Effects

Rheumatoid arthritis patients receiving tofacitinib 5 or 10 mg twice daily monotherapy or in combination with DMARDs (≥2%): Diarrhea, headache, nasopharyngitis, upper respiratory tract infection.

Psoriatic arthritis and ankylosing spondylitis: Adverse effects similar to those observed in patients with rheumatoid arthritis.

Ulcerative colitis (≥5%): Nasopharyngitis, elevated cholesterol concentrations, headache, upper respiratory tract infection, increased blood creatine kinase (CK, creatine phosphokinase, CPK) concentrations, rash, diarrhea, herpes zoster.

Polyarticular-course JIA: Adverse effects generally consistent with those reported in adults with rheumatoid arthritis.

Drug Interactions

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

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

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

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

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors (e.g., ketoconazole): Increased tofacitinib concentrations. Reduce tofacitinib dosage (see Table 4).

Drugs (or drug combinations) that result in both moderate CYP3A4 inhibition and potent CYP2C19 inhibition (e.g., fluconazole): Increased tofacitinib concentrations. Reduce tofacitinib dosage (see Table 4).

Drugs that inhibit only CYP2C19: Pharmacokinetic interaction unlikely.

Potent CYP3A4 inducers (e.g., rifampin): Decreased tofacitinib concentrations; possible decreased tofacitinib efficacy or loss of efficacy. Concomitant use not recommended.

Drugs Metabolized by Hepatic Microsomal Enzymes

Pharmacokinetic interaction unlikely.

Drugs Affecting P-Glycoprotein Transport

P-glycoprotein inhibitors: Pharmacokinetic interaction unlikely.

Biologic Antirheumatic Agents

Concomitant use with biologic agents used in the management of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis, or polyarticular course juvenile idiopathic arthritis not recommended.

Immunosuppressive Agents

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

Vaccines

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

Specific Drugs

Tofacitinib Pharmacokinetics

Absorption

Bioavailability

Conventional tablets or oral solution: Peak plasma concentrations attained within 0.5–1 hour following oral administration. Absolute oral bioavailability (as conventional tablets) is 74%.

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

Peak concentrations and AUC are similar at dosages of 5 mg twice daily as conventional tablets or 11 mg once daily as extended-release tablets; also similar at dosages of 10 mg twice daily as conventional tablets or 22 mg once daily as extended-release tablets.

Food

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

Extended-release tablets: High-fat meal increases peak plasma concentration by 19–27% and delays time to peak concentration by approximately 1 hour, but does not alter AUC.

Special Populations

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

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

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

In pediatric patients with polyarticular-course JIA, body weight affects systemic exposure, leading to recommendation for weight-based dosing; pharmacokinetic analyses indicate no need for dosage adjustment based on age, sex, race, or disease severity.

Distribution

Extent

Distributes equally between RBCs and plasma.

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

Plasma Protein Binding

Approximately 40% (primarily albumin).

Elimination

Metabolism

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

Elimination Route

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

Half-life

Conventional tablets or oral solution: Approximately 3 hours.

Extended-release tablets: Approximately 6–8 hours.

Stability

Storage

Oral

Solution

20–25°C (excursions permitted between 15–30°C). Store in original bottle and carton to protect from light. Discard 60 days after opening.

Tablets (Conventional or Extended-release)

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

Actions

• Inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. JAKs mediate signaling of cytokines and growth factors important for hematopoiesis and immune function.

• 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. Tofacitinib prevents phosphorylation and activation of STATs.

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

• 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. Decreases CRP concentrations in patients with rheumatoid arthritis or active psoriatic arthritis.

Advice to Patients

• Discuss 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. Importance of providing a copy of the manufacturer's instructions for use of the oral solution when this formulation is prescribed.

• Store tofacitinib conventional or extended-release tablets in the original container.

• Increased susceptibility to infection. Risk of herpes zoster, which may be serious. Importance of not initiating tofacitinib therapy if active infection is present. 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.

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

• Risk of major adverse cardiovascular events, including MI, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers and those with other cardiovascular risk factors, to monitor for the development of signs and symptoms of cardiovascular events.

• Importance of discontinuing tofacitinib therapy 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.

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

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

• 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, hepatitis B virus or hepatitis C virus infection, other chronic or recurring infections, or thrombotic or cardiac disease.

• Importance of periodic laboratory monitoring.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Women with reproductive potential should be advised of the potential risk to the fetus, and those who become pregnant while receiving tofacitinib should be advised that a pregnancy registry is available. Women should be advised to avoid breast-feeding during tofacitinib therapy and for at least 18 hours after the last dose is given as conventional tablets or 36 hours after the last dose is given as extended-release tablets.

• Potential for tofacitinib to impair fertility in females. It is not known whether this effect is reversible.

• 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.

• 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.

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Frequently asked questions

• What are the new drugs for rheumatoid arthritis (RA)?
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