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Xeljanz

Generic Name: Tofacitinib Citrate
Class: Disease-modifying Antirheumatic Drugs
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

Warning(s)

  • 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 tuberculin skin test, during and after treatment.1 If serious infection develops, discontinue tofacitinib until infection is controlled.1

  • 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

REMS:

FDA approved a REMS for tofacitinib to ensure that the benefits outweigh the risks. The REMS may apply to one or more preparations of tofacitinib and consists of the following: medication guide, communication plan. See the FDA REMS page (http: / / www.fda.gov / Drugs / DrugSafety / PostmarketDrugSafetyInformationforPatientsandProviders / ucm111350.htm) or the ASHP REMS Resource Center (http://www.ashp.org/REMS).

Introduction

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

Uses for Xeljanz

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

Slideshow: Drug Treatment for Rheumatoid Arthritis - What Are Your Options?

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., tocilizumab), not recommended.1

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

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

Concomitant Therapy

  • Methotrexate, other nonbiologic DMARDs, NSAIAs, and corticosteroids may be continued in patients with rheumatoid arthritis.1 3 5 6

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

Administration

Oral Administration

Administer orally without regard to meals.1

Dosage

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

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.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 cells/mm3

Maintain tofacitinib dosage

<500 cells/mm3 (confirmed by repeat testing)

Discontinue tofacitinib

Treatment Interruptions for Neutropenia
Table 2. Treatment Interruptions Based on ANC1

ANC

Recommendation

>1000 cells/mm3

Maintain tofacitinib dosage

500–1000 cells/mm3

For persistent decreases in this range, interrupt tofacitinib until ANC >1000, then resume tofacitinib 5 mg twice daily

<500 cells/mm3 (confirmed by repeat testing)

Discontinue tofacitinib

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

Hemoglobin Concentration

Recommendation

Decrease of ≤2 g/dL when concentration remains ≥9 g/dL

Maintain tofacitinib dosage

Decrease of >2 g/dL or concentration of <8 g/dL (confirmed by repeat testing)

Interrupt tofacitinib until hemoglobin concentration has normalized

Special Populations

Hepatic Impairment

Mild hepatic impairment: No dosage adjustment needed.1

Moderate hepatic impairment: 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: 5 mg once daily.1

Supplemental doses following dialysis 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 Xeljanz

Contraindications

  • No known contraindications.1

Warnings/Precautions

Warnings

Infectious Complications

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

Do not initiate tofacitinib in patients with 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 tuberculin skin test, for active tuberculosis.1

Viral reactivation, including herpes zoster reactivation, reported.1 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.1

Malignancies and Lymphoproliferative Disorders

Lymphoma and other malignancies observed.1 4 5

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

Other Warnings/Precautions

GI Perforation

GI perforation reported;1 4 role of JAK inhibition by tofacitinib not known.1

Caution in patients at increased risk for GI perforation (e.g., patients with history of diverticulitis).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 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

Specific Populations

Pregnancy

Category C.1 Pregnancy registry at 877-311-8972.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.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 Dosage adjustment for moderate hepatic impairment (see Hepatic Impairment under Dosage and Administration).1

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

Renal Impairment

Safety and efficacy not evaluated in patients with rheumatoid arthritis with baseline Clcr <40 mL/minute.1 Dosage adjustment for moderate to severe renal impairment (see Renal Impairment under Dosage and Administration).1

Common Adverse Effects

Diarrhea,1 3 4 6 nasopharyngitis,1 3 4 6 upper respiratory tract infection,1 3 4 6 headache,1 3 4 6 hypertension.1 3 4

Interactions for Xeljanz

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.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 anionic or cationic transport proteins at clinically relevant concentrations.1

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP3A4 inhibitors: Pharmacokinetic interaction (increased tofacitinib concentrations).1 Reduce tofacitinib dosage 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 Reduce tofacitinib dosage 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.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 DMARDS 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

No data available on response to vaccination.1 (See Immunizations under Cautions.)

No data available on secondary transmission of infection from individuals receiving live vaccines to tofacitinib-treated patients.1

Specific Drugs

Drug

Interaction

Comments

Azathioprine

Increased risk of immunosuppression1

Concomitant use in rheumatoid arthritis not studied to date1

Concomitant use not recommended1

Cyclosporine

Increased risk of immunosuppression1

Decreased clearance and increased AUC of cyclosporine1 13

Concomitant use in rheumatoid arthritis not studied to date1

Concomitant use not recommended1

Fluconazole

Increased tofacitinib concentrations1 13

Reduce tofacitinib dosage to 5 mg once daily1

Ketoconazole

Increased tofacitinib concentrations1 13

Reduce tofacitinib dosage 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 concentrations1 13

May reduce tofacitinib efficacy1

Tacrolimus

Increased risk of immunosuppression1

Slight decrease in clearance and increase in AUC of tacrolimus1 13

Concomitant use in rheumatoid arthritis not studied to date1

Concomitant use not recommended1

Xeljanz Pharmacokinetics

Absorption

Bioavailability

Peak plasma concentrations attained within 0.5–1 hour following oral administration.1 9

Absolute oral bioavailability is 74%.1 8

Food

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

Approximately 3 hours.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

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

Stability

Storage

Oral

Tablets

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

  • JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression.1 3 8 12 Tofacitinib prevents phosphorylation and activation of STATs.1 7 8 11

  • 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

Advice to Patients

  • Medication guide must be provided to the patient each time the drug is dispensed.1 (See REMS.) 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.2

  • Importance of storing tofacitinib tablets in the original container.1

  • Increased susceptibility to infection.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.2

  • 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.2

  • Risk of GI perforation.1 Importance of promptly notifying clinicians of persistent fever and abdominal pain or changes in bowel function.2

  • 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, or other chronic or recurring infections.2

  • Importance of periodic laboratory monitoring.1 2

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.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.

Tofacitinib Citrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

5 mg (of tofacitinib)

Xeljanz

Pfizer

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions August 1, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer Labs. Xeljanz (tofacitinib citrate) tablets prescribing information. New York, NY; 2012 Nov.

2. Pfizer Labs. Xeljanz (tofacitinib citrate) tablets medication guide. New York, NY; 2012 Nov.

3. Fleischmann R, Kremer J, Cush J et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012; 367:495-507. [PubMed 22873530]

4. van Vollenhoven RF, Fleischmann R, Cohen S et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012; 367:508-19. [PubMed 22873531]

5. van der Heijde D, Tanaka Y, Fleischmann R et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013; 65:559-70. [PubMed 23348607]

6. Burmester GR, Blanco R, Charles-Schoeman C et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013; 381:451-60. [PubMed 23294500]

7. Fox DA. Kinase inhibition--a new approach to the treatment of rheumatoid arthritis. N Engl J Med. 2012; 367:565-7. [PubMed 22873537]

8. de Lartigue J. Tofacitinib for the treatment of moderate to severe rheumatoid arthritis. Drugs Today (Barc). 2012; 48:533-43. [PubMed 22916341]

9. Cohen S, Zwillich SH, Chow V et al. Co-administration of the JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Br J Clin Pharmacol. 2010; 69:143-51. [PubMed 20233177]

10. Gupta P, Alvey C, Wang R et al. Lack of effect of tofacitinib (CP-690,550) on the pharmacokinetics of the CYP3A4 substrate midazolam in healthy volunteers: confirmation of in vitro data. Br J Clin Pharmacol. 2012; 74:109-15. [PubMed 22233204]

11. . Tofacitinib (Xeljanz) for rheumatoid arthritis. Med Lett Drugs Ther. 2013; 55:1-3. [PubMed 23288133]

12. Kyttaris VC. Kinase inhibitors: a new class of antirheumatic drugs. Drug Des Devel Ther. 2012; 6:245-50. [PubMed 23055694]

13. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203214Orig1s000: Clinical pharmacology and biopharmaceutics review(s). From FDA website.

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203214Orig1s000: Summary review. From FDA website.

15. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 203214Orig1s000: Medical review(s). From FDA website.

16. Felson DT, Anderson JJ, Boers M et al. American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38:727-35. [PubMed 7779114]

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