Tofacitinib

Introduction Overview

Generic Name

tofacitinib

Brand Name

Xeljanz

Dosage Form

oral tablet, extended-release tablet, oral solution

Drug Class

Antirheumatics

Pharmacokinetics

Absorption:
Tofacitinib is rapidly absorbed following oral administration, with peak plasma concentrations typically attained within 0.5 to 1 hour for immediate-release formulations, and around 4 hours for extended-release forms (Xeljanz XR). The absorption is not significantly affected by food intake, allowing administration with or without food. The bioavailability of immediate-release tablets and oral solution is approximately 74%, while the extended-release formulation provides a more sustained plasma concentration profile to facilitate once-daily dosing. Studies have demonstrated low interpatient variability in absorption.

Distribution:
Tofacitinib exhibits moderate distribution into body tissues and fluids. It is approximately 40% protein-bound, largely to albumin, which is relatively low compared to many other drugs, minimizing potential for protein binding related drug interactions. The volume of distribution is about 87 L, indicating extensive distribution beyond the blood compartment. Tofacitinib can penetrate into synovial fluid, relevant to its efficacy in rheumatoid arthritis and other inflammatory joint diseases. Its distribution profile supports systemic exposure required for immunomodulatory effects.

Metabolism:
Tofacitinib is primarily metabolized hepatically, predominantly by cytochrome P450 isoenzyme CYP3A4 with a minor contribution from CYP2C19. Oxidative metabolism leads to several metabolites, mostly inactive, which are then further conjugated. The metabolic clearance comprises about 70% of total clearance. Potent inhibitors or inducers of CYP3A4 and CYP2C19 can alter tofacitinib plasma levels, requiring dose adjustments. Nonhepatic metabolism plays a minor role. Hepatic impairment moderately reduces clearance, thus necessitating cautious dosing.

Elimination:
Tofacitinib is eliminated through both renal and fecal routes, with approximately 30% excreted unchanged in the urine and the remainder as metabolites. The elimination half-life is approximately 3 hours for immediate-release and 6-8 hours for extended-release formulations, supporting twice-daily and once-daily dosing regimens, respectively. Renal impairment reduces clearance, requiring dose modifications in moderate renal impairment. The elimination kinetics are linear, allowing predictable plasma concentrations with adjusted dosing. There is no evidence of significant accumulation with chronic dosing.

Dosage Forms

Available Dosage Forms:
Xeljanz is available in immediate-release oral tablets and oral solution, while Xeljanz XR is an extended-release tablet formulation enabling once-daily dosing. Specifically:
- Oral Tablets: 5 mg and 10 mg tofacitinib
- Extended-Release Tablets (Xeljanz XR): 11 mg and 22 mg tofacitinib
- Oral Solution: 1 mg/mL tofacitinib with grape flavor

Dosages for Adults and Adolescents:
Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis:
- Immediate-release Xeljanz: 5 mg orally twice daily
- XR formulation: 11 mg once daily
Dose reduction to 5 mg once daily is recommended for moderate renal impairment and moderate hepatic impairment. For psoriatic arthritis, combination with nonbiologic DMARDs such as methotrexate is advised.

Ulcerative Colitis:
- Induction therapy (minimum 8 weeks, up to 16 weeks): 10 mg orally twice daily or XR 22 mg once daily
- Maintenance therapy: 5 mg orally twice daily or XR 11 mg once daily
Dose escalation to induction dose may be considered for loss of response during maintenance therapy, but lowest effective dose should be used.

Polyarticular Juvenile Idiopathic Arthritis (age ≥2 years):
Dosing is weight-based:
- 10-20 kg: Oral solution 3.2 mg twice daily
- 20-40 kg: Oral solution 4 mg twice daily
- ≥40 kg: Oral solution or tablets 5 mg twice daily
Dose adjustments are made as the child's weight changes.

Specific Patient Populations:
- Moderate renal impairment or moderate hepatic impairment: reduce immediate-release dose to 5 mg once daily.
- Not recommended for severe hepatic impairment.
- The extended-release tablets are not approved for patients younger than 18 years.
- Regular laboratory monitoring is essential in all populations to monitor for hematological and hepatic changes.
- Oral solution should be measured precisely with supplied device; do not use household utensils.
- Xeljanz XR tablets must be swallowed whole without crushing or chewing to maintain extended-release properties.

Mechanism Of Action

Tofacitinib, the active ingredient in Xeljanz, functions as an oral Janus kinase (JAK) inhibitor, targeting multiple JAK enzymes (JAK1, JAK2, JAK3, and TYK2) that play critical roles in cytokine-mediated signal transduction pathways. By selectively inhibiting these intracellular tyrosine kinases, tofacitinib disrupts the JAK-STAT signaling cascade, which is pivotal for transmitting extracellular cytokine signals to the cell nucleus and initiating gene expression leading to inflammatory responses.

This inhibition results in the downregulation of several inflammatory pathways involved in the pathogenesis of autoimmune diseases such as rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and ulcerative colitis. Specifically, the blockade of JAK activity reduces transcription of pro-inflammatory cytokines including interleukins (IL-2, IL-6, IL-7, IL-12, IL-15, IL-21), interferons, and other immune mediators, leading to diminished activation, proliferation, and function of immune cells such as T cells, B cells, and natural killer cells.

Biochemically, tofacitinib's inhibition of JAK1 and JAK3 affects common gamma-chain cytokine signaling, impairing lymphocyte function, while JAK2 inhibition influences signaling pathways related to hematopoiesis and inflammation. This broad targeting explains both its immunomodulatory efficacy and the potential for hematological side effects. Compared to biologic agents such as TNF inhibitors, tofacitinib offers oral administration and affects multiple cytokine pathways simultaneously rather than a single target.

Clinical studies have demonstrated rapid onset of action with symptom improvement in as little as three days for ulcerative colitis and within weeks for joint diseases. Research supports that JAK inhibition effectively reduces immune system overactivity, improving clinical outcomes in patients with refractory or inadequate response to conventional immunosuppressive therapies.

Pharmacological Actions

Selective inhibition of Janus kinase enzymes (JAK1, JAK2, JAK3, TYK2) involved in cytokine signaling.
Modulation of immune response by suppressing pro-inflammatory cytokine production and activity.
Reduction of lymphocyte activation and proliferation, leading to decreased immune-mediated inflammation.
Oral disease-modifying antirheumatic drug (DMARD) with rapid onset of immunosuppressive action.
Efficacious in multiple autoimmune and inflammatory diseases including rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis.
Inhibition of the JAK-STAT pathway leading to downregulation of gene transcription involved in inflammation.
Immunosuppressant effects contributing to reduced joint and tissue damage progression.
Potential hematological impacts due to effects on hematopoietic cytokines.
Dual formulation availability (immediate and extended-release) for flexible dosing strategies.
Demonstrates dose-dependent effects with tailored regimens for induction and maintenance therapy.
Crosses synovial membranes for effective treatment of joint inflammation.
Alters lipid metabolism, often causing elevated cholesterol levels during therapy.
Minimal protein binding, enabling effective tissue distribution.
Metabolized mainly by CYP3A4 and CYP2C19 enzymes, affecting pharmacokinetics in hepatic impairment.

Therapeutic Or Clinical Uses

Treatment of moderate to severe rheumatoid arthritis in adults with inadequate response or intolerance to other DMARDs or TNF inhibitors.
Management of active psoriatic arthritis, including combination therapy with nonbiologic DMARDs.
Induction and maintenance therapy for moderate to severe ulcerative colitis in adults.
Treatment of ankylosing spondylitis in adult patients.
Treatment of polyarticular juvenile idiopathic arthritis in patients aged 2 years and older with inadequate response to TNF blockers.
Alternative therapy option for patients unable to tolerate or respond to biologic agents.
Use in reducing symptoms and disease progression in autoimmune inflammatory conditions.
Employed for patients with refractory disease who have failed first-line treatments.
Off-label use in autoimmune conditions involving dysregulated cytokine signaling.
Suitable as monotherapy or in combination with other nonbiologic immunosuppressants.
Use in patients seeking oral options rather than injectable biologics.
Treatment aimed at improving joint function, reducing swelling, and slowing structural damage.
Therapeutic option for patients with active systemic inflammation and extra-articular manifestations.
Maintains disease remission with flexible dosing adjustments based on clinical response.

Side Or Adverse Effects

Common skin reactions including rash and acneiform eruptions.
Increased susceptibility to upper respiratory tract infections and cold-like symptoms such as nasal congestion, sneezing, and sore throat.
Incidence of herpes zoster (shingles), particularly at higher dosages or in ulcerative colitis patients.
Diarrhea and gastrointestinal upset including nausea and vomiting.
Elevations in blood pressure noted during therapy.
Abnormal laboratory test results such as lymphopenia, neutropenia, anemia, and elevated liver enzymes.
Increases in blood cholesterol and lipid levels requiring monitoring.
Headache and fever episodes reported in some patients.
Serious infections including tuberculosis, bacterial, viral, and fungal infections; some leading to fatalities.
Risk of major cardiovascular events such as heart attack and stroke, especially in patients over 50 with cardiovascular risk factors.
Increased risk of malignancies including lymphoma and lung cancer, particularly in current or past smokers.
Occurrence of blood clots (deep vein thrombosis, pulmonary embolism, arterial thrombosis), with associated mortality in vulnerable populations.
Gastrointestinal perforations, especially when used with NSAIDs, corticosteroids, or methotrexate.
Allergic reactions ranging from mild hives to serious angioedema involving lips, tongue, or throat.
Activation or reactivation of hepatitis B or C in carriers, necessitating screening prior to initiation.

Precautions

Avoid use in patients with active serious infections or severe immunodeficiency.
Pre-treatment screening for latent tuberculosis is essential; regular monitoring during therapy required.
Use caution in patients with a history of recurrent infections or chronic infections such as HIV or hepatitis.
Adjustment of dose recommended in moderate renal or hepatic impairment; avoid in severe hepatic disease.
Regular laboratory monitoring for hematological parameters, liver function, and lipid profile is necessary.
Avoid live vaccines during and shortly after treatment due to immunosuppression risk.
Assess risk factors for cardiovascular disease prior to initiating therapy, especially in patients over 50 years.
Smoking cessation advised as smoking increases risk of serious adverse events including malignancy.
Extreme caution when used concomitantly with other immunosuppressive or biologic agents due to increased infection risk.
Pregnancy and breastfeeding considerations warrant careful risk-benefit assessment; registry enrollment encouraged for pregnant women.
Educate patients on recognizing signs of infection, blood clots, and cardiovascular symptoms requiring immediate medical attention.
Monitor for signs of gastrointestinal perforation, especially in patients on concomitant NSAIDs or corticosteroids.
Be vigilant for symptoms indicative of allergic reactions and discontinue drug if they occur.
Counsel patients on potential alterations in laboratory tests and implications for ongoing management.

Warnings

Boxed warning for serious infections including tuberculosis, bacterial, viral, and fungal infections; some cases have been fatal.
Increased risk of mortality and major adverse cardiovascular events (MACE) such as myocardial infarction and stroke, particularly in patients aged 50 and older with cardiovascular risk factors.
Elevated risk of malignancies including lymphoma and lung cancer, notably in current or former smokers.
Higher incidence of blood clots including pulmonary embolism, deep vein thrombosis, and arterial thrombosis; some leading to death.
Potential for gastrointestinal perforations, more common when used with NSAIDs, corticosteroids, or methotrexate.
Risk of serious allergic reactions, including anaphylaxis and angioedema.
Reactivation of hepatitis B and C viruses in carriers undergoing treatment.
Potential for laboratory abnormalities such as reductions in lymphocytes, neutrophils, red blood cells, and liver enzyme elevations; treatment interruption may be warranted.
Use is contraindicated in patients with low lymphocyte, neutrophil, or hemoglobin levels below recommended thresholds.
Not recommended for patients with active serious infections or severe liver disease.
Use caution in special populations such as pregnant or breastfeeding women due to unknown fetal risks.
Avoid live vaccines during therapy due to increased risk of infection.
Patients should be monitored for signs and symptoms suggestive of blood clots and infections and advised to seek immediate care if these occur.
Not interchangeable between immediate-release and extended-release formulations; improper substitution may affect efficacy and safety.

Contraindication

Known hypersensitivity to tofacitinib or any inactive ingredients in Xeljanz formulations.
Patients with active serious or localized infections, including tuberculosis and other opportunistic infections.
Individuals with severely low lymphocyte counts, neutrophils, or hemoglobin levels below recommended thresholds.
Severe hepatic impairment (Child-Pugh class C) due to altered metabolism and increased exposure.
Patients with sepsis or other severe systemic infections.
Concurrent use with potent immunosuppressive agents contraindicated without close medical supervision.
Patients with active malignancy or history of malignancy in whom benefit-risk ratio is unfavorable.
Use of live vaccines during treatment or within prescribed washout periods.
Known hypersensitivity to excipients present in specific formulations, such as coloring agents or preservatives.
Children under 2 years of age and patients younger than 18 years for XR formulation.
Contraindicated if any previous severe allergic reaction to other Janus kinase inhibitors.

Drug Interactions

Concurrent use with biologic DMARDs or potent immunosuppressants increases risk of infection and is generally not recommended.
Moderate CYP3A4 inhibitors (e.g., fluconazole) and strong CYP2C19 inhibitors can increase tofacitinib plasma concentrations, necessitating dose adjustment.
Strong CYP3A4 inducers (e.g., rifampin) can decrease tofacitinib levels, potentially reducing efficacy.
Strong CYP3A4 inhibitors (e.g., ketoconazole) significantly elevate tofacitinib exposure, requiring dose reduction.
Use caution with drugs metabolized by CYP enzymes to avoid altered drug levels.
Concomitant administration with tacrolimus may alter pharmacokinetics; close monitoring is advised.
Potential additive immunosuppression with other agents such as methotrexate, corticosteroids, or biologics.
May affect or be affected by drugs altering liver enzyme activity.
No noted significant interactions with common over-the-counter medications but caution advised with herbal supplements that affect CYP enzymes.
Avoid live vaccines due to immunosuppressive effects of tofacitinib.
No significant interactions with food; tofacitinib can be taken with or without meals.
Inflammation or hepatic impairment can indirectly affect tofacitinib metabolism and interactions.
Patients should inform healthcare providers about all medications including vitamins and herbal supplements due to potential unknown interactions.
Regular monitoring is recommended when initiating or discontinuing interacting medications.
Drug interaction checker tools and pharmacist consultation encouraged for polypharmacy patients.

Preparations Of The Drug

Xeljanz 5 mg oral tablets containing tofacitinib citrate and excipients including croscarmellose sodium, HPMC 2910/Hypromellose 6cP, lactose monohydrate, macrogol/PEG3350, magnesium stearate, microcrystalline cellulose, titanium dioxide, and triacetin.
Xeljanz 10 mg oral tablets with similar excipients plus FD& C Blue #1/Brilliant Blue FCF Aluminum Lake and FD& C Blue #2/Indigo Carmine Aluminum Lake for coloration.
Xeljanz XR extended-release tablets available in 11 mg and 22 mg strengths with excipients such as cellulose acetate, copovidone, hydroxyethyl cellulose, hydroxypropyl cellulose, HPMC 2910/Hypromellose, magnesium stearate, red or yellow iron oxide, sorbitol, titanium dioxide, triacetin, along with a proprietary printing ink.
Xeljanz oral solution supplied as 1 mg/mL tofacitinib citrate oral liquid with grape flavor, hydrochloric acid, lactic acid, purified water, sodium benzoate (preservative), sucralose (sweetener), and xylitol (sweetener).
All formulations are manufactured by Pfizer Inc.
Tablets are formulated for oral administration with immediate or extended release profiles.
Oral solution supplied with a calibrated measuring device for accurate dosing, especially for pediatric patients.
Storage instructions specify room temperature maintenance (68°F to 77°F; 20°C to 25°C) protected from light.
Oral solution requires discarding 60 days after opening to maintain sterility and potency.
Packaging designed to protect formulation integrity and ensure patient compliance.
Inactive ingredients selected to ensure stability, palatability, and manufacturability.
Non-interchangeability between immediate-release and extended-release tablets due to distinct release mechanisms.
Tablets may contain coloring agents such as iron oxides and FD&C dyes to aid identification.
Excipients chosen to optimize tablet disintegration (immediate-release) or sustained release characteristics (XR).