Tofacitinib

Usage

Tofacitinib is prescribed for the treatment of:

• Rheumatoid Arthritis (RA): Moderate to severe active RA in adult patients who have had an inadequate response or intolerance to methotrexate (MTX) or other non-biologic disease-modifying antirheumatic drugs (DMARDs). It can be used as monotherapy or in combination with MTX.
• Psoriatic Arthritis (PsA): Active PsA in adult patients who have had an inadequate response or intolerance to a prior DMARD. It can be used with or without MTX.
• Ulcerative Colitis (UC): Moderately to severely active UC in adults who have had an inadequate response or intolerance to tumor necrosis factor (TNF) blockers or other therapies.
• Polyarticular Course Juvenile Idiopathic Arthritis (pcJIA): In children 2 years of age and older who have had an inadequate response or intolerance to MTX. It can be used as monotherapy or in combination with MTX.
• Ankylosing Spondylitis (AS): Active AS in adult patients who have had an inadequate response to NSAIDs.

Pharmacological Classification: Tofacitinib is a Janus kinase (JAK) inhibitor.

Mechanism of Action: Tofacitinib primarily inhibits JAK1 and JAK3, intracellular enzymes that mediate signaling pathways involved in immune and inflammatory responses. By inhibiting these enzymes, tofacitinib modulates the signaling of various cytokines involved in the pathogenesis of immune-mediated inflammatory diseases.

Alternate Names

International Nonproprietary Name (INN): Tofacitinib citrate

Brand Names: Xeljanz, Xeljanz XR

How It Works

Pharmacodynamics: Tofacitinib selectively inhibits JAK1 and JAK3, reducing the activity of signaling pathways involved in inflammation and immune responses. This leads to decreased production of inflammatory cytokines and a reduction in joint inflammation and other symptoms of immune-mediated inflammatory diseases.

Pharmacokinetics:

• Absorption: Orally administered tofacitinib is rapidly absorbed, reaching peak plasma concentrations within approximately 0.5 to 1 hour (immediate-release) and 2 hours (extended-release).
• Metabolism: Primarily metabolized by the liver, mostly by CYP3A4 and to a lesser extent by CYP2C19.
• Elimination: Primarily eliminated via the kidneys (approximately 70%) with the remainder excreted in feces. The half-life is approximately 3 hours for the immediate-release formulation and 7 hours for the extended-release formulation.

Mode of Action: Tofacitinib binds to the catalytic site of JAK enzymes, preventing their activation and subsequent phosphorylation of STAT proteins. This disruption of the JAK-STAT signaling pathway reduces the expression of genes involved in inflammation and immune responses.

Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: Tofacitinib selectively inhibits JAK1 and JAK3 enzymes.

Elimination Pathways: Primarily renal excretion (approximately 70%), with the remaining amount excreted in feces. Hepatic metabolism by CYP3A4 and CYP2C19 plays a role.

Dosage

Standard Dosage

Adults:

• Rheumatoid Arthritis, Psoriatic Arthritis, Ankylosing Spondylitis:
  • Immediate-release tablets: 5 mg twice daily.
  • Extended-release tablets: 11 mg once daily.
• Ulcerative Colitis:
  • Induction: 10 mg twice daily (immediate-release) or 22 mg once daily (extended-release) for 8 weeks. May extend to 16 weeks if needed.
  • Maintenance: 5 mg twice daily (immediate-release) or 11 mg once daily (extended-release). For patients with loss of response, 10 mg twice daily (immediate-release) or 22 mg once daily (extended-release) may be considered for the shortest duration possible.

Children (pcJIA, ages 2 to 17 years):

• Oral Solution or Immediate-Release Tablets: Weight-based dosing twice daily. Please consult a pediatric dosing guide or the full prescribing information for specific weight-based recommendations.

Special Cases:

• Elderly Patients: No dose adjustment is generally required, but monitor for adverse events.
• Patients with Renal Impairment:
  • Moderate to severe: 5 mg once daily when the usual dose is 5 mg twice daily (immediate-release) or 11 mg once daily (extended-release). Administer after dialysis on dialysis days.
• Patients with Hepatic Dysfunction:
  • Moderate: 5 mg once daily when the usual dose is 5 mg twice daily (immediate-release) or 11 mg once daily (extended-release). For UC, 5 mg twice daily when the usual dose is 10 mg twice daily (immediate release), or 11 mg once daily (extended-release) when the usual dose is 22 mg once daily (extended-release).
  • Severe: Tofacitinib is contraindicated.
• Patients with Comorbid Conditions: Consider comorbidities and potential drug interactions when determining the appropriate dose. Use with caution in patients at risk for cardiovascular events, malignancy, or venous thromboembolism (VTE).

Clinical Use Cases

Tofacitinib is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest. Its use is limited to the treatment of specific immune-mediated inflammatory diseases mentioned in the “Usage” section.

Dosage Adjustments

Dose adjustments are based on renal/hepatic function as described above. Monitor for laboratory abnormalities, including lymphopenia, neutropenia, and anemia. Dosage interruption or discontinuation may be necessary based on the severity of these abnormalities. Consult the full prescribing information for specific guidelines on laboratory monitoring and dosage adjustments.

Side Effects

Common Side Effects:

• Upper respiratory tract infections
• Headache
• Diarrhea
• Nausea

Rare but Serious Side Effects:

• Serious infections (e.g., tuberculosis, opportunistic infections)
• Malignancy (e.g., lymphoma)
• Gastrointestinal perforations
• Blood clots (e.g., deep vein thrombosis, pulmonary embolism)

Long-Term Effects:

Long-term safety data is still being collected, but potential long-term effects may include an increased risk of infections, malignancy, and cardiovascular events.

Adverse Drug Reactions (ADR):

Clinically significant ADRs include severe infections, malignancy, gastrointestinal perforations, and blood clots. These require immediate medical attention.

Contraindications

• Severe hepatic impairment
• Hypersensitivity to tofacitinib

Drug Interactions

Tofacitinib has numerous drug interactions. Significant interactions include:

• CYP3A4 Inhibitors/Inducers: Adjust dosage accordingly.
• Biologics, Immunosuppressants: Avoid concomitant use or use with extreme caution due to increased risk of infections.
• Live Vaccines: Contraindicated.

Pregnancy and Breastfeeding

• Pregnancy: Not recommended due to potential teratogenic effects. Use effective contraception during treatment and for at least 4 weeks after discontinuation.
• Breastfeeding: Not recommended. Tofacitinib passes into breast milk. Discontinue breastfeeding or discontinue the drug.

Drug Profile Summary

• Mechanism of Action: JAK1 and JAK3 inhibitor.
• Side Effects: Upper respiratory tract infections, headache, diarrhea, nausea, serious infections, malignancy, gastrointestinal perforations, blood clots.
• Contraindications: Severe hepatic impairment, hypersensitivity.
• Drug Interactions: CYP3A4 inhibitors/inducers, biologics, immunosuppressants, live vaccines.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: See dosage section above for specific dosing guidelines.
• Monitoring Parameters: Lymphocyte count, neutrophil count, hemoglobin, liver enzymes, lipids.

Popular Combinations

Tofacitinib is often used in combination with MTX for the treatment of RA and pcJIA.

Precautions

• Monitor for infections, malignancies, gastrointestinal symptoms, and cardiovascular events.
• Screen for tuberculosis before and during treatment.
• Monitor laboratory parameters.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tofacitinib?

A: See detailed dosage information in the “Dosage” section above.

Q2: What are the serious side effects of Tofacitinib?

A: Serious side effects include serious infections, malignancies, gastrointestinal perforations, and blood clots.

Q3: Can Tofacitinib be used during pregnancy?

A: Tofacitinib is not recommended for use during pregnancy.

Q4: Can Tofacitinib be used during breastfeeding?

A: Tofacitinib is not recommended during breastfeeding.

Q5: What are the common drug interactions with Tofacitinib?

A: Common drug interactions include CYP3A4 inhibitors/inducers, biologics, immunosuppressants, and live vaccines.

Q6: What laboratory monitoring is required for patients taking Tofacitinib?

A: Monitor lymphocyte count, neutrophil count, hemoglobin, liver enzymes, and lipids.

Q7: What conditions is Tofacitinib contraindicated in?

A: Tofacitinib is contraindicated in patients with severe hepatic impairment and hypersensitivity to the drug.

Q8: Can Tofacitinib be used in children?

A: Tofacitinib is approved for the treatment of pcJIA in children 2 years of age and older.

Q9: How does Tofacitinib work?

A: Tofacitinib works by inhibiting JAK1 and JAK3 enzymes, which reduces inflammation and modulates the immune response.