Tofanib XR

Approved Indications:

• Rheumatoid Arthritis (RA): Moderately to severely active RA in adults who have had an inadequate response or intolerance to methotrexate.
• Psoriatic Arthritis (PsA): Active PsA in adults who have had inadequate response or intolerance to one or more disease-modifying antirheumatic drugs (DMARDs).
• Ulcerative Colitis (UC): Moderately to severely active UC in adults who have had an inadequate response, loss of response, or intolerance to tumor necrosis factor (TNF) blockers.
• Polyarticular Juvenile Idiopathic Arthritis (JIA): In children ≥2 years old, for active polyarticular course JIA.
• Ankylosing Spondylitis (AS): For active AS in adults (approved in some regions).

Off-label/Clinically Accepted Uses:

• Alopecia Areata (AA): In patients with extensive or refractory alopecia areata.
• Dermatomyositis and Lupus Erythematosus (SLE): Investigational and compassionate use in autoimmune dermatologic conditions.
• COVID-19 Cytokine Storm: Used off-label in hospitalized adults with severe COVID-19 pneumonia and hyperinflammation (under specific protocols).

Adults:

• Rheumatoid Arthritis & Psoriatic Arthritis: 5 mg orally twice daily or 11 mg extended-release once daily.
• Ulcerative Colitis: Induction: 10 mg twice daily for 8 weeks (may extend to 16 weeks); Maintenance: 5 mg twice daily or 11 mg once daily.
• Ankylosing Spondylitis: 5 mg orally twice daily (where approved).

Pediatrics (≥2 years, for JIA):

• Dose based on body weight:
• 10 kg to <20 kg: 3.2 mg orally twice daily.
• 20 kg to <40 kg: 4 mg orally twice daily.
• ≥40 kg: 5 mg orally twice daily.
• Available as oral solution for pediatric use.

Renal/Hepatic Impairment:

• Moderate renal impairment or moderate hepatic impairment: Reduce to 5 mg once daily.
• Severe hepatic impairment: Not recommended.

Administration Notes:

• Can be taken with or without food.
• Extended-release tablets must be swallowed whole.
• Dose adjustments required for CYP3A4 inhibitors and other interacting agents.

Tofacitinib is an oral Janus kinase (JAK) inhibitor, selectively targeting JAK1 and JAK3, with some activity on JAK2 and TYK2. It blocks intracellular signaling pathways involved in the immune response by preventing phosphorylation and activation of Signal Transducers and Activators of Transcription (STATs). This reduces cytokine-mediated inflammation associated with autoimmune diseases, particularly IL-6, IL-2, IL-4, IL-15, and interferon-gamma. This targeted immunomodulation decreases inflammatory activity and halts disease progression in autoimmune conditions.

• Absorption: Rapidly absorbed; peak plasma concentration in 0.5–1 hour.
• Bioavailability: Approximately 74%.
• Distribution: Volume of distribution ~87 L; 40% protein-bound.
• Metabolism: Primarily hepatic via CYP3A4 (main) and CYP2C19 (minor).
• Half-life: 3 hours (immediate-release); ~6 hours (extended-release).
• Elimination: 70% via urine (as metabolites), 30% in feces.
• Steady-state: Achieved within 24–48 hours with twice-daily dosing.

• Pregnancy: Not assigned to an FDA pregnancy category. Animal studies show fetal risk (e.g., skeletal malformations). Human data are limited. Should be used during pregnancy only if clearly needed. Avoid during pregnancy when possible.
• Lactation: Tofacitinib is excreted in animal milk; human data are lacking. Breastfeeding is not recommended during and for at least 18 hours after the last dose of tofacitinib (36 hours for 11 mg once-daily formulation) due to potential immunosuppressive effects on the infant.

• Primary Class: Janus Kinase (JAK) Inhibitor
• Subclass: Selective JAK1/JAK3 Inhibitor
• Drug Category: Disease-Modifying Antirheumatic Drug (DMARD); Immunosuppressant

• Known hypersensitivity to tofacitinib or any excipients.
• Active serious infections (e.g., tuberculosis, sepsis).
• Severe hepatic impairment.
• Concomitant use with other potent immunosuppressants (e.g., azathioprine, cyclosporine).
• Absolute neutrophil count <1000 cells/mm³ or lymphocyte count <500 cells/mm³.
• Hemoglobin <9 g/dL.

• Infections: Increased risk of serious and opportunistic infections including tuberculosis, fungal, and viral reactivation. Screen for TB before initiation.
• Malignancy: Increased risk of lymphoma, lung cancer, and skin cancer, especially in long-term use.
• Thrombosis: Risk of deep vein thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis; monitor in high-risk patients.
• Cardiovascular Risk: Elevated risk of major adverse cardiovascular events (MACE) in some patients.
• Gastrointestinal Perforation: Rare but serious; caution in patients with diverticulitis.
• Hematologic Abnormalities: Monitor for anemia, neutropenia, and lymphopenia.
• Liver Enzyme Elevations: Monitor ALT, AST during treatment.

Common:

• Gastrointestinal: Nausea, diarrhea
• Infections: Upper respiratory tract infection, herpes zoster
• Hematologic: Anemia, neutropenia
• Skin: Rash, acne

Serious/Rare:

• Tuberculosis and other opportunistic infections
• Pulmonary embolism, deep vein thrombosis
• Malignancy (lymphoma, lung cancer)
• Liver dysfunction
• Gastrointestinal perforation

Timing: Many adverse events are dose-dependent and occur within the first 3–6 months.

• CYP3A4 Inhibitors (e.g., ketoconazole): May increase tofacitinib levels; reduce dose.
• CYP3A4 Inducers (e.g., rifampin): May reduce efficacy.
• CYP2C19 Inhibitors (e.g., fluconazole): May increase exposure; dose adjustment may be needed.
• Immunosuppressants (e.g., biologic DMARDs, cyclosporine): Avoid combination due to increased infection risk.
• Live Vaccines: Avoid concurrent administration during and for a few weeks after treatment.

• FDA Boxed Warning (2021–2023): Strengthened warnings for cardiovascular events, cancer, thrombosis, and mortality based on post-marketing studies.
• EMA Restrictions (2022): Recommends limiting use in high-risk individuals over 65 or with cardiovascular risk.
• New Indications (2021–2024): Expanded pediatric use for polyarticular JIA and off-label investigations in dermatologic autoimmune diseases.

• Storage Temperature: Store below 25°C (77°F); excursions permitted between 15°C to 30°C.
• Humidity: Store in a dry place; protect from moisture.
• Light Protection: No special protection needed.
• Handling: Keep in original packaging. Do not crush or chew extended-release tablets.
• Oral Solution (if applicable): Store refrigerated between 2°C to 8°C; use within prescribed duration after opening.