Tofacitinib Citrate (3 brand names, 3 dosage forms, 1 route)
Available dosage forms: TABLET, TABLET, EXTENDED RELEASE, SOLUTION.
Routes of administration: ORAL.
Brand Names
- TOFACITINIB CITRATE
- XELJANZ
- XELJANZ XR
Boxed Warning
SERIOUS INFECTIONS Patients treated with tofacitinib extended-release tablets are at increased risk for developing serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB), that may lead to hospitalization or death [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Reported infections included: • Active TB, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent TB before tofacitinib extended-release tablets use and during therapy. Treatment for latent infection should be initiated prior to tofacitinib extended-release tablets use. • Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. • Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens. The risks and benefits of tofacitinib extended-release tablets treatment should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after tofacitinib extended-release tablets treatment, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. If a serious infection develops, interrupt tofacitinib extended-release tablets until the infection is controlled [see Warnings and Precautions (5.1)]. MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing tofacitinib tablets 5 mg or 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed
Contraindications
None.
Adverse Reactions
The following clinically significant adverse reactions are described elsewhere in the labeling: •Serious Infections [see Warnings and Precautions (5.1)] •Increased Risk of Mortality [see Warnings and Precautions (5.2)] •Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions (5.3)] •Major Adverse Cardiovascular Events [see Warnings and Precautions (5.4)] •Thrombosis [see Warnings and Precautions (5.5)] •Gastrointestinal Perforations [see Warnings and Precautions (5.6)] •Hypersensitivity Reactions [see Warnings and Precautions (5.7)] •Laboratory Abnormalities [see Warnings and Precautions (5.8)]
Drug Interactions
Table 7 includes drugs with clinically significant drug interactions when concomitantly used with tofacitinib extended-release tablets and instructions for preventing or managing them. Table 7: Clinically Significant Interactions Affecting Tofacitinib Extended-Release Tablets When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib extended-release tablets is recommended [see Dosage and Administration (2), Clinical Pharmacology, Figure 3 (12.3)] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of tofacitinib extended-release tablets is recommended [see Dosage and Administration (2), Clinical Pharmacology, Figure 3 (12.3)] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with tofacitinib extended-release tablets is not recommended [see Clinical Pharmacology, Figure 3 (12.3)] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of tofacitinib extended-release tablets with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, or AS. Intervention Concomitant use with tofacitinib extended-release tablets is not recommended [see Indications and Usage (1), Clinical Pharmacology, Figure 3 (12.3)]
Mechanism of Action
Tofacitinib is a Janus kinase (JAK) inhibitor. JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor-receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.
Overdosage
There is no specific antidote for overdose with tofacitinib extended-release tablets. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. In a study in patients with end-stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus, limits the value of hemodialysis for treatment of overdose with tofacitinib extended-release tablets. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdose management recommendations.