XELJANZ- tofacitinib citrate tablet, film coated
U.S. Pharmaceuticals
WARNING: SERIOUS INFECTIONS AND MALIGNANCY
SERIOUS INFECTIONS
Patients treated with XELJANZ are at increased risk for developing serious infections 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.
If a serious infection develops, interrupt XELJANZ until the infection is controlled.
Reported infections include:
Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.
Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
Bacterial, viral, and other infections due to opportunistic pathogens.
The risks and benefits of treatment with XELJANZ 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 treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions (5.1)].
MALIGNANCIES
Lymphoma and other malignancies have been observed in patients treated with XELJANZ. Epstein Barr Virus- associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications [see Warnings and Precautions (5.2)].
1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis
XELJANZ (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs).
XELJANZ should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.
2 DOSAGE AND ADMINISTRATION
XELJANZ is given orally with or without food.
2.1 Rheumatoid Arthritis
XELJANZ may be used as monotherapy or in combination with methotrexate or other nonbiologic disease modifying antirheumatic drugs (DMARDs). The recommended dose of XELJANZ is 5 mg twice daily.
Dose interruption is recommended for management of lymphopenia, neutropenia and anemia [see Dosage and Administration (2.3), Warnings and Precautions (5.4), and Adverse Reactions (6.1)].
XELJANZ dosage should be reduced to 5 mg once daily in patients:
with moderate or severe renal insufficiency
with moderate hepatic impairment
receiving potent inhibitors of Cytochrome P450 3A4 (CYP3A4) (e.g., ketoconazole)
receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole).
2.2 General Considerations for Administration
XELJANZ should not be used in patients with severe hepatic impairment.
It is recommended that XELJANZ not be initiated in patients with a lymphocyte count less than 500 cells/mm3 , an absolute neutrophil count (ANC) less than 1000 cells/mm3 , or who have hemoglobin levels less than 9 g/dL.
Coadministration of XELJANZ with potent inducers of CYP3A4 (e.g., rifampin) may result in loss of or reduced clinical response to XELJANZ.
DOSAGE FORMS AND STRENGTHS
XELJANZ is provided as 5 mg tofacitinib (equivalent to 8 mg tofacitinib citrate) tablets: White, round, immediate-release film-coated tablets, debossed with "Pfizer" on one side, and "JKI 5″ on the other side.
DESCRIPTION
XELJANZ is the citrate salt of tofacitinib, a JAK inhibitor.
Tofacitinib citrate is a white to off-white powder with the following 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) . It is freely soluble in water.
Tofacitinib citrate has a molecular weight of 504.5 Daltons (or 312.4 Daltons as the tofacitinib free base) and a molecular formula of C16 H20 N6 O�C6 H8 O7
CLINICAL PHARMACOLOGY
12.1 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.
