Tofacitinib

XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) are Janus kinase (JAK) inhibitors. XELJANZ tablets and XELJANZ XR are indicated for the treatment of adult patients with: • Moderately to severely active rheumatoid arthritis (RA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active psoriatic arthritis (PsA), who have had an inadequate response or intolerance to one or more TNF blockers. • Active ankylosing spondylitis (AS), who have had an inadequate response or intolerance to one or more TNF blockers. • Moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers.

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 IC 50 of 406, 56, and 1377 nM, respectively.

Recommended Evaluations and Immunization Prior to Treatment Initiation • Prior to initiating XELJANZ/XELJANZ XR, consider performing an active and latent TB evaluation, viral hepatitis screening, a complete blood count, and updating immunizations. Avoid XELJANZ or XELJANZ XR initiation if absolute lymphocyte count <500 cells/mm 3, an absolute neutrophil count (ANC) <1000 cells/mm 3 or hemoglobin <9 g/dL. Important Administration Instructions • XELJANZ XR (extended-release tablets) is not substitutable with XELJANZ (tablets and oral solution). • Switching between XELJANZ and XELJANZ XR should be made by the healthcare provider. Recommended Dosage Adult Patients with RA, PsA or AS • XELJANZ tablets 5 mg twice daily or XELJANZ XR (extended-release tablets) 11 mg once daily.

None. None.

Boxed warning: Increased risk of serious bacterial, fungal, viral, and opportunistic infections, including tuberculosis (TB), leading to hospitalization or death. Interrupt XELJANZ/XELJANZ XR treatment if serious infection occurs until the infection is controlled. Test for latent TB before and during therapy, treat latent TB prior to use. Monitor all patients for active TB during treatment, even patients with initial negative latent TB test. • Serious Infections: Avoid use of XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) during an active serious infection, including localized infections. • Gastrointestinal Perforations: Promptly evaluate patients at increased risk for gastrointestinal perforation who present with new onset abdominal symptoms.

The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections • Increased Risk of Mortality • Malignancy and Lymphoproliferative Disorders • Major Adverse Cardiovascular Events • Thrombosis • Gastrointestinal Perforations • Hypersensitivity Reactions • Hypoglycemia in Patients with Diabetes • Laboratory Abnormalities Most common adverse reactions are: • RA, PsA, and AS: Reported in ≥2% of adult patients treated with XELJANZ tablets monotherapy or in combination with DMARDs: upper respiratory tract infection (URI), nasopharyngitis, diarrhea, and headache. • PcJIA: Consistent with common adverse reactions reported in adult patients with RA.

Table 7 includes drugs with clinically significant drug interactions when concomitantly used with XELJANZ (tablets and oral solution) and XELJANZ XR (extended-release tablets) and instructions for preventing or managing them.

for XELJANZ Tablets/XELJANZ XR Store XELJANZ tablets and XELJANZ XR at 20°C to 25°C (68°F to 77°F). Storage and Handling for XELJANZ Oral Solution Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (between 59°F and 86°F). Store in the original bottle and carton to protect from light.