Tofacitinibdosage

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. Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Who Weigh At Least 10 kg

XELJANZ (tablets or oral solution) 5 mg twice daily for those ≥40 kg or weight-based equivalent twice daily for those <40 kg. Adult Patients with UC

Induction: XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed, continue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily for a maximum of 16 weeks. Discontinue XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved.

Maintenance: XELJANZ tablets 5 mg twice daily or XELJANZ XR 11 mg once daily. For patients with loss of response during maintenance treatment, XELJANZ tablets 10 mg twice daily or XELJANZ XR 22 mg once daily may be considered and limited to the shortest duration, with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. Dosage in Patients with Renal Impairment or Hepatic Impairment

Use of XELJANZ (tablets and oral solution) or XELJANZ XR in patients with severe HI is not recommended.

See full prescribing information (FPI) for recommended dosage in patients with moderate or severe RI or moderate HI. Dosage Modification See the full prescribing information for dosage modification by indication for patients who concomitantly use CYP2C19 and/or CYP3A4 inhibitors and patients with lymphopenia, neutropenia, or anemia.

2.1 Recommended

Evaluations and Immunization Prior to Treatment Initiation Prior to initiating XELJANZ (tablets and oral solution) or XELJANZ XR (extended-release tablets), consider performing the following:

Active and latent tuberculosis (TB) infection evaluation: If the patient has latent TB, treat for TB prior to XELJANZ/XELJANZ XR treatment.

Viral hepatitis screening in accordance with clinical guidelines.

A complete blood count: Avoid initiation of XELJANZ/XELJANZ XR treatment in patients with a lymphocyte count less than 500 cells/mm 3, absolute neutrophil count less than 1000 cells/mm 3, or hemoglobin level less than 9 g/dL.

Baseline hepatic function evaluation: XELJANZ/XELJANZ XR is not recommended for patients with severe hepatic impairment.

Update immunizations according to current immunization guidelines. The interval between live vaccinations and initiation of XELJANZ/XELJANZ XR should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

2.2 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.

Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia.

Interrupt use of XELJANZ/XELJANZ XR if a patient develops a serious infection until the infection is controlled.

Take XELJANZ/XELJANZ XR with or without food.

Swallow XELJANZ XR whole and intact. Do not crush, split, or chew the extended-release tablets.

2.3 Recommended

Dosage in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, and Ankylosing Spondylitis Table 1 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) for adults with RA, PsA, and AS with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment. The table also displays the recommended dosage modifications for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia.

Table 1: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC <1000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. 5 mg twice daily 11 mg once daily Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) 5 mg twice daily 11 mg once daily Moderate RI (CLcr ≥30 and ≤50 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily Severe RI (CLcr <30 mL/min) 5 mg once daily XELJANZ tablets 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) 5 mg twice daily 11 mg once daily Moderate HI (Child-Pugh B) 5 mg once daily XELJANZ tablets 5 mg once daily Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) 5 mg twice daily 11 mg once daily Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) 5 mg once daily XELJANZ tablets 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3, confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily. Interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets 5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg.

2.4 Recommended

Dosage in Pediatric Patients 2 Years of Age and Older with Psoriatic Arthritis or Polyarticular Course Juvenile Idiopathic Arthritis Table 2 displays the recommended body weight-based dosages for XELJANZ tablets and XELJANZ oral solution in pediatric patients 2 years of age and older with PsA or pcJIA with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment. The table also includes recommended dosage modification for pediatric patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and pediatric patients with lymphopenia, neutropenia, or anemia. Administer XELJANZ oral solution using the included press-in bottle adapter and oral dosing syringe. Table 2: Recommended Dosage of XELJANZ Tablets and XELJANZ Oral Solution in Pediatric Patients 2 Years of Age and Older with PsA or pcJIA Pediatric Patients 2 Years of Age and Older XELJANZ tablets and XELJANZ oral solution Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ (tablets and oral solution) with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC <1000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL.

10 kg ≤ body weight <20 kg: 3.2 mg (3.2 mL oral solution) twice daily

20 kg ≤ body weight <40 kg: 4 mg (4 mL oral solution) twice daily

Body weight ≥40 kg: 5 mg (one 5 mg tablet or 5 mL oral solution) twice daily Patients treated with XELJANZ oral solution 5 mL may be switched to XELJANZ tablets 5 mg. Recommended Dosage in Patients with Renal Impairment (RI) Mild RI Same as patients with normal renal function. Moderate RI

10 kg ≤ body weight <20 kg: 3.2 mg once daily

20 kg ≤ body weight <40 kg: 4 mg once daily

Body weight ≥40 kg: 5 mg once daily Severe RI

10 kg ≤ body weight <20 kg: 3.2 mg once daily

20 kg ≤ body weight <40 kg: 4 mg once daily

Body weight ≥40 kg: 5 mg once daily For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI Same as patients with normal hepatic function. Moderate HI

10 kg ≤ body weight <20 kg: 3.2 mg once daily

20 kg ≤ body weight <40 kg: 4 mg once daily

Body weight ≥40 kg: 5 mg once daily Severe HI Use of XELJANZ tablets/XELJANZ oral solution is not recommended. Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole)

10 kg ≤ body weight <20 kg: 3.2 mg once daily

20 kg ≤ body weight <40 kg: 4 mg once daily

Body weight ≥40 kg: 5 mg once daily Strong CYP3A4 inhibitor(s) Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Patients with lymphocyte count less than 500 cells/mm 3, confirmed by repeat testing Discontinue dosing. Patients with ANC less than 500 cells/mm 3 Discontinue dosing. Patients with ANC 500 to 1000 cells/mm 3 Interrupt dosing until ANC is greater than 1000 cells/mm 3. Patients with hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized.

2.5 Recommended

Dosage in Adults with Ulcerative Colitis Table 3 displays the recommended dosage of XELJANZ tablets and XELJANZ XR (extended-release tablets) in adult patients with ulcerative colitis (UC) with and without renal impairment (including those who are undergoing hemodialysis) or hepatic impairment. Table 4 displays the recommended dosage modification for patients concomitantly using CYP2C19 and/or CYP3A4 inhibitors, and patients with lymphopenia, neutropenia, or anemia. Table 3: Recommended Dosage of XELJANZ Tablets and XELJANZ XR in Adults with Ulcerative Colitis With and Without Renal Impairment or Hepatic Impairment Adults XELJANZ tablets XELJANZ XR (extended-release tablets) Patients with Normal Renal and Hepatic Function Excludes patients who concomitantly use XELJANZ tablets/XELJANZ XR with strong CYP3A4 inhibitor(s) or moderate CYP3A4 inhibitor(s) and strong CYP2C19 inhibitor(s), as well as patients with lymphocyte count less than 500 cells/mm 3, ANC <1000 cells/mm 3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. Induction: 10 mg twice daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 10 mg twice daily for a maximum of 16 weeks. Discontinue 10 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 22 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 22 mg once daily for a maximum of 16 weeks. Discontinue 22 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg twice daily. For patients with loss of response during maintenance treatment, may consider a dosage of 10 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: 11 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 22 mg once daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dose needed to maintain response. Recommended Dosage in Patients with Renal Impairment (RI) Tofacitinib PK was evaluated in subjects with varying degrees of renal impairment, where the severity of renal impairment was defined based on creatinine clearance (CLcr) estimated using the Cockcroft‑Gault equation: CLcr >80 mL/min (normal renal function); CLcr >50 and ≤80 mL/min (mild renal impairment); ≥30 and ≤50 mL/min (moderate renal impairment); <30 mL/min (severe renal impairment). Mild RI (CLcr >50 and ≤80 mL/min) Same as patients with normal renal function. Moderate RI (CLcr ≥30 and ≤50 mL/min) Induction: 5 mg twice daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Severe RI (CLcr <30 mL/min) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate or Severe RI. For patients undergoing hemodialysis, administer the dose after the dialysis session on dialysis days. If a dose was taken before the dialysis procedure, supplemental doses are not recommended after dialysis. Recommended Dosage in Patients with Hepatic Impairment (HI) Mild HI (Child-Pugh A) Same as patients with normal hepatic function. Moderate HI (Child-Pugh B) Induction: 5 mg twice daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate HI. Severe HI (Child-Pugh C) Use of XELJANZ tablets/XELJANZ XR is not recommended. Table 4: Dosage Modifications of XELJANZ Tablets and XELJANZ XR Due to Drug Interactions and for Lymphopenia, Neutropenia or Anemia in Adults with Ulcerative Colitis Adults XELJANZ Tablets XELJANZ XR (extended-release tablets) Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) Strong CYP2C19 inhibitor(s) No dosage modification is recommended. Moderate CYP2C19 inhibitor(s) Moderate CYP3A4 inhibitor(s) Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) Induction: 5 mg twice daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 5 mg twice daily for a maximum of 16 weeks. Discontinue 5 mg twice daily after 16 weeks if adequate therapeutic response is not achieved. Induction: 11 mg once daily for at least 8 weeks; evaluate patients and transition to maintenance therapy depending on therapeutic response. If needed continue 11 mg once daily for a maximum of 16 weeks. Discontinue 11 mg once daily after 16 weeks if adequate therapeutic response is not achieved. Strong CYP3A4 inhibitor(s) Maintenance: 5 mg once daily. For patients with loss of response during maintenance treatment, may consider a dosage of 5 mg twice daily (limited to the shortest duration), with careful consideration of the benefits and risks for the individual patient. Use the lowest effective dosage needed to maintain response. Maintenance: XELJANZ XR is not recommended. see Maintenance Dosage for XELJANZ tablets for Strong CYP3A4 inhibitors. Dosage Modifications for Lymphopenia, Neutropenia, or Anemia Lymphocyte count less than 500 cells/mm 3, confirmed by repeat testing Discontinue dosing. ANC less than 500 cells/mm 3 Discontinue dosing. ANC 500 to 1000 cells/mm 3 If taking:

10 mg twice daily, reduce to 5 mg twice daily. When ANC is greater than 1000, increase to 10 mg twice daily based on clinical response.

5 mg twice daily, interrupt dosing. When ANC is greater than 1000, resume 5 mg twice daily. If taking:

22 mg once daily, reduce to 11 mg once daily. When ANC is greater than 1000, increase to 22 mg once daily based on clinical response.

11 mg once daily, interrupt dosing. When ANC is greater than 1000, resume 11 mg once daily. Hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL Interrupt dosing until hemoglobin values have normalized. Switching from XELJANZ Tablets to XELJANZ XR Extended-Release Tablets Patients treated with XELJANZ tablets:

5 mg twice daily may be switched to XELJANZ XR extended-release tablets 11 mg once daily the day following the last dose of XELJANZ tablets 5 mg.

10 mg twice daily may be switched to XELJANZ XR extended-release tablets 22 mg once daily the day following the last dose of XELJANZ tablets 10 mg.