Tofacitinib extended-release
Other products: Tofacitinib
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Boxed warning
WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, and THROMBOSIS 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 XELJANZ 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 with XELJANZ tablets 5 mg or 10 mg twice a day [see Warnings and Precautions (5.2) ]. XELJANZ 10 mg twice daily and tofacitinib extended-release tablets 22 mg once daily dosages are not recommended for the treatment of RA, psoriatic arthritis (PsA), or ankylosing spondylitis (AS) [see Dosage and Administration (2.3) ] .
MALIGNANCIES Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory…
Handling and access
NIOSH hazardous drug
Table 2NIOSH lists tofacitinib as a hazardous drug. AHFS class: 92:36 disease-modifying antirheumatic drugs; 92:20 immunomodulatory agents.
- Meets the NIOSH definition of a hazardous drug (carcinogenicity, developmental or reproductive toxicity, organ toxicity at low doses, or genotoxicity) without MSHI or a Group 1 or 2A carcinogen classification.
Handle with the precautions your facility uses for hazardous drugs (USP <800>). NIOSH's Managing Hazardous Drug Exposures lists controls by drug form and activity.
Dosing in kidney impairment
Renal Impairment Moderate and Severe Renal Impairment XELJANZ-treated patients with moderate renal impairment (RI) (CLcr ≥ 30 and ≤ 50 mL/minute) or severe RI (< 30 mL/minute) had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function (CLcr > 80 mL/minute). The recommended dosage of tofacitinib extended-release tablets in patients with moderate or severe RI (including those with severe RI who are undergoing hemodialysis) is lower than the recommended dosage in patients with normal renal function [see Dosage and Administration (2.3 , 2.5) ] .
Mild Renal Impairment The recommended dosage in patients with mild RI (CLcr > 50 and ≤ 80 mL/minute) is the same as patients with normal renal function.
| Adults | Tofacitinib extended-release tablets |
|---|---|
| Patients with Normal Renal and Hepatic FunctionExcludes patients who concomitantly use XELJANZ tablets/tofacitinib extended-release tablets 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/mm3, ANC < 1000 cells/mm3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. | 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) | 11 mg once daily |
| Moderate RI (CLcr ≥ 30 and ≤ 50 mL/min) | XELJANZ tablets 5 mg once daily |
| Severe RI (CLcr < 30 mL/min) | 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) | 11 mg once daily |
| Moderate HI (Child-Pugh B) | XELJANZ tablets 5 mg once daily |
| Severe HI (Child-Pugh C) | Use of XELJANZ tablets/tofacitinib extended-release tablets is not recommended. |
| Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) | |
| Strong CYP2C19 inhibitor(s) | 11 mg once daily |
| Moderate CYP2C19 inhibitor(s) | |
| Moderate CYP3A4 inhibitor(s) | |
| Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) | 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/mm3, confirmed by repeat testing | Discontinue dosing. |
| Patients with ANC less than 500 cells/mm3 | Discontinue dosing. |
| Patients with ANC 500 to 1,000 cells/mm3 | Interrupt dosing. When ANC is greater than 1,000, 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. |
| Adults | Tofacitinib Extended Release Tablets |
| Patients with Normal Renal and Hepatic FunctionExcludes patients who concomitantly use tofacitinib extended-release tablets 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/mm3, ANC < 1,000 cells/mm3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. | 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: 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: 11 mg once daily for atleast 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: Tofacitinib extended release tablets 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. |
| Severe RI (CLcr < 30 mL/min) | |
| 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: 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: Tofacitinib extended release tablets is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate HI. |
| Severe HI (Child-Pugh C) | Use of tofacitinib extended release tablets is not recommended. |
Dosing in liver impairment
Hepatic Impairment Severe Hepatic Impairment Tofacitinib extended-release tablets has not been studied in patients with severe hepatic impairment (HI) (Child-Pugh C); therefore, use of tofacitinib extended-release tablets in patients with severe HI is not recommended. Moderate Hepatic Impairment XELJANZ-treated patients with moderate hepatic impairment (Child-Pugh B) had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function [see Clinical Pharmacology ].
Higher blood concentrations may increase the risk of some adverse reactions. The recommended tofacitinib extended-release tablets dosage in patients with moderate HI is lower than the recommended dosage in patients with normal hepatic function [see Dosage and Administration (2.3 , 2.5) ] . Mild Hepatic Impairment The recommended dosage of tofacitinib extended-release tablets in patients with mild hepatic impairment (Child-Pugh A) is the same as patients with normal hepatic function.
Hepatitis B or C Serology The safety and efficacy of tofacitinib extended-release tablets have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.
| Adults | Tofacitinib extended-release tablets |
|---|---|
| Patients with Normal Renal and Hepatic FunctionExcludes patients who concomitantly use XELJANZ tablets/tofacitinib extended-release tablets 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/mm3, ANC < 1000 cells/mm3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. | 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) | 11 mg once daily |
| Moderate RI (CLcr ≥ 30 and ≤ 50 mL/min) | XELJANZ tablets 5 mg once daily |
| Severe RI (CLcr < 30 mL/min) | 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) | 11 mg once daily |
| Moderate HI (Child-Pugh B) | XELJANZ tablets 5 mg once daily |
| Severe HI (Child-Pugh C) | Use of XELJANZ tablets/tofacitinib extended-release tablets is not recommended. |
| Dosage Modifications with Concomitant Use of CYP3A4 and/or CYP2C19 Inhibitor(s) | |
| Strong CYP2C19 inhibitor(s) | 11 mg once daily |
| Moderate CYP2C19 inhibitor(s) | |
| Moderate CYP3A4 inhibitor(s) | |
| Moderate CYP3A4 inhibitor(s) with strong CYP2C19 inhibitor(s) (e.g., fluconazole) | 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/mm3, confirmed by repeat testing | Discontinue dosing. |
| Patients with ANC less than 500 cells/mm3 | Discontinue dosing. |
| Patients with ANC 500 to 1,000 cells/mm3 | Interrupt dosing. When ANC is greater than 1,000, 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. |
| Adults | Tofacitinib Extended Release Tablets |
| Patients with Normal Renal and Hepatic FunctionExcludes patients who concomitantly use tofacitinib extended-release tablets 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/mm3, ANC < 1,000 cells/mm3, or hemoglobin less than 8 g/dL or a decrease of more than 2 g/dL. | 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: 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: 11 mg once daily for atleast 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: Tofacitinib extended release tablets 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. |
| Severe RI (CLcr < 30 mL/min) | |
| 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: 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: Tofacitinib extended release tablets is not recommended. See Maintenance Dosage for XELJANZ tablets for Moderate HI. |
| Severe HI (Child-Pugh C) | Use of tofacitinib extended release tablets is not recommended. |
Preparation and administration
Important Administration Instructions Tofacitinib extended-release tablets are not substitutable with XELJANZ (tablets and oral solution). Switching between XELJANZ and tofacitinib extended-release tablets should be made by the healthcare provider. Dose interruption is recommended for management of lymphopenia, neutropenia, and anemia [see Warnings and Precautions and Adverse Reactions ] .
Interrupt use of tofacitinib extended-release tablets if a patient develops a serious infection until the infection is controlled [see Warnings and Precautions ]. Take tofacitinib extended-release tablets with or without food [see Clinical Pharmacology ] . Swallow tofacitinib extended-release tablets whole and intact. Do not crush, split, or chew the extended-release tablets [see Clinical Pharmacology ].
Therapeutic interchange
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Drug interactions
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- Tofacitinib extended-release
Label text (1 paragraph)
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, AS, or UC. Intervention Concomitant use with tofacitinib extended-release tablets is not recommended [see Indications and Usage (1) , Clinical Pharmacology, Figure 3 (12.3) ] See FPI for clinically significant drug interactions. ( 2 , 7 )
Contraindications
None. None. ( 4 )
Safety data
Reported adverse events (FAERS)
Liver injury (LiverTox)
E*Likelihood score E*: Suspected but unproven rare cause of clinically apparent liver injury with the potential to cause reactivation of hepatitis B.
Tofacitinib is an oral, small molecule inhibitor of Janus kinases that is used to treat moderate-to-severe rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Tofacitinib is associated with transient and usually mild elevations in serum aminotransferase levels during therapy, but has yet to be linked to cases of clinically apparent acute liver injury.
ABCDEA: well known cause; E: unlikely cause. [HD]: high doses only.
Pregnancy and lactation
Pregnancy
8.1 Pregnancy Risk Summary The available data with tofacitinib extended-release tablets from a pregnancy exposure registry that enrolled exposed pregnant females, pharmacovigilance, and published literature are insufficient to draw conclusions about a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with RA and UC in pregnancy (see Clinical Considerations ).
In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively. Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dosage of 5 mg twice daily and approximately 36 times the maximum recommended dosage of 10 mg twice daily, respectively (see Data ) .
The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk: Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with RA or UC.
Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2,500 grams) infants, and small for gestational age at birth. Data Animal Data : In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).
Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric…
Lactation
8.3 Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dosage of 5 mg twice daily and 6.3 times the maximum recommended dosage of 10 mg twice daily demonstrated adverse embryo-fetal findings [see Use in Specific Populations (8.1) ] . However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dosage. Consider pregnancy planning and prevention for females of reproductive potential.
Infertility Females Based on findings in rats, treatment with tofacitinib extended-release tablets may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible [see Nonclinical Toxicology (13.1) ] .
Breastfeeding (LactMed)
Data from 3 mothers indicate that the amount in milk is low, and no adverse effects were seen in infants who were exclusively breastfed during maternal tofacitinib use. Until more data become available, tofacitinib should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Expert opinion considers breastfeeding to be unadvisable during tofacitinib use at this time.- The manufacturer and an expert panel recommend that breastfeeding be discontinued during tofacitinib therapy and for 18 hours after the last dose of the immediate-release product or 36 hours after the last dose of the sustained-release product.
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