CLASSES

Other Specific Antirheumatics

BOXED WARNING

Do not initiate tofacitinib in patients with an active infection including localized infections. Evaluate and test patients for latent or active tuberculosis infection before tofacitinib administration. Treat patients with latent tuberculosis with standard antimycobacterial therapy before tofacitinib administration. Tofacitinib receipt increases the risk of serious including fatal infections such as pulmonary or extrapulmonary tuberculosis; invasive fungal infections; and bacterial, viral, and opportunistic infections. During and after tofacitinib receipt, closely monitor patients for the development of signs and symptoms of infection including the possible development of tuberculosis in patients who tested negative for latent tuberculosis before tofacitinib initiation. If a serious infection develops, interrupt tofacitinib receipt until the infection is controlled. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or an opportunistic infection, who have resided in or traveled to areas of endemic tuberculosis or endemic mycoses, or with underlying conditions that may predispose them to infection. Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Invasive fungal infections such as cryptococcosis and pneumocystosis may present with disseminated disease. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients who have been exposed to tuberculosis. Consider anti-tuberculosis therapy before tofacitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Lastly, carefully consider the risks and benefits of tofacitinib before starting the drug in patients with comorbidities that may increase the infection risk such as diabetes mellitus, human immunodeficiency virus (HIV) infection, and immunosuppression. Most patients who developed serious infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Tofacitinib may be inappropriate for patients with a current or past malignancy, as the drug may precipitate a secondary malignancy. Lymphoma and other types of neoplastic disease have been noted among tofacitinib recipients. Also, Epstein Barr virus- associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressives. Consider the risks and benefits of tofacitinib before initiating the drug in patients with a known malignancy other than a successfully treated non-melanoma skin cancer.

DEA CLASS

Rx

DESCRIPTION

Oral janus kinase inhibitor that blocks signals arising from cytokine interactions on the cellular membrane
For adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate
Serious infections and malignancy may occur

COMMON BRAND NAMES

Xeljanz, Xeljanz XR

HOW SUPPLIED

Xeljanz Oral Tab: 5mg
Xeljanz XR Oral Tab ER: 11mg

DOSAGE & INDICATIONS

MAXIMUM DOSAGE

10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets.

10 mg/day PO for immediate-release tablets or 11 mg/day PO for extended-release tablets.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Mild impairment (Child-Pugh class A, total score of 5 or 6): No dosage adjustment required.
Moderate impairment (Child-Pugh class B, total score of 7 to 9): Reduce dose to 5 mg once daily.
Severe impairment (Child-Pugh class C, total score greater than 10): Not recommended.

Mild renal impairment: No dosage adjustment needed.
Moderate renal impairment: Reduce dose to 5 mg once daily.
Severe renal impairment: Reduce dose to 5 mg once daily.

ADMINISTRATION

STORAGE

Xeljanz:
- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
Xeljanz XR:
- Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Consideration of vaccination status and administration of needed vaccines are advised before tofacitinib initiation, as concurrent live vaccine and tofacitinib receipt is not recommended.

Do not initiate tofacitinib in patients with an active infection including localized infections. Evaluate and test patients for latent or active tuberculosis infection before tofacitinib administration. Treat patients with latent tuberculosis with standard antimycobacterial therapy before tofacitinib administration. Tofacitinib receipt increases the risk of serious including fatal infections such as pulmonary or extrapulmonary tuberculosis; invasive fungal infections; and bacterial, viral, and opportunistic infections. During and after tofacitinib receipt, closely monitor patients for the development of signs and symptoms of infection including the possible development of tuberculosis in patients who tested negative for latent tuberculosis before tofacitinib initiation. If a serious infection develops, interrupt tofacitinib receipt until the infection is controlled. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or an opportunistic infection, who have resided in or traveled to areas of endemic tuberculosis or endemic mycoses, or with underlying conditions that may predispose them to infection. Ask patients if they have lived or have traveled to the Ohio and Mississippi River valleys or the Southwest because of an increased chance of acquiring certain kinds of fungal infections such as histoplasmosis, coccidioidomycosis, or blastomycosis. Invasive fungal infections such as cryptococcosis and pneumocystosis may present with disseminated disease. Carefully consider the risks and benefits of tofacitinib before starting the drug in patients who have been exposed to tuberculosis. Consider anti-tuberculosis therapy before tofacitinib administration in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Lastly, carefully consider the risks and benefits of tofacitinib before starting the drug in patients with comorbidities that may increase the infection risk such as diabetes mellitus, human immunodeficiency virus (HIV) infection, and immunosuppression. Most patients who developed serious infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Tofacitinib may be inappropriate for patients with a current or past malignancy, as the drug may precipitate a secondary malignancy. Lymphoma and other types of neoplastic disease have been noted among tofacitinib recipients. Also, Epstein Barr virus- associated post-transplant lymphoproliferative disorder (PTLD) has been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressives. Consider the risks and benefits of tofacitinib before initiating the drug in patients with a known malignancy other than a successfully treated non-melanoma skin cancer.

Avoidance or cautious use of tofacitinib is needed for patients with hepatic disease. Tofacitinib is not recommended for patients with severe hepatic impairment, and dose modification is needed for patients with moderate hepatic impairment. The safety and efficacy of tofacitinib have not been established for patients with positive hepatitis B virus or hepatitis C virus serology; the impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Screen patients for viral hepatitis before initiating tofacitinib therapy. Of note, tofacitinib is approximately 70% cleared by hepatic metabolism and may cause hepatotoxicity.

Cautious use of tofacitinib is advised for patients who may be at increased risk for gastrointestinal perforation such as patients with a history of diverticulitis, peptic ulcer disease, or ulcerative colitis. Gastrointestinal perforation has been noted among tofacitinib recipients. Use the extended-release formulation of tofacitinib with caution in patients with pre-existing severe gastrointestinal narrowing (e.g., GI obstruction). The extended-release formulation of tofacitinib utilizes a non-deformable extended release system. There have been rare reports of obstructive symptoms in patients with known GI strictures with the administration of other drugs utilizing a non-deformable extended release formulation.

Determine neutrophil and lymphocyte counts before tofacitinib initiation, and do not start the drug in patients with a lymphocyte count < 500 cells/mm3 or neutropenia defined as an ANC < 1000 cells/mm3. Tofacitinib may cause lymphopenia and neutropenia. For patients who have an ANC > 1000 cells/mm3, monitor neutrophil counts after 4—8 weeks of tofacitinib receipt and every 3 months thereafter. For patients who have a lymphocyte count > 500 cells/mm3, monitor lymphocyte counts every 3 months.

Determine the hemoglobin concentration before tofacitinib initiation, and do not start the drug in patients with anemia defined as hemoglobin < 9 g/dl. Tofacitinib may cause anemia. For patients who have hemoglobin >= 9 g/dl, monitor the hemoglobin concentration after 4—8 weeks of tofacitinib receipt and every 3 months thereafter.

Tofacitinib is a FDA pregnancy category C drug. Use tofacitinib during pregnancy only if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies in pregnant women exist. In rats and rabbits, tofacitinib is fetocidal and teratogenic when given at exposures at least 13 times the maximum recommended human dose (MRHD). No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD. If a pregnant woman is exposed to tofacitinib, enrollment in the pregnancy registry is encouraged by calling 1—877—311—8972.

According to the manufacturer, discontinue tofacitinib or breast-feeding because of the potential for serious adverse reactions in nursing infants from tofacitinib. Secretion of tofacitinib in human breast milk is unknown, but tofacitinib was secreted in milk of lactating rats. Also, the low molecular weight of tofacitinib increases the likelihood of secretion into breast milk, and a longer duration of pharmacodynamic activity as compared with the pharmacokinetic half life appears likely. Consider the potential for adverse effects on an infant's immune system. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assess indication and patient specific factors before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

The safety and efficacy of tofacitinib in neonates, infants, children, and adolescents have not been established.

Cautious tofacitinib use among geriatric patients may be warranted, as the frequency of serious infection among patients at least 65 years of age was higher than the frequency among those under the age of 65.

Cautious use of tofacitinib may be warranted for patients with renal disease, as increases in serum creatinine have been noted. Further, as 30% of the parent drug is cleared by renal excretion, tofacitinib dose reduction to 5 mg once daily is needed for patients with moderate or severe renal impairment. No dose adjustment is required in patients with mild renal impairment. In clinical trials of rheumatoid arthritis, tofacitinib was not evaluated in patients with baseline creatinine clearance < 40 ml/min.

Cautious use of tofacitinib may be advisable for patients with hypercholesterolemia or cardiac disease. In trials, tofacitinib receipt was associated with increases in total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol.

Reactivation of viral infection, including herpes infection (e.g., herpes zoster), was observed in tofacitinib clinical trials. The risk of herpes zoster infection in patients treated with tolfacitinib appears to be higher in those treated in Japan (Asian patients).

ADVERSE REACTIONS

post-transplant lymphoproliferative disorder (PTLD) / Delayed / 2.3-2.3
GI perforation / Delayed / Incidence not known

hypertension / Early / 1.6-1.6
elevated hepatic enzymes / Delayed / 0-1.3
neutropenia / Delayed / Incidence not known
lymphocytosis / Delayed / Incidence not known
lymphopenia / Delayed / Incidence not known
anemia / Delayed / Incidence not known
secondary malignancy / Delayed / Incidence not known
steatosis / Delayed / Incidence not known
erythema / Early / Incidence not known
dyspnea / Early / Incidence not known
peripheral edema / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
candidiasis / Delayed / Incidence not known
dehydration / Delayed / Incidence not known
gastritis / Delayed / Incidence not known

infection / Delayed / 20.0-20.0
headache / Early / 4.3-4.3
diarrhea / Early / 4.0-4.0
pharyngitis / Delayed / 3.8-3.8
fatigue / Early / Incidence not known
pruritus / Rapid / Incidence not known
rash (unspecified) / Early / Incidence not known
paresthesias / Delayed / Incidence not known
insomnia / Early / Incidence not known
abdominal pain / Early / Incidence not known
nausea / Early / Incidence not known
vomiting / Early / Incidence not known
dyspepsia / Early / Incidence not known

DRUG INTERACTIONS

Abatacept: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Amprenavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as amprenavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Anakinra: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Aprepitant, Fosaprepitant: Use caution if tofacitinib and aprepitant, fosaprepitant are used concurrently and monitor for an increase in tofacitinib-related adverse effects for several days after administration of a multi-day aprepitant regimen. Tofacitinib is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of tofacitinib. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Azathioprine: Do not use tofacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Do not use tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Bacillus Calmette-Guerin Vaccine, BCG: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Barbiturates: Barbiturates are CYP3A4 inducers, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Bexarotene: Bexarotene is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Boceprevir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as boceprevir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Bosentan: Bosentan is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Brigatinib: Monitor for decreased efficacy of tofacitinib if coadministration with brigatinib is necessary. Tofacitinib is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of tofacitinib may decrease.
Carbamazepine: Carbamazepine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Cyclosporine: Do not use tofacitinib in combination with potent immunosuppressants such as cyclosporine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Cyclosporine is also an inhibitor of CYP3A4, and tofacitinib is a CYP3A4 substrate. Increased systemic exposure of tofacitinib has been noted with concurrent cyclosporine administration. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Dalfopristin; Quinupristin: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as dalfopristin; quinupristin. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Delavirdine: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as delavirdine. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Dexamethasone: Dexamethasone is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Efavirenz: Efavirenz is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Efavirenz; Emtricitabine; Tenofovir: Efavirenz is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Elbasvir; Grazoprevir: Administering tofacitinib with elbasvir; grazoprevir may result in elevated tofacitinib plasma concentrations. Tofacitinib is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Enzalutamide: Enzalutamide is a strong CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. Of note, enzalutamide is also a moderate CYP2C19 inducer, and tofacitinib is primarily metabolized by CYP3A4 with minor contribution from CYP2C19. A loss of response or reduced clinical response to tofacitinib may occur.
Etravirine: Etravirine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Fluconazole: If used concurrently with fluconazole, the adult dose of tofacitinib must be reduced to 5 mg once daily. Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19, such as fluconazole. In one study, the mean AUC and Cmax of tofacitinib were increased by 79% and 27%, respectively, when administered with fluconazole.
Fosphenytoin: Phenytoin (or fosphenytoin) is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Grapefruit juice: Tofacitinib exposure may be increased when coadministered with grapefruit juice, which inhibits CYP3A4. A reduction of the tofacitinib dose to 5 mg once daily is recommended when used with a moderate inhibitor of CYP3A4. However, no recommendations are available for grapefruit juice. As with many similar drugs, it is best to counsel the patient to avoid grapefruit juice during tofacitinib therapy.
Griseofulvin: Griseofulvin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Indinavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as indinavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Intranasal Influenza Vaccine: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Isavuconazonium: Concomitant use of isavuconazonium with tofacitinib may result in increased serum concentrations of tofacitinib. Tofacitinib is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isoniazid, INH: Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur. Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
Isoniazid, INH; Rifampin: Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur. Tofacitinib exposure is increased when coadministered with moderate inhibitors of CYP3A4 and potent inhibitors of CYP2C19 such as isoniazid, INH. Reduce the tofacitinib dose to 5 mg once daily when used with a moderate inhibitor of CYP3A4 and a potent inhibitor of CYP2C19.
Itraconazole: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as itraconazole. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Japanese Encephalitis Virus Vaccine: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Ketoconazole: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ketoconazole. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Lesinurad: Lesinurad may decrease the systemic exposure and therapeutic efficacy of tofacitinib; monitor for potential reduction in efficacy. Tofacitinib is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Live Vaccines: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Lopinavir; Ritonavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Lumacaftor; Ivacaftor: Coadministration of tofacitinib and lumacaftor; ivacaftor may result in loss of or reduced clinical response to tofacitinib. Tofacitinib metabolism is primarily mediated by CYP3A4, and lumacaftor is a strong CYP3A inducer.
Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Measles/Mumps/Rubella Vaccines, MMR: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Mitotane: Use caution if mitotane and tofacitinib are used concomitantly, and monitor for decreased efficacy of tofacitinib and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and tofacitinib is a CYP3A4 substrate; coadministration may result in decreased plasma concentrations of tofacitinib.
Modafinil: Modafinil is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Nafcillin: Nafcillin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Ofatumumab: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Ombitasvir; Paritaprevir; Ritonavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Phenytoin: Phenytoin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Ribociclib: Use caution if coadministration of ribociclib with tofacitinib is necessary, as the systemic exposure of tofacitinib may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of tofacitinib if necessary. If the patient is also receiving a concomitant medication that results in strong CYP2C19 inhibition along with ribociclib (a moderate CYP3A4 inhibitor), reduce the dose of tofacitinib to 5 mg once daily. Ribociclib is a moderate CYP3A4 inhibitor and tofacitinib is a CYP3A4 substrate.
Ribociclib; Letrozole: Use caution if coadministration of ribociclib with tofacitinib is necessary, as the systemic exposure of tofacitinib may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of tofacitinib if necessary. If the patient is also receiving a concomitant medication that results in strong CYP2C19 inhibition along with ribociclib (a moderate CYP3A4 inhibitor), reduce the dose of tofacitinib to 5 mg once daily. Ribociclib is a moderate CYP3A4 inhibitor and tofacitinib is a CYP3A4 substrate.
Rifabutin: Rifabutin is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Rifampin: Tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers such as rifampin. A loss of response or reduced clinical response to tofacitinib may occur.
Rifapentine: Rifapentine is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Ritonavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Rituximab: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Rituximab; Hyaluronidase: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers, tocilizumab, IL-1R antagonists such as anakinra, anti-CD20 monoclonal antibodies like rituximab and ofatumumab, and selective costimulation modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Rotavirus Vaccine: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Rubella Virus Vaccine Live: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Smallpox Vaccine, Vaccinia Vaccine: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
St. John's Wort, Hypericum perforatum: St. John's Wort, Hypericum perforatum is a CYP3A4 inducer, and tofacitinib exposure is decreased when coadministered with potent CYP3A4 inducers. A loss of response or reduced clinical response to tofacitinib may occur.
Streptogramins: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as dalfopristin; quinupristin. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Tacrolimus: Do not use tofacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Do not use tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
Telotristat Ethyl: Use caution if coadministration of telotristat ethyl and tofacitinib is necessary, as the systemic exposure of tofacitinib may be decreased resulting in reduced efficacy. If these drugs are used together, monitor patients for suboptimal efficacy of tofacitinib; consider increasing the dose of tofacitinib if necessary. Tofacitinib is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate.
Tipranavir: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as tipranavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Tocilizumab: Avoid using tocilizumab with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as tofacitinib has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.
Tumor Necrosis Factor modifiers: Do not use tofacitinib in combination with biologic disease-modifying antirheumatic drugs (DMARDs) such as tumor necrosis factor (TNF) modifiers,because of the possibility of increased immunosuppression and increased infection risk. Tofacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs. Most patients taking tofacitinib who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids.
Typhoid Vaccine: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Varicella-Zoster Virus Vaccine, Live: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.
Yellow Fever Vaccine, Live: Do not administer live virus vaccines to patients taking tofacitinib, as no data are available on the secondary transmission of infection by live vaccines. Also, no data are available on the response to vaccination with any vaccine during tofacitinib receipt. Before tofacitinib initiation, review the vaccination status of patients, and update immunizations in agreement with current immunization guidelines.

PREGNANCY AND LACTATION

Tofacitinib is a FDA pregnancy category C drug. Use tofacitinib during pregnancy only if the potential benefit justifies the potential risk to the fetus. No adequate and well-controlled studies in pregnant women exist. In rats and rabbits, tofacitinib is fetocidal and teratogenic when given at exposures at least 13 times the maximum recommended human dose (MRHD). No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the MRHD. If a pregnant woman is exposed to tofacitinib, enrollment in the pregnancy registry is encouraged by calling 1—877—311—8972.

According to the manufacturer, discontinue tofacitinib or breast-feeding because of the potential for serious adverse reactions in nursing infants from tofacitinib. Secretion of tofacitinib in human breast milk is unknown, but tofacitinib was secreted in milk of lactating rats. Also, the low molecular weight of tofacitinib increases the likelihood of secretion into breast milk, and a longer duration of pharmacodynamic activity as compared with the pharmacokinetic half life appears likely. Consider the potential for adverse effects on an infant's immune system. Etanercept and infliximab may be potential alternatives to consider during breast-feeding. However, assess indication and patient specific factors before choosing an alternative agent. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.

MECHANISM OF ACTION

Tofacitinib is an oral janus kinase inhibitor. Janus kinases (JAKs) are intracellular enzymes that transmit signals arising from cytokine or growth factor receptor interactions such as interferons, interleukins, and erythropoetin on the cellular membrane to influence cellular processes of immune cell function and hematopoiesis. Janus kinase-mediated signaling is pivotal in immune activation, as cytokine receptors are expressed on most immune cells. Upon ligand and receptor interaction, JAKs are activated and, thus, phosphorylate their receptors and activate the signal transducers and activators of transcription proteins, which modulate intracellular activity including gene expression. Tofacitinib affects the signaling pathway at the point of JAKs. Janus kinases transmit cytokine signaling through pairing of JAKs such as JAK1/JAK3, JAK1/JAK2, and JAK2/JAK2. Tofacitinib primarily inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. For example, tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. The primary inhibition of JAK1 and JAK3 by tofacitinib is thought to be advantageous in terms of potential hematologic toxicity because hematopoietic cytokine receptors, such as the erythropoietin receptor, associate with JAK2 homodimers. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

PHARMACOKINETICS

Tofacitinib is administered orally. Protein binding is approximately 40%, and it binds predominantly to albumin; it does not appear to bind to alpha-1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. Metabolism is primarily mediated by CYP3A4 with minor contribution from CYP2C19. Approximately 70% is cleared by hepatic metabolism and 30% is cleared by renal excretion of the parent drug. After oral administration, the elimination half-life is around 3 hours. Rapid decreases in serum C-reactive protein (CRP) were observed and maintained throughout the treatment period among patients with rheumatoid arthritis. The observed changes in CRP do not reverse fully within 2 weeks after discontinuation, which indicates a longer duration of activity as compared with the pharmacokinetic half-life. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4 and CYP2C19
Tofacitinib is a substrate of primarily CYP3A4 with minor contributions from CYP2C19. The potential for tofacitinib to inhibit transporters such as P-glycoprotein (P-gp) and organic anionic or cationic transporters at therapeutic concentrations is low. In vitro, it does not significantly inhibit or induce the activity of the major human drug-metabolizing CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) at concentrations exceeding 185 times the steady state Cmax of a 5 mg twice daily dose. In vivo, no changes in the pharmacokinetic parameters of the CYP3A4 substrate midazolam were noted when coadministered. In patients with rheumatoid arthritis, the oral clearance does not vary with time, which indicates that tofacitinib does not normalize CYP enzyme activity in these patients. Thus, it is not expected to result in clinically relevant increases in the metabolism of CYP substrates.[52315]