Tofacitinib

312.3696

312.37

1806241-263-5

87LA6FU830

DTXSID90197271

C95800

Yellow foam

L04AA29|L - Antineoplastic and immunomodulating agents

29335990

88.9

1.5

1.3±0.1 g/cm3

White crystalline solid. MP: 199-206 °C /Tofacitinib monocitrate/

585.845ºC at 760 mmHg

308.1±30.1 °C

1.646

In water, 155.1 mg/L at 25 deg C (est)

Keep container tightly closed in a dry and well-ventilated place. /Tofacitinib citrate/

1.32X10-10 mm Hg at 25 deg C (est)

Specific optical rotation: +10.4 deg at 25 °C/D (c = 0.64 in methanol)

Henry's Law constant = 3.17X10-21 atm-cu m/mol at 25 °C (est)

pKa1 = 8.46 (cyano); pKa2 = 13.56 (secondary amine)

Hydroxyl radical reaction rate constant = 2.57X10-10 cu cm/molec-sec at 25 °C (est)

Stable under recommended storage conditions. /Tofacitinib citrate/

P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P311, P312, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, P501

H301

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.|Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product. /Tofacitinib citrate/

Incompatible materials: Strong oxidizing agents /Tofacitinib citrate/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including tofacitinib citrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Tofacitinib citrate/

|Danger|H301 (25%): Toxic if swallowed [Danger Acute toxicity, oral]|P201, P202, P260, P261, P264, P270, P271, P280, P281, P301+P310, P301+P312, P302+P352, P304+P340, P305+P351+P338, P308+P313, P311, P312, P314, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, and P501|Aggregated GHS information provided by 4 companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Tofacitinib citrate/|Skin protection: Handle with gloves. /Tofacitinib citrate/|Body Protection: Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Tofacitinib citrate/|Respiratory protection: Respiratory protection is not required. Where protection from nuisance levels of dusts are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Tofacitinib citrate/

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Tofacitinib citrate/|Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Tofacitinib citrate/

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Avoid dust formation. Avoid breathing vapors, mist or gas; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Sweep up and shovel. Keep in suitable, closed containers for disposal. /Tofacitinib citrate/

Precautions for safe handling: Provide appropriate exhaust ventilation at places where dust is formed. /Tofacitinib citrate/|Appropriate engineering controls: General industrial hygiene practice. /Tofacitinib citrate/|Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Tofacitinib citrate/|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known.|IDENTIFICATION AND USE: Tofacitinib is a yellow foam. As the drug Xeljanz, it is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). HUMAN EXPOSURE AND TOXICITY: According to epidemiological studies, the overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time. Within the global tofacitinib RA development program, tuberculosis was the most common opportunistic infection reported but was rare in regions of low and medium TB incidence. In a genotoxicity study, increases in chromosomal abnormalities were observed in a human lymphocyte in vitro cytogenetic assay, at high cytotoxic concentrations with metabolic activation, but no effects were observed without metabolic activation. ANIMAL STUDIES: In cynomolgus monkeys, emesis and decreased activity were observed as a result of acute exposure. Xeljanz caused death in rats at single oral doses of >/= 500 mg/kg. Immune and hematopoietic organ systems were identified as main targets in repeat-dose toxicity studies on animals. In a peri/postnatal development study in rats, Xeljanz decreased the number of delivered and live born pups, and reduced pup survival at oral doses of 50 mg/kg/day. Xeljanz was teratogenic (external, visceral and skeletal abnormalities) in rabbits and rats at oral doses of 30 and 100 mg/kg/day, respectively. Xeljanz was not mutagenic in the bacterial reverse mutation assay. Xeljanz was not mutagenic in mammalian cells (in vitro CHO/HGPRT assay) and did not induce primary DNA damage in an in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay. Xeljanz was also negative in the in vivo rat micronucleus test. In a 2-year rat carcinogenicity study, Xeljanz induced benign Leydig cell tumors and malignant hibernomas at oral doses of >/= 30 mg/kg/day and benign thymomas at 100/75 mg/kg/day. In a 39-week repeat-dose toxicity study in adult monkeys, lymphomas were observed at the high dose of 5 mg/kg twice daily, but not at the lower dose of 1 mg/kg twice daily (approximately equivalent to human exposure).

In the large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to less than 1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity associated with its use but a proportion of patients do develop serum aminotransferase elevations which in some cases leads to drug discontinuation. While other Janus kinase inhibitors such as ruxolitinib have been associated with episodes of reactivation of hepatitis B, spontaneous reports of clinically apparent reactivation of hepatitis during tofacitinib therapy have not been reported. On the other hand, retrospective studies on patients with HBsAg and inactive liver disease who were treated with tofacitinib have been reported to develop rising levels of HBV DNA and modest elevations in serum aminotransferase levels without symptoms. In contrast, studies of patients with anti-HBc without HBsAg in serum have shown no evidence of HBV DNA rises and appearance of HBsAg. Thus, reactivation of hepatitis B during therapy can occur, although it is generally mild and self-limited in course. Whether reactivation of hepatitis B can arise after therapy of susceptible patients with tofacitinib for severe COVID-19 pneumonia is unknown, but there have been no such reports to date.|In the large prelicensure clinical trials in rheumatoid arthritis, serum aminotransferase elevations occurred in up to 17% of baricitinib treated subjects compared to 11% in placebo recipients. These elevations were typically mild and transient and values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on baricitinib. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies in rheumatoid arthritis and other rheumatic and immune-mediated disorders, there were no instances of clinically apparent liver injury attributed to baricitinib. Since approval and more wide scale availability of baricitinib, there have been no published reports of hepatotoxicity associated with its use.

In healthy individuals, the CYP3A inducer rifampin (600 mg orally once daily for 7 days) decreased peak plasma concentrations and AUC of tofacitinib (single oral dose of 30 mg) by 74 and 84%, respectively. Concomitant use of rifampin may decrease efficacy of tofacitinib.|There is a risk of added immunosuppression when Xeljanz is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose Xeljanz with potent immunosuppressants has not been studied in rheumatoid arthritis. Use of Xeljanz in combination with biologic disease-modifying antirheumatic drugs (DMARDS) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.|Concomitant use of tofacitinib with potent immunosuppressive agents (e.g., azathioprine, cyclosporine, tacrolimus) increases the risk of immunosuppression and is not recommended. Concomitant use of tofacitinib with such agents in patients with rheumatoid arthritis has not been studied to date. In healthy individuals, cyclosporine (200 mg orally every 12 hours for 5 days) decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 73% increase in the AUC of tofacitinib, accompanied by a 17% decrease in peak plasma tofacitinib concentrations. In healthy individuals, tacrolimus (5 mg orally every 12 hours for 7 days) slightly decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 21% increase in the AUC of tofacitinib, accompanied by a 9% decrease in peak plasma tofacitinib concentrations.|Tofacitinib exposure is decreased when Xeljanz is coadministered with potent CYP3A4 inducers (e.g., rifampin).|For more Interactions (Complete) data for Tofacitinib (9 total), please visit the HSDB record page.

The risks and benefits of tofacitinib should be considered prior to initiating therapy in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer) or when considering whether to continue tofacitinib in patients who develop a malignancy.|Tofacitinib therapy should not be initiated in patients with active infections, including localized infections.|Anemia has been reported in patients receiving tofacitinib. Initiation of tofacitinib therapy should be avoided in patients with hemoglobin concentrations of less than 9 g/dL.|Treatment with tofacitinib is associated with an increased incidence of neutropenia (neutrophil count less than 2000/cu mm) compared with placebo. A clear relationship between neutropenia and the occurrence of serious infection has not been demonstrated. Initiation of tofacitinib therapy should be avoided in patients with an absolute neutrophil count (ANC) of less than 1000/cu mm.

40%, mostly bound to albumin.

For the treatment of moderate to severe rheumatoid arthritis which is resistant or intolerant to methotrexate therapy. It may also be used as an adjunct to methotrexate therapy, or other non-biologic disease-modifying antirheumatic drugs (DMARDS), when methotrexate alone is not sufficient. Tofacitinib has also been investigated as a preventative therapy for kidney transplant rejections, and as a treatment for psoriasis, ulcerative colitis, and ankylosing spondylitis. It is not to be initiated in patients with a history of chronic or recurrent infections, or in the presence of active infection, even if localized, due to reports of serious and sometimes fatal infections (commonly pneumonia, herpes zoster and urinary tract infections). Use of tofacitinib is also discouraged in those who have been, or are likely to be, exposed to TB. An increased likelihood of exposure may be encountered by traveling to certain areas. In addition, tofacitinib is not to be used in patients with severe hepatic impairment, or low hemoglobin (less than 9g/dL). Cautioned is advised when using tofacitinib in patients at risk of gastrointestinal perforation, and in the elderly who are more susceptible to infection.|FDA Label|Rheumatoid arthritisTofacitinib in combination with methotrexate (MTX) is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs) (see section 5.1). Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see sections 4.4 and 4.5).Psoriatic arthritisTofacitinib in combination with MTX is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease modifying antirheumatic drug (DMARD) therapy (see section 5.1).Ulcerative colitisTofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent (see section 5.1). Juvenile idiopathic arthritis (JIA)Tofacitinib is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (rheumatoid factor positive [RF+]or negative [RF-] polyarthritis and extended oligoarthritis), and juvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequately to previous therapy with DMARDs. Tofacitinib can be given in combination with methotrexate (MTX) or as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.|Treatment of rheumatoid arthritis.|Treatment of psoriasis|Treatment of chronic idiopathic arthritis (including rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis)|Treatment of ulcerative colitis

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.|Baricitinib is an orally available small molecule inhibitor of Janus kinases that is used to treat moderate-to-severe rheumatoid arthritis and in late 2020 was given emergency use authorization as therapy in combination with remdesivir for severe COVID-19. Baricitinib 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.

Antirheumatic Agents

Protein Kinase Inhibitors|/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Tofacitinib is included in the database.|Xeljanz (tofacitinib) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). /Included in US product label/|EXPL Tofacitinib is an oral Janus kinase inhibitor that is being investigated for psoriasis and psoriatic arthritis. Japanese patients aged 20 years or more with moderate to severe plaque psoriasis and/or psoriatic arthritis were double-blindly randomized 1:1 to tofacitinib 5 or 10 mg b.i.d. for 16 weeks, open-label 10 mg b.i.d. for 4 weeks, then variable 5 or 10 mg b.i.d. to Week 52. Primary end-points at Week 16 were the proportion of patients achieving at least a 75% reduction in Psoriasis Area and Severity Index (PASI75) and Physician's Global Assessment of "clear" or "almost clear" (PGA response) for psoriasis, and 20% or more improvement in American College of Rheumatology criteria (ACR20) for patients with psoriatic arthritis. Safety was assessed throughout. Eighty-seven patients met eligibility criteria for moderate to severe plaque psoriasis (5 mg b.i.d., n = 43; 10 mg b.i.d., n = 44), 12 met eligibility criteria for psoriatic arthritis (5 mg b.i.d., n = 4; 10 mg b.i.d., n = 8) including five who met both criteria (10 mg b.i.d.). At Week 16, 62.8% and 72.7% of patients achieved PASI75 with tofacitinib 5 and 10 mg b.i.d., respectively; 67.4% and 68.2% achieved PGA responses; all patients with psoriatic arthritis achieved ACR20. Responses were maintained through Week 52. Adverse events occurred in 83% of patients through Week 52, including four (4.3%) serious adverse events and three (3.2%) serious infections (all herpes zoster). No malignancies, cardiovascular events or deaths occurred. Tofacitinib (both doses) demonstrated efficacy in patients with moderate to severe plaque psoriasis and/or psoriatic arthritis through 52 weeks; safety findings were generally consistent with prior studies.|EXPL The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.

/BOXED WARNING/ WARNING: SERIOUS INFECTIONS. Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. If a serious infection develops, interrupt Xeljanz until the infection is controlled. Reported infections include: Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before Xeljanz use and during therapy. Treatment for latent infection should be initiated prior to Xeljanz use. Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Bacterial, viral, and other infections due to opportunistic pathogens. The risks and benefits of treatment with Xeljanz should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Xeljanz, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy|/BOXED WARNING/ MALIGNANCIES. Lymphoma and other malignancies have been observed in patients treated with Xeljanz. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with Xeljanz and concomitant immunosuppressive medications|Patients receiving tofacitinib are at increased risk of developing serious infections that may require hospitalization or result in death. Opportunistic infections caused by bacterial, mycobacterial, invasive fungal, viral, or other opportunistic organisms-including cryptococcosis, pneumocystosis, tuberculosis and other mycobacterial infections, esophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, and BK virus infection-have been reported in patients with rheumatoid arthritis receiving tofacitinib. Patients with invasive fungal infections may present with disseminated, rather than localized, disease. Patients should be closely monitored during and after treatment with tofacitinib for the development of signs or symptoms of infection (e.g., fever, malaise, weight loss, sweats, cough, dyspnea, pulmonary infiltrates, serious systemic illness including shock). Most patients who developed serious infections were receiving concomitant therapy with immunosuppressive agents such as methotrexate or corticosteroids.|Tofacitinib therapy should not be initiated in patients with active infections, including localized infections. Tofacitinib should be discontinued in patients who develop a serious infection, opportunistic infection, or sepsis and should not be resumed until the infection is controlled. Clinicians should consider potential risks and benefits of tofacitinib prior to initiating therapy in patients with a history of chronic, recurring, serious, or opportunistic infections; patients with underlying conditions that may predispose them to infections; and patients who have been exposed to tuberculosis or who reside or have traveled in regions where tuberculosis or mycoses are endemic. Any patient who develops a new infection while receiving tofacitinib should undergo a thorough diagnostic evaluation (appropriate for an immunocompromised patient), appropriate anti-infective therapy should be initiated, and the patient should be closely monitored.|For more Drug Warnings (Complete) data for Tofacitinib (22 total), please visit the HSDB record page.

Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life.

Agents that inhibit PROTEIN KINASES. (See all compounds classified as Protein Kinase Inhibitors.)

74% oral absorption (absolute bioavailability), with peak plasma concentrations (T _max) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%.|70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug.|Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma.|The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to a1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.|The absolute oral bioavailability of tofacitinib is 74%. Coadministration of Xeljanz with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, Xeljanz was administered without regard to meals.|Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. 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. The pharmacologic activity of tofacitinib is attributed to the parent molecule.|Following oral administration of Xeljanz /to humans/, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is approximately 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.|/MILK/ Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk.

Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive.|Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. 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. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

~3 hours|The elimination half-life of tofacitinib /in humans/ is approximately 3 hours.

Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well.|Tofacitinib citrate, a Janus kinase (JAK) inhibitor, is an immunomodulating agent and a disease-modifying antirheumatic drug (DMARD). JAKs are intracellular enzymes that mediate the signaling of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. Tofacitinib inhibits JAK1 and JAK3 and, to a lesser extent, JAK2. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK2/JAK2). In vitro, tofacitinib inhibited the activity of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 (concentration that inhibits activity by 50%) values of 406, 56, and 1377 nM, respectively. The relevance of specific JAK combinations to the therapeutic efficacy of tofacitinib is not known. /Tofacitinib citrate/|Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-beta. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/CASE REPORTS/ Tofacitinib is a novel drug that inhibits the JAK-STAT signaling pathway. It has been approved for the treatment of psoriatic arthritis and it is under investigation for the treatment of psoriasis and other inflammatory disorders. We report a case of pulmonary cryptococcosis in an otherwise immunocompetent patient taking tofacitinib for psoriasis. We hypothesized that tofacitinib contributed to this infection through inhibition of cytokines required for differentiation of T cells and suppression of macrophage activation. As dermatologists begin to use this drug they should be aware of the potential for cryptococcocal infection, because delay of diagnosis may increase the risk of a life-threatening outcome.|/EPIDEMIOLOGY STUDIES/ /The purpose of this study was/ to determine the rate of infection and all-cause mortality across tofacitinib phase II, phase III, and long-term extension (LTE) studies in patients with moderately to severely active rheumatoid arthritis (RA). Pooled data from studies of tofacitinib in patients with RA were analyzed. In these studies, tofacitinib was administered as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs. ... Across phase II, phase III, and LTE studies, 4,789 patients received tofacitinib (8,460 patient-years of exposure). The overall rate of serious infection was 3.09 events per 100 patient-years (95% confidence interval [95% CI] 2.73-3.49), and rates were stable over time. A Cox proportional hazards model showed that age, corticosteroid dose, diabetes, and tofacitinib dose were independently linked to the risk of serious infection. Lymphocyte counts of <0.5 X 10(3)/cu mm were rare but were associated with an increased risk of treated and/or serious infection. Overall, all-cause mortality rates were 0.30 events per 100 patient-years (95% CI 0.20-0.44). The overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time.|/EPIDEMIOLOGY STUDIES/ Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Tofacitinib modulates the signaling of cytokines that are integral to lymphocyte activation, proliferation, and function. Thus, tofacitinib therapy may result in suppression of multiple elements of the immune response. Serious infections have been reported in tofacitinib RA trials. However, limited head-to-head comparator data were available within the tofacitinib RA development program to directly compare rates of serious infections with tofacitinib relative to biologic agents, and specifically adalimumab (employed as an active control agent in two randomized controlled trials of tofacitinib). A systematic literature search of data from interventional randomized controlled trials and long-term extension studies with biologics in RA was carried out. Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) consensus was followed for reporting results of the review and meta-analysis. Incidence rates (unique patients with events/100 patient-years) for each therapy were estimated based on data from randomized controlled trials and long-term extension studies using a random-effects model. Relative and absolute risk comparisons versus placebo used Mantel-Haenszel methods. RESULTS: The search produced 657 hits. In total, 66 randomized controlled trials and 22 long-term extension studies met the selection criteria. Estimated incidence rates (95% confidence intervals [CIs]) for abatacept, rituximab, tocilizumab, and tumor necrosis factor inhibitors were 3.04 (2.49, 3.72), 3.72 (2.99, 4.62), 5.45 (4.26, 6.96), and 4.90 (4.41, 5.44), respectively. Incidence rates (95% CIs) for tofacitinib 5 and 10 mg twice daily (BID) in phase 3 trials were 3.02 (2.25, 4.05) and 3.00 (2.24, 4.02), respectively. Corresponding incidence rates in long-term extension studies were 2.50 (2.05, 3.04) and 3.19 (2.74, 3.72). The risk ratios (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 2.21 (0.60, 8.14) and 2.02 (0.56, 7.28), respectively. Risk differences (95% CIs) versus placebo for tofacitinib 5 and 10 mg BID were 0.38% (-0.24%, 0.99%) and 0.40% (-0.22%, 1.02%), respectively. In interventional studies, the risk of serious infections with tofacitinib is comparable to published rates for biologic disease-modifying antirheumatic drugs in patients with moderate to severely active RA.|/EPIDEMIOLOGY STUDIES/ /The purpose of this study was/ to evaluate the risk of opportunistic infections (OIs) in patients with rheumatoid arthritis (RA) treated with tofacitinib. Phase II, III and long-term extension clinical trial data (April 2013 data-cut) from the tofacitinib RA program were reviewed. OIs defined a priori included mycobacterial and fungal infections, multidermatomal herpes zoster and other viral infections associated with immunosuppression. For OIs, we calculated crude incidence rates (IRs; per 100 patient-years (95% CI)); for tuberculosis (TB) specifically, we calculated rates stratified by patient enrolment region according to background TB IR (per 100 patient-years): low (< or = 0.01), medium (>0.01 to < or = 0.05) and high (>0.05). We identified 60 OIs among 5671 subjects; all occurred among tofacitinib-treated patients. TB (crude IR 0.21, 95% CI of (0.14 to 0.30)) was the most common OI (n=26); median time between drug start and diagnosis was 64 weeks (range 15-161 weeks). Twenty-one cases (81%) occurred in countries with high background TB IR, and the rate varied with regional background TB IR: low 0.02 (0.003 to 0.15), medium 0.08 (0.03 to 0.21) and high 0.75 (0.49 to 1.15). In Phase III studies, 263 patients diagnosed with latent TB infection were treated with isoniazid and tofacitinib concurrently; none developed TB. For OIs other than TB, 34 events were reported (crude IR 0.25 (95% CI 0.18 to 0.36)). Within the global tofacitinib RA development program, TB was the most common OI reported but was rare in regions of low and medium TB incidence. Patients who screen positive for latent TB can be treated with isoniazid during tofacitinib therapy.|For more Human Toxicity Excerpts (Complete) data for Tofacitinib (7 total), please visit the HSDB record page.

CP 690,550

Oral: Tablets, film-coated, 5 mg (of tofacitinib), Xeljanz (Pfizer).

LC/LC-MS determination in blood.

Human drugs -> Xeljanz -> EMA Drug Category|Immunosuppressants -> Human pharmacotherapeutic group|Human Drugs -> EU pediatric investigation plans|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients