The information below is based on the summary of product characteristics approved by regulatory authorities. For full details from the SmPC, please click here: https://www.medicines.org.uk/emc/product/2500/smpc
Additional related ECCO e-Learning resources can be found under IBD Curriculum Topic 6.1-6.11
Introduction and Mechanism of Action
Tofacitinib is a potent, selective inhibitor of the JAK family. In enzymatic assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent TyK2. In contrast, tofacitinib has a high degree of selectivity against other kinases in the human genome. In human cells, tofacitinib preferentially inhibits signalling by heterodimeric cytokine receptors that associate with JAK3 and/or JAK1 with functional selectivity over cytokine receptors that signal via pairs of JAK2. Inhibition of JAK1 and JAK3 by tofacitinib attenuates signalling of interleukins (IL-2, -4, -6, -7, -9, -15, -21) and type I and type II interferons, which will result in modulation of the immune and inflammatory response.
Ulcerative Colitis: Tofacitinib 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
Crohn's Disease: Tofacitinib is not licenced for Crohn’s disease
Dosing, administration, and monitoring (ulcerative colitis)
Induction and Maintenance dosing
The recommended dose is 10 mg given orally twice daily for induction for 8 weeks and 5 mg given twice daily for maintenance.
For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.
For some patients, such as those who have failed prior tumour necrosis factor (TNF) antagonist therapy, consideration should be given to continuation of the 10 mg twice daily dose for maintenance in order to maintain therapeutic benefit (see section 5.1 of full SmPC).
Patients who experience a decrease in response on tofacitinib 5 mg twice daily maintenance therapy may benefit from an increase to tofacitinib 10 mg administered twice daily.
In patients who have responded to treatment with tofacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.
If therapy is interrupted, restarting treatment with tofacitinib can be considered. If there has been a loss of response, reinduction with tofacitinib 10 mg twice daily may be considered. The treatment interruption period in clinical studies extended up to 1 year. Efficacy may be regained by 8 weeks of 10 mg twice daily therapy (see section 5.1 of full SmPC).
Dose interruption and discontinuation
Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. Recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities.
It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.
Hypersensitivity to the active substance or to any of the excipients
Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections
Severe hepatic impairment (Dose adjustments may be necessary – see SmPC
Pregnancy and lactation
Combination with other therapies
Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporine and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection.
There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies.
Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving tofacitinib. The risk of opportunistic infections is higher in Asian geographic regions (see section 4.8 of full SmPC).
Tofacitinib should not be initiated in patients with active infections, including localised infections.
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
• with recurrent infections,
• with a history of a serious or an opportunistic infection,
• who have resided or travelled in areas of endemic mycoses,
• who have underlying conditions that may predispose them to infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with tofacitinib. Treatment should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes.
Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection.
The risks and benefits of treatment should be considered prior to initiating tofacitinib in patients:
• who have been exposed to TB,
• who have resided or travelled in areas of endemic TB.
Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of tofacitinib.
Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapy before administering tofacitinib.
Antituberculosis therapy should also be considered prior to administration of tofacitinib in patients who test negative for TB but who have a past history of latent or active TB and where an adequate course of treatment cannot be confirmed; or those who test negative but who have risk factors for TB infection. Consultation with a healthcare professional with expertise in the treatment of TB is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient. Patients should be closely monitored for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.
Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) were observed in clinical studies with tofacitinib. In patients treated with tofacitinib, the incidence of herpes zoster appears to be increased in:
• Japanese or Korean patients.
• Patients with an ALC less than 1,000 cells/mm3 (see section 4.2 of full SmPC).
• Patients treated with 10 mg twice daily.
The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with tofacitinib.
Malignancy and lymphoproliferative disorder
The risks and benefits of tofacitinib treatment should be considered prior to initiating therapy in patients with current or a history of malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing tofacitinib in patients who develop a malignancy. The possibility exists for tofacitinib to affect host defences against malignancies.
Lymphomas have been observed in patients treated with tofacitinib. Patients with RA, particularly those with highly active disease may be at a higher risk (up to several-fold) than the general population for the development of lymphoma. The effect of tofacitinib on the development of lymphoma is uncertain.
Other malignancies were observed in clinical studies and the post-marketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.
The effect of tofacitinib on the development and course of malignancies is not known.
Recently the European Medicines Agency has highlighted an increased risk of thromboembolic events (predominantly pulmonary embolism) in patients being treated with the higher dose of 10mg BD tofacitinib for rheumatoid arthritis in an ongoing clinical trial. All patients in this study were aged greater than 50 years and had one additional cardiovascular risk factor (https://www.ema.europa.eu/en/news/increased-risk-blood-clots-lungs-death-higher-dose-xeljanz-tofacitinib-rheumatoid-arthritis). Consideration of additional risk factors for thromboembolic disease is recommended for patients with ulcerative colitis being treated with 10mg bd tofacitinib for extended periods of time.
Non-melanoma skin cancer
NMSCs have been reported in patients treated with tofacitinib. The risk of NMSC may be higher in patients treated with tofacitinib 10 mg twice daily than in patients treated with 5 mg twice daily. Periodic skin examination is recommended for patients who are at increased risk for skin cancer (see Table 6 in section 4.8 of full SmPC).
Interstitial lung disease
Caution is also recommended in patients with a history of chronic lung disease as they may be more prone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have been reported in patients treated with tofacitinib in RA clinical trials and in the post-marketing setting although the role of Janus kinase (JAK) inhibition in these events is not known. Asian RA patients are known to be at higher risk of interstitial lung disease, thus caution should be exercised in treating these patients.
Events of gastrointestinal perforation have been reported in clinical trials although the role of JAK inhibition in these events is not known. Tofacitinib should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis, patients with concomitant use of corticosteroids and/or nonsteroidal anti-inflammatory drugs). Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of gastrointestinal perforation.
Rheumatoid Arthritis and psoriatic Arthritis patients have an increased risk for cardiovascular disorders. Patients treated with tofacitinib should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care.
Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation in some patients (see section 4.8 of full SmPC liver enzyme tests). Caution should be exercised when considering initiation of tofacitinib treatment in patients with elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST), particularly when initiated in combination with potentially hepatotoxic medicinal products such as MTX. Following initiation, routine monitoring of liver tests and prompt investigation of the causes of any observed liver enzyme elevations are recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of tofacitinib should be interrupted until this diagnosis has been excluded.
In post-marketing experience, cases of drug hypersensitivity associated with tofacitinib administration have been reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred. If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately.
Laboratory parameters and Monitoring
Treatment with tofacitinib was associated with an increased incidence of lymphopenia compared to placebo. Lymphocyte counts less than 750 cells/mm3 were associated with an increased incidence of serious infections. It is not recommended to initiate or continue tofacitinib treatment in patients with a confirmed lymphocyte count less than 750 cells/mm3. Lymphocytes should be monitored at baseline and every 3 months thereafter.
Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than 2,000 cells/mm3) compared to placebo. It is not recommended to initiate tofacitinib treatment in patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3. ANC should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
Treatment with tofacitinib has been associated with decreases in haemoglobin levels. It is not recommended to initiate tofacitinib treatment in patients with a haemoglobin value less than 9 g/dL. Haemoglobin should be monitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter.
Treatment with tofacitinib was associated with increases in lipid parameters such as total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. Assessment of lipid parameters should be performed after 8 weeks following initiation of tofacitinib therapy. Patients should be managed according to clinical guidelines for the management of hyperlipidaemia. Increases in total and LDL cholesterol associated with tofacitinib may be decreased to pre-treatment levels with statin therapy.
Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines. It is recommended that live vaccines not be given concurrently with tofacitinib. The decision to use live vaccines prior to tofacitinib treatment should take into account the pre-existing immunosuppression in a given patient.
Prophylactic zoster vaccination should be considered in accordance with vaccination guidelines. If live zoster vaccine is administered; it should only be administered to patients with a known history of chickenpox or those that are seropositive for varicella zoster virus (VZV). If the history of chickenpox is considered doubtful or unreliable it is recommended to test for antibodies against VZV.
Vaccination with live vaccines should occur at least 2 weeks but preferably 4 weeks prior to initiation of tofacitinib or in accordance with current vaccination guidelines regarding immunomodulatory medicinal products. No data are available on the secondary transmission of infection by live vaccines to patients receiving tofacitinib.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Interactions with other Drugs
Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole)
Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin).
Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporine (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC. Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response. Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporine and rifampicin decreased tofacitinib Cmax.
Special situations (e.g. pregnancy)
There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development.
As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated.
Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose.
It is not known whether tofacitinib is secreted in human milk. A risk to the breast-fed child cannot be excluded. Tofacitinib was secreted in the milk of lactating rats. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated.
Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats.