Xeljanz

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 5 mg film-coated tablets 
XELJANZ 10 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
XELJANZ 5 mg film-coated tablets 
 
Each film-coated tablet contains tofacitinib citrate, equivalent to 5 mg tofacitinib. 
 
Excipient with known effect 
Each film-coated tablet contains 59.44 mg of lactose. 
 
XELJANZ 10 mg film-coated tablets 
 
Each film-coated tablet contains tofacitinib citrate, equivalent to 10 mg tofacitinib. 
 
Excipient with known effect 
Each film-coated tablet contains 118.88 mg of lactose. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
Tofacitinib 5 mg film-coated tablets 
 
White, round tablet of 7.9 mm diameter, debossed “Pfizer” on one side and “JKI 5” on the other. 
 
Tofacitinib 10 mg film-coated tablets 
 
Blue, round tablet of 9.5 mm diameter, debossed “Pfizer” on one side and “JKI 10” on the other. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indication 
 
Rheumatoid arthritis 
 
Tofacitinib 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. 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). 
 



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Psoriatic arthritis 
 
Tofacitinib 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 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 (see section 5.1).  
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and 
treatment of conditions for which tofacitinib is indicated. 
 
Posology 
 
Rheumatoid arthritis and psoriatic arthritis 
 
The recommended dose is 5 mg administered twice daily, which should not be exceeded. 
 
Rheumatoid arthritis 
 
Switching between tofacitinib 5 mg film-coated tablets and tofacitinib 11 mg prolonged-release tablets 
Patients treated with tofacitinib 5 mg film-coated tablets twice daily may be switched to tofacitinib 11 mg 
prolonged-release tablets once daily on the day following the last dose of tofacitinib 5 mg film-coated 
tablets.  
 
Patients treated with tofacitinib 11 mg prolonged-release tablets once daily may be switched to tofacitinib 
5 mg film-coated tablets twice daily on the day following the last dose of tofacitinib 11 mg 
prolonged-release tablets. 
 
Dose adjustment  
 
No dose adjustment is required when used in combination with MTX. 
 
Ulcerative colitis 
 
Induction treatment 
The recommended dose is 10 mg given orally twice daily for induction for 8 weeks.  
 
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. 
 
Maintenance treatment 
The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily. 
 
Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who 
have known venous thromboembolism (VTE) risk factors, unless there is no suitable alternative treatment 
available (see section 4.4 and 4.8). 
 



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For patients with UC who are not at increased risk for VTE (see section 4.4), tofacitinib 10 mg orally 
twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice 
daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis 
factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should 
be used for the shortest duration possible. The lowest effective dose needed to maintain response should 
be used. 
 
In patients who have responded to treatment with tofacitinib, corticosteroids may be reduced and/or 
discontinued in accordance with standard of care. 
 
Retreatment in UC 
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).  
 
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. As described in Tables 1, 2 and 3 below, recommendations for 
temporary dose interruption or permanent discontinuation of treatment are made according to the severity 
of laboratory abnormalities (see section 4.4). 
 
It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 
750 cells/mm3. 
 
Table 1: Low absolute lymphocyte count 

Low absolute lymphocyte count (ALC) (see section 4.4) 
Lab value 
(cells/mm3) 

Recommendation 

ALC greater than or equal 
to 750 

Dose should be maintained. 

ALC 500-750 For persistent (2 sequential values in this range on routine testing) 
decrease in this range, dosing should be reduced or interrupted until 
ALC is greater than 750.  
 
For patients receiving tofacitinib 10 mg twice daily, dosing should be 
reduced to tofacitinib 5 mg twice daily. 
 
For patients receiving tofacitinib 5 mg twice daily, dosing should be 
interrupted. 
 
When ALC is greater than 750, treatment should be resumed as 
clinically appropriate. 

ALC less than 500 
 

If lab value confirmed by repeat testing within 7 days, dosing should 
be discontinued. 

 
It is recommended not to initiate dosing in patients with an absolute neutrophil count (ANC) less than 
1,000 cells/mm3. 
 



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Table 2: Low absolute neutrophil count 
Low absolute neutrophil count (ANC) (see section 4.4) 

Lab Value 
(cells/mm3) 

Recommendation 

ANC greater than 1,000 Dose should be maintained. 
ANC 500-1,000 For persistent (2 sequential values in this range on routine testing) 

decreases in this range, dosing should be reduced or interrupted until 
ANC is greater than 1,000. 
 
For patients receiving tofacitinib 10 mg twice daily, dosing should be 
reduced to tofacitinib 5 mg twice daily. 
 
For patients receiving tofacitinib 5 mg twice daily, dosing should be 
interrupted. 
 
When ANC is greater than 1,000, treatment should be resumed as 
clinically appropriate. 

ANC less than 500 
 

If lab value confirmed by repeat testing within 7 days, dosing should 
be discontinued.  

 
It is recommended not to initiate dosing in patients with haemoglobin less than 9 g/dL. 
 
Table 3: Low haemoglobin value 

Low haemoglobin value (Section 4.4) 
Lab value 

(g/dL) 
Recommendation 

Less than or equal to 2 g/dL 
decrease and greater than or 
equal to 9.0 g/dL 

Dose should be maintained. 

Greater than 2 g/dL 
decrease or less than 
8.0 g/dL 
(confirmed by repeat 
testing) 

Dosing should be interrupted until haemoglobin values have 
normalised. 

 
Drug-drug interactions 
Tofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors of cytochrome 
P450 (CYP) 3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitant medicinal products 
that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., 
fluconazole) (see section 4.5) as follows: 
• Tofacitinib dose should be reduced to 5 mg once daily in patients receiving 5 mg twice daily. 
• Tofacitinib dose should be reduced to 5 mg twice daily in patients receiving 10 mg twice daily.  
 
Special populations 
 
Elderly 
No dose adjustment is required in patients aged 65 years and older. There are limited data in patients aged 
75 years and older. 
 



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Hepatic impairment 
  
Table 4:  Dose adjustment for hepatic impairment  
Hepatic 
impairment 
category 

Classification Dose adjustment in hepatic impairment for different 
strength tablets 

Mild Child Pugh A No dose adjustment required. 
Moderate Child Pugh B Dose should be reduced to 5 mg once daily when the 

indicated dose in the presence of normal hepatic function 
is 5 mg twice daily. 
 
Dose should be reduced to 5 mg twice daily when the 
indicated dose in the presence of normal hepatic function 
is 10 mg twice daily (see section 5.2). 

Severe Child Pugh C Tofacitinib should not be used in patients with severe 
hepatic impairment (see section 4.3). 

 
Renal impairment 
  
Table 5:  Dose adjustment for renal impairment  
Renal 
impairment 
category 

Creatinine 
clearance 

Dose adjustment in renal impairment for different 
strength tablets 

Mild 50-80 mL/min No dose adjustment required. 
Moderate 30-49 mL/min No dose adjustment required. 
Severe (including 
patients 
undergoing 
haemodialysis) 

< 30 mL/min Dose should be reduced to 5 mg once daily when the 
indicated dose in the presence of normal renal function is 
5 mg twice daily. 
 
Dose should be reduced to 5 mg twice daily when the 
indicated dose in the presence of normal renal function is 
10 mg twice daily.  
 
Patients with severe renal impairment should remain on a 
reduced dose even after haemodialysis (see section 5.2). 

 
Paediatric population 
The safety and efficacy of tofacitinib in children aged 0 to less than 18 years have not been established. 
 
No data are available. 
 
Method of administration 
 
Oral use.  
 
Tofacitinib is given orally with or without food. 
 
For patients who have difficulties swallowing, tofacitinib tablets may be crushed and taken with water.  
 



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4.3 Contraindications 
 

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections (see 

section 4.4). 
• Severe hepatic impairment (see section 4.2). 
• Pregnancy and lactation (see section 4.6). 

 
4.4 Special warnings and precautions for use 
 
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. 
 
The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in 
tofacitinib clinical studies. 
 
Venous thromboembolism (VTE)  
 
Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein 
thrombosis (DVT), have been observed in patients taking tofacitinib. A dose dependent increased risk for 
VTE was observed in a clinical study with tofacitinib compared to TNF inhibitors (see sections 4.8 and 
5.1). 
 
Tofacitnib should be used with caution in patients with known risk factors for VTE, regardless of 
indication and dosage.  
 
Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who 
have known VTE risk factors, unless there is no suitable alternative treatment available (see section 4.2).  
 
VTE risk factors include previous VTE, patients undergoing major surgery, immobilisation, myocardial 
infarction (within previous 3 months), heart failure, use of combined hormonal contraceptives or hormone 
replacement therapy, inherited coagulation disorder, malignancy. Additional VTE risk factors such as age, 
obesity (BMI ≥30), diabetes, hypertension, smoking status should also be considered. Patients should be 
re-evaluated periodically during tofacitinib treatment to assess for changes in VTE risk. 
 
Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with 
suspected VTE, regardless of dose or indication. 
 
Serious infections 
 
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). Rheumatoid arthritis patients taking 
corticosteroids may be predisposed to infection. 
 
Tofacitinib should not be initiated in patients with active infections, including localised infections. 
 



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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, 
• who are over 65 years of age 

 
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 (see section 4.8). In patients 
over 65 years of age tofacitinib should only be considered if no suitable alternative treatment is available 
(see section 5.1). 
 
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. Discontinuation and 
monitoring criteria for lymphopenia are discussed in section 4.2. 
 
Tuberculosis 
 
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 
 
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). 
• Patients with long standing RA who have previously received two or more biological disease 

modifying antirheumatic drugs (DMARDs).  
• Patients treated with 10 mg twice daily. 

 



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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. 
 
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). 
 
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. 
 
Gastrointestinal perforations 
 
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. 
 
Cardiovascular risk 
 
RA and PsA 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. 
 
Liver enzymes 
 
Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation in some 
patients (see section 4.8 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 



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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. 
 
Hypersensitivity 
 
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 
 
Lymphocytes 
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. For recommended modifications based on lymphocyte counts, see section 4.2. 
 
Neutrophils 
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 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. For recommended modifications based on ANC, see section 4.2. 
 
Haemoglobin 
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. For recommended modifications based on haemoglobin level, see section 4.2. 
 
Lipid monitoring 
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 pretreatment levels with statin therapy. 
 
Vaccinations 
 
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. Particular 
consideration should be given to patients with longstanding RA who have previously received two or 
more biological DMARDs. 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. 
 



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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. 
 
Excipients with known effect 
 
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, 
total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib 
 
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) (see 
section 4.2). 
 
Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). 
Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib. 
 
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 (see Figure 1). 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. Concomitant administration with 
MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1). 
 



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Figure 1. Impact of other medicinal products on PK of tofacitinib 

Note: Reference group is administration of tofacitinib alone. 
a Tofacitinib dose should be reduced to 5 mg twice daily in patients receiving 10 mg twice daily. Tofacitinib dose should be 

reduced to 5 mg once daily in patients receiving 5 mg twice daily (see section 4.2). 
 
Potential for tofacitinib to influence the PK of other medicinal products 
 
Coadministration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and 
ethinyl estradiol, in healthy female volunteers. 
 
In RA patients, coadministration of tofacitinib with MTX 15-25 mg once weekly decreased the AUC and 
Cmax of MTX by 10% and 13%, respectively. The extent of decrease in MTX exposure does not warrant 
modifications to the individualised dosing of MTX. 
 
4.6 Fertility, pregnancy and lactation 
 
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 (see section 5.3). 
 
As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (see section 4.3). 
 
Women of childbearing potential/contraception in females 
 
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. 
 

0 0.5 1 1.5 2 2.5 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC CYP3A Inhibitor Ketoconaz

l  

CYP3A & CYP2C19 
Inhibitor Fluconazole 

CYP Inducer 
Rifampicin 

Methotrexate 

Tacrolimus 

Ciclosporine 

Tofacitinib dose should be reduced a 
 

Tofacitinib dose should be reduced a 
 

Efficacy may be decreased 

No dose adjustment 

Combined use of tofacitinib with  
tacrolimus should be avoided 

Combined use of tofacitinib with  
 ciclosporine should be avoided 

Ratio relative to reference 

Coadminist
 Drug 

PK  Ratio and 90% CI Recommendation 



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Breast-feeding 
 
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 (see section 5.3). As a precautionary 
measure, the use of tofacitinib during breast-feeding is contraindicated (see section 4.3). 
 
Fertility 
 
Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired 
female fertility but not male fertility in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Tofacitinib has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 
Rheumatoid arthritis 
The most common serious adverse reactions were serious infections (see section 4.4). The most common 
serious infections reported with tofacitinib were pneumonia, cellulitis, herpes zoster, urinary tract 
infection, diverticulitis, and appendicitis. Among opportunistic infections, TB and other mycobacterial 
infections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster, 
cytomegalovirus, BK virus infections and listeriosis were reported with tofacitinib. Some patients have 
presented with disseminated rather than localised disease. Other serious infections that were not reported 
in clinical studies may also occur (e.g., coccidioidomycosis). 
 
The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were 
headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension (see 
Table 6, Adverse Drug Reactions [ADRs] based on all study durations). 
 
The proportion of patients who discontinued treatment due to adverse reactions during first 3 months of 
the double-blind, placebo or MTX controlled studies was 3.8% for patients taking tofacitinib. The most 
common infections resulting in discontinuation of therapy were herpes zoster and pneumonia. 
 
Psoriatic arthritis 
Overall, the safety profile observed in patients with active PsA treated with tofacitinib was consistent with 
the safety profile observed in patients with RA treated with tofacitinib. 
 
Ulcerative colitis 
The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the 
induction studies were headache, nasopharyngitis, nausea, and arthralgia.  
 
In the induction and maintenance studies, across tofacitinib and placebo treatment groups, the most 
common categories of serious adverse reactions were gastrointestinal disorders and infections, and the 
most common serious adverse reaction was worsening of UC. 
 
Overall, the safety profile observed in patients with UC treated with tofacitinib was consistent with the 
safety profile of tofacitinib in the RA indication. 
 
Tabulated list of adverse reactions 
 
The ADRs listed in the table below are from clinical studies in patients with RA, PsA, and UC and are 
presented by System Organ Class (SOC) and frequency categories, defined using the following 



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convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare 
(≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), or not known (cannot be estimated from the available 
data). Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. 
 
Table 6: Adverse drug reactions 

System organ 
class 

Common 
≥1/100 to <1/10 

 

Uncommon 
≥1/1,000 to 

<1/100 

Rare 
≥1/10,000 to 

<1/1,000 

Very rare 
<1/10,000 

Not known 
(cannot be 

estimated from 
the available 

data) 
Infections and 
infestations 

Pneumonia 
Influenza 
Herpes zoster 
Urinary tract 
infection 
Sinusitis 
Bronchitis 
Nasopharyngitis 
Pharyngitis 

Tuberculosis  
Diverticulitis 
Pyelonephritis 
Cellulitis 
Herpes simplex 
Gastroenteritis viral 
Viral infection  
 
 

Sepsis 
Urosepsis 
Disseminated 
TB 
Necrotizing 
fasciitis 
Bacteraemia 
Staphylococcal 
bacteraemia 
Pneumocystis 
jirovecii 
pneumonia 
Pneumonia 
pneumococcal 
Pneumonia 
bacterial 
Encephalitis 
Atypical 
mycobacterial 
infection 
Cytomegaloviru
s infection 
Arthritis 
bacterial 

Tuberculosis 
of central 
nervous 
system 
Meningitis 
cryptococcal 
Mycobacteriu
m avium 
complex 
infection 
 

 

Neoplasms benign, 
malignant and 
unspecified (incl 
cysts and polyps) 

 Non-melanoma skin 
cancers 

   

Blood and 
lymphatic system 
disorders 

Anaemia Leukopenia 
Lymphopenia 
Neutropenia 

   

Immune system 
disorders 

    Drug 
hypersensitivity* 
Angioedema* 
Urticaria* 

Metabolism and 
nutrition disorders 

 Dyslipidaemia 
Hyperlipidaemia 
Dehydration 

   

Psychiatric 
disorders 

 Insomnia    

Nervous system 
disorders 

Headache Paraesthesia    

Vascular disorders Hypertension Venous 
thromboembolism** 

   

Respiratory, 
thoracic and 
mediastinal 
disorders 

Cough Dyspnoea 
Sinus congestion 

   

Gastrointestinal 
disorders 

Abdominal pain 
Vomiting 
Diarrhoea 
Nausea 
Gastritis 
Dyspepsia 

    



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System organ 
class 

Common 
≥1/100 to <1/10 

 

Uncommon 
≥1/1,000 to 

<1/100 

Rare 
≥1/10,000 to 

<1/1,000 

Very rare 
<1/10,000 

Not known 
(cannot be 

estimated from 
the available 

data) 
Hepatobiliary 
disorders 

 Hepatic steatosis 
Hepatic enzyme  
increased 
Transaminases 
increased 
Liver function test 
abnormal 
Gamma glutamyl-
transferase increased 

   

Skin and 
subcutaneous 
tissue disorders 

Rash Erythema 
Pruritus 

   

Musculoskeletal 
and connective 
tissue disorders  

Arthralgia Musculoskeletal pain 
Joint swelling 
Tendonitis 

   

General disorders 
and administration 
site conditions  

Pyrexia 
Oedema peripheral 
Fatigue 

    

Investigations  
 

Blood creatine 
phosphokinase 
increased 

Blood creatinine 
increased 
Blood cholesterol 
increased 
Low density 
lipoprotein increased 
Weight increased 

   

Injury, poisoning 
and procedural 
complications 

 Ligament sprain 
Muscle strain 

   

*Spontaneous reporting data 
**Venous thromboembolism includes PE and DVT 
 
Description of selected adverse reactions 
 
Venous thromboembolism 
 
Rheumatoid arthritis 
In a large, randomised post-authorisation safety surveillance study of rheumatoid arthritis patients who 
were 50 years of age and older and had at least one cardiovascular (CV) risk factor, VTE was observed at 
an increased and dose-dependent incidence in patients treated with tofacitinib compared to TNF inhibitors. 
The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE 
for tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, and TNF inhibitors were 0.54 (0.32-0.87), 
0.27 (0.12-0.52), and 0.09 (0.02-0.26) patients with events per 100 patient-years, respectively. Compared 
with TNF inhibitors, the hazard ratio (HR) for PE was 5.96 (1.75-20.33) and 2.99 (0.81-11.06) for 
tofacitinib 10 mg twice daily and tofacitinib 5 mg twice daily, respectively (see section 5.1).  
 
In a subgroup analysis in patients with VTE risk factors in the above-mentioned study, the risk for PE was 
further increased. Compared with TNF inhibitors, the HR for PE was 9.14 (2.11-39.56) for tofacitinib 
10 mg twice daily and 3.92 (0.83-18.48) for tofacitinib 5 mg twice daily. 
 



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Ulcerative colitis (UC) 
In the UC ongoing extension trial, cases of PE and DVT have been observed in patients using tofacitinib 
10 mg twice daily and with underlying VTE risk factor(s). 
 
Overall infections 
 
Rheumatoid arthritis 
In controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg twice daily (total 
616 patients) and 10 mg twice daily (total 642 patients) tofacitinib monotherapy groups were 16.2% 
(100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo 
group (total 122 patients). In controlled phase 3 clinical studies with background DMARDs, the rates of 
infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 
969 patients) tofacitinib plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), 
respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients). 
 
The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% 
and 3.2%, respectively). 
 
The overall incidence rate of infections with tofacitinib in the long-term safety all exposure population 
(total 4,867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with 
events for 5 mg and 10 mg twice daily, respectively). For patients (total 1,750) on monotherapy, the rates 
were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, 
respectively. For patients (total 3,117) on background DMARDs, the rates were 41.0 and 50.3 patients 
with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. 
 
Ulcerative colitis 
In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 
21.1% (198 patients) in the tofacitinib 10 mg twice daily group compared to 15.2% (43 patients) in the 
placebo group. In the randomised 52-week phase 3 maintenance study, the proportion of patients with 
infections were 35.9% (71 patients) in the 5 mg twice daily and 39.8% (78 patients) in the 10 mg twice 
daily tofacitinib groups, compared to 24.2% (48 patients) in the placebo group.  
 
In the entire treatment experience with tofacitinib, the most commonly reported infection was 
nasopharyngitis, occurring in 18.2% of patients (211 patients).  
 
In the entire treatment experience with tofacitinib, the overall incidence rate of infections was 60.3 events 
per 100 patient-years (involving 49.4% of patients; total 572 patients).  
 
Serious infections 
 
Rheumatoid arthritis 
In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice 
daily tofacitinib monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice 
daily tofacitinib monotherapy group the rate was 1.6 patients with events per 100 patient-years, the rate 
was 0 events per 100 patient-years for the placebo group, and the rate was 1.9 patients with events per 
100 patient-years for the MTX group. 
 
In studies of 6-, 12-, or 24-month duration, the rates of serious infections in the 5 mg twice daily and 
10 mg twice daily tofacitinib plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-
years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus 
DMARD group. 

In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 
3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily tofacitinib groups, 
respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract 



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infection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have been reported 
(see section 4.4). 
 
Ulcerative colitis 
The incidence rates and types of serious infections in the UC clinical studies were generally similar to 
those reported in RA clinical studies with tofacitinib monotherapy treatment groups. 
 
Serious infections in the elderly 
Of the 4,271 patients who enrolled in RA studies I-VI (see section 5.1), a total of 608 RA patients were 
65 years of age and older, including 85 patients 75 years and older. The frequency of serious infection 
among tofacitinib-treated patients 65 years of age and older was higher than those under the age of 65 (4.8 
per 100 patient-years versus 2.4 per 100 patient-years, respectively). 
 
As there is a higher incidence of infections in the elderly population in general, caution should be used 
when treating the elderly (see section 4.4).  
 
Viral reactivation 
 
Patients treated with tofacitinib who are Japanese or Korean, or patients with long standing RA who have 
previously received two or more biological DMARDs, or patients with an ALC less than 1,000 cells/mm3, 
or patients treated with 10 mg twice daily may have an increased risk of herpes zoster (see section 4.4). 
 
Laboratory tests 
 
Lymphocytes 
In the controlled RA clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in 0.3% 
of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twice daily and 
10 mg twice daily doses combined. 
 
In the RA long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in 
1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twice daily 
and 10 mg twice daily doses combined. 
 
Confirmed ALC less than 750 cells/mm3 were associated with an increased incidence of serious infections 
(see section 4.4). 
 
In the clinical studies in UC, changes in ALC observed with tofacitinib treatment were similar to the 
changes observed in clinical studies in RA. 
 
Neutrophils 
In the controlled RA clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 
0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no 
confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear 
relationship between neutropenia and the occurrence of serious infections. 
 
In the RA long-term safety population, the pattern and incidence of confirmed decreases in ANC remained 
consistent with what was seen in the controlled clinical studies (see section 4.4). 
 
In the clinical studies in UC, changes in ANC observed with tofacitinib treatment were similar to the 
changes observed in clinical studies in RA. 
 
Liver enzyme tests 
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were 
uncommonly observed in RA patients. In those patients experiencing liver enzyme elevation, modification 



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of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or 
reduction in tofacitinib dose, resulted in decrease or normalisation of liver enzymes. 
 
In the controlled portion of the RA phase 3 monotherapy study (0-3 months) (study I, see section 5.1), 
ALT elevations greater than 3x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving 
placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 
3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, tofacitinib 5 mg and 10 mg 
twice daily, respectively. 
 
In the RA phase 3 monotherapy study (0-24 months) (study VI, see section 5.1), ALT elevations greater 
than 3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving MTX, tofacitinib 5 mg and 
10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 
3.3%, 1.6% and 1.5% of patients receiving MTX, tofacitinib 5 mg and 10 mg twice daily, respectively. 
 
In the controlled portion of the RA phase 3 studies on background DMARDs (0-3 months) (studies II-V, 
see section 5.1), ALT elevations greater than 3x ULN were observed in 0.9%, 1.24% and 1.14% of 
patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In these studies, AST 
elevations greater than 3x ULN were observed in 0.72%, 0.5% and 0.31% of patients receiving placebo, 
tofacitinib 5 mg and 10 mg twice daily, respectively. 
 
In the RA long-term extension studies, on monotherapy, ALT elevations greater than 3x ULN were 
observed in 1.1% and 1.4% of patients receiving tofacitinib 5 mg and 10 mg twice daily, respectively. 
AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg and 10 mg 
twice daily groups. 
 
In the RA long-term extension studies, on background DMARDs, ALT elevations greater than 3x ULN 
were observed in 1.8% and 1.6% of patients receiving tofacitinib 5 mg and 10 mg twice daily, 
respectively. AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg 
and 10 mg twice daily groups.  
 
In the clinical studies in UC, changes in liver enzyme tests observed with tofacitinib treatment were 
similar to the changes observed in clinical studies in RA.  
 
Lipids 
Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were 
first assessed at 1 month following initiation of tofacitinib in the controlled double-blind clinical trials of 
RA. Increases were observed at this time point and remained stable thereafter. 
 
Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled 
clinical studies in RA are summarised below: 
 
• Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 20% in the 

tofacitinib 10 mg twice daily arm at month 12, and increased by 16% in the tofacitinib 5 mg twice 
daily arm and 19% in the tofacitinib 10 mg twice daily arm at month 24. 

• Mean HDL cholesterol increased by 17% in the tofacitinib 5 mg twice daily arm and 18% in the 
tofacitinib 10 mg twice daily arm at month 12, and increased by 19% in the tofacitinib 5 mg twice 
daily arm and 20% in the tofacitinib 10 mg twice daily arm at month 24. 

 
Upon withdrawal of tofacitinib treatment, lipid levels returned to baseline. 
 
Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 ratios were 
essentially unchanged in tofacitinib-treated patients. 
 



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In an RA controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment 
levels in response to statin therapy. 
 
In the RA long-term safety populations, elevations in the lipid parameters remained consistent with what 
was seen in the controlled clinical studies. 
 
In the clinical studies in UC, changes in lipids observed with tofacitinib treatment were similar to the 
changes observed in clinical studies in RA. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse 
reactions. There is no specific antidote for overdose with tofacitinib. Treatment should be symptomatic 
and supportive. 
 
Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more 
than 95% of the administered dose is expected to be eliminated within 24 hours. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic groups: Immunosuppressants, Selective Immunosuppressants; ATC code: L04AA29 
 
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. 
 
Pharmacodynamic effects 
 
In patients with RA, treatment up to 6 months with tofacitinib was associated with dose-dependent 
reductions of circulating CD16/56+ natural killer (NK) cells, with estimated maximum reductions 
occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 
2-6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated with dose-
dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte 
subsets (CD3+, CD4+ and CD8+) were small and inconsistent. 
 
Following long-term treatment (median duration of tofacitinib treatment of approximately 5 years), CD4+ 
and CD8+ counts showed median reductions of 28% and 27%, respectively, from baseline. In contrast to 
the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showed a median 
increase of 73% from baseline. CD19+ B cell counts showed no further increases after long-term 
tofacitinib treatment. All these lymphocyte subset changes returned toward baseline after temporary 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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discontinuation of treatment. There was no evidence of a relationship between serious or opportunistic 
infections or herpes zoster and lymphocyte subset counts (see section 4.2 for absolute lymphocyte count 
monitoring). 
 
Changes in total serum IgG, IgM, and IgA levels over 6-month tofacitinib dosing in patients with RA were 
small, not dose-dependent and similar to those seen on placebo, indicating a lack of systemic humoral 
suppression. 
 
After treatment with tofacitinib in RA patients, rapid decreases in serum C-reactive protein (CRP) were 
observed and maintained throughout dosing. Changes in CRP observed with tofacitinib treatment do not 
reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic 
activity compared to the half-life. 
 
Vaccine studies 
 
In a controlled clinical trial of patients with RA initiating tofacitinib 10 mg twice daily or placebo, the 
number of responders to influenza vaccine was similar in both groups: tofacitinib (57%) and placebo 
(62%). For pneumococcal polysaccharide vaccine the number of responders was as follows: 32% in 
patients receiving both tofacitinib and MTX; 62% for tofacitinib monotherapy; 62% for MTX 
monotherapy; and 77% for placebo. The clinical significance of this is unknown, however, similar results 
were obtained in a separate vaccine study with influenza and pneumococcal polysaccharide vaccines in 
patients receiving long-term tofacitinib 10 mg twice daily. 
 
A controlled study was conducted in patients with RA on background MTX immunised with a live 
attenuated virus vaccine (Zostavax®) 2 to 3 weeks before initiating a 12-week treatment with tofacitinib 
5 mg twice daily or placebo. Evidence of humoral and cell-mediated responses to VZV was observed in 
both tofacitinib and placebo-treated patients at 6 weeks. These responses were similar to those observed in 
healthy volunteers aged 50 years and older. A patient with no previous history of varicella infection and 
no anti-varicella antibodies at baseline experienced dissemination of the vaccine strain of varicella 
16 days after vaccination. Tofacitinib was discontinued and the patient recovered after treatment with 
standard doses of antiviral medication. This patient subsequently made a robust, though delayed, humoral 
and cellular response to the vaccine (see section 4.4). 
 
Clinical efficacy and safety 
 
Rheumatoid arthritis 
The efficacy and safety of tofacitinib were assessed in 6 randomised, double-blind, controlled multicentre 
studies in patients greater than 18 years of age with active RA diagnosed according to American College 
of Rheumatology (ACR) criteria. Table 7 provides information regarding the pertinent study design and 
population characteristics. 
 
Table 7: Phase 3 clinical trials of tofacitinib 5 mg and 10 mg twice daily doses in patients with RA 

Studies Study I 
(ORAL 

Solo) 

Study II 
(ORAL 
Sync) 

Study III 
(ORAL 

Standard) 

Study IV 
(ORAL 
Scan) 

Study V 
(ORAL 
Step) 

Study VI 
(ORAL 
Start) 

Study VII 
(ORAL 

Strategy) 
Population DMARD-IR DMARD-IR MTX-IR MTX-IR TNFi-IR MTX-naïvea MTX-IR 
Control Placebo Placebo Placebo Placebo Placebo MTX MTX, 

ADA 
Background 
treatment 

Noneb csDMARDs MTX MTX MTX Noneb 3 Parallel arms: 
• Tofacitinib 

monotherapy 
• Tofacitinib+MTX 
• ADA+MTX 



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Studies Study I 
(ORAL 

Solo) 

Study II 
(ORAL 
Sync) 

Study III 
(ORAL 

Standard) 

Study IV 
(ORAL 
Scan) 

Study V 
(ORAL 
Step) 

Study VI 
(ORAL 
Start) 

Study VII 
(ORAL 

Strategy) 
Key features Monotherapy Various 

csDMARDs 
Active 
control 
(ADA) 

X-Ray TNFi-IR Monotherapy, 
Active 
comparator 
(MTX),  
X-Ray 

Tofacitinib with and 
without MTX in 
comparison to ADA 
with MTX 

Number of 
patients 
treated 

610 792 717 797 399 956 1,146 

Total study 
duration 

6 months 1 year 1 year 2 years 6 months 2 years 1 year 

Co-primary 
efficacy 
endpointsc 

Month 3: 
ACR20 
HAQ-DI 
DAS28-
4(ESR)<2.6 

Month 6: 
ACR20 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 6: 
ACR20 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 6: 
ACR20 
mTSS 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 3: 
ACR20 
HAQ-DI 
DAS28-
4(ESR)<2.6 

Month 6: 
mTSS 
ACR70 
 

Month 6: 
ACR50 

Time of 
mandatory 
placebo rescue 
to tofacitinib 5 
or 10 mg 
twice daily 

Month 3 Month 6 (placebo subjects with < 20% 
improvement in swollen and tender joint 
counts advanced to tofacitinib at month 3) 

Month 3 NA NA 

a. ≤3 weekly doses (MTX-naïve). 
b.Antimalarials were allowed. 
c. Co-primary endpoints as follows: mean change from baseline in mTSS; percent of subjects achieving ACR20 or ACR70 

responses; mean change from baseline in HAQ-DI; percent of subjects achieving a DAS28-4(ESR) <2.6 (remission). 
mTSS=modified Total Sharp Score, ACR20(70)=American College of Rheumatology ≥20% (≥70%) improvement, 
DAS28=Disease Activity Score 28 joints, ESR=Erythrocyte Sedimentation Rate, HAQ-DI=Health Assessment Questionnaire 
Disability Index, DMARD=disease-modifying antirheumatic drug, IR=inadequate responder, csDMARD=conventional synthetic 
DMARD, TNFi=tumour necrosis factor inhibitor, NA=not applicable, ADA=adalimumab, MTX=methotrexate. 
 
Clinical response 
 
ACR response 
The percentages of tofacitinib-treated patients achieving ACR20, ACR50 and ACR70 responses in studies 
ORAL Solo, ORAL Sync, ORAL Standard, ORAL Scan, ORAL Step, ORAL Start, and ORAL Strategy 
are shown in Table 8. In all studies, patients treated with either 5 mg or 10 mg twice daily tofacitinib had 
statistically significant ACR20, ACR50 and ACR70 response rates at month 3 and month 6 versus placebo 
(or versus MTX in ORAL Start) treated patients. 
 
Over the course of ORAL Strategy, responses with tofacitinib 5 mg twice daily + MTX were numerically 
similar compared to adalimumab 40 mg + MTX and both were numerically higher than tofacitinib 5 mg 
twice daily. 
 
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, or 
disease status. Time to onset was rapid (as early as week 2 in studies ORAL Solo, ORAL Sync, and 
ORAL Step) and the magnitude of response continued to improve with duration of treatment. As with the 
overall ACR response in patients treated with 5 mg or 10 mg twice daily tofacitinib, each of the 
components of the ACR response was consistently improved from baseline including: tender and swollen 
joint counts; patient and physician global assessment; disability index scores; pain assessment and CRP 
compared to patients receiving placebo plus MTX or other DMARDs in all studies. 
 



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Table 8:  Proportion (%) of patients with an ACR response  
ORAL Solo: DMARD inadequate responders 

Endpoint Time Placebo N=122 

Tofacitinib 5 mg twice 
daily monotherapy  

N=241 

Tofacitinib 10 mg 
twice daily 

monotherapy 
N=243 

ACR20 Month 3 26 60*** 65*** Month 6 NA 69 71 

ACR50 Month 3 12 31*** 37*** Month 6 NA 42 47 

ACR70 Month 3 6 15* 20*** Month 6 NA 22 29 
ORAL Sync: DMARD inadequate responders 

Endpoint Time 
Placebo + DMARD(s) 

 
N=158 

Tofacitinib 5 mg twice 
daily + DMARD(s) 

N=312 

Tofacitinib 10 mg 
twice daily + 
DMARD(s) 

N=315 

ACR20 
Month 3 27 56*** 63*** 
Month 6 31 53*** 57*** 

Month 12 NA 51 56 

ACR50 
Month 3 9 27*** 33*** 
Month 6 13 34*** 36*** 

Month 12 NA 33 42 

ACR70 
Month 3 2 8** 14*** 
Month 6 3 13*** 16*** 

Month 12 NA 19 25 
ORAL Standard: MTX inadequate responders 

Endpoint Time Placebo Tofacitinib twice daily + MTX 

Adalimumab 40 mg 
QOW 

+ MTX 

ACR20 

  
N=105 

5 mg 
N=198 

10 mg 
N=197 

 
N=199 

Month 3 26 59*** 57*** 56*** 
Month 6 28 51*** 51*** 46** 

Month 12 NA 48 49 48 

ACR50 
Month 3 7 33*** 27*** 24*** 
Month 6 12 36*** 34*** 27** 

Month 12 NA 36 36 33 

ACR70 
Month 3 2 12** 15*** 9* 
Month 6 2 19*** 21*** 9* 

Month 12 NA 22 23 17 
ORAL Scan: MTX inadequate responders 

Endpoint Time Placebo + MTX N=156 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=316 

Tofacitinib 10 mg 
twice daily 

 + MTX 
N=309 

ACR20 

Month 3 27 55*** 66*** 
Month 6 25 50*** 62*** 

Month 12 NA 47 55 
Month 24 NA 40 50 

ACR50 
Month 3 8 28*** 36*** 
Month 6 8 32*** 44*** 

Month 12 NA 32 39 



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Month 24 NA 28 40 

ACR70 

Month 3 3 10** 17*** 
Month 6 1 14*** 22*** 

Month 12 NA 18 27 
Month 24 NA 17 26 

ORAL Step: TNF Inhibitor inadequate responders 

Endpoint Time Placebo + MTX N=132 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=133 

Tofacitinib 10 mg 
twice daily 

 + MTX 
N=134 

ACR20 Month 3 24 41* 48*** Month 6 NA 51 54 

ACR50 Month 3 8 26*** 28*** Month 6 NA 37 30 

ACR70 Month 3 2 14*** 10* Month 6 NA 16 16 
ORAL Start: MTX-naïve 

Endpoint Time MTX N=184 

Tofacitinib 5 mg twice 
daily monotherapy 

N=370 

Tofacitinib 10 mg 
twice daily 

monotherapy 
N=394 

ACR20 

Month 3 52 69*** 77*** 
Month 6 51 71*** 75*** 

Month 12 51 67** 71*** 
Month 24 42 63*** 64*** 

ACR50 

Month 3 20 40*** 49*** 
Month 6 27 46*** 56*** 

Month 12 33 49** 55*** 
Month 24 28 48*** 49*** 

ACR70 

Month 3 5 20*** 26*** 
Month 6 12 25*** 37*** 

Month 12 15 28** 38*** 
Month 24 15 34*** 37*** 

ORAL Strategy: MTX inadequate responders 

Endpoint Time 
Tofacitinib 5 mg twice 

daily 
N=384 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=376 

Adalimumab 
 + MTX 
N=386 

ACR20 
Month 3 62.50 70.48ǂ 69.17 
Month 6 62.84 73.14ǂ 70.98 

Month 12 61.72 70.21ǂ 67.62 

ACR50 
Month 3 31.51 40.96ǂ 37.31 
Month 6 38.28 46.01ǂ 43.78 

Month 12 39.31 47.61ǂ 45.85 

ACR70 
Month 3 13.54 19.41ǂ 14.51 
Month 6 18.23 25.00ǂ 20.73 

Month 12 21.09 28.99ǂ 25.91 
*p<0.05 
**p<0.001 
***p<0.0001 verses placebo (versus MTX for ORAL Start) 
ǂp<0.05 – tofacitinib 5 mg + MTX versus tofacitinib 5 mg for ORAL Strategy (normal p-values without multiple comparison 
adjustment) 
QOW=every other week, N=number of subjects analysed, ACR20/50/70=American College of Rheumatology ≥20, 50, 70% 
improvement, NA=not applicable, MTX=methotrexate. 

 



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DAS28-4(ESR) response 
Patients in the phase 3 studies had a mean Disease Activity Score (DAS28-4[ESR]) of 6.1-6.7 at baseline. 
Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2.0 and 1.9-2.2 were 
observed in patients treated with 5 mg and 10 mg twice daily doses, respectively, compared to placebo-
treated patients (0.7-1.1) at month 3. The proportion of patients achieving a DAS28 clinical remission 
(DAS28-4(ESR) < 2.6) in ORAL Step, ORAL Sync, and ORAL Standard is shown in Table 9. 
 
Table 9: Number (%) of subjects achieving DAS28-4(ESR) < 2.6 remission at months 3 and 6  

 Time Point N % 
ORAL Step: TNF Inhibitor inadequate responders  

Tofacitinib 5 mg twice daily + MTX Month 3 133 6 
Tofacitinib 10 mg twice daily + MTX Month 3 134 8* 
Placebo + MTX Month 3 132 2 

ORAL Sync: DMARD inadequate responders  
Tofacitinib 5 mg twice daily Month 6 312 8* 
Tofacitinib 10 mg twice daily Month 6 315 11*** 
Placebo Month 6 158 3 

ORAL Standard: MTX inadequate responders  
Tofacitinib 5 mg twice daily + MTX Month 6 198 6* 
Tofacitinib 10 mg twice daily + MTX Month 6 197 11*** 
Adalimumab 40 mg SC QOW + MTX Month 6 199 6* 
Placebo + MTX Month 6 105 1 

*p <0.05, ***p<0.0001 versus placebo, SC=subcutaneous, QOW=every other week, N=number of subjects analysed, 
DAS28=Disease Activity Scale 28 joints, ESR=Erythrocyte Sedimentation Rate. 
 
Radiographic response 
In ORAL Scan and ORAL Start, inhibition of progression of structural joint damage was assessed 
radiographically and expressed as mean change from baseline in mTSS and its components, the erosion 
score and joint space narrowing (JSN) score, at months 6 and 12.  
 
In ORAL Scan, tofacitinib 10 mg twice daily plus background MTX resulted in significantly greater 
inhibition of the progression of structural damage compared to placebo plus MTX at months 6 and 12. 
When given at a dose of 5 mg twice daily, tofacitinib plus MTX exhibited similar effects on mean 
progression of structural damage (not statistically significant). Analysis of erosion and JSN scores were 
consistent with overall results.  
 
In the placebo plus MTX group, 78% of patients experienced no radiographic progression (mTSS change 
less than or equal to 0.5) at month 6 compared to 89% and 87% of patients treated with tofacitinib 5 or 
10 mg (plus MTX) twice daily respectively, (both significant versus placebo plus MTX). 
 
In ORAL Start, tofacitinib monotherapy resulted in significantly greater inhibition of the progression of 
structural damage compared to MTX at months 6 and 12 as shown in Table 10, which was also maintained 
at month 24. Analyses of erosion and JSN scores were consistent with overall results. 
 
In the MTX group, 70% of patients experienced no radiographic progression at month 6 compared to 83% 
and 90% of patients treated with tofacitinib 5 or 10 mg twice daily respectively, both significant versus 
MTX. 
 



25 
 

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Table 10:  Radiographic changes at months 6 and 12 
 ORAL Scan: MTX inadequate responders 
 Placebo + 

MTX 
N=139 

Mean (SD)a 

Tofacitinib 5 mg 
twice daily + 

MTX 
N=277 

Mean (SD)a 

Tofacitinib 
5 mg 

twice daily + MTX 
Mean difference 

from placebob (CI)  

Tofacitinib 
10 mg 

twice daily + 
MTX 
N=290 

Mean (SD)a 

Tofacitinib 
10 mg 

twice daily + MTX 
Mean difference 
from placebob 

(CI) 
mTSSc 
Baseline 
Month 6 
Month 12 

 
33 (42) 

0.5 (2.0) 
1.0 (3.9) 

 
31 (48) 

0.1 (1.7) 
0.3 (3.0) 

 
- 

-0.3 (-0.7, 0.0) 
-0.6 (-1.3, 0.0) 

 
37 (54) 

0.1 (2.0) 
0.1 (2.9) 

 
- 

-0.4 (-0.8, 0.0) 
-0.9 (-1.5, -0.2) 

 ORAL Start: MTX-naïve 
 MTX 

N=168 
Mean (SD)a 

Tofacitinib 
5 mg 

twice daily 
N=344 

Mean (SD)a 

Tofacitinib 
5 mg 

twice daily  
Mean difference 
from MTXd (CI) 

Tofacitinib 
10 mg 

twice daily 
N=368 

Mean (SD)a 

Tofacitinib 
10 mg 

twice daily  
Mean difference 
from MTXd (CI) 

mTSSc 
Baseline 
Month 6 
Month 12 

 
16 (29) 

0.9 (2.7) 
1.3 (3.7) 

 
20 (41)  

0.2 (2.3) 
0.4 (3.0) 

 
- 

-0.7 (-1.0, -0.3) 
-0.9 (-1.4, -0.4) 

 
19 (39) 

0.0 (1.2) 
0.0 (1.5) 

 
- 

-0.8 (-1.2, -0.4) 
-1.3 (-1.8, -0.8) 

a SD = Standard Deviation 
b Difference between least squares means tofacitinib minus placebo (95% CI = 95% confidence interval) 
c Month 6 and month 12 data are mean change from baseline 
d Difference between least squares means tofacitinib minus MTX (95% CI = 95% confidence interval) 
 
Physical function response and health-related outcomes 
 
Tofacitinib, alone or in combination with MTX, has shown improvements in physical function, as 
measured by the HAQ-DI. Patients receiving tofacitinib 5 or 10 mg twice daily demonstrated significantly 
greater improvement from baseline in physical functioning compared to placebo at month 3 (studies 
ORAL Solo, ORAL Sync, ORAL Standard, and ORAL Step) and month 6 (studies ORAL Sync and 
ORAL Standard). Tofacitinib 5 or 10 mg twice daily-treated patients demonstrated significantly greater 
improvement in physical functioning compared to placebo as early as week 2 in ORAL Solo and ORAL 
Sync. Changes from baseline in HAQ-DI in studies ORAL Standard, ORAL Step and ORAL Sync are 
shown in Table 11. 
 



26 
 

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Table 11: LS mean change from baseline in HAQ-DI at month 3 
 Placebo + MTX Tofacitinib 

5 mg twice daily 
+ MTX 

Tofacitinib 
10 mg twice daily 

+ MTX 

Adalimumab 
40 mg QOW 

+ MTX 
ORAL Standard: MTX inadequate responders 

N=96 N=185 N=183 N=188 
-0.24 -0.54*** -0.61*** -0.50*** 
ORAL Step: TNF inhibitor inadequate responders 
N=118 N=117 N=125 NA 
-0.18 -0.43*** -0.46*** NA 

Placebo + DMARD(s) Tofacitinib 
5 mg twice daily + 

DMARD(s) 

Tofacitinib 
10 mg twice daily 

+ DMARD(s) 

 

ORAL Sync: DMARD inadequate responders 
N=147 N=292 N=292 NA 
-0.21 -0.46*** -0.56*** NA 

*** p<0.0001, tofacitinib versus placebo + MTX, LS = least squares, N = number of patients, QOW = every other week, 
NA = not applicable, HAQ-DI = Health Assessment Questionnaire Disability Index 

 
Health-related quality of life was assessed by the Short Form Health Survey (SF-36). Patients receiving 
either 5 or 10 mg tofacitinib twice daily experienced significantly greater improvement from baseline 
compared to placebo in all 8 domains as well as the Physical Component Summary and Mental 
Component Summary scores at month 3 in ORAL Solo, ORAL Scan and ORAL Step. In ORAL Scan, 
mean SF-36 improvements were maintained to 12 months in tofacitinib-treated patients. 
 
Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F) scale at month 3 in all studies. Patients receiving tofacitinib 5 or 10 mg twice daily 
demonstrated significantly greater improvement from baseline in fatigue compared to placebo in all 
5 studies. In ORAL Standard and ORAL Scan, mean FACIT-F improvements were maintained to 
12 months in tofacitinib-treated patients. 
 
Improvement in sleep was assessed using the Sleep Problems Index I and II summary scales of the 
Medical Outcomes Study Sleep (MOS-Sleep) measure at month 3 in all studies. Patients receiving 
tofacitinib 5 or 10 mg twice daily demonstrated significantly greater improvement from baseline in both 
scales compared to placebo in ORAL Sync, ORAL Standard and ORAL Scan. In ORAL Standard and 
ORAL Scan, mean improvements in both scales were maintained to 12 months in tofacitinib-treated 
patients. 
 
Durability of clinical responses 
 
Durability of effect was assessed by ACR20, ACR50, ACR70 response rates in studies of duration of up 
to two years. Changes in mean HAQ-DI and DAS28-4(ESR) were maintained in both tofacitinib treatment 
groups through to the end of the studies. 
 
Evidence of persistence of efficacy with tofacitinib treatment for up to 7 years is also provided from data 
in the one ongoing and one completed open-label, long-term follow-up studies. 
 
Long-term controlled safety data 
 
Study ORAL Surveillance (A3921133) is a large (N=4362), ongoing, randomised active-controlled 
post-authorisation safety surveillance study of rheumatoid arthritis patients who were at least 50 years of 
age and older and had at least one cardiovascular risk factor (CV risk factors defined as: current cigarette 
smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, 
history of coronary artery disease including a history of revascularization procedure, coronary artery 
bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and 



27 
 

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presence of extra-articular disease associated with RA, e.g. nodules, Sjögren’s syndrome, anemia of 
chronic disease, pulmonary manifestations). 
 
Patients were randomised to open-label tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, or a 
TNF inhibitor (TNF inhibitor was either etanercept 50 mg once weekly or adalimumab 40 mg every other 
week) in a 1:1:1 ratio. The co-primary endpoints are adjudicated malignancy (excluding NMSC) and 
adjudicated major adverse cardiovascular events (MACE); cumulative incidence and statistical assessment 
of endpoints are blinded. The study is an event-powered study that also requires at least 1500 patients to 
be followed for 3 years. The study treatment of tofacitinib 10 mg twice daily has been stopped and 
patients were switched to 5 mg twice daily because of a dose-dependent signal of venous thromboembolic 
events (VTE). 
 
Venous thromboembolism (VTE) 
In an interim analysis of study A3921133, an increased and dose-dependent incidence of VTE was 
observed in patients treated with tofacitinib compared to TNF inhibitors (see section 4.8). The majority of 
these events were serious and some cases of PE resulted in death. The incidence rates (95% CI) for PE for 
tofacitinib 10 mg twice daily, 5 mg twice daily, and TNF inhibitors were 0.54 (0.32-0.87), 
0.27 (0.12-0.52), and 0.09 (0.02-0.26) patients with events per 100 patient-years, respectively. Compared 
with TNF inhibitors, the HR for PE with tofacitinib 10 mg twice daily was 5.96 (1.75-20.33), and for 5 mg 
twice daily the HR was 2.99 (0.81-11.06). The incidence rates (95% CI) for DVT for tofacitinib 10 mg 
twice daily, 5 mg twice daily, and TNF inhibitors were 0.38 (0.20-0.67), 0.30 (0.14-0.55), and 
0.18 (0.07-0.39) patients with events per 100 patient-years, respectively. Compared with TNF inhibitors, 
the HR for DVT with tofacitinib 10 mg twice daily was 2.13 (0.80-5.69), and for 5 mg twice daily the HR 
was 1.66 (0.60-4.57). 
 
Mortality 
In an interim analysis of study A3921133, increased mortality within 28 days of last treatment was 
observed in patients treated with tofacitinib compared to TNF inhibitors. The incidence rates (95% CI) 
were 0.89 (0.59-1.29) for tofacitinib 10 mg twice daily, 0.57 (0.34-0.89) for tofacitinib 5 mg twice daily, 
and 0.27 (0.12-0.51) for TNF-inhibitors; with a HR (95% CI) of 3.28 (1.55-6.95) for tofacitinib 10 mg 
twice daily and of 2.11 (0.96-4.67) for tofacitinib 5 mg twice daily, versus TNF inhibitors. Mortality was 
mainly due to cardiovascular events, infections and malignancies.  

For cardiovascular mortality within 28 days of last treatment, the incidence rates (95% CI) per 
100 patients-years were 0.45 (0.24-0.75) for tofacitinib 10 mg twice daily, 0.24 (0.10-0.47) for tofacitinib 
5 mg twice daily, and 0.21 (0.08-0.43) for TNF inhibitors; with an incident rate ratio (IRR) (95% CI) of 
2.12 (0.80-6.20) for tofacitinib 10 mg twice daily and of 1.14 (0.36-3.70) for tofacitinib 5 mg twice daily, 
versus TNF inhibitors.  

For fatal infections within 28 days of last treatment, the incidence rates per 100 patient-years (95% CI) 
were 0.22 (0.09-0.46), 0.18 (0.07-0.39), and 0.06 (0.01-0.22) for tofacitinib 10 mg twice daily and 5 mg 
twice daily, and TNF inhibitors, respectively; with an IRR (95% CI) of 3.70 (0.71-36.5) for 10 mg twice 
daily and of 3.00 (0.54-30.4) for tofacitinib 5 mg twice daily, versus TNF inhibitors. 
 
Serious infections 
For non-fatal serious infections, the incidence rates (95% CI) per 100 patient-years were 3.51 (2.93-4.16), 
3.35 (2.78-4.01), and 2.79 (2.28-3.39), for tofacitinib 10 mg and 5 mg twice daily and TNF inhibitors, 
respectively. The risk of serious (fatal and non-fatal) infections was further increased in patients over 65 
years of age, as compared to younger patients in study A3921133. 
 
Psoriatic arthritis 
The efficacy and safety of tofacitinib were assessed in 2 randomised, double-blind, placebo-controlled 
Phase 3 studies in adult patients with active PsA (≥ 3 swollen and ≥ 3 tender joints). Patients were 



28 
 

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required to have active plaque psoriasis at the screening visit. For both studies, the primary endpoints were 
ACR20 response rate and change from baseline in HAQ-DI at month 3. 
 
Study PsA-I (OPAL BROADEN) evaluated 422 patients who had a previous inadequate response (due to 
lack of efficacy or intolerance) to a csDMARD (MTX for 92.7% of patients); 32.7% of the patients in this 
study had a previous inadequate response to > 1 csDMARD or 1 csDMARD and a targeted synthetic 
DMARD (tsDMARD). In OPAL BROADEN, previous treatment with TNF inhibitor was not allowed. All 
patients were required to have 1 concomitant csDMARD; 83.9% of patients received concomitant MTX, 
9.5% of patients received concomitant sulfasalazine, and 5.7% of patients received concomitant 
leflunomide. The median PsA disease duration was 3.8 years. At baseline, 79.9% and 56.2% of patients 
had enthesitis and dactylitis, respectively. Patients randomised to tofacitinib received 5 mg twice daily or 
tofacitinib 10 mg twice daily for 12 months. Patients randomised to placebo were advanced in a blinded 
manner at month 3 to either tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily and received 
treatment until month 12. Patients randomised to adalimumab (active-control arm) received 40 mg 
subcutaneously every 2 weeks for 12 months. 
 
Study PsA-II (OPAL BEYOND) evaluated 394 patients who had discontinued a TNF inhibitor due to lack 
of efficacy or intolerance; 36.0% had a previous inadequate response to > 1 biological DMARD. All 
patients were required to have 1 concomitant csDMARD; 71.6% of patients received concomitant MTX, 
15.7% of patients received concomitant sulfasalazine, and 8.6% of patients received concomitant 
leflunomide. The median PsA disease duration was 7.5 years. At baseline, 80.7% and 49.2% of patients 
had enthesitis and dactylitis, respectively. Patients randomised to tofacitinib received 5 mg twice daily or 
tofacitinib 10 mg twice daily for 6 months. Patients randomised to placebo were advanced in a blinded 
manner at month 3 to either tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily and received 
treatment until month 6.  
 
Signs and symptoms 
Treatment with tofacitinib resulted in significant improvements in some signs and symptoms of PsA, as 
assessed by the ACR20 response criteria compared to placebo at month 3. The efficacy results for 
important endpoints assessed are shown in Table 12. 
 
Table 12: Proportion (%) of PsA patients who achieved clinical response and mean change from 

baseline in OPAL BROADEN and OPAL BEYOND studies 
 Conventional synthetic DMARD  

inadequate respondersa (TNFi-Naïve) 
TNFi  

inadequate respondersb 
 OPAL BROADEN OPAL BEYONDc 
Treatment 
group 

Placebo Tofacitinib 5 mg 
twice daily 

Adalimumab 40 mg 
SC q2W 

Placebo Tofacitinib 5 mg 
twice daily 

N 105 107 106 131 131 
ACR20 
Month 3 
Month 6 
Month 12 

 
 33% 
 NA 
 NA 

 
 50%d,* 
 59% 
 68% 

 
 52%* 
 64% 
 60% 

 
 24% 
 NA 
 - 

 
 50%d,*** 
 60% 
 - 

ACR50 
Month 3 
Month 6 
Month 12 

 
 10% 
 NA 
 NA 

 
 28%e,** 
 38% 
 45% 

 
 33%*** 
 42% 
 41% 

 
 15% 
 NA 
 - 

 
 30%e,* 
 38% 
 - 



29 
 

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ACR70 
Month 3 
Month 6 
Month 12 

 
 5% 
 NA 
 NA 

 
 17%e,* 
 18% 
 23% 

 
 19%* 
 30% 
 29% 

 
 10% 
 NA 
 - 

 
 17% 
 21% 
 - 

∆LEIf 
Month 3 
Month 6 
Month 12 

 
 -0.4 
 NA 
 NA 

 
 -0.8 
 -1.3 
 -1.7 

 
 -1.1* 
 -1.3 
 -1.6 

 
 -0.5 
 NA 
 - 

 
 -1.3* 
 -1.5 
 - 

∆DSSf 
Month 3 
Month 6 
Month 12 

 
 -2.0 
 NA 
 NA 

 
 -3.5 
 -5.2 
 -7.4 

 
 -4.0 
 -5.4 
 -6.1 

 
 -1.9 
 NA 
 - 

 
 -5.2* 
 -6.0 
 - 

PASI75g 
Month 3 
Month 6 
Month 12 

 
 15% 
 NA 
 NA 

 
 43%d,*** 
 46% 
 56% 

 
 39%** 
 55% 
 56% 

 
 14% 
 NA 
 - 

 
 21% 
 34% 
 - 

* Nominal p≤0.05; ** Nominal p<0.001; *** Nominal p<0.0001 for active treatment versus placebo at month 3. 
Abbreviations: BSA=body surface area; ∆LEI=change from baseline in Leeds Enthesitis Index; ∆DSS=change 
from baseline in Dactylitis Severity Score; ACR20/50/70=American College of Rheumatology ≥ 20%, 50%, 70% 
improvement; csDMARD=conventional synthetic disease-modifying antirheumatic drug; N=number of 
randomised and treated patients; NA=Not applicable, as data for placebo treatment is not available beyond month 
3 due to placebo advanced to tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily; SC 
q2w=subcutaneously once every 2 weeks; TNFi=tumour necrosis factor inhibitor; PASI=Psoriasis Area and 
Severity index; PASI75=≥ 75% improvement in PASI. 
a Inadequate response to at least 1 csDMARD due to lack of efficacy and/or intolerability. 
b Inadequate response to a least 1 TNFi due to lack of efficacy and/or intolerability. 
c  OPAL BEYOND had a duration of 6 months. 
d  Achieved statistical significance globally at p≤ 0.05 per the pre-specified step-down testing procedure. 
e  Achieved statistical significance within the ACR family (ACR50 and ACR70) at p≤ 0.05 per the pre-specified 

step-down testing procedure. 
f  For patients with Baseline score > 0. 
g  For patients with Baseline BSA ≥ 3% and PASI > 0. 
 
Both TNF inhibitor naïve and TNF inhibitor inadequate responder tofacitinib 5 mg BID -treated patients 
had significantly higher ACR20 response rates compared to placebo at month 3. Examination of age, sex, 
race, baseline disease activity and PsA subtype did not identify differences in response to tofacitinib. The 
number of patients with arthritis mutilans or axial involvement was too small to allow meaningful 
assessment. Statistically significant ACR20 response rates were observed with tofacitinib 5 mg BID in 
both studies as early as week 2 (first post-baseline assessment) in comparison to placebo. 
 
In OPAL BROADEN, Minimal Disease Activity (MDA) response was achieved by 26.2%, 25.5% and 
6.7% of tofacitinib 5 mg BID, adalimumab and placebo treated patients, respectively (tofacitinib 5 mg 
BID treatment difference from placebo 19.5% [95% CI: 9.9, 29.1]) at month 3. In OPAL BEYOND, MDA 
was achieved by 22.9% and 14.5% of tofacitinib 5 mg BID and placebo treated patients, respectively, 
however tofacitinib 5 mg BID did not achieve nominal statistical significance (treatment difference from 
placebo 8.4% [95% CI: -1.0, 17.8] at month 3). 
 
Radiographic response  
In study OPAL BROADEN, the progression of structural joint damage was assessed radiographically 
utilising the van der Heijde modified Total Sharp Score (mTSS) and the proportion of patients with 
radiographic progression (mTSS increase from baseline greater than 0.5) was assessed at month 12. At 
month 12, 96% and 98% of patients receiving tofacitinib 5 mg twice daily, and adalimumab 40 mg 
subcutaneously every 2 weeks, respectively, did not have radiographic progression (mTSS increase from 
baseline less than or equal to 0.5). 
 



30 
 

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Physical function and health-related quality of life 
Improvement in physical functioning was measured by the HAQ-DI. Patients receiving tofacitinib 5 mg 
twice daily demonstrated greater improvement (p≤ 0.05) from baseline in physical functioning compared 
to placebo at month 3 (see Table 13).  
 
Table 13: Change from baseline in HAQ-DI in PsA studies OPAL BROADEN and OPAL 

BEYOND 
 Least squares mean change from baseline in HAQ-DI 

Conventional synthetic DMARD 
inadequate respondersa (TNFi-naïve) 

TNFi 
inadequate respondersb 

OPAL BROADEN OPAL BEYOND 
Treatment 
group 

Placebo Tofacitinib 5 mg 
twice daily  

Adalimumab 40 mg 
SC q2W 

Placebo Tofacitinib 5 mg 
twice daily 

N  104  107  106  131  129 
Month 3  -0.18  -0.35c,*  -0.38*  -0.14  -0.39c,*** 
Month 6  NA  -0.45  -0.43  NA  -0.44 
Month 12  NA  -0.54  -0.45  NA  NA 
* Nominal p≤0.05; *** Nominal p<0.0001 for active treatment versus placebo at month 3. 
Abbreviations: DMARD=disease-modifying antirheumatic drug; HAQ-DI=Health Assessment Questionnaire 
Disability Index; N=total number of patients in the statistical analysis; SC q2w=subcutaneously once every 
2 weeks; TNFi=tumour necrosis factor inhibitor. 
a  Inadequate response to at least one conventional synthetic DMARD (csDMARD) due to lack of efficacy 

and/or intolerability. 
b  Inadequate response to a least one TNF inhibitor (TNFi) due to lack of efficacy and/or intolerability. 
c Achieved statistical significance globally at p≤ 0.05 per the pre-specified step-down testing procedure. 
 
The HAQ-DI responder rate (response defined as having decrease from baseline of ≥ 0.35) at month 3 in 
studies OPAL BROADEN and OPAL BEYOND was 53% and 50%, respectively in patients receiving 
tofacitinib 5 mg twice daily, 31% and 28%, respectively in patients receiving placebo, and 53% in 
patients receiving adalimumab 40 mg subcutaneously once every 2 weeks (OPAL BROADEN only). 
 
Health-related quality of life was assessed by SF-36v2, fatigue was assessed by the FACIT-F. Patients 
receiving tofacitinib 5 mg twice daily demonstrated greater improvement from baseline compared to 
placebo in the SF-36v2 physical functioning domain, the SF-36v2 physical component summary score, 
and FACIT-F scores at month 3 in studies OPAL BROADEN and OPAL BEYOND (nominal p≤ 0.05). 
Improvements from baseline in SF-36v2 and FACIT-F were maintained through month 6 (OPAL 
BROADEN and OPAL BEYOND) and month 12 (OPAL BROADEN). 
 
Patients receiving tofacitinib 5 mg twice daily demonstrated a greater improvement in arthritis pain (as 
measured on a 0-100 visual analogue scale) from baseline at week 2 (first post-baseline assessment) 
through month 3 compared to placebo in studies OPAL BROADEN and OPAL BEYOND (nominal 
p≤ 0.05). 
 
Ulcerative colitis 
The efficacy and safety of tofacitinib for the treatment of adult patients with moderately to severely active 
UC (Mayo score 6 to 12 with endoscopy subscore ≥ 2 and rectal bleeding subscore ≥ 1) were assessed in 
3 multicentre, double-blind, randomised, placebo-controlled studies: 2 identical induction studies 
(OCTAVE Induction 1 and OCTAVE Induction 2) followed by 1 maintenance study (OCTAVE Sustain). 
Enrolled patients had failed at least 1 conventional therapy, including corticosteroids, immunomodulators, 
and/or a TNF inhibitor. Concomitant stable doses of oral aminosalicylates and corticosteroids (prednisone 
or equivalent daily dose up to 25 mg) were permitted with taper of corticosteroids to discontinuation 
mandated within 15 weeks of entering the maintenance study. Tofacitinib was administered as 
monotherapy (i.e., without concomitant use of biologics and immunosuppressants) for UC.  
 



31 
 

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Table 14 provides additional information regarding pertinent study design and population characteristics.  
 
Table 14: Phase 3 clinical studies of tofacitinib 5 mg and 10 mg twice daily doses in patients with 

UC 
 OCTAVE Induction 1 OCTAVE Induction 2 OCTAVE Sustain 

Treatment groups 
(randomisation ratio)  

Tofacitinib 10 mg 
twice daily 

placebo 
(4:1) 

Tofacitinib 10 mg 
twice daily 

placebo 
(4:1) 

Tofacitinib 5 mg 
twice daily 

Tofacitinib 10 mg 
twice daily 

placebo 
(1:1:1) 

Number of patients 
enrolled 

598 541 593 

Study duration 8 weeks 8 weeks 52 weeks 
Primary efficacy 
endpoint 

Remission Remission Remission 

Key secondary efficacy 
endpoints 

Improvement of 
endoscopic appearance of 

the mucosa 

Improvement of 
endoscopic appearance 

of the mucosa 

Improvement of endoscopic 
appearance of the mucosa 

 
Sustained corticosteroid-free 
remission among patients in 

remission at baseline 
Prior TNFi failure 51.3% 52.1% 44.7% 
Prior corticosteroid 
failure 

74.9% 71.3% 75.0% 

Prior 
immunosuppressant 
failure 

74.1% 69.5% 69.6% 

Baseline corticosteroid 
use 

45.5% 46.8% 50.3% 

Abbreviations: TNFi=tumour necrosis factor inhibitor; UC=ulcerative colitis. 
 
In addition, safety and efficacy of tofacitinib were assessed in an open-label long-term extension study 
(OCTAVE Open). Patients who completed 1 of the induction studies (OCTAVE Induction 1 or OCTAVE 
Induction 2) but did not achieve clinical response or patients who completed or withdrew early due to 
treatment failure in the maintenance study (OCTAVE Sustain) were eligible for OCTAVE Open. Patients 
from OCTAVE Induction 1 or OCTAVE Induction 2 who did not achieve clinical response after 8 weeks 
in OCTAVE Open were to be discontinued from OCTAVE Open. Corticosteroid tapering was also 
required upon entrance into OCTAVE Open.  
 
Induction efficacy data (OCTAVE Induction 1 and OCTAVE Induction 2)  
The primary endpoint of OCTAVE Induction 1 and OCTAVE Induction 2 was the proportion of patients 
in remission at week 8, and the key secondary endpoint was the proportion of patients with improvement 
of endoscopic appearance of the mucosa at week 8. Remission was defined as clinical remission (a total 
Mayo score ≤ 2 with no individual subscore > 1) and rectal bleeding subscore of 0. Improvement of 
endoscopic appearance of the mucosa was defined as endoscopy subscore of 0 or 1.  
 
A significantly greater proportion of patients treated with tofacitinib 10 mg twice daily achieved 
remission, improvement of endoscopic appearance of the mucosa, and clinical response at week 8 
compared to placebo in both studies, as shown in Table 15.  
 
The efficacy results based on the endoscopic readings at the study sites were consistent with the results 
based on the central endoscopy readings.  
 



32 
 

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Table 15: Proportion of patients meeting efficacy endpoints at week 8 (OCTAVE induction 
study 1 and OCTAVE induction study 2) 

 OCTAVE induction study 1 
Central endoscopy read Local endoscopy read 

Endpoint Placebo Tofacitinib 
10 mg 

twice daily 

Placebo Tofacitinib 
10 mg 

twice daily 
 N=122 N=476 N=122 N=476 
Remissiona 8.2% 18.5%‡ 11.5% 24.8%‡ 
Improvement of endoscopic 
appearance of the mucosab 

15.6% 31.3%† 23.0% 42.4%* 

Normalisation of endoscopic 
appearance of the mucosac 

1.6% 6.7%‡ 2.5% 10.9%‡ 

Clinical responsed 32.8% 59.9%* 34.4% 60.7%* 
 OCTAVE induction study 2 

Central endoscopy read Local endoscopy read 
Endpoint Placebo Tofacitinib 

10 mg 
twice daily 

Placebo Tofacitinib 
10 mg 

twice daily 
 N=112 N=429 N=112 N=429 
Remissiona 3.6% 16.6%† 5.4% 20.7%† 
Improvement of endoscopic 
appearance of the mucosab 

11.6% 28.4%† 15.2% 36.4%* 

Normalisation of endoscopic 
appearance of the mucosac 

1.8% 7.0%‡ 0.0% 9.1%‡ 

Clinical responsed 28.6% 55.0%* 29.5% 58.0%* 
* p<0.0001; † p<0.001; ‡ p<0.05. 
N=number of patients in the analysis set. 
a. Primary endpoint: Remission was defined as clinical remission (a Mayo score ≤ 2 with no individual subscore > 1) and 

rectal bleeding subscore of 0.  
b. Key secondary endpoint: Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy 

subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern). 
c. Normalisation of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. 
d. Clinical response was defined as a decrease from baseline in Mayo score of ≥ 3 points and ≥ 30%, with an 

accompanying decrease in the subscore for rectal bleeding of ≥ 1 point or absolute subscore for rectal bleeding of 0 or 1. 
 
In both subgroups of patients with or without prior TNF inhibitor failure, a greater proportion of patients 
treated with tofacitinib 10 mg twice daily achieved remission and improvement of endoscopic appearance 
of the mucosa at week 8 as compared to placebo. This treatment difference was consistent between the 2 
subgroups (Table 16).  
 



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Table 16.  Proportion of patients meeting primary and key secondary efficacy endpoints at week 8 
by TNF inhibitor therapy subgroups (OCTAVE induction study 1 and OCTAVE 
induction study 2, central endoscopy read) 

OCTAVE induction study 1 
Endpoint Placebo 

N=122 
Tofacitinib 10 mg 

twice daily 
N=476 

Remissiona 
   With prior TNF inhibitor failure 1.6% 

(1/64) 
11.1% 

(27/243) 
   Without prior TNF inhibitor failureb 15.5% 

(9/58) 
26.2% 

(61/233) 
Improvement of endoscopic appearance of the mucosac 
    With prior TNF inhibitor failure 6.3% 

(4/64) 
22.6% 

(55/243) 
    Without prior TNF inhibitor failureb 25.9% 

(15/58) 
40.3% 

(94/233) 
OCTAVE induction study 2 

Endpoint Placebo 
N=112 

Tofacitinib 10 mg 
twice daily 

N=429 
Remissiona 
   With prior TNF inhibitor failure 0.0% 

(0/60) 
11.7% 

(26/222) 
   Without prior TNF inhibitor failureb 7.7% 

(4/52) 
21.7% 

(45/207) 
Improvement of endoscopic appearance of the mucosac 
    With prior TNF inhibitor failure 6.7% 

(4/60) 
21.6% 

(48/222) 
    Without prior TNF inhibitor failureb 17.3% 

(9/52) 
35.7% 

(74/207) 
TNF=tumour necrosis factor; N=number of patients in the analysis set. 
a. Remission was defined as clinical remission (a Mayo score ≤ 2 with no individual subscore > 1) and rectal bleeding subscore 

of 0. 
b. Included TNF Inhibitor naïve patients  
c. Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive 

disease) or 1 (erythema, decreased vascular pattern). 
 
As early as week 2, the earliest scheduled study visit, and at each visit thereafter, significant differences 
were observed between tofacitinib 10 mg twice daily and placebo in the change from baseline in rectal 
bleeding and stool frequency, and partial Mayo score. 
 
Maintenance (OCTAVE Sustain) 
Patients who completed 8 weeks in 1 of the induction studies and achieved clinical response were 
re-randomised into OCTAVE Sustain; 179 out of 593 (30.2%) patients were in remission at baseline of 
OCTAVE Sustain.  
 
The primary endpoint in OCTAVE Sustain was the proportion of patients in remission at week 52. The 2 
key secondary endpoints were the proportion of patients with improvement of endoscopic appearance at 
week 52, and the proportion of patients with sustained corticosteroid-free remission at both week 24 and 
week 52 among patients in remission at baseline of OCTAVE Sustain.  
 
A significantly greater proportion of patients in both the tofacitinib 5 mg twice daily and tofacitinib 10 mg 
twice daily treatment groups achieved the following endpoints at week 52 as compared to placebo: 
remission, improvement of endoscopic appearance of the mucosa, normalisation of endoscopic appearance 



34 
 

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of the mucosa, maintenance of clinical response, remission among patients in remission at baseline, and 
sustained corticosteroid-free remission at both week 24 and week 52 among patients in remission at 
baseline, as shown in Table 17.  
 
Table 17: Proportion of patients meeting efficacy endpoints at week 52 (OCTAVE sustain) 
 Central endoscopy read Local endoscopy read 
Endpoint Placebo 

N=198 
Tofacitinib 

5 mg 
twice daily 

N=198 

Tofacitinib 
10 mg 

twice daily 
N=197 

Placebo 
N=198 

Tofacitinib 
5 mg 

twice daily 
N=198 

Tofacitinib 
10 mg 

twice daily 
N=197 

Remissiona 11.1% 34.3%* 40.6%* 13.1% 39.4%* 47.7%* 
Improvement of 
endoscopic 
appearance of the 
mucosab 

13.1% 37.4%* 45.7%* 15.7% 44.9%* 53.8%* 

Normalisation of 
endoscopic 
appearance of the 
mucosac 

4.0% 14.6%** 16.8%* 5.6% 22.2%* 29.4%* 

Maintenance of 
clinical responsed 

20.2% 51.5%* 61.9%* 20.7% 51.0%* 61.4%* 

Remission among 
patients in remission 
at baselinea,f 

10.2% 46.2%* 56.4%* 11.9% 50.8%* 65.5%* 

Sustained 
corticosteroid-free 
remission at both 
week 24 and week 52 
among patients in 
remission at baselinee,f 

5.1% 35.4%* 47.3%* 11.9% 47.7%* 58.2%* 

Corticosteroid-free 
remission among 
patients taking 
corticosteroids at 
baselinea,g  

10.9% 27.7%† 27.6%† 13.9% 32.7%† 31.0%† 

* p<0.0001; **p<0.001; †p<0.05 for tofacitinib versus placebo. 
N=number of patients in the analysis set.  
a. Remission was defined as clinical remission (a Mayo score ≤ 2 with no individual subscore > 1) and rectal bleeding subscore 

of 0.  
b. Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive 

disease) or 1 (erythema, decreased vascular pattern). 
c. Normalisation of endoscopic appearance of the mucosa was defined as a Mayo endoscopic subscore of 0. 
d. Maintenance of clinical response was defined by a decrease from the induction study (OCTAVE Induction 1, OCTAVE 

Induction 2) baseline Mayo score of ≥ 3 points and ≥ 30%, with an accompanying decrease in the rectal bleeding subscore of 
≥ 1 point or rectal bleeding subscore of 0 or 1. Patients were to be in clinical response at baseline of the maintenance study 
OCTAVE Sustain. 

e. Sustained corticosteroid-free remission was defined as being in remission and not taking corticosteroids for at least 4 weeks 
prior to the visit at both week 24 and week 52.  

f. N=59 for placebo, N=65 for tofacitinib 5 mg twice daily, N=55 for tofacitinib 10 mg twice daily. 
g. N=101 for placebo, N=101 for tofacitinib 5 mg twice daily, N=87 for tofacitinib 10 mg twice daily. 
 
In both subgroups of patients with or without prior TNF inhibitor failure, a greater proportion of patients 
treated with either tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily achieved the following 
endpoints at week 52 of OCTAVE Sustain as compared to placebo: remission, improvement of 
endoscopic appearance of the mucosa, or sustained corticosteroid-free remission at both week 24 and 
week 52 among patients in remission at baseline (Table 18). This treatment difference from placebo was 
similar between tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily in the subgroup of patients 



35 
 

Classified as public by the European Medicines Agency 

without prior TNF inhibitor failure. In the subgroup of patients with prior TNF inhibitor failure, the 
observed treatment difference from placebo was numerically greater for tofacitinib 10 mg twice daily than 
tofacitinib 5 mg twice daily by 9.7 to 16.7 percentage points across the primary and key secondary 
endpoints.  
 
Table 18: Proportion of patients meeting primary and key secondary efficacy endpoints at week 52 

by TNF inhibitor therapy subgroup (OCTAVE sustain, central endoscopy read) 
Endpoint Placebo 

N=198 
Tofacitinib 

5 mg 
twice daily 

N=198 

Tofacitinib 
10 mg 

twice daily 
N=197 

Remissiona 
With prior TNF inhibitor failure 10/89 

(11.2%) 
20/83 

(24.1%) 
34/93 

(36.6%) 
Without prior TNF inhibitor failureb 12/109 

(11.0%) 
48/115 
(41.7%) 

46/104 
(44.2%) 

Improvement of endoscopic appearance of the mucosac 
With prior TNF inhibitor failure 11/89 

(12.4%) 
25/83 

(30.1%) 
37/93 

(39.8%) 
Without prior TNF inhibitor failureb 15/109 

(13.8%) 
49/115 
(42.6%) 

53/104 
(51.0%) 

Sustained corticosteroid-free remission at both week 24 and week 52 among patients in remission at 
baselined 

With prior TNF inhibitor failure 1/21 
(4.8%) 

4/18 
(22.2%) 

7/18 
(38.9%) 

Without prior TNF inhibitor failureb 2/38 
(5.3%) 

19/47 
(40.4%) 

19/37 
(51.4%) 

TNF=tumour necrosis factor; N=number of patients in the analysis set.  
a. Remission was defined as clinical remission (a Mayo score ≤ 2 with no individual subscore > 1) and rectal bleeding subscore 

of 0.  
b. Included TNF Inhibitor naïve patients. 
c. Improvement of endoscopic appearance of the mucosa was defined as Mayo endoscopy subscore of 0 (normal or inactive 

disease) or 1 (erythema, decreased vascular pattern). 
d. Sustained corticosteroid-free remission was defined as being in remission and not taking corticosteroids for at least 4 weeks 

prior to the visit at both week 24 and week 52. 
 
The proportion of patients in both tofacitinib groups who had treatment failure was lower compared to 
placebo at each time point as early as week 8, the first time point where treatment failure was assessed, as 
shown in Figure 2.  



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Figure 2. Time to treatment failure in maintenance study OCTAVE sustain (Kaplan-Meier Curves)  

 
p<0.0001 for tofacitinib 5 mg twice daily versus placebo. 
p<0.0001 for tofacitinib 10 mg twice daily versus placebo. 
BID=twice daily. 
Treatment failure was defined as an increase in Mayo score of ≥ 3 points from maintenance study baseline, accompanied by an 
increase in rectal bleeding subscore by ≥ 1 point, and an increase of endoscopic subscore of ≥ 1 point yielding an absolute 
endoscopic subscore of ≥ 2 after a minimum treatment of 8 weeks in the study.  
 
Health-related and quality of life outcomes 
Tofacitinib 10 mg twice daily demonstrated greater improvement from baseline compared to placebo in 
physical component summary (PCS) and mental component summary (MCS) scores, and in all 8 domains 
of the SF-36 in the induction studies (OCTAVE Induction 1, OCTAVE Induction 2). In the maintenance 
study (OCTAVE Sustain), tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily demonstrated 
greater maintenance of improvement compared to placebo in PCS and MCS scores, and in all 8 domains 
of the SF-36 at week 24 and week 52.  
 
Tofacitinib 10 mg twice daily demonstrated greater improvement from baseline compared to placebo at 
week 8 in the total and all 4 domain scores of the Inflammatory Bowel Disease Questionnaire (IBDQ) 
(bowel symptoms, systemic function, emotional function, and social function) in the induction studies 
(OCTAVE Induction 1, OCTAVE Induction 2). In the maintenance study (OCTAVE Sustain), tofacitinib 
5 mg twice daily or tofacitinib 10 mg twice daily demonstrated greater maintenance of improvement 
compared to placebo in the total and all 4 domain scores of the IBDQ at week 24 and week 52. 
 
Improvements were also observed in the EuroQoL 5-Dimension (EQ-5D) and various domains of the 
Work Productivity and Activity Impairment (WPAI-UC) questionnaire in both induction and maintenance 
studies compared to placebo. 
 
Open-label extension study (OCTAVE Open) 
Patients who did not achieve clinical response in one of the induction studies (OCTAVE Induction 1 or 
OCTAVE Induction 2) after 8 weeks of tofacitinib 10 mg twice daily were allowed to enter an open-label 
extension study (OCTAVE Open). After an additional 8 weeks of tofacitinib 10 mg twice daily in 
OCTAVE Open, 53% (154/293) patients achieved clinical response and 14% (42/293) patients achieved 
remission.  
 



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Patients who achieved clinical response in 1 of the induction studies (OCTAVE Induction 1 or OCTAVE 
Induction 2) with tofacitinib 10 mg twice daily but experienced treatment failure after their dose was 
reduced to tofacitinib 5 mg twice daily or following treatment interruption in OCTAVE Sustain (i.e., were 
randomised to placebo), had their dose increased to tofacitinib 10 mg twice daily in OCTAVE Open. After 
8 weeks on tofacitinib 10 mg twice daily in OCTAVE Open, remission was achieved in 35% (20/58) 
patients who received tofacitinib 5 mg twice daily in OCTAVE Sustain and 40% (40/99) patients with 
dose interruption in OCTAVE Sustain. At month 12 in OCTAVE Open, 52% (25/48) and 45% (37/83) of 
these patients achieved remission, respectively.  
 
Furthermore, at month 12 of study OCTAVE Open, 74% (48/65) of patients who achieved remission at 
the end of study OCTAVE Sustain on either tofacitinib 5 mg twice daily or tofacitinib 10 mg twice daily 
remained in remission while receiving tofacitinib 5 mg twice daily. 
 
Paediatric population 
The European Medicines Agency has deferred the obligation to submit results of studies with tofacitinib in 
one or more subsets of the paediatric population in juvenile idiopathic arthritis and in ulcerative colitis 
(see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
The PK profile of tofacitinib is characterised by rapid absorption (peak plasma concentrations are reached 
within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases in systemic 
exposure. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice 
daily administration. 
 
Absorption and distribution 
 
Tofacitinib is well-absorbed, with an oral bioavailability of 74%. Coadministration of tofacitinib with a 
high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, tofacitinib 
was administered without regard to meal. 
 
After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating 
tofacitinib is bound to plasma proteins. Tofacitinib binds predominantly to albumin and does not appear to 
bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. 
 
Biotransformation and elimination 
 
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 radiolabelled study, more than 65% of the total circulating 
radioactivity was accounted for by unchanged active substance, with the remaining 35% attributed to 
8 metabolites, each accounting for less than 8% of total radioactivity. All metabolites have been observed 
in animal species and are predicted to have less than 10-fold potency than tofacitinib for JAK1/3 
inhibition. No evidence of stereo conversion in human samples was detected. The pharmacologic activity 
of tofacitinib is attributed to the parent molecule. In vitro, tofacitinib is a substrate for MDR1, but not for 
breast cancer resistance protein (BCRP), OATP1B1/1B3, or OCT1/2. 
 
Pharmacokinetics in patients 
 
The enzymatic activity of CYP enzymes is reduced in RA patients due to chronic inflammation. In RA 
patients, the oral clearance of tofacitinib does not vary with time, indicating that treatment with tofacitinib 
does not normalise CYP enzyme activity. 
 
Population PK analysis in RA patients indicated that systemic exposure (AUC) of tofacitinib in the 
extremes of body weight (40 kg, 140 kg) were similar (within 5%) to that of a 70 kg patient. Elderly 



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patients 80 years of age were estimated to have less than 5% higher AUC relative to the mean age of 
55 years. Women were estimated to have 7% lower AUC compared to men. The available data have also 
shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. 
An approximate linear relationship between body weight and volume of distribution was observed, 
resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this 
difference is not considered to be clinically relevant. The between-subject variability (percentage 
coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%. 
 
Results from population PK analysis in patients with active PsA or moderate to severe UC were consistent 
with those in patients with RA. 
 
Renal impairment 
 
Subjects with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), 
and severe (creatinine clearance < 30 mL/min) renal impairment had 37%, 43% and 123% higher AUC, 
respectively, compared to subjects with normal renal function (see section 4.2). In subjects with end-stage 
renal disease (ESRD), contribution of dialysis to the total clearance of tofacitinib was relatively small. 
Following a single dose of 10 mg, mean AUC in subjects with ESRD based on concentrations measured 
on a non-dialysis day was approximately 40% (90% confidence intervals: 1.5-95%) higher compared to 
subjects with normal renal function. In clinical trials, tofacitinib was not evaluated in patients with 
baseline creatinine clearance values (estimated by Cockroft-Gault equation) less than 40 mL/min (see 
section 4.2). 
 
Hepatic impairment 
 
Subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had 3%, and 65% 
higher AUC, respectively, compared to subjects with normal hepatic function. In clinical trials, tofacitinib 
was not evaluated in subjects with severe (Child Pugh C) hepatic impairment (see sections 4.2 and 4.4), or 
in patients screened positive for hepatitis B or C. 
 
Drug interactions 
 
Tofacitinib is not an inhibitor or inducer of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4) and is not an inhibitor of UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and 
UGT2B7). Tofacitinib is not an inhibitor of MDR1, OATP1B1/1B3, OCT2, OAT1/3, or MRP at clinically 
meaningful concentrations. 
 
5.3 Preclinical safety data 
 
In non-clinical studies, effects were observed on the immune and haematopoietic systems that were 
attributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects from 
immunosuppression, such as bacterial and viral infections and lymphoma were observed at clinically 
relevant doses. Lymphoma was observed in 3 of 8 adult monkeys at 6 or 3 times the clinical tofacitinib 
exposure level (unbound AUC in humans at a dose of 5 mg or 10 mg twice daily), and 0 of 14 juvenile 
monkeys at 5 or 2.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Exposure in monkeys 
at the no observed adverse effect level (NOAEL) for the lymphomas was approximately 1 or 0.5 times the 
clinical exposure level of 5 mg or 10 mg twice daily. Other findings at doses exceeding human exposures 
included effects on the hepatic and gastrointestinal systems. 
 
Tofacitinib is not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for 
gene mutations and chromosomal aberrations. 
 
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity 
and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice at exposures up to 38 or 
19 times the clinical exposure level at 5 mg or 10 mg twice daily. Benign testicular interstitial (Leydig) 



39 
 

Classified as public by the European Medicines Agency 

cell tumours were observed in rats: benign Leydig cell tumours in rats are not associated with a risk of 
Leydig cell tumours in humans. Hibernomas (malignancy of brown adipose tissue) were observed in 
female rats at exposures greater than or equal to 83 or 41 times the clinical exposure level at 5 mg or 
10 mg twice daily. Benign thymomas were observed in female rats at 187 or 94 times the clinical exposure 
level at 5 mg or 10 mg twice daily. 
 
Tofacitinib was shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility 
(decreased pregnancy rate; decreases in the numbers of corpora lutea, implantation sites, and viable 
foetuses; and an increase in early resorptions), parturition, and peri/postnatal development. Tofacitinib had 
no effects on male fertility, sperm motility or sperm concentration. Tofacitinib was secreted in milk of 
lactating rats at concentrations approximately 2-fold those in serum from 1 to 8 hours postdose. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
microcrystalline cellulose 
lactose monohydrate 
croscarmellose sodium 
magnesium stearate 
 
Film coat 
 
hypromellose 6cP (E464) 
titanium dioxide (E171) 
lactose monohydrate 
macrogol 3350 
triacetin (E1518) 
FD&C Blue #2/Indigo Carmine Aluminum Lake (E132) (10 mg strength only)  
FD&C Blue #1/Brilliant Blue FCF Aluminum Lake (E133) (10 mg strength only) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. 
 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
XELJANZ 5 mg film-coated tablets 
 
HDPE bottles with silica gel desiccant and child-resistant polypropylene closure containing 60 or 
180 film-coated tablets. 
 



40 
 

Classified as public by the European Medicines Agency 

Aluminium foil/PVC backed aluminium foil blisters containing 14 film-coated tablets. Each pack contains 
56, 112, or 182 film-coated tablets. 
 
XELJANZ 10 mg film-coated tablets 
 
HDPE bottles with silica gel desiccant and child-resistant polypropylene closure containing 60 or 
180 film-coated tablets. 
 
Aluminium foil/PVC backed aluminium foil blisters containing 14 film-coated tablets. Each pack contains 
56, 112, or 182 film-coated tablets. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1178/001 
EU/1/17/1178/002 
EU/1/17/1178/003 
EU/1/17/1178/004 
EU/1/17/1178/005 
EU/1/17/1178/006 
EU/1/17/1178/007 
EU/1/17/1178/008 
EU/1/17/1178/009 
EU/1/17/1178/014 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 March 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


41 
 

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This medicinal product is subject to additional monitoring. This will allow quick identification of new 
safety information. Healthcare professionals are asked to report any suspected adverse reactions. See 
section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 11 mg prolonged-release tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each prolonged-release tablet contains tofacitinib citrate, equivalent to 11 mg tofacitinib. 
 
Excipient with known effect 
 
Each prolonged-release tablet contains 152.23 mg of sorbitol. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Prolonged-release tablets 
 
Pink, oval tablet of approximate average dimension of 10.8 mm × 5.5  mm × 4.4 mm (length by width by 
thickness) with a drilled hole at one end of the tablet band and “JKI 11” printed on one side of the tablet. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indication 
 
Tofacitinib 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. 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). 
 
4.2 Posology and method of administration 
 
Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and 
treatment of rheumatoid arthritis. 
 
Posology 
 
The recommended dose is one 11 mg prolonged-release tablet administered once daily, which should not 
be exceeded. 
 
Switching between tofacitinib 11 mg prolonged-release tablets and tofacitinib 5mg film-coated tablets 
Patients treated with tofacitinib 5 mg film-coated tablets twice daily may be switched to tofacitinib 11 mg 
prolonged-release tablets once daily on the day following the last dose of tofacitinib 5 mg film-coated 
tablets.  
 



42 
 

Classified as public by the European Medicines Agency 

Patients treated with tofacitinib 11 mg prolonged-release tablets once daily may be switched to tofacitinib 
5 mg film-coated tablets twice daily on the day following the last dose of tofacitinib 11 mg prolonged-
release tablets. 
 
Tofacitinib 11 mg prolonged-release tablets once daily has demonstrated pharmacokinetic equivalence 
(AUC and Cmax) to tofacitinib 5 mg film-coated tablets twice daily.  
 
Dose adjustment  
No dose adjustment is required when used in combination with MTX. 
 
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. As described in Tables 1, 2 and 3 below, recommendations for 
temporary dose interruption or permanent discontinuation of treatment are made according to the severity 
of laboratory abnormalities (see section 4.4). 
 
It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 
750 cells/mm3. 
 
Table 1: Low absolute lymphocyte count 

Low absolute lymphocyte count (ALC) (see section 4.4) 
Lab value 
(cells/mm3) 

Recommendation 

ALC greater than or equal 
to 750 

Dose should be maintained. 

ALC 500-750 For persistent (2 sequential values in this range on routine testing) 
decrease in this range, tofacitinib 11 mg prolonged-release dosing 
should be interrupted until ALC is greater than 750.  
 
When ALC is greater than 750, treatment should be resumed as 
clinically appropriate. 

ALC less than 500 
 

If lab value confirmed by repeat testing within 7 days, dosing should 
be discontinued. 

 
It is recommended not to initiate dosing in patients with an absolute neutrophil count (ANC) less than 
1,000 cells/mm3. 
 
Table 2: Low absolute neutrophil count 

Low absolute neutrophil count (ANC) (see section 4.4) 
Lab Value 
(cells/mm3) 

Recommendation 

ANC greater than 1,000 Dose should be maintained. 
ANC 500-1,000 For persistent (2 sequential values in this range on routine testing) 

decreases in this range, tofacitinib 11 mg prolonged-release dosing 
should be interrupted until ANC is greater than 1,000. 
 
When ANC is greater than 1,000, treatment should be resumed as 
clinically appropriate. 

ANC less than 500 
 

If lab value confirmed by repeat testing within 7 days, dosing should 
be discontinued.  



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It is recommended not to initiate dosing in patients with haemoglobin less than 9 g/dL. 
 
Table 3: Low haemoglobin value 

Low haemoglobin value (Section 4.4) 
Lab Value 

(g/dL) 
Recommendation 

Less than or equal to 2 g/dL 
decrease and greater than or 
equal to 9.0 g/dL 

Dose should be maintained. 

Greater than 2 g/dL 
decrease or less than 
8.0 g/dL 
(confirmed by repeat 
testing) 

Dosing should be interrupted until haemoglobin values have 
normalised. 

 
Drug-drug interactions 
Tofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors of cytochrome 
P450 (CYP) 3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitant medicinal products 
that result in both moderate inhibition of CYP3A4 as well as potent inhibition of CYP2C19 (e.g., 
fluconazole) (see section 4.5). 
 
Tofacitinib dose should be reduced to 5 mg film-coated tablet once daily in patients receiving 11 mg 
prolonged-release tablet once daily. 
 
Special populations 
 
Elderly 
No dose adjustment is required in patients aged 65 years and older. There are limited data in patients aged 
75 years and older. 
 
Hepatic impairment 
  
Table 4:  Dose adjustment for hepatic impairment  
Hepatic 
impairment 
category 

Classification Dose adjustment in hepatic impairment for different 
strength tablets 

Mild Child Pugh A No dose adjustment required. 
Moderate Child Pugh B Dose should be reduced to 5 mg film-coated tablets once 

daily when the indicated dose in the presence of normal 
hepatic function is 11 mg prolonged-release tablet once 
daily (see section 5.2). 

Severe Child Pugh C Tofacitinib should not be used in patients with severe 
hepatic impairment (see section 4.3). 

 



44 
 

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Renal impairment 
  
Table 5:  Dose adjustment for renal impairment  
Renal 
impairment 
category 

Creatinine 
clearance 

Dose adjustment in renal impairment for different 
strength tablets 

Mild 50-80 mL/min No dose adjustment required. 
Moderate 30-49 mL/min No dose adjustment required. 
Severe (including 
patients 
undergoing 
haemodialysis) 

< 30 mL/min Dose should be reduced to 5 mg film-coated tablet once 
daily when the indicated dose in the presence of normal 
renal function is 11 mg prolonged-release tablet once 
daily (see section 5.2). 
 
Patients with severe renal impairment should remain on a 
reduced dose even after haemodialysis (see section 5.2). 

 
Paediatric population 
The safety and efficacy of tofacitinib in children aged 0 to less than 18 years have not been established. 
 
No data are available. 
 
Method of administration 
 
Oral use.  
 
Tofacitinib is given orally with or without food. 
 
Tofacitinib 11 mg prolonged-release tablets must be taken whole in order to ensure the entire dose is 
delivered correctly. They must not be crushed, split or chewed. 
 
4.3 Contraindications 
 
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
• Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections (see 

section 4.4). 
• Severe hepatic impairment (see section 4.2). 
• Pregnancy and lactation (see section 4.6). 
 
4.4 Special warnings and precautions for use 
 
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, 
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. 
 



45 
 

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Venous thromboembolism (VTE)  
 
Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep vein 
thrombosis (DVT), have been observed in patients taking tofacitinib. A dose dependent increased risk for 
VTE was observed in a clinical study with tofacitinib compared to TNF inhibitors (see sections 4.8 and 
5.1). 
 
Tofacitnib should be used with caution in patients with known risk factors for VTE, regardless of 
indication and dosage.  
 
VTE risk factors include previous VTE, patients undergoing major surgery, immobilisation, myocardial 
infarction (within previous 3 months), heart failure, use of combined hormonal contraceptives or hormone 
replacement therapy, inherited coagulation disorder, malignancy. Additional VTE risk factors such as age, 
obesity (BMI ≥30), diabetes, hypertension, smoking status should also be considered. Patients should be 
re-evaluated periodically during tofacitinib treatment to assess for changes in VTE risk. 
 
Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patients with 
suspected VTE, regardless of dose or indication. 
 
Serious infections 
 
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). Rheumatoid arthritis patients taking 
corticosteroids may be predisposed to infection. 
 
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, 
• who are over 65 years of age 

 
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 (see section 4.8). In patients 
over 65 years of age tofacitinib should only be considered if no suitable alternative treatment is available 
(see section 5.1). 
 
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. Discontinuation and 
monitoring criteria for lymphopenia are discussed in section 4.2. 
 



46 
 

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Tuberculosis 
 
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 
 
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). 
• Patients with long standing RA who have previously received two or more biological disease 

modifying antirheumatic drugs (DMARDs).  
• 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. 
 
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 



47 
 

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skin examination is recommended for patients who are at increased risk for skin cancer (see Table 6 in 
section 4.8). 
 
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. 
 
Gastrointestinal perforations 
 
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. 
 
Cardiovascular risk 
 
RA 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. 
 
Liver enzymes 
 
Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation in some 
patients (see section 4.8 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. 
 
Hypersensitivity 
 
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 
 
Lymphocytes 
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. For recommended modifications based on lymphocyte counts (see section 4.2). 
 
Neutrophils 
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 



48 
 

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with an 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. For recommended modifications based on ANC (see section 4.2). 
 
Haemoglobin 
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. For recommended modifications based on haemoglobin level (see section 4.2). 
 
Lipid monitoring 
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 pretreatment levels with statin therapy. 
 
Vaccinations 
 
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. Particular 
consideration should be given to patients with longstanding RA who have previously received two or 
more biological DMARDs. 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. 
 
Gastrointestinal obstruction with a non-deformable prolonged-release formulation 
 
Caution should be used when administering tofacitinib 11 mg prolonged-release tablets to patients with 
pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of 
obstructive symptoms in patients with known strictures in association with the ingestion of other 
medicinal products utilising a non-deformable prolonged-release formulation. 
 
Excipients with known effect 
 
Tofacitinib 11 mg prolonged-release tablets contains sorbitol. The additive effect of concomitantly 
administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should 
be taken into account. 
 
The content of sorbitol in medicinal products for oral use may affect the bioavailability of other medicinal 
products for oral use administered concomitantly. 
 



49 
 

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4.5 Interaction with other medicinal products and other forms of interaction 
 
Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib 
 
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) (see 
section 4.2). 
 
Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). 
Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib. 
 
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 (see Figure 1). 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. Concomitant administration with 
MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1). 
 
Figure 1. Impact of other medicinal products on PK of tofacitinib 

 

Note: Reference group is administration of tofacitinib alone. 
a Tofacitinib dose should be reduced to 5 mg (as film-coated  tablet) once daily in patients receiving 11 mg (as prolonged-release 

tablet) once daily (see section 4.2). 
 

0 0.5 1 1.5 2 2.5 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC 

Cmax 
AUC CYP3A Inhibitor Ketoconazole 

CYP3A & CYP2C19 Inhibitor 
Fluconazole 

CYP Inducer 
Rifampicin 

Methotrexate 

Tacrolimus 

Ciclosporine 

Tofacitinib dose should be reduced a 
 

Tofacitinib dose should be reduced a 
 

Efficacy may be decreased 

No dose adjustment 

Combined use of tofacitinib with  
tacrolimus should be avoided 

Combined use of tofacitinib with  
 ciclosporine should be avoided 

Ratio relative to reference 

Coadministered 
Drug 

PK  Ratio and 90% CI Recommendation 



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Potential for tofacitinib to influence the PK of other medicinal products 
 
Coadministration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestrel and 
ethinyl estradiol, in healthy female volunteers. 
 
In RA patients, coadministration of tofacitinib with MTX 15-25 mg once weekly decreased the AUC and 
Cmax of MTX by 10% and 13%, respectively. The extent of decrease in MTX exposure does not warrant 
modifications to the individualised dosing of MTX. 
 
4.6 Fertility, pregnancy and lactation 
 
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 (see section 5.3). 
 
As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (see section 4.3). 
 
Women of childbearing potential/contraception in females 
 
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. 
 
Breast-feeding 
 
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 (see section 5.3). As a precautionary 
measure, the use of tofacitinib during breast-feeding is contraindicated (see section 4.3). 
 
Fertility 
 
Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired 
female fertility but not male fertility in rats (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Tofacitinib has no or negligible influence on the ability to drive and use machines. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
 
The most common serious adverse reactions were serious infections (see section 4.4). The most common 
serious infections reported with tofacitinib were pneumonia, cellulitis, herpes zoster, urinary tract 
infection, diverticulitis, and appendicitis. Among opportunistic infections, TB and other mycobacterial 
infections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster, 
cytomegalovirus, BK virus infections and listeriosis were reported with tofacitinib. Some patients have 
presented with disseminated rather than localised disease. Other serious infections that were not reported 
in clinical studies may also occur (e.g., coccidioidomycosis). 
 
The most commonly reported adverse reactions during the first 3 months in controlled clinical trials were 
headache, upper respiratory tract infections, nasopharyngitis, diarrhoea, nausea and hypertension (see 
Table 6, Adverse Drug Reactions [ADRs] based on all study durations). 
 



51 
 

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The proportion of patients who discontinued treatment due to adverse reactions during first 3 months of 
the double-blind, placebo or MTX controlled studies was 3.8% for patients taking tofacitinib. The most 
common infections resulting in discontinuation of therapy were herpes zoster and pneumonia. 
 
Tabulated list of adverse reactions 
 
The ADRs listed in the table below are from clinical studies in patients with RA, PsA, and UC and are 
presented by System Organ Class (SOC) and frequency categories, defined using the following 
convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare 
(≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), or not known (cannot be estimated from the available 
data). Within each frequency grouping, undesirable effects are presented in order of decreasing 
seriousness. 
 
Table 6: Adverse drug reactions 

System organ 
class 

Common 
≥1/100 to <1/10 

 

Uncommon 
≥1/1,000 to 

<1/100 

Rare 
≥1/10,000 to 

<1/1,000 

Very rare 
<1/10,000 

Not known 
(cannot be 

estimated from 
the available 

data) 
Infections and 
infestations 

Pneumonia 
Influenza 
Herpes zoster 
Urinary tract 
infection 
Sinusitis 
Bronchitis 
Nasopharyngitis 
Pharyngitis 

Tuberculosis  
Diverticulitis 
Pyelonephritis 
Cellulitis 
Herpes simplex 
Gastroenteritis viral 
Viral infection  
 
 

Sepsis 
Urosepsis 
Disseminated 
TB 
Necrotizing 
fasciitis 
Bacteraemia 
Staphylococcal 
bacteraemia 
Pneumocystis 
jirovecii  
pneumonia 
Pneumonia 
pneumococcal 
Pneumonia 
bacterial 
Encephalitis 
Atypical 
mycobacterial 
infection 
Cytomegaloviru
s infection 
Arthritis 
bacterial 

Tuberculosis of 
central nervous 
system 
Meningitis 
cryptococcal 
Mycobacterium 
avium complex 
infection 
 

 

Neoplasms benign, 
malignant and 
unspecified (incl 
cysts and polyps) 

 Non-melanoma skin 
cancers 

   

Blood and 
lymphatic system 
disorders 

Anaemia Leukopenia 
Lymphopenia 
Neutropenia 

   

Immune system 
disorders 

    Drug 
hypersensitivity* 
Angioedema* 
Urticaria* 

Metabolism and 
nutrition disorders 

 Dyslipidaemia 
Hyperlipidaemia 
Dehydration 

   

Psychiatric 
disorders 

 Insomnia    

Nervous system 
disorders 

Headache Paraesthesia    

Vascular disorders Hypertension Venous 
thromboembolism** 

   



52 
 

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System organ 
class 

Common 
≥1/100 to <1/10 

 

Uncommon 
≥1/1,000 to 

<1/100 

Rare 
≥1/10,000 to 

<1/1,000 

Very rare 
<1/10,000 

Not known 
(cannot be 

estimated from 
the available 

data) 
Respiratory, 
thoracic and 
mediastinal 
disorders 

Cough Dyspnoea 
Sinus congestion 

   

Gastrointestinal 
disorders 

Abdominal pain 
Vomiting 
Diarrhoea 
Nausea 
Gastritis 
Dyspepsia 

    

Hepatobiliary 
disorders 

 Hepatic steatosis 
Hepatic enzyme  
increased 
Transaminases 
increased 
Liver function test 
abnormal 
Gamma glutamyl-
transferase increased 
 

   

Skin and 
subcutaneous 
tissue disorders 

Rash Erythema 
Pruritus 

   

Musculoskeletal 
and connective 
tissue disorders  

Arthralgia Musculoskeletal pain 
Joint swelling 
Tendonitis 

   

General disorders 
and administration 
site conditions  

Pyrexia 
Oedema 
peripheral 
Fatigue 

    

Investigations  
 

Blood creatine 
phosphokinase 
increased 

Blood creatinine 
increased 
Blood cholesterol 
increased 
Low density 
lipoprotein increased 
Weight increased 

   

Injury, poisoning 
and procedural 
complications 

 Ligament sprain 
Muscle strain 

   

*Spontaneous reporting data 
**Venous thromboembolism includes PE and DVT 
 
Description of selected adverse reactions 
 
Venous thromboembolism 
 
In a large, randomised post-authorisation safety surveillance study of rheumatoid arthritis patients who 
were 50 years of age and older and had at least one cardiovascular (CV) risk factor, VTE was observed at 
an increased and dose-dependent incidence in patients treated with tofacitinib compared to TNF inhibitors. 
The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE 
for tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, and TNF inhibitors were 0.54 (0.32-0.87), 
0.27 (0.12-0.52), and 0.09 (0.02-0.26) patients with events per 100 patient-years, respectively. Compared 
with TNF inhibitors, the hazard ratio (HR) for PE was 5.96 (1.75-20.33) and 2.99 (0.81-11.06) for 
tofacitinib 10 mg twice daily and tofacitinib 5 mg twice daily, respectively (see section 5.1).  
 



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In a subgroup analysis in patients with VTE risk factors in the above-mentioned study, the risk for PE was 
further increased. Compared with TNF inhibitors, the HR for PE was 9.14 (2.11-39.56) for tofacitinib 
10 mg twice daily and 3.92 (0.83-18.48) for tofacitinib 5 mg twice daily. 
 
Overall infections 
 
In controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg film-coated 
tablets twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) tofacitinib monotherapy 
groups were 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) 
in the placebo group (total 122 patients). In controlled phase 3 clinical studies with background DMARDs, 
the rates of infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twice daily 
(total 969 patients) tofacitinib plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), 
respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients). 
 
The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% 
and 3.2%, respectively). 
 
The overall incidence rate of infections with tofacitinib in the long-term safety all exposure population 
(total 4,867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with 
events for 5 mg and 10 mg twice daily, respectively). For patients (total 1,750) on monotherapy, the rates 
were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, 
respectively. For patients (total 3,117) on background DMARDs, the rates were 41.0 and 50.3 patients 
with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. 
 
Serious infections 
 
In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice 
daily tofacitinib monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice 
daily tofacitinib monotherapy group the rate was 1.6 patients with events per 100 patient-years, the rate 
was 0 events per 100 patient-years for the placebo group, and the rate was 1.9 patients with events per 
100 patient-years for the MTX group. 
 
In studies of 6-, 12-, or 24-month duration, the rates of serious infections in the 5 mg twice daily and 
10 mg twice daily tofacitinib plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-
years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus 
DMARD group. 

In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 
3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily tofacitinib groups, 
respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract 
infection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have been reported 
(see section 4.4). 
 
Viral reactivation 
 
Patients treated with tofacitinib who are Japanese or Korean, or patients with long standing RA who have 
previously received two or more biological DMARDs, or patients with an ALC less than 1,000 cells/mm3, 
or patients treated with 10 mg twice daily may have an increased risk of herpes zoster (see section 4.4). 
 



54 
 

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Laboratory tests 
 
Lymphocytes 
In the controlled RA clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in 0.3% 
of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twice daily and 
10 mg twice daily doses combined. 
 
In the RA long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in 
1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twice daily 
and 10 mg twice daily doses combined. 
 
Confirmed ALC less than 750 cells/mm3 were associated with an increased incidence of serious infections 
(see section 4.4). 
 
Neutrophils 
In the controlled RA clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 
0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no 
confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear 
relationship between neutropenia and the occurrence of serious infections. 
 
In the RA long-term safety population, the pattern and incidence of confirmed decreases in ANC remained 
consistent with what was seen in the controlled clinical studies (see section 4.4). 
 
Liver enzyme tests 
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were 
uncommonly observed in RA patients. In those patients experiencing liver enzyme elevation, modification 
of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or 
reduction in tofacitinib dose, resulted in decrease or normalisation of liver enzymes. 
 
In the controlled portion of the RA phase 3 monotherapy study (0-3 months) (study I, see section 5.1), 
ALT elevations greater than 3x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving 
placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 
3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, tofacitinib 5 mg and 10 mg 
twice daily, respectively. 
 
In the RA phase 3 monotherapy study (0-24 months) (study VI, see section 5.1), ALT elevations greater 
than 3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving MTX, tofacitinib 5 mg and 
10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 
3.3%, 1.6% and 1.5% of patients receiving MTX, tofacitinib 5 mg and 10 mg twice daily, respectively. 
 
In the controlled portion of the RA phase 3 studies on background DMARDs (0-3 months) (studies II-V, 
see section 5.1), ALT elevations greater than 3x ULN were observed in 0.9%, 1.24% and 1.14% of 
patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In these studies, AST 
elevations greater than 3x ULN were observed in 0.72%, 0.5% and 0.31% of patients receiving placebo, 
tofacitinib 5 mg and 10 mg twice daily, respectively. 
 
In the RA long-term extension studies, on monotherapy, ALT elevations greater than 3x ULN were 
observed in 1.1% and 1.4% of patients receiving tofacitinib 5 mg and 10 mg twice daily, respectively. 
AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg and 10 mg 
twice daily groups. 
 
In the RA long-term extension studies, on background DMARDs, ALT elevations greater than 3x ULN 
were observed in 1.8% and 1.6% of patients receiving tofacitinib 5 mg and 10 mg twice daily, 
respectively. AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg 
and 10 mg twice daily groups.  



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Lipids 
Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were 
first assessed at 1 month following initiation of tofacitinib in the controlled double-blind clinical trials of 
RA. Increases were observed at this time point and remained stable thereafter. 
 
Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled 
clinical studies in RA are summarised below: 
 
• Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 20% in the 

tofacitinib 10 mg twice daily arm at month 12, and increased by 16% in the tofacitinib 5 mg twice 
daily arm and 19% in the tofacitinib 10 mg twice daily arm at month 24. 

• Mean HDL cholesterol increased by 17% in the tofacitinib 5 mg twice daily arm and 18% in the 
tofacitinib 10 mg twice daily arm at month 12, and increased by 19% in the tofacitinib 5 mg twice 
daily arm and 20% in the tofacitinib 10 mg twice daily arm at month 24. 

 
Upon withdrawal of tofacitinib treatment, lipid levels returned to baseline. 
 
Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 ratios were 
essentially unchanged in tofacitinib-treated patients. 
 
In an RA controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment 
levels in response to statin therapy. 
 
In the RA long-term safety populations, elevations in the lipid parameters remained consistent with what 
was seen in the controlled clinical studies. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows 
continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are 
asked to report any suspected adverse reactions via the national reporting system listed in Appendix V. 
 
4.9 Overdose 
 
In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse 
reactions. There is no specific antidote for overdose with tofacitinib. Treatment should be symptomatic 
and supportive. 
 
Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate that more 
than 95% of the administered dose is expected to be eliminated within 24 hours. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic groups: Immunosuppressants, Selective Immunosuppressants; ATC code: L04AA29 
 
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 

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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. 
 
Pharmacodynamic effects 
 
In patients with RA, treatment up to 6 months with tofacitinib was associated with dose-dependent 
reductions of circulating CD16/56+ natural killer (NK) cells, with estimated maximum reductions 
occurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolved within 
2-6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated with dose-
dependent increases in B cell counts. Changes in circulating T-lymphocyte counts and T-lymphocyte 
subsets (CD3+, CD4+ and CD8+) were small and inconsistent. 
 
Following long-term treatment (median duration of tofacitinib treatment of approximately 5 years), CD4+ 
and CD8+ counts showed median reductions of 28% and 27%, respectively, from baseline. In contrast to 
the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showed a median 
increase of 73% from baseline. CD19+ B cell counts showed no further increases after long-term 
tofacitinib treatment. All these lymphocyte subset changes returned toward baseline after temporary 
discontinuation of treatment. There was no evidence of a relationship between serious or opportunistic 
infections or herpes zoster and lymphocyte subset counts (see section 4.2 for absolute lymphocyte count 
monitoring). 
 
Changes in total serum IgG, IgM, and IgA levels over 6-month tofacitinib dosing in patients with RA were 
small, not dose-dependent and similar to those seen on placebo, indicating a lack of systemic humoral 
suppression. 
 
After treatment with tofacitinib in RA patients, rapid decreases in serum C-reactive protein (CRP) were 
observed and maintained throughout dosing. Changes in CRP observed with tofacitinib treatment do not 
reverse fully within 2 weeks after discontinuation, indicating a longer duration of pharmacodynamic 
activity compared to the half-life. 
 
Vaccine studies 
 
In a controlled clinical trial of patients with RA initiating tofacitinib 10 mg twice daily or placebo, the 
number of responders to influenza vaccine was similar in both groups: tofacitinib (57%) and placebo 
(62%). For pneumococcal polysaccharide vaccine the number of responders was as follows: 32% in 
patients receiving both tofacitinib and MTX; 62% for tofacitinib monotherapy; 62% for MTX 
monotherapy; and 77% for placebo. The clinical significance of this is unknown, however, similar results 
were obtained in a separate vaccine study with influenza and pneumococcal polysaccharide vaccines in 
patients receiving long-term tofacitinib 10 mg twice daily. 
 
A controlled study was conducted in patients with RA on background MTX immunised with a live 
attenuated virus vaccine (Zostavax®) 2 to 3 weeks before initiating a 12-week treatment with tofacitinib 
5 mg twice daily or placebo. Evidence of humoral and cell-mediated responses to VZV was observed in 
both tofacitinib and placebo-treated patients at 6 weeks. These responses were similar to those observed in 
healthy volunteers aged 50 years and older. A patient with no previous history of varicella infection and 
no anti-varicella antibodies at baseline experienced dissemination of the vaccine strain of varicella 
16 days after vaccination. Tofacitinib was discontinued and the patient recovered after treatment with 
standard doses of antiviral medication. This patient subsequently made a robust, though delayed, humoral 
and cellular response to the vaccine (see section 4.4). 
 



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Clinical efficacy and safety 
 
The efficacy and safety of tofacitinib were assessed in 6 randomised, double-blind, controlled multicentre 
studies in patients greater than 18 years of age with active RA diagnosed according to American College 
of Rheumatology (ACR) criteria. Table 7 provides information regarding the pertinent study design and 
population characteristics. 
 
Table 7: Phase 3 clinical trials of tofacitinib 5 mg and 10 mg twice daily doses in patients with RA 

Studies Study I 
(ORAL 

Solo) 

Study II 
(ORAL 
Sync) 

Study III 
(ORAL 

Standard) 

Study IV 
(ORAL 
Scan) 

Study V 
(ORAL 
Step) 

Study VI 
(ORAL 
Start) 

Study VII 
(ORAL 

Strategy) 
Population DMARD-IR DMARD-IR MTX-IR MTX-IR TNFi-IR MTX-naïvea MTX-IR 
Control Placebo Placebo Placebo Placebo Placebo MTX MTX, 

ADA 
Background 
treatment 

Noneb csDMARDs MTX MTX MTX Noneb 3 Parallel arms: 
• Tofacitinib 

monotherapy 
• Tofacitinib+MTX 
• ADA+MTX 

Key features Monotherapy Various 
csDMARDs 

Active 
control 
(ADA) 

X-Ray TNFi-IR Monotherapy, 
Active 
comparator 
(MTX),  
X-Ray 

Tofacitinib with and 
without MTX in 
comparison to ADA 
with MTX 

Number of 
patients 
treated 

610 792 717 797 399 956 1,146 

Total study 
duration 

6 months 1 year 1 year 2 years 6 months 2 years 1 year 

Co-primary 
efficacy 
endpointsc 

Month 3: 
ACR20 
HAQ-DI 
DAS28-
4(ESR)<2.6 

Month 6: 
ACR20 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 6: 
ACR20 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 6: 
ACR20 
mTSS 
DAS28-
4(ESR)<2.6 
Month 3: 
HAQ-DI 

Month 3: 
ACR20 
HAQ-DI 
DAS28-
4(ESR)<2.6 

Month 6: 
mTSS 
ACR70 
 

Month 6: 
ACR50 

Time of 
mandatory 
placebo rescue 
to tofacitinib 
5 mg or 10 mg 
twice daily 

Month 3 Month 6 (placebo subjects with < 20% 
improvement in swollen and tender joint 
counts advanced to tofacitinib at month 3) 

Month 3 NA NA 

a. ≤3 weekly doses (MTX-naïve). 
b.Antimalarials were allowed. 
c. Co-primary endpoints as follows: mean change from baseline in mTSS; percent of subjects achieving ACR20 or ACR70 

responses; mean change from baseline in HAQ-DI; percent of subjects achieving a DAS28-4(ESR) <2.6 (remission). 
mTSS=modified Total Sharp Score, ACR20(70)=American College of Rheumatology ≥20% (≥70%) improvement, 
DAS28=Disease Activity Score 28 joints, ESR=Erythrocyte Sedimentation Rate, HAQ-DI=Health Assessment Questionnaire 
Disability Index, DMARD=disease-modifying antirheumatic drug, IR=inadequate responder, csDMARD=conventional synthetic 
DMARD, TNFi=tumour necrosis factor inhibitor, NA=not applicable, ADA=adalimumab, MTX=methotrexate. 
 



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Clinical response 
 
ACR response 
The percentages of tofacitinib-treated patients achieving ACR20, ACR50 and ACR70 responses in studies 
ORAL Solo, ORAL Sync, ORAL Standard, ORAL Scan, ORAL Step, ORAL Start, and ORAL Strategy 
are shown in Table 8. In all studies, patients treated with either 5 mg or 10 mg twice daily tofacitinib had 
statistically significant ACR20, ACR50 and ACR70 response rates at month 3 and month 6 versus placebo 
(or versus MTX in ORAL Start) treated patients. 
 
Over the course of ORAL Strategy, responses with tofacitinib 5 mg twice daily + MTX were numerically 
similar compared to adalimumab 40 mg + MTX and both were numerically higher than tofacitinib 5 mg 
twice daily. 
 
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, or 
disease status. Time to onset was rapid (as early as week 2 in studies ORAL Solo, ORAL Sync, and 
ORAL Step) and the magnitude of response continued to improve with duration of treatment. As with the 
overall ACR response in patients treated with 5 mg or 10 mg twice daily tofacitinib, each of the 
components of the ACR response was consistently improved from baseline including: tender and swollen 
joint counts; patient and physician global assessment; disability index scores; pain assessment and CRP 
compared to patients receiving placebo plus MTX or other DMARDs in all studies. 
 
Table 8:  Proportion (%) of patients with an ACR response  

ORAL Solo: DMARD inadequate responders 

Endpoint Time Placebo N=122 

Tofacitinib 5 mg twice 
daily monotherapy  

N=241 

Tofacitinib 10 mg 
twice daily 

monotherapy 
N=243 

ACR20 Month 3 26 60*** 65*** Month 6 NA 69 71 

ACR50 Month 3 12 31*** 37*** Month 6 NA 42 47 

ACR70 Month 3 6 15* 20*** Month 6 NA 22 29 
ORAL Sync: DMARD inadequate responders 

Endpoint Time 
Placebo + DMARD(s) 

 
N=158 

Tofacitinib 5 mg twice 
daily + DMARD(s) 

N=312 

Tofacitinib 10 mg 
twice daily + 
DMARD(s) 

N=315 

ACR20 
Month 3 27 56*** 63*** 
Month 6 31 53*** 57*** 

Month 12 NA 51 56 

ACR50 
Month 3 9 27*** 33*** 
Month 6 13 34*** 36*** 

Month 12 NA 33 42 

ACR70 
Month 3 2 8** 14*** 
Month 6 3 13*** 16*** 

Month 12 NA 19 25 



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ORAL Standard: MTX inadequate responders 

Endpoint Time Placebo 
Tofacitinib 

twice daily + MTX 
Adalimumab 40 mg 

QOW 
+ MTX 

ACR20 

  
N=105 

5 mg 
N=198 

10 mg 
N=197 

 
N=199 

Month 3 26 59*** 57*** 56*** 
Month 6 28 51*** 51*** 46** 

Month 12 NA 48 49 48 

ACR50 
Month 3 7 33*** 27*** 24*** 
Month 6 12 36*** 34*** 27** 

Month 12 NA 36 36 33 

ACR70 
Month 3 2 12** 15*** 9* 
Month 6 2 19*** 21*** 9* 

Month 12 NA 22 23 17 
ORAL Scan: MTX inadequate responders 

Endpoint Time Placebo + MTX N=156 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=316 

Tofacitinib 10 mg 
twice daily 

 + MTX 
N=309 

ACR20 

Month 3 27 55*** 66*** 
Month 6 25 50*** 62*** 

Month 12 NA 47 55 
Month 24 NA 40 50 

ACR50 

Month 3 8 28*** 36*** 
Month 6 8 32*** 44*** 

Month 12 NA 32 39 
Month 24 NA 28 40 

ACR70 

Month 3 3 10** 17*** 
Month 6 1 14*** 22*** 

Month 12 NA 18 27 
Month 24 NA 17 26 

ORAL Step: TNF inhibitor inadequate responders 

Endpoint Time Placebo + MTX N=132 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=133 

Tofacitinib 10 mg 
twice daily 

 + MTX 
N=134 

ACR20 Month 3 24 41* 48*** Month 6 NA 51 54 

ACR50 Month 3 8 26*** 28*** Month 6 NA 37 30 

ACR70 Month 3 2 14*** 10* Month 6 NA 16 16 



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ORAL Start: MTX-naïve 

Endpoint Time MTX N=184 

Tofacitinib 5 mg twice 
daily monotherapy 

N=370 

Tofacitinib 10 mg 
twice daily 

monotherapy 
N=394 

ACR20 

Month 3 52 69*** 77*** 
Month 6 51 71*** 75*** 

Month 12 51 67** 71*** 
Month 24 42 63*** 64*** 

ACR50 

Month 3 20 40*** 49*** 
Month 6 27 46*** 56*** 

Month 12 33 49** 55*** 
Month 24 28 48*** 49*** 

ACR70 

Month 3 5 20*** 26*** 
Month 6 12 25*** 37*** 

Month 12 15 28** 38*** 
Month 24 15 34*** 37*** 

ORAL Strategy: MTX inadequate responders 

Endpoint Time 

Tofacitinib 5 mg twice 
daily 

N=384 

Tofacitinib 5 mg twice 
daily 

 + MTX 
N=376 

Adalimumab 
 + MTX 
N=386 

ACR20 
Month 3 62.50 70.48ǂ 69.17 
Month 6 62.84 73.14ǂ 70.98 

Month 12 61.72 70.21ǂ 67.62 

ACR50 
Month 3 31.51 40.96ǂ 37.31 
Month 6 38.28 46.01ǂ 43.78 

Month 12 39.31 47.61ǂ 45.85 

ACR70 
Month 3 13.54 19.41ǂ 14.51 
Month 6 18.23 25.00ǂ 20.73 

Month 12 21.09 28.99ǂ 25.91 
*p<0.05 
**p<0.001 
***p<0.0001 verses placebo (versus MTX for ORAL Start) 
ǂp<0.05 – tofacitinib 5 mg + MTX versus tofacitinib 5 mg for ORAL Strategy (normal p-values without multiple comparison 
adjustment) 
QOW=every other week, N=number of subjects analysed, ACR20/50/70=American College of Rheumatology ≥20, 50, 70% 
improvement, NA=not applicable, MTX=methotrexate. 

 
DAS28-4(ESR) response 
Patients in the phase 3 studies had a mean Disease Activity Score (DAS28-4[ESR]) of 6.1-6.7 at baseline. 
Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2.0 and 1.9-2.2 were 
observed in patients treated with 5 mg and 10 mg twice daily doses, respectively, compared to placebo-
treated patients (0.7-1.1) at month 3. The proportion of patients achieving a DAS28 clinical remission 
(DAS28-4(ESR) < 2.6) in ORAL Step, ORAL Sync, and ORAL Standard is shown in Table 9. 
 
Table 9: Number (%) of subjects achieving DAS28-4(ESR) < 2.6 remission at months 3 and 6  

 Time point N % 
ORAL Step: TNF inhibitor inadequate responders  

Tofacitinib 5 mg twice daily + MTX Month 3 133 6 
Tofacitinib 10 mg twice daily + MTX Month 3 134 8* 
Placebo + MTX Month 3 132 2 

ORAL Sync: DMARD inadequate responders  
Tofacitinib 5 mg twice daily Month 6 312 8* 



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Tofacitinib 10 mg twice daily Month 6 315 11*** 
Placebo Month 6 158 3 

ORAL Standard: MTX inadequate responders  
Tofacitinib 5 mg twice daily + MTX Month 6 198 6* 
Tofacitinib 10 mg twice daily + MTX Month 6 197 11*** 
Adalimumab 40 mg SC QOW + MTX Month 6 199 6* 
Placebo + MTX Month 6 105 1 

*p <0.05, ***p<0.0001 versus placebo, SC=subcutaneous, QOW=every other week, N=number of subjects analysed, 
DAS28=Disease Activity Scale 28 joints, ESR=Erythrocyte Sedimentation Rate. 
 
Radiographic response 
In ORAL Scan and ORAL Start, inhibition of progression of structural joint damage was assessed 
radiographically and expressed as mean change from baseline in mTSS and its components, the erosion 
score and joint space narrowing (JSN) score, at months 6 and 12.  
 
In ORAL Scan, tofacitinib 10 mg twice daily plus background MTX resulted in significantly greater 
inhibition of the progression of structural damage compared to placebo plus MTX at months 6 and 12. 
When given at a dose of 5 mg twice daily, tofacitinib plus MTX exhibited similar effects on mean 
progression of structural damage (not statistically significant). Analysis of erosion and JSN scores were 
consistent with overall results.  
 
In the placebo plus MTX group, 78% of patients experienced no radiographic progression (mTSS change 
less than or equal to 0.5) at month 6 compared to 89% and 87% of patients treated with tofacitinib 5 mg or 
10 mg (plus MTX) twice daily respectively, (both significant versus placebo plus MTX). 
 
In ORAL Start, tofacitinib monotherapy resulted in significantly greater inhibition of the progression of 
structural damage compared to MTX at months 6 and 12 as shown in Table 10, which was also maintained 
at month 24. Analyses of erosion and JSN scores were consistent with overall results. 
 
In the MTX group, 70% of patients experienced no radiographic progression at month 6 compared to 83% 
and 90% of patients treated with tofacitinib 5 mg or 10 mg twice daily respectively, both significant versus 
MTX. 
 



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Table 10:  Radiographic changes at months 6 and 12 
 ORAL Scan: MTX inadequate responders 
 Placebo + 

MTX 
N=139 

Mean (SD)a 

Tofacitinib 
5 mg 

twice daily + 
MTX 
N=277 

Mean (SD)a 

Tofacitinib 
5 mg  

twice daily + MTX 
Mean difference 

from placebob (CI)  

Tofacitinib 
10 mg 

twice daily + 
MTX 
N=290 

Mean (SD)a 

Tofacitinib 
10 mg 

twice daily + MTX 
Mean difference 
from placebob 

(CI) 
mTSSc 
Baseline 
Month 6 
Month 12 

 
33 (42) 

0.5 (2.0) 
1.0 (3.9) 

 
31 (48) 

0.1 (1.7) 
0.3 (3.0) 

 
- 

-0.3 (-0.7, 0.0) 
-0.6 (-1.3, 0.0) 

 
37 (54) 

0.1 (2.0) 
0.1 (2.9) 

 
- 

-0.4 (-0.8, 0.0) 
-0.9 (-1.5, -0.2) 

 ORAL Start: MTX-naïve 
 MTX 

N=168 
Mean (SD)a 

Tofacitinib 
5 mg 

twice daily 
N=344 

Mean (SD)a 

Tofacitinib 
5 mg  

twice daily  
Mean difference 
from MTXd (CI) 

Tofacitinib 
10mg 

twice daily 
N=368 

Mean (SD)a 

Tofacitinib 
10 mg 

twice daily  
Mean difference 
from MTXd (CI) 

mTSSc 
Baseline 
Month 6 
Month 12 

 
16 (29) 

0.9 (2.7) 
1.3 (3.7) 

 
20 (41)  

0.2 (2.3) 
0.4 (3.0) 

 
- 

-0.7 (-1.0, -0.3) 
-0.9 (-1.4, -0.4) 

 
19 (39) 

0.0 (1.2) 
0.0 (1.5) 

 
- 

-0.8 (-1.2, -0.4) 
-1.3 (-1.8, -0.8) 

a SD = Standard Deviation 
b Difference between least squares means tofacitinib minus placebo (95% CI = 95% confidence interval) 
c Month 6 and month 12 data are mean change from baseline 
d Difference between least squares means tofacitinib minus MTX (95% CI = 95% confidence interval) 
 
Physical function response and health-related outcomes 
 
Tofacitinib, alone or in combination with MTX, has shown improvements in physical function, as 
measured by the HAQ-DI. Patients receiving tofacitinib 5 mg or 10 mg twice daily demonstrated 
significantly greater improvement from baseline in physical functioning compared to placebo at month 3 
(studies ORAL Solo, ORAL Sync, ORAL Standard, and ORAL Step) and month 6 (studies ORAL Sync 
and ORAL Standard). Tofacitinib 5 mg or 10 mg twice daily-treated patients demonstrated significantly 
greater improvement in physical functioning compared to placebo as early as week 2 in ORAL Solo and 
ORAL Sync. Changes from baseline in HAQ-DI in studies ORAL Standard, ORAL Step and ORAL Sync 
are shown in Table 11. 
 



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Table 11: LS Mean change from baseline in HAQ-DI at month 3 
 Placebo + MTX Tofacitinib 

5 mg twice daily 
+ MTX 

Tofacitinib 
10 mg twice daily 

+ MTX 

Adalimumab 
40 mg QOW 

+ MTX 
ORAL Standard: MTX inadequate responders 

N=96 N=185 N=183 N=188 
-0.24 -0.54*** -0.61*** -0.50*** 
ORAL Step: TNF inhibitor inadequate responders 
N=118 N=117 N=125 NA 
-0.18 -0.43*** -0.46*** NA 

Placebo + DMARD(s) Tofacitinib 
5 mg twice daily + 

DMARD(s) 

Tofacitinib 
10 mg twice daily 

+ DMARD(s) 

 

ORAL Sync: DMARD inadequate responders 
N=147 N=292 N=292 NA 
-0.21 -0.46*** -0.56*** NA 

*** p<0.0001, tofacitinib versus placebo + MTX, LS = least squares, N = number of patients, QOW = every other week, 
NA = not applicable, HAQ-DI = Health Assessment Questionnaire Disability Index 

 
Health-related quality of life was assessed by the Short Form Health Survey (SF-36). Patients receiving 
either 5 mg or 10 mg tofacitinib twice daily experienced significantly greater improvement from baseline 
compared to placebo in all 8 domains as well as the Physical Component Summary and Mental 
Component Summary scores at month 3 in ORAL Solo, ORAL Scan and ORAL Step. In ORAL Scan, 
mean SF-36 improvements were maintained to 12 months in tofacitinib-treated patients. 
 
Improvement in fatigue was evaluated by the Functional Assessment of Chronic Illness Therapy-Fatigue 
(FACIT-F) scale at month 3 in all studies. Patients receiving tofacitinib 5 mg or 10 mg twice daily 
demonstrated significantly greater improvement from baseline in fatigue compared to placebo in all 
5 studies. In ORAL Standard and ORAL Scan, mean FACIT-F improvements were maintained to 
12 months in tofacitinib-treated patients. 
 
Improvement in sleep was assessed using the Sleep Problems Index I and II summary scales of the 
Medical Outcomes Study Sleep (MOS-Sleep) measure at month 3 in all studies. Patients receiving 
tofacitinib 5 mg or 10 mg twice daily demonstrated significantly greater improvement from baseline in 
both scales compared to placebo in ORAL Sync, ORAL Standard and ORAL Scan. In ORAL Standard 
and ORAL Scan, mean improvements in both scales were maintained to 12 months in tofacitinib-treated 
patients. 
 
Durability of clinical responses 
 
Durability of effect was assessed by ACR20, ACR50, ACR70 response rates in studies of duration of up 
to two years. Changes in mean HAQ-DI and DAS28-4(ESR) were maintained in both tofacitinib treatment 
groups through to the end of the studies. 
 
Evidence of persistence of efficacy with tofacitinib treatment for up to 7 years is also provided from data 
in the one ongoing and one completed open-label, long-term follow-up studies. 
 
Long-term controlled safety data 
 
Study ORAL Surveillance (A3921133) is a large (N=4362), ongoing, randomised active-controlled 
post-authorisation safety surveillance study of rheumatoid arthritis patients who were at least 50 years of 
age and older and had at least one cardiovascular risk factor (CV risk factors defined as: current cigarette 
smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronary heart disease, 
history of coronary artery disease including a history of revascularization procedure, coronary artery 
bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronary syndrome, and 



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presence of extra-articular disease associated with RA, e.g. nodules, Sjögren’s syndrome, anemia of 
chronic disease, pulmonary manifestations). 
 
Patients were randomised to open-label tofacitinib 10 mg twice daily, tofacitinib 5 mg twice daily, or a 
TNF inhibitor (TNF inhibitor was either etanercept 50 mg once weekly or adalimumab 40 mg every other 
week) in a 1:1:1 ratio. The co-primary endpoints are adjudicated malignancy (excluding NMSC) and 
adjudicated major adverse cardiovascular events (MACE); cumulative incidence and statistical assessment 
of endpoints are blinded. The study is an event-powered study that also requires at least 1500 patients to 
be followed for 3 years. The study treatment of tofacitinib 10 mg twice daily has been stopped and 
patients were switched to 5 mg twice daily because of a dose-dependent signal of venous thromboembolic 
events (VTE). 
 
Venous thromboembolism (VTE) 
In an interim analysis of study A3921133, an increased and dose-dependent incidence of VTE was 
observed in patients treated with tofacitinib compared to TNF inhibitors (see section 4.8). The majority of 
these events were serious and some cases of PE resulted in death. The incidence rates (95% CI) for PE for 
tofacitinib 10 mg twice daily, 5 mg twice daily, and TNF inhibitors were 0.54 (0.32-0.87), 
0.27 (0.12-0.52), and 0.09 (0.02-0.26) patients with events per 100 patient-years, respectively. Compared 
with TNF inhibitors, the HR for PE with tofacitinib 10 mg twice daily was 5.96 (1.75-20.33), and for 5 mg 
twice daily the HR was 2.99 (0.81-11.06). The incidence rates (95% CI) for DVT for tofacitinib 10 mg 
twice daily, 5 mg twice daily, and TNF inhibitors were 0.38 (0.20-0.67), 0.30 (0.14-0.55), and 
0.18 (0.07-0.39) patients with events per 100 patient-years, respectively. Compared with TNF inhibitors, 
the HR for DVT with tofacitinib 10 mg twice daily was 2.13 (0.80-5.69), and for 5 mg twice daily the HR 
was 1.66 (0.60-4.57). 
 
Mortality 
In an interim analysis of study A3921133, increased mortality within 28 days of last treatment was 
observed in patients treated with tofacitinib compared to TNF inhibitors. The incidence rates (95% CI) 
were 0.89 (0.59-1.29) for tofacitinib 10 mg twice daily, 0.57 (0.34-0.89) for tofacitinib 5 mg twice daily, 
and 0.27 (0.12-0.51) for TNF-inhibitors; with a HR (95% CI) of 3.28 (1.55-6.95) for tofacitinib 10 mg 
twice daily and of 2.11 (0.96-4.67) for tofacitinib 5 mg twice daily, versus TNF inhibitors. Mortality was 
mainly due to cardiovascular events, infections and malignancies.  

For cardiovascular mortality within 28 days of last treatment, the incidence rates (95% CI) per 
100 patients-years were 0.45 (0.24-0.75) for tofacitinib 10 mg twice daily, 0.24 (0.10-0.47) for tofacitinib 
5 mg twice daily, and 0.21 (0.08-0.43) for TNF inhibitors; with an incident rate ratio (IRR) (95% CI) of 
2.12 (0.80-6.20) for tofacitinib 10 mg twice daily and of 1.14 (0.36-3.70) for tofacitinib 5 mg twice daily, 
versus TNF inhibitors.  

For fatal infections within 28 days of last treatment, the incidence rates per 100 patient-years (95% CI) 
were 0.22 (0.09-0.46), 0.18 (0.07-0.39), and 0.06 (0.01-0.22) for tofacitinib 10 mg twice daily and 5 mg 
twice daily, and TNF inhibitors, respectively; with an IRR (95% CI) of 3.70 (0.71-36.5) for 10 mg twice 
daily and of 3.00 (0.54-30.4) for tofacitinib 5 mg twice daily, versus TNF inhibitors. 
 
Serious infections 
For non-fatal serious infections, the incidence rates (95% CI) per 100 patient-years were 3.51 (2.93-4.16), 
3.35 (2.78-4.01), and 2.79 (2.28-3.39), for tofacitinib 10 mg and 5 mg twice daily and TNF inhibitors, 
respectively. The risk of serious (fatal and non-fatal) infections was further increased in patients over 65 
years of age, as compared to younger patients in study A3921133. 
 



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Paediatric population 
 
The European Medicines Agency has deferred the obligation to submit results of studies with tofacitinib in 
one or more subsets of the paediatric population in juvenile idiopathic arthritis and in ulcerative colitis 
(see section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Following oral administration of tofacitinib 11 mg prolonged-release tablet, peak plasma concentrations 
are reached at 4 hours and half-life is ~6 hours. Steady state concentrations are achieved within 48 hours 
with negligible accumulation after once daily administration. Steady-state AUC and Cmax of tofacitinib for 
tofacitinib 11 mg prolonged-release tablet administered once daily are equivalent to those of tofacitinib 
5 mg film-coated tablets administered twice daily. 
 
Absorption and distribution 
 
Coadministration of tofacitinib 11 mg prolonged-release tablet with a high-fat meal resulted in no changes 
in AUC while Cmax was increased by 27%. 
 
After intravenous administration, the volume of distribution is 87 L. Approximately 40% of circulating 
tofacitinib is bound to plasma proteins. Tofacitinib binds predominantly to albumin and does not appear to 
bind to α1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma. 
 
Biotransformation and elimination 
 
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 radiolabelled study, more than 65% of the total circulating 
radioactivity was accounted for by unchanged active substance, with the remaining 35% attributed to 
8 metabolites, each accounting for less than 8% of total radioactivity. All metabolites have been observed 
in animal species and are predicted to have less than 10-fold potency than tofacitinib for JAK1/3 
inhibition. No evidence of stereo conversion in human samples was detected. The pharmacologic activity 
of tofacitinib is attributed to the parent molecule. In vitro, tofacitinib is a substrate for MDR1, but not for 
breast cancer resistance protein (BCRP), OATP1B1/1B3, or OCT1/2.   
 
Pharmacokinetics in patients 
 
The enzymatic activity of CYP enzymes is reduced in RA patients due to chronic inflammation. In RA 
patients, the oral clearance of tofacitinib does not vary with time, indicating that treatment with tofacitinib 
does not normalise CYP enzyme activity. 
 
Population PK analysis in RA patients indicated that systemic exposure (AUC) of tofacitinib in the 
extremes of body weight (40 kg, 140 kg) were similar (within 5%) to that of a 70 kg patient. Elderly 
patients 80 years of age were estimated to have less than 5% higher AUC relative to the mean age of 
55 years. Women were estimated to have 7% lower AUC compared to men. The available data have also 
shown that there are no major differences in tofacitinib AUC between White, Black and Asian patients. 
An approximate linear relationship between body weight and volume of distribution was observed, 
resulting in higher peak (Cmax) and lower trough (Cmin) concentrations in lighter patients. However, this 
difference is not considered to be clinically relevant. The between-subject variability (percentage 
coefficient of variation) in AUC of tofacitinib is estimated to be approximately 27%. 
 
Renal impairment 
 
Subjects with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance 30-49 mL/min), 
and severe (creatinine clearance < 30 mL/min) renal impairment had 37%, 43% and 123% higher AUC, 



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respectively, compared to subjects with normal renal function (see section 4.2). In subjects with end-stage 
renal disease (ESRD), contribution of dialysis to the total clearance of tofacitinib was relatively small. 
Following a single dose of 10 mg, mean AUC in subjects with ESRD based on concentrations measured 
on a non-dialysis day was approximately 40% (90% confidence intervals: 1.5-95%) higher compared to 
subjects with normal renal function. In clinical trials, tofacitinib was not evaluated in patients with 
baseline creatinine clearance values (estimated by Cockroft-Gault equation) less than 40 mL/min (see 
section 4.2). 
 
Hepatic impairment 
 
Subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had 3%, and 65% 
higher AUC, respectively, compared to subjects with normal hepatic function. In clinical trials, tofacitinib 
was not evaluated in subjects with severe (Child Pugh C) hepatic impairment (see sections 4.2 and 4.4), or 
in patients screened positive for hepatitis B or C. 
 
Drug interactions 
 
Tofacitinib is not an inhibitor or inducer of CYPs (CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, 
CYP2D6, and CYP3A4) and is not an inhibitor of UGTs (UGT1A1, UGT1A4, UGT1A6, UGT1A9, and 
UGT2B7). Tofacitinib is not an inhibitor of MDR1, OATP1B1/1B3, OCT2, OAT1/3, or MRP at clinically 
meaningful concentrations. 
 
5.3 Preclinical safety data 
 
In non-clinical studies, effects were observed on the immune and haematopoietic systems that were 
attributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects from 
immunosuppression, such as bacterial and viral infections and lymphoma were observed at clinically 
relevant doses. Lymphoma was observed in 3 of 8 adult monkeys at 6 or 3 times the clinical tofacitinib 
exposure level (unbound AUC in humans at a dose of 5 mg or 10 mg twice daily), and 0 of 14 juvenile 
monkeys at 5 or 2.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Exposure in monkeys 
at the no observed adverse effect level (NOAEL) for the lymphomas was approximately 1 or 0.5 times the 
clinical exposure level of 5 mg or 10 mg twice daily. Other findings at doses exceeding human exposures 
included effects on the hepatic and gastrointestinal systems. 
 
Tofacitinib is not mutagenic or genotoxic based on the results of a series of in vitro and in vivo tests for 
gene mutations and chromosomal aberrations. 
 
The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mouse carcinogenicity 
and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice at exposures up to 38 or 
19 times the clinical exposure level at 5 mg or 10 mg twice daily. Benign testicular interstitial (Leydig) 
cell tumours were observed in rats: benign Leydig cell tumours in rats are not associated with a risk of 
Leydig cell tumours in humans. Hibernomas (malignancy of brown adipose tissue) were observed in 
female rats at exposures greater than or equal to 83 or 41 times the clinical exposure level at 5 mg or 
10 mg twice daily. Benign thymomas were observed in female rats at 187 or 94 times the clinical exposure 
level at 5 mg or 10 mg twice daily. 
 
Tofacitinib was shown to be teratogenic in rats and rabbits, and have effects in rats on female fertility 
(decreased pregnancy rate; decreases in the numbers of corpora lutea, implantation sites, and viable 
foetuses; and an increase in early resorptions), parturition, and peri/postnatal development. Tofacitinib had 
no effects on male fertility, sperm motility or sperm concentration. Tofacitinib was secreted in milk of 
lactating rats at concentrations approximately 2-fold those in serum from 1 to 8 hours postdose. 
 
 



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6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
sorbitol (E420) 
hydroxyethyl cellulose 
copovidone 
magnesium stearate 
 
Film coat 
 
cellulose acetate 
hydroxypropyl cellulose (E463) 
hypromellose (E464) 
titamium dioxide (E171) 
triacetin (E1518) 
red iron oxide (E172) 
 
Printing ink 
 
shellac (E904) 
ammomium hydroxide (E527) 
propylene glycol (E1520) 
black iron oxide (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. 
 
Store in the original package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
HDPE bottles with 2 silica gel desiccants and child-resistant, polypropylene closure containing 30 or 
90 prolonged-release tablets. 
 
Aluminium foil/PVC backed aluminium foil blisters containing 7 prolonged-release tablets. Each pack 
contains 28 or 91 prolonged-release tablets. 
 
Not all pack sizes may be marketed. 
 



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6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/17/1178/010  
EU/1/17/1178/011 
EU/1/17/1178/012 
EU/1/17/1178/013 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 22 March 2017 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.  

http://www.ema.europa.eu/


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ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 
SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 



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A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE  
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE 

USE OF THE MEDICINAL PRODUCT   
 
• Risk management plan (RMP) 

 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached. 

 
• Additional risk minimisation measures 
 
Prior to launch of XELJANZ in each Member State, the MAH must agree about the content and 
format of the educational programme, including communication media, distribution modalities, and 
any other aspects of the programme, with the National Competent Authority. The MAH shall ensure 
that in each Member State where XELJANZ is marketed, healthcare professionals who intend to 
prescribe XELJANZ have been provided with an educational package. 
 
The main objective of the programme is to increase awareness about the risks of the product, 
specifically in regards to serious infections, venous thromboembolism (deep vein thrombosis [DVT] 
and pulmonary embolism [PE]), herpes zoster, tuberculosis (TB) and other opportunistic infections, 
malignancy, gastrointestinal perforations, interstitial lung disease, and laboratory abnormalities.  
 



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The MAH shall ensure that in each Member State where XELJANZ is marketed, all healthcare 
professionals and patients/carers who are expected to prescribe or use XELJANZ have access to/are 
provided with the following educational package: 

• Physician educational material  
• Patient information pack 

 
• The physician educational material should contain: 

o The Summary of Product Characteristics 
o Guide for healthcare professionals 
o Prescriber checklist 
o Patient alert card 
o A reference to the website with the educational material and patient alert card 
 

• The Guide for healthcare professionals shall contain the following key elements: 
o Relevant information of the safety concerns addressed by the aRMM (e.g. seriousness, 

severity, frequency, time to onset, reversibility of the AE as applicable) 
o Details of the population at higher risk for the safety concern addressed by the aRMM (i.e. 

contraindications, risk factors, increased risk by interactions with certain medicine) 
o The above key element needs to be updated with details on the VTE risk including the 

VTE risk factors as well as with details on the risk of serious infections in patients >65 
years old.  

o Details on how to minimise the safety concern addressed by the aRMM through appropriate 
monitoring and management (i.e. what to do, what not do, and who is most likely be impacted 
according to different scenarios, like when to limit or stop prescribing/ingestion, how to 
administer the medicine, when to increase/decrease the dosage according to laboratory 
measurements, signs and symptoms) 

o The above key element should be updated with details on the VTE risk should be 
minimised in clinical practice, i.e., that tofacitinib should be used with caution in 
patients with known VTE risk factors and that 10 mg twice daily is not recommended 
for maintenance treatment in UC patients with known VTE risk factors unless there is 
no suitable alternative treatment available. In addition, details on how to minimize the 
risk of serious infections in patients >65 years old should be provided as well.   

o Key message to convey in patients counselling  
o Instructions on how to handle possible adverse events 
o Information about the BSRBR, ARTIS, RABBIT and BIODABASER and UC registries and 

the importance of contributing to these 
 

• The Prescriber checklist shall contain the following key messages: 
o Lists of tests to be conducted during the initial screening and maintenance of the patient 
o Vaccination course to be completed before treatment 
o A specific reference to the fact that the patient has been informed and understands that 

tofacitinib is contraindicated during pregnancy and breast-feeding and women of childbearing 
potential should use effective contraception during treatment with tofacitinib and for at least 
4 weeks after the last dose 

o That the benefit risk of tofacitinib should be discussed with the patient, and the patient alert 
card should be given to and discussed with the patient 

o Relevant comorbidities for which caution is advised when XELJANZ is administered and 
conditions in which XELJANZ should not be administered 

o List of concomitant medications which are not compatible with treatment with XELJANZ 
o The need to discuss with the patients the risks associated with the use of XELJANZ, 

specifically in regards to infections, venous thromboembolism (deep vein thrombosis [DVT] 
and pulmonary embolism [PE]), herpes zoster, tuberculosis (TB) and other opportunistic 
infections, malignancy, gastrointestinal perforations, interstitial lung disease, and laboratory 
abnormalities 



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o The need to monitor for any signs and symptoms and laboratory abnormalities for early 
identification of the abovementioned risks. 

 
• The Patient alert card shall contain the following key messages:  

o A warning message for HCPs treating the patient at any time, including in conditions of 
emergency, that the patient is using XELJANZ 

o That treatment with XELJANZ may increase the risk of infections and non melanoma skin 
cancer 

o That patients should inform health professionals if they are planning to receive any vaccine or 
become pregnant 

o Signs or symptoms of the following safety concern and/or when to seek attention from a HCP: 
infections, venous thromboembolism (deep vein thrombosis [DVT] and pulmonary embolism 
[PE]), herpes zoster reactivation, non-melanoma skin cancer, transaminase elevation and 
potential for drug-induced liver injury, gastrointestinal perforation, interstitial lung disease, 
increased immunosuppression when used in combination with biologics and 
immunosuppressants including B lymphocyte depleting agents, increased risk of adverse 
events when XELJANZ is administered in combination with MTX, increased exposure to 
XELJANZ when co-administered with CYP3A4 and CYP2C19 inhibitors, effects on 
pregnancy and foetus, use in breast-feeding, effect on vaccination efficacy and the use of 
live/attenuated vaccines. 

o Contact details of the prescriber  
 

• The website repository shall contain:  
o The educational material in digital format 
o The patient alert card in digital format 

 
• The patient information pack should contain: 

o Patient information leaflet 
o The patient alert card 

 
  



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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
  



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A. LABELLING 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON FOR 5 MG BLISTER PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 5 mg film-coated tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 5 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
112 film-coated tablets 
182 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/003 56 film-coated tablets 
EU/1/17/1178/004 182 film-coated tablets 
EU/1/17/1178/014 112 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 5 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
 
BLISTER FOR 5 MG TABLETS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 5 mg tablets 
tofacitinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA holder logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon., Tue., Wed., Thu., Fri., Sat., Sun. 
 
 
   



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL FOR 5 MG BOTTLE IMMEDIATE PACKAGING  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 5 mg film-coated tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 5 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
180 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the dessicant. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  



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10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/001 60 film-coated tablets 
EU/1/17/1178/002 180 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 5 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER-HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON FOR 10 MG BLISTER PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 10 mg film-coated tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
56 film-coated tablets 
112 film-coated tablets 
182 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



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9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/007 56 film-coated tablets 
EU/1/17/1178/008 112 film-coated tablets 
EU/1/17/1178/009 182 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 10 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



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18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
 
BLISTER FOR 10 MG TABLETS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 10 mg tablets 
tofacitinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA holder logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon., Tue., Wed., Thu., Fri., Sat., Sun. 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL FOR 10 MG BOTTLE IMMEDIATE PACKAGING  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 10 mg film-coated tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 10 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 film-coated tablets 
180 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Do not swallow the desiccant. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



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Store in the original package in order to protect from moisture.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/005 60 film-coated tablets 
EU/1/17/1178/006 180 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 10 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC 
SN 
NN 
  



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTON FOR 11 MG BLISTER PACK  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 11 mg prolonged-release tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 11 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sorbitol (E420). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
28 prolonged-release tablets 
91 prolonged-release tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
Do not crush, split or chew. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Once daily 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



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9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/012 28 prolonged-release tablets 
EU/1/17/1178/013 91 prolonged-release tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 11 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN



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MINIMUM PARTICULARS TO APPEAR ON BLISTER OR STRIPS 
 
BLISTER FOR 11 MG TABLETS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 11 mg prolonged-release tablets  
tofacitinib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG (as MA holder logo) 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Mon., Tue., Wed., Thu., Fri., Sat., Sun. 
 
 
 
   



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
LABEL FOR 11 MG BOTTLE IMMEDIATE PACKAGING  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
XELJANZ 11 mg prolonged-release tablets 
tofacitinib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each prolonged-release tablet contains 11 mg of tofacitinib (as tofacitinib citrate). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sorbitol (E420). See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
30 prolonged-release tablets 
90 prolonged-release tablets 
2 silica gel desiccants 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For oral use. 
Do not crush, split or chew 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF 

THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Once daily 
Do not swallow the desiccant. 
 
 



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8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture.  
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 

WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/17/1178/010 30 prolonged-release tablets 
EU/1/17/1178/011 90 prolonged-release tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
XELJANZ 11 mg 
 
 
17. UNIQUE IDENTIFIER - 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



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18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN  



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B. PACKAGE LEAFLET 



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Package leaflet: Information for the patient 
XELJANZ 5 mg film-coated tablets 

XELJANZ 10 mg film-coated tablets 
tofacitinib 

 
This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
In addition to this leaflet, your doctor will also give you a Patient Alert Card, which contains important 
safety information that you need to be aware of before you are given XELJANZ and during treatment with 
XELJANZ. Keep this Patient Alert Card with you. 
 
What is in this leaflet 
1. What XELJANZ is and what it is used for 
2. What you need to know before you take XELJANZ 
3. How to take XELJANZ 
4. Possible side effects 
5. How to store XELJANZ 
6. Contents of the pack and other information 
 
 
1. What XELJANZ is and what it is used for 
 
XELJANZ is a medicine that contains the active substance tofacitinib.  
 
XELJANZ is used for the treatment of the following inflammatory diseases: 
• rheumatoid arthritis 
• psoriatic arthritis 
• ulcerative colitis 
 
Rheumatoid arthritis 
XELJANZ is used to treat adult patients with moderate to severe active rheumatoid arthritis, a long-term 
disease that mainly causes pain and swelling of your joints. 
 
XELJANZ is used together with methotrexate when previous rheumatoid arthritis treatment was not 
sufficient or was not well tolerated. XELJANZ can also be taken on its own in those cases where 
methotrexate treatment is not tolerated or treatment with methotrexate is not advised. 
 
XELJANZ has been shown to reduce pain and swelling of the joints and improve the ability to perform 
daily activities, when given on its own or together with methotrexate. 
 
Psoriatic arthritis 
XELJANZ is used to treat a condition called psoriatic arthritis. This condition is an inflammatory disease 
of the joints, often accompanied by psoriasis. If you have active psoriatic arthritis you will be first given 



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another medicine to treat your psoriatic arthritis. If you do not respond well enough or the medicine is not 
tolerated, you may be given XELJANZ to reduce the sign and symptoms of active psoriatic arthritis and 
improve the ability to perform daily activities.  
 
XELJANZ is used together with methotrexate to treat adult patients with active psoriatic arthritis.  
 
Ulcerative colitis 
Ulcerative colitis is an inflammatory disease of the large bowel. XELJANZ is used to reduce the signs and 
symptoms of ulcerative colitis when you did not respond well enough or were intolerant to previous 
ulcerative colitis treatment. 
 
 
2. What you need to know before you take XELJANZ 

 
Do not take XELJANZ 
- if you are allergic to tofacitinib or any of the other ingredients of this medicine (listed in section 6) 
- if you have a severe infection such as bloodstream infection or active tuberculosis  
- if you have been informed that you have severe liver problems, including cirrhosis (scarring of the 

liver)  
- if you are pregnant or breast-feeding 
 
If you are not sure regarding any of the information provided above, please contact your doctor.  
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking XELJANZ: 
- if you think you have an infection or have symptoms of an infection such as fever, sweating, chills, 

muscle aches, cough, shortness of breath, new phlegm or change in phlegm, weight loss, warm or 
red or painful skin or sores on your body, difficulty or pain when swallowing, diarrhoea or stomach 
pain, burning when you urinate or urinating more often than normal, feeling very tired 

- if you have any condition that increases your chance of infection (e.g., diabetes, HIV/AIDS, or a 
weak immune system) 

- if you have any kind of infection, are being treated for any infection, or if you have infections that 
keep coming back. Tell your doctor immediately if you feel unwell. XELJANZ can reduce your 
body’s ability to respond to infections and may make an existing infection worse or increase the 
chance of getting a new infection 

- if you have or have a history of tuberculosis or have been in close contact with someone with 
tuberculosis. Your doctor will test you for tuberculosis before starting XELJANZ and may retest 
during treatment 

- if you have any chronic lung disease 
- if you have liver problems 
- if you have or had hepatitis B or hepatitis C (viruses that affect the liver). The virus may become 

active while you are taking XELJANZ. Your doctor may do blood tests for hepatitis before you start 
treatment with XELJANZ and while you are taking XELJANZ 

- if you have ever had any type of cancer. XELJANZ may increase your risk of certain cancers. 
Lymphoma and other cancers (such as lung, breast, melanoma, prostate and pancreatic) have been 
reported in patients treated with XELJANZ. If you develop cancer while taking XELJANZ your 
doctor will review whether to stop XELJANZ treatment. 

- if you are at high risk of developing skin cancer, your doctor may recommend that you have regular 
skin examinations while taking XELJANZ.  

- if you have had diverticulitis (a type of inflammation of the large intestine) or ulcers in stomach or 
intestines (see section 4) 

- if you have kidney problems 
- if you are planning to get vaccinated, tell your doctor. Certain types of vaccines should not be given 

when taking XELJANZ. Before you start XELJANZ, you should be up to date with all 



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recommended vaccinations. Your doctor will decide whether you need to have herpes zoster 
vaccination.  

- if you have heart problems, high blood pressure, or high cholesterol 
 
There have been reports of patients treated with XELJANZ who have developed blood clots in the lungs 
or veins. Your doctor will evaluate your risk to develop blood clots in the lungs or veins and determine if 
XELJANZ is appropriate for you. If you have already had problems on developing blood clots in lungs 
and veins or have an increased risk for developing this (for example: if you are seriously overweight, if 
you have cancer, heart problems, diabetes, experienced a heart attack (within previous 3 months), recent 
major surgery, if you use hormonal contraceptives\hormonal replacement therapy, if a coagulation defect 
is identified in you or your close relatives), if you are of older age, or if you smoke, your doctor may 
decide that XELJANZ is not suitable for you. 
 
Talk to your doctor straight away if you develop sudden shortness of breath or difficulty breathing, chest 
pain or pain in upper back, swelling of the leg or arm, leg pain or tenderness, or redness or discoloration in 
the leg or arm while taking XELJANZ, as these may be signs of a clot in the lungs or veins. 
 
Additional monitoring tests 
Your doctor should perform blood tests before you start taking XELJANZ, and after 4 to 8 weeks of 
treatment and then every 3 months, to determine if you have a low white blood cell (neutrophil or 
lymphocyte) count, or a low red blood cell count (anaemia).  
 
You should not receive XELJANZ if your white blood cell (neutrophil or lymphocyte) count or red blood 
cell count is too low. If needed, your doctor may interrupt your XELJANZ treatment to reduce the risk of 
infection (white blood cell counts) or anaemia (red blood cell counts). 
 
Your doctor may also perform other tests, for example to check your blood cholesterol levels or monitor 
the health of your liver. Your doctor should test your cholesterol levels 8 weeks after you start receiving 
XELJANZ. Your doctor should perform liver tests periodically. 
 
Elderly 
There is a higher rate of infections in patients aged 65 years and older. Tell your doctor as soon as you 
notice any signs or symptoms of infections. 
 
Asian patients 
There is a higher rate of shingles in Japanese and Korean patients. Tell your doctor if you notice any 
painful blisters on your skin.  
 
You may also be at higher risk of certain lung problems. Tell your doctor if you notice any breathing 
difficulties. 
 
Children and adolescents 
XELJANZ is not recommended for use in children or adolescents under 18 years of age. The safety and 
benefits of XELJANZ in children or adolescents have not yet been established. 
 
Other medicines and XELJANZ 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
Some medicines should not be taken with XELJANZ. If taken with XELJANZ, they could alter the level 
of XELJANZ in your body, and the dose of XELJANZ may require adjustment. You should tell your 
doctor if you are using medicines (taken by mouth) that contain any of the following active substances: 

• antibiotics such as rifampicin, used to treat bacterial infections 
• fluconazole, ketoconazole, used to treat fungal infections 

 



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XELJANZ is not recommended for use with medicines that depress the immune system, including 
so-called targeted biologic (antibody) therapies, such as those that inhibit tumour necrosis factor, 
interleukin-17, interleukin-12/interleukin-23, anti-integrins, and strong chemical immunosuppressants 
including azathioprine, mercaptopurine, ciclosporine, and tacrolimus. Taking XELJANZ with these 
medicines may increase your risk of side effects including infection. 
 
Serious infections may happen more often in people who also take corticosteroids (e.g., prednisone). 
 
Pregnancy and breast-feeding 
If you are a woman of childbearing age, you should use effective birth control during treatment with 
XELJANZ and for at least 4 weeks after the last dose. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor for advice before taking this medicine. XELJANZ must not be used during pregnancy. Tell your 
doctor right away if you become pregnant while taking XELJANZ. 
 
If you are taking XELJANZ and breast-feeding, you must stop breast-feeding until you talk to your doctor 
about stopping treatment with XELJANZ. 
 
Driving and using machines 
XELJANZ has no or limited effect on your ability to drive or use machines. 
 
XELJANZ contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3. How to take XELJANZ 
 
This medicine is provided to you and supervised by a specialised doctor who knows how to treat your 
condition. 
 
Always take this medicine exactly as your doctor has told you, the recommended dose should not be 
exceeded. Check with your doctor or pharmacist if you are not sure. 
 
Rheumatoid arthritis 

• The recommended dose is 5 mg twice a day. 
 
Psoriatic arthritis 

• The recommended dose is 5 mg twice a day.  
 
Ulcerative colitis 
• The recommended dose is 10 mg twice a day for 8 weeks, followed by 5 mg twice a day. 
• Your doctor may decide to extend the initial 10 mg twice a day treatment by an additional 8 weeks 

(16 weeks in total), followed by 5 mg twice a day. 
• Your doctor may decide to stop XELJANZ if XELJANZ does not work for you within 16 weeks. 
• For patients, who have previously taken biologic medicines to treat ulcerative colitis (such as those 

that block the activity of tumour necrosis factor in the body) and these medicines did not work, the 
doctor may decide to increase your dose of XELJANZ to 10 mg twice a day if you do not respond 
sufficiently to 5 mg twice a day. Your doctor will consider the potential risks, including that of 
developing blood clots in the lungs or veins, and potential benefits to you. Your doctor will tell you 
if this applies to you. 

• If your treatment is interrupted, your doctor may decide to restart your treatment.  
 



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Try to take your tablet at the same time every day (one tablet in the morning and one tablet in the 
evening). 
 
Tofacitinib tablets may be crushed and taken with water. 
 
Your doctor may reduce the dose if you have liver or kidney problems or if you are prescribed certain 
other medicines. Your doctor may also stop treatment temporarily or permanently if blood tests show low 
white blood cell or red blood cell counts.  
 
XELJANZ is for oral use. You can take XELJANZ with or without food. 
 
If you take more XELJANZ than you should  
If you take more tablets than you should, immediately tell your doctor or pharmacist. 
 
If you forget to take XELJANZ 
Do not take a double dose to make up for a forgotten tablet. Take your next tablet at the usual time and 
continue as before. 
 
If you stop taking XELJANZ 
You should not stop taking XELJANZ without discussing this with your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Some may be serious and need medical attention. 
 
Possible serious side effects  
In rare cases, infection may be life-threatening  
 
If you notice any of the following serious side effects you need to tell a doctor straight away. 
 
Signs of serious infections (common) include 

• fever and chills 
• cough 
• skin blisters 
• stomach ache 
• persistent headaches 

 
Signs of ulcers or holes in your stomach (uncommon) include 

• fever  
• stomach or abdominal pain  
• blood in the stool 
• unexplained changes in bowel habits 

 
Holes in stomach or intestines happen most often in people who also take nonsteroidal anti-inflammatory 
drugs or corticosteroids (e.g., prednisone). 
 
Signs of allergic reactions (unknown) include 

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• wheezing  



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• severe dizziness or light-headedness 
• swelling of the lips, tongue or throat 
• hives (itching or skin rash)  

 
Signs of blood clots in lungs or veins (uncommon: venous thromboembolism) include 

• sudden shortness of breath or difficulty breathing 
•  chest pain or pain in upper back 
• swelling of the leg or arm 
• leg pain or tenderness 
• redness or discoloration in the leg or arm 

 
Other side effects which have been observed with XELJANZ are listed below.  
 
Common (may affect up to 1 in 10 people): lung infection (pneumonia and bronchitis), shingles (herpes 
zoster), infections of nose, throat or the windpipe (nasopharyngitis), influenza, sinusitis, urinary bladder 
infection (cystitis), sore throat (pharyngitis), increased muscle enzymes in the blood (sign of muscle 
problems), stomach (belly) pain (which may be from inflammation of the stomach lining), vomiting, 
diarrhoea, feeling sick (nausea), indigestion, low red blood cell count (anaemia), fever, fatigue (tiredness), 
swelling of the feet and hands, headache, high blood pressure (hypertension), cough, rash. 
 
Uncommon (may affect up to 1 in 100 people): tuberculosis, kidney infection, skin infection, herpes 
simplex or cold sores (oral herpes), low white blood cell counts, increased liver enzymes in the blood (sign 
of liver problems), blood creatinine increased (a possible sign of kidney problems), increased cholesterol 
(including increased LDL), weight gain, dehydration, muscle strain, pain in the muscles and joints, 
tendonitis, joint swelling, joint sprain, abnormal sensations, poor sleep, sinus congestion, shortness of 
breath or difficulty breathing, skin redness, itching, fatty liver, painful inflammation of small pockets in 
the lining of your intestine (diverticulitis), viral infections, viral infections affecting the gut, some types of 
skin cancers (non-melanoma-types). 
 
Rare (may affect up to 1 in 1,000 people): blood infection (sepsis), disseminated tuberculosis involving 
bones and other organs, other unusual infections, joint infections.  
 
Very rare (may affect up to 1 in 10,000 people): tuberculosis involving the brain and spinal cord, 
meningitis. 
 
In general, fewer side effects were seen when XELJANZ was used alone than in combination with 
methotrexate in rheumatoid arthritis. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed 
in Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store XELJANZ 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month. 
 
This medicine does not require any special temperature storage conditions. 
 
Store in the original package in order to protect from moisture. 

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Do not use this medicine if you notice the tablets show visible signs of deterioration (for example, are 
broken or discoloured). 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What XELJANZ contains  
 
XELJANZ 5 mg film-coated tablet 
- The active substance is tofacitinib. 
- Each 5 mg film-coated tablet contains 5 mg of tofacitinib (as tofacitinib citrate). 
- The other ingredients are microcrystalline cellulose, lactose monohydrate (see section 2), 

croscarmellose sodium, magnesium stearate, hypromellose (E464), titanium dioxide (E171), 
macrogol, and triacetin (E1518). 

 
XELJANZ 10 mg film-coated tablet 
-  The active substance is tofacitinib. 
- Each 10 mg film-coated tablet contains 10 mg of tofacitinib (as tofacitinib citrate). 
- The other ingredients are microcrystalline cellulose, lactose monohydrate (see section 2), 

croscarmellose sodium, magnesium stearate, hypromellose (E464), titanium dioxide (E171), 
macrogol, triacetin (E1518), FD&C Blue #2/Indigo Carmine Aluminum Lake (E132), and FD&C 
Blue #1/Brilliant Blue FCF Aluminum Lake (E133). 

 
What XELJANZ looks like and contents of the pack 
 
XELJANZ 5 mg film-coated tablets 
XELJANZ 5 mg film-coated tablet is white and round in appearance. 
 
The tablets are provided in blisters containing 14 tablets. Each pack contains 56, 112, or 182 tablets and 
each bottle contains 60 or 180 tablets. 
 
XELJANZ 10 mg film-coated tablets 
XELJANZ 10 mg film-coated tablet is blue and round in appearance. 
 
The tablets are provided in blisters containing 14 tablets. Each pack contains 56, 112, or 182 tablets and 
each bottle contains 60 or 180 tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 



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Manufacturer  
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België /Belgique / Belgien Lietuva 
Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 
Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 
  
България Luxembourg/Luxemburg 
Пфайзер Люксембург САРЛ, Клон България Pfizer S.A. 
Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 
  
Česká republika Magyarország 
Pfizer PFE, spol. s r.o. Pfizer Kft. 
Tel: +420 283 004 111 Tel.: +36 1 488 37 00 
  
Danmark Malta 
Pfizer ApS Vivian Corporation Ltd. 
Tlf: +45 44 20 11 00 Tel: +35621 344610 
  
Deutschland Nederland 
Pfizer Pharma GmbH Pfizer bv 
Tel: +49 (0)30 550055-51000 Tel: +31 (0)10 406 43 01 
  
Eesti Norge 
Pfizer Luxembourg SARL Eesti filiaal Pfizer Norge AS 
Tel: +372 666 7500 Tlf: +47 67 52 61 00 
  
Ελλάδα Österreich 
PFIZER ΕΛΛΑΣ A.E. Pfizer Corporation Austria Ges.m.b.H. 
Τηλ: +30 210 67 85 800 Tel: +43 (0)1 521 15-0 
  
España Polska 
Pfizer S.L. Pfizer Polska Sp. z o.o., 
Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 
  
France Portugal 
Pfizer  Pfizer Biofarmacêutica, Sociedade Unipessoal,  
Tél: +33 (0)1 58 07 34 40 Lda. 
 Tel: +351 21 423 5500 
  
Hrvatska România 
Pfizer Croatia d.o.o. Pfizer Romania S.R.L. 
Tel: +385 1 3908 777 Tel: +40 21 207 28 00 
  



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Ireland Slovenija 
Pfizer Healthcare Ireland Pfizer Luxembourg SARL 
Tel: 1800 633 363 (toll free) Pfizer, podružnica za svetovanje s področja 
+44 (0)1304 616161 farmacevtske dejavnosti, Ljubljana 
 Tel: +386 (0) 1 52 11 400 
  
Ísland Slovenská republika 
Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  
Sími: +354 540 8000  Tel: +421-2-3355 5500 
  
Italia Suomi/Finland 
Pfizer S.r.l. Pfizer Oy 
Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 430 040 
  
Κύπρος Sverige  
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH) 
Τηλ: +357 22 817690 

Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 

  
Latvija United Kingdom 
Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 
Tel: +371 670 35 775 Tel: +44 (0)1304 616161 
 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web 
site: http://www.ema.europa.eu. 
 

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Package leaflet: Information for the patient 
XELJANZ 11 mg prolonged-release tablets 

tofacitinib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new safety 
information. You can help by reporting any side effects you may get. See the end of section 4 for how to 
report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains important 
information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even 

if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. See section 4. 
 
In addition to this leaflet, your doctor will also give you a Patient Alert Card, which contains important 
safety information that you need to be aware of before you are given XELJANZ and during treatment with 
XELJANZ. Keep this Patient Alert Card with you. 
 
What is in this leaflet 
1. What XELJANZ is and what it is used for 
2. What you need to know before you take XELJANZ 
3. How to take XELJANZ 
4. Possible side effects 
5. How to store XELJANZ 
6. Contents of the pack and other information 
 
 
1. What XELJANZ is and what it is used for 
 
XELJANZ is a medicine that contains the active substance tofacitinib.  
 
XELJANZ11 mg prolonged-release tablets are used to treat adult patients with moderate to severe active 
rheumatoid arthritis, a long-term disease that mainly causes pain and swelling of your joints. 
 
XELJANZ 11 mg prolonged-release tablets are used together with methotrexate when previous 
rheumatoid arthritis treatment was not sufficient or was not well tolerated. XELJANZ 11 mg 
prolonged-release tablets can also be taken on its own in those cases where methotrexate treatment is not 
tolerated or treatment with methotrexate is not advised. 
 
XELJANZ 11 mg prolonged-release tablets have been shown to reduce pain and swelling of the joints and 
improve the ability to perform daily activities, when given on its own or together with methotrexate. 
 
 
2. What you need to know before you take XELJANZ 

 
Do not take XELJANZ 
- if you are allergic to tofacitinib or any of the other ingredients of this medicine (listed in section 6) 
- if you have a severe infection such as bloodstream infection or active tuberculosis  
- if you have been informed that you have severe liver problems, including cirrhosis (scarring of the 

liver)  
- if you are pregnant or breast-feeding 
 



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If you are not sure regarding any of the information provided above, please contact your doctor.  
 
Warnings and precautions 
Talk to your doctor or pharmacist before taking XELJANZ: 
- if you think you have an infection or have symptoms of an infection such as fever, sweating, chills, 

muscle aches, cough, shortness of breath, new phlegm or change in phlegm, weight loss, warm or 
red or painful skin or sores on your body, difficulty or pain when swallowing, diarrhoea or stomach 
pain, burning when you urinate or urinating more often than normal, feeling very tired 

- if you have any condition that increases your chance of infection (e.g., diabetes, HIV/AIDS, or a 
weak immune system) 

- if you have any kind of infection, are being treated for any infection, or if you have infections that 
keep coming back. Tell your doctor immediately if you feel unwell. XELJANZ can reduce your 
body’s ability to respond to infections and may make an existing infection worse or increase the 
chance of getting a new infection 

- if you have or have a history of tuberculosis or have been in close contact with someone with 
tuberculosis. Your doctor will test you for tuberculosis before starting XELJANZ and may retest 
during treatment 

- if you have any chronic lung disease 
- if you have liver problems 
- if you have or had hepatitis B or hepatitis C (viruses that affect the liver). The virus may become 

active while you are taking XELJANZ. Your doctor may do blood tests for hepatitis before you start 
treatment with XELJANZ and while you are taking XELJANZ 

- if you have ever had any type of cancer. XELJANZ may increase your risk of certain cancers. 
Lymphoma and other cancers (such as lung, breast, melanoma, prostate and pancreatic) have been 
reported in patients treated with XELJANZ. If you develop cancer while taking XELJANZ your 
doctor will review whether to stop XELJANZ treatment 

- if you are at high risk of developing skin cancer, your doctor may recommend that you have regular 
skin examinations while taking XELJANZ  

- if you have had diverticulitis (a type of inflammation of the large intestine) or ulcers in stomach or 
intestines (see section 4) 

- if you have kidney problems 
- if you are planning to get vaccinated, tell your doctor. Certain types of vaccines should not be given 

when taking XELJANZ. Before you start XELJANZ, you should be up to date with all 
recommended vaccinations. Your doctor will decide whether you need to have herpes zoster 
vaccination  

- if you have heart problems, high blood pressure, or high cholesterol 
- if you have narrowing of the digestive tract tell your doctor as there have been rare reports of 

blockage in the digestive tract in patients taking other medicines using similar prolonged-release 
tablets 

- when you take XELJANZ 11 mg prolonged-release tablets, you may see something in your stool 
that looks like a tablet. This is the empty shell from the prolonged-release tablet after the medicine 
has been absorbed by your body. This is to be expected and you should not be concerned 

 
There have been reports of patients treated with XELJANZ who have developed blood clots in the lungs 
or veins. Your doctor will evaluate your risk to develop blood clots in the lungs or veins and determine if 
XELJANZ is appropriate for you. If you have already had problems on developing blood clots in lungs 
and veins or have an increased risk for developing this (for example: if you are seriously overweight, if 
you have cancer, heart problems, diabetes, experienced a heart attack (within previous 3 months), recent 
major surgery, if you use hormonal contraceptives\hormonal replacement therapy, if a coagulation defect 
is identified in you or your close relatives), if you are of older age, or if you smoke, your doctor may 
decide that XELJANZ is not suitable for you. 
 
Talk to your doctor straight away if you develop sudden shortness of breath or difficulty breathing, chest 
pain or pain in upper back, swelling of the leg or arm, leg pain or tenderness, or redness or discoloration in 
the leg or arm while taking XELJANZ, as these may be signs of a clot in the lungs or veins. 



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Additional monitoring tests 
Your doctor should perform blood tests before you start taking XELJANZ, and after 4 to 8 weeks of 
treatment and then every 3 months, to determine if you have a low white blood cell (neutrophil or 
lymphocyte) count, or a low red blood cell count (anaemia).  
 
You should not receive XELJANZ if your white blood cell (neutrophil or lymphocyte) count or red blood 
cell count is too low. If needed, your doctor may interrupt your XELJANZ treatment to reduce the risk of 
infection (white blood cell counts) or anaemia (red blood cell counts). 
 
Your doctor may also perform other tests, for example to check your blood cholesterol levels or monitor 
the health of your liver. Your doctor should test your cholesterol levels 8 weeks after you start receiving 
XELJANZ. Your doctor should perform liver tests periodically. 
 
Elderly 
There is a higher rate of infections in patients aged 65 years and older. Tell your doctor as soon as you 
notice any signs or symptoms of infections. 
 
Asian patients 
There is a higher rate of shingles in Japanese and Korean patients. Tell your doctor if you notice any 
painful blisters on your skin.  
 
You may also be at higher risk of certain lung problems. Tell your doctor if you notice any breathing 
difficulties. 
 
Children and adolescents 
XELJANZ is not recommended for use in children or adolescents under 18 years of age. The safety and 
benefits of XELJANZ in children or adolescents have not yet been established. 
 
Other medicines and XELJANZ 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. 
 
Some medicines should not be taken with XELJANZ. If taken with XELJANZ, they could alter the level 
of XELJANZ in your body, and the dose of XELJANZ may require adjustment. You should tell your 
doctor if you are using medicines (taken by mouth) that contain any of the following active substances: 
• antibiotics such as rifampicin, used to treat bacterial infections 
• fluconazole, ketoconazole, used to treat fungal infections 
 
XELJANZ is not recommended for use with medicines that depress the immune system, including 
so-called targeted biologic (antibody) therapies, such as those that inhibit tumour necrosis factor and 
strong chemical immunosuppressants including azathioprine, mercaptopurine, ciclosporine, and 
tacrolimus. Taking XELJANZ with these medicines may increase your risk of side effects including 
infection. 
 
Serious infections may happen more often in people who also take corticosteroids (e.g., prednisone). 
 
Pregnancy and breast-feeding 
If you are a woman of childbearing age, you should use effective birth control during treatment with 
XELJANZ and for at least 4 weeks after the last dose. 
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor for advice before taking this medicine. XELJANZ must not be used during pregnancy. Tell your 
doctor right away if you become pregnant while taking XELJANZ. 
 



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If you are taking XELJANZ and breast-feeding, you must stop breast-feeding until you talk to your doctor 
about stopping treatment with XELJANZ. 
 
Driving and using machines 
XELJANZ has no or limited effect on your ability to drive or use machines. 
 
XELJANZ 11 mg prolonged-release tablet contains sorbitol 
This medicine contains approximately 152 mg sorbitol in each prolonged-release tablet. 
 
 
3. How to take XELJANZ 
 
Always take this medicine exactly as your doctor has told you, the recommended dose should not be 
exceeded. Check with your doctor or pharmacist if you are not sure. 
 
The recommended dose is one 11 mg prolonged-release tablet administered once daily.  
 
Your doctor may reduce the dose if you have liver or kidney problems or if you are prescribed certain 
other medicines. Your doctor may also stop treatment temporarily or permanently if blood tests show low 
white blood cell or red blood cell counts. 
 
If you suffer from rheumatoid arthritis, your doctor may switch your tablets from XELJANZ 5 mg 
film-coated tablets twice daily to XELJANZ 11 mg prolonged-release tablets once daily. You can start the 
Xeljanz 11 mg prolonged-release tablets once daily the day following the last dose of XELJANZ 5 mg 
film-coated tablets. You should not switch between the XELJANZ 5 mg film-coated tablet and the 
XELJANZ 11 mg prolonged-release tablet unless instructed by your doctor. 
 
XELJANZ is for oral use. You can take XELJANZ with or without food. 
 
Try to take your tablet (one 11 mg prolonged-release tablet) at the same time each day, e.g., morning or 
evening. 
 
Swallow XELJANZ 11 mg prolonged-release tablets whole in order to ensure the entire dose is delivered 
correctly. Do not crush, split, or chew.  
 
If you take more XELJANZ than you should  
If you take more 11 mg prolonged-release tablets than you should, immediately tell your doctor or 
pharmacist. 
 
If you forget to take XELJANZ 
Do not take a double dose to make up for a forgotten 11 mg prolonged-release tablet. Take your next 
11 mg prolonged-release tablet at the usual time and continue as before. 
 
If you stop taking XELJANZ 
You should not stop taking XELJANZ without discussing this with your doctor. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Some may be serious and need medical attention. 
 



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Possible serious side effects  
In rare cases, infection may be life-threatening.  
 
If you notice any of the following serious side effects you need to tell a doctor straight away. 
 
Signs of serious infections (common) include 
• fever and chills 
• cough 
• skin blisters 
• stomach ache 
• persistent headaches 
 
Signs of ulcers or holes in your stomach (uncommon) include  
• fever  
• stomach or abdominal pain  
• blood in the stool 
• unexplained changes in bowel habits 
 
Holes in stomach or intestines happen most often in people who also take nonsteroidal anti-inflammatory 
drugs or corticosteroids (e.g., prednisone). 
 
Signs of allergic reactions (unknown) include 
• chest tightness 
• wheezing  
• severe dizziness or light-headedness 
• swelling of the lips, tongue or throat 
• hives (itching or skin rash)  
 
Signs of blood clots in lungs or veins (uncommon: venous thromboembolism) include 

• sudden shortness of breath or difficulty breathing 
•  chest pain or pain in upper back 
• swelling of the leg or arm 
• leg pain or tenderness 
• redness or discoloration in the leg or arm 

 
Other side effects which have been observed with XELJANZ are listed below.  
 
Common (may affect up to 1 in 10 people): lung infection (pneumonia and bronchitis), shingles (herpes 
zoster), infections of nose, throat or the windpipe (nasopharyngitis), influenza, sinusitis, urinary bladder 
infection (cystitis), sore throat (pharyngitis), increased muscle enzymes in the blood (sign of muscle 
problems), stomach (belly) pain (which may be from inflammation of the stomach lining), vomiting, 
diarrhoea, feeling sick (nausea), indigestion, low red blood cell count (anaemia), fever, fatigue (tiredness), 
swelling of the feet and hands, headache, high blood pressure (hypertension), cough, rash. 
 
Uncommon (may affect up to 1 in 100 people): tuberculosis, kidney infection, skin infection, herpes 
simplex or cold sores (oral herpes), low white blood cell counts, increased liver enzymes in the blood (sign 
of liver problems), blood creatinine increased (a possible sign of kidney problems), increased cholesterol 
(including increased LDL), weight gain, dehydration, muscle strain, pain in the muscles and joints, 
tendonitis, joint swelling, joint sprain, abnormal sensations, poor sleep, sinus congestion, shortness of 
breath or difficulty breathing, skin redness, itching, fatty liver, painful inflammation of small pockets in 
the lining of your intestine (diverticulitis), viral infections, viral infections affecting the gut, some types of 
skin cancers (non-melanoma-types). 
 



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Rare (may affect up to 1 in 1,000 people): blood infection (sepsis), disseminated tuberculosis involving 
bones and other organs, other unusual infections, joint infections.  
 
Very rare (may affect up to 1 in 10,000 people): tuberculosis involving the brain and spinal cord, 
meningitis. 
 
In general, fewer side effects were seen when XELJANZ was used alone than in combination with 
methotrexate in rheumatoid arthritis. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed 
in Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store XELJANZ 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label. The expiry date refers to the last 
day of that month. 
 
This medicine does not require any special temperature storage conditions. 
 
Store in the original package in order to protect from moisture. 
 
Do not use this medicine if you notice the tablets show visible signs of deterioration (for example, are 
broken or discoloured). 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw 
away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What XELJANZ contains  
 
- The active substance is tofacitinib. 
- Each 11 mg prolonged-release tablet contains 11 mg of tofacitinib (as tofacitinib citrate). 
- The other ingredients are sorbitol (E420) (see section 2), hydroxyethyl cellulose, copovidone, 

magnesium stearate, cellulose acetate, hydroxypropyl cellulose (E463), hypromellose (E464), 
titanium dioxide (E171), triacetin (E1518), red iron oxide (E172), shellac (E904), ammonium 
hydroxide (E527), propylene glycol (E1520) and black iron oxide (E172).  
 

What XELJANZ looks like and contents of the pack 
 
- XELJANZ 11 mg prolonged-release tablet is pink and oval in appearance. 
- The 11 mg prolonged-release tablets are provided in blisters containing 7 prolonged-release tablets. 

Each pack contains 28 or 91 prolonged-release tablets. 
- The prolonged-release tablets are also available in bottles with silica gel desiccant containing 30 or 

90 prolonged-release tablets. 
 
Not all pack sizes may be marketed. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer  
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België /Belgique / Belgien Lietuva 
Pfizer S.A./N.V.  Pfizer Luxembourg SARL filialas Lietuvoje 
Tél/Tel: +32 (0)2 554 62 11 Tel. +3705 2514000 
  
България Luxembourg/Luxemburg 
Пфайзер Люксембург САРЛ, Клон България Pfizer S.A. 
Тел.: +359 2 970 4333 Tél/Tel: +32 (0)2 554 62 11 
  
Česká republika Magyarország 
Pfizer PFE, spol. s r.o. Pfizer Kft. 
Tel: +420 283 004 111 Tel.: +36 1 488 37 00 
  
Danmark Malta 
Pfizer ApS Vivian Corporation Ltd. 
Tlf: +45 44 20 11 00 Tel : +35621 344610 
  
Deutschland Nederland 
Pfizer Pharma GmbH Pfizer bv 
Tel: +49 (0)30 550055-51000 Tel: +31 (0)10 406 43 01 
  
Eesti Norge 
Pfizer Luxembourg SARL Eesti filiaal Pfizer Norge AS 
Tel: +372 666 7500 Tlf: +47 67 52 61 00 
  
Ελλάδα Österreich 
PFIZER ΕΛΛΑΣ A.E. Pfizer Corporation Austria Ges.m.b.H. 
Τηλ: +30 210 67 85 800 Tel: +43 (0)1 521 15-0 
  
España Polska 
Pfizer S.L. Pfizer Polska Sp. z o.o., 
Tel: +34 91 490 99 00 Tel.: +48 22 335 61 00 
  
France Portugal 
Pfizer  Pfizer Biofarmacêutica, Sociedade Unipessoal,  
Tél: +33 (0)1 58 07 34 40 Lda. 
 Tel: +351 21 423 5500 



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Hrvatska România 
Pfizer Croatia d.o.o. Pfizer Romania S.R.L. 
Tel: +385 1 3908 777 Tel: +40 21 207 28 00 
  
Ireland Slovenija 
Pfizer Healthcare Ireland Pfizer Luxembourg SARL 
Tel: 1800 633 363 (toll free) Pfizer, podružnica za svetovanje s področja 
+44 (0)1304 616161 farmacevtske dejavnosti, Ljubljana 
 Tel: +386 (0) 1 52 11 400 
  
Ísland Slovenská republika 
Icepharma hf. Pfizer Luxembourg SARL, organizačná zložka  
Sími: +354 540 8000  Tel: +421-2-3355 5500 
  
Italia Suomi/Finland 
Pfizer S.r.l. Pfizer Oy 
Tel: +39 06 33 18 21 Puh/Tel: +358 (0)9 430 040 
  
Κύπρος Sverige  
PFIZER ΕΛΛΑΣ Α.Ε. (CYPRUS BRANCH) 
Τηλ: +357 22 817690 

Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 

  
Latvija United Kingdom 
Pfizer Luxembourg SARL filiāle Latvijā Pfizer Limited 
Tel: +371 670 35 775 Tel: +44 (0)1304 616161 
 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web 
site: http://www.ema.europa.eu. 

 
 
 
  

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Annex IV