XELJANZ 11mg prolonged-release tablets medication leaflet

XELJANZ 11 mg prolonged-release tablets

Each prolonged-release tablet contains tofacitinib citrate, equivalent to 11 mg tofacitinib.

Each prolonged-release tablet contains 152.23 mg of sorbitol.

For the full list of excipients, see section 6.1.

Prolonged-release tablet

Pink, oval tablet of approximate average dimension of 10.8 mm × 5.5 mm × 4.4 mm (length by widthby thickness) with a drilled hole at one end of the tablet band and “JKI 11” printed on one side of thetablet.

Tofacitinib in combination with methotrexate (MTX) is indicated for the treatment of moderate tosevere active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or whoare intolerant to one or more disease-modifying antirheumatic drugs (DMARDs) (see section 5.1).

Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTXis inappropriate (see sections 4.4 and 4.5).

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 priordisease-modifying antirheumatic drug (DMARD) therapy (see section 5.1).

Tofacitinib is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) whohave responded inadequately to conventional therapy.

Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis andtreatment of conditions for which tofacitinib is indicated.

Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

The recommended dose is one 11 mg prolonged-release tablet administered once daily, which shouldnot be exceeded.

No dose adjustment is required when used in combination with MTX.

For information on switching between tofacitinib film-coated tablets and tofacitinib prolonged-releasetablets see Table 1.

Table 1: Switching between tofacitinib film-coated tablets and tofacitinib prolonged-release tablets

Switching between tofacitinib Treatment with tofacitinib 5 mg film-coated tablets twice daily and5 mg film-coated tablets and tofacitinib 11 mg prolonged-release tablet once daily may be switchedtofacitinib 11 mg between each other on the day following the last dose of either tablet.prolonged-release tabletaa See section 5.2 for comparison of pharmacokinetics of prolonged-release and film-coated formulations.

Tofacitinib treatment should be interrupted if a patient develops a serious infection until the infectionis controlled.

Interruption of dosing may be needed for management of dose-related laboratory abnormalitiesincluding lymphopenia, neutropenia, and anaemia. As described in Tables 2, 3 and 4 below,recommendations for temporary dose interruption or permanent discontinuation of treatment are madeaccording 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 than750 cells/mm3.

Table 2: Low absolute lymphocyte count

Low absolute lymphocyte count (ALC) (see section 4.4)

Laboratory value Recommendation(cells/mm3)

ALC greater than or equal Dose should be maintained.to 750

ALC 500-750 For persistent (2 sequential values in this range on routine testing)decrease in this range, tofacitinib 11 mg prolonged-release dosingshould be interrupted.

When ALC is greater than 750, treatment should be resumed asclinically appropriate.

ALC less than 500 If laboratory value confirmed by repeat testing within 7 days, dosingshould be discontinued.

It is recommended not to initiate dosing in patients with an absolute neutrophil count (ANC) less than1,000 cells/mm3.

Table 3: Low absolute neutrophil count

Low absolute neutrophil count (ANC) (see section 4.4)

Laboratory Value Recommendation(cells/mm3)

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 dosingshould be interrupted.

When ANC is greater than 1,000, treatment should be resumed asclinically appropriate.

ANC less than 500 If laboratory value confirmed by repeat testing within 7 days, dosingshould be discontinued.

It is recommended not to initiate dosing in patients with haemoglobin less than 9 g/dL.

Table 4: Low haemoglobin value

Low haemoglobin value (Section 4.4)

Laboratory Value Recommendation(g/dL)

Less than or equal to Dose should be maintained.2 g/dL decrease and greaterthan or equal to 9.0 g/dL

Greater than 2 g/dL Dosing should be interrupted until haemoglobin values havedecrease or less than normalised.8.0 g/dL(confirmed by repeattesting)

Tofacitinib total daily dose should be reduced by half in patients receiving potent inhibitors ofcytochrome P450 (CYP) 3A4 (e.g., ketoconazole) and in patients receiving 1 or more concomitantmedicinal 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 film-coated tablet once daily in patientsreceiving 11 mg prolonged-release tablet once daily.

Dose discontinuation in AS

Available data suggest that clinical improvement in AS is observed within 16 weeks of initiation oftreatment with tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibitingno clinical improvement within this timeframe.

No dose adjustment is required in patients 65 years of age and older. There are limited data in patientsaged 75 years and older. See section 4.4 for Use in patients 65 years of age and older.

Table 5: Dose adjustment for hepatic impairment

Hepatic Classification Dose adjustment in hepatic impairment for differentimpairment strength tabletscategory

Mild Child Pugh A No dose adjustment required.

Moderate Child Pugh B Dose should be reduced to 5 mg film-coated tablet oncedaily when the indicated dose in the presence of normalhepatic function is 11 mg prolonged-release tablet oncedaily (see section 5.2).

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

Table 6: Dose adjustment for renal impairment

Renal Creatinine Dose adjustment in renal impairment for differentimpairment clearance strength tablets

Category

Mild 50-80 mL/min No dose adjustment required.

Moderate 30-49 mL/min No dose adjustment required.

Severe (including < 30 mL/min Dose should be reduced to 5 mg film-coated tablet oncepatients daily when the indicated dose in the presence of normalundergoing renal function is 11 mg prolonged-release tablet oncehaemodialysis) daily (see section 5.2).

Patients with severe renal impairment should remain ona reduced dose even after haemodialysis (seesection 5.2).

The safety and efficacy of tofacitinib prolonged-release formulation in children aged 0 to less than18 years have not been established. No data are available.

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 isdelivered correctly. They must not be crushed, split or chewed.

- 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).

Tofacitinib should only be used if no suitable treatment alternatives are available in patients:

- 65 years of age and older;

- patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors(such as current or past long-time smokers);

- patients with malignancy risk factors (e.g. current malignancy or history of malignancy)

Use in patients 65 years of age and older

Considering the increased risk of serious infections, myocardial infarction, malignancies and all causemortality with tofacitinib in patients 65 years of age and older, tofacitinib should only be used in thesepatients if no suitable treatment alternatives are available (see further details below in section 4.4 andsection 5.1).

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 monoclonalantibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulationmodulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin andtacrolimus 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 versustofacitinib as monotherapy in RA clinical studies.

The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied intofacitinib clinical studies.

Serious VTE events including pulmonary embolism (PE), some of which were fatal, and deep veinthrombosis (DVT), have been observed in patients taking tofacitinib. In a randomisedpost-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or olderwith at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE wasobserved with tofacitinib compared to TNF inhibitors (see sections 4.8 and 5.1).

In a post hoc exploratory analysis within this study, in patients with known VTE risk factors,occurrences of subsequent VTEs were observed more frequently in tofacitinib-treated patients that, at12 months treatment, had D-dimer level ≥2× ULN versus those with D-dimer level <2×ULN; this wasnot evident in TNF inhibitor-treated patients. Interpretation is limited by the low number of VTEevents and restricted D-dimer test availability (only assessed at Baseline, Month 12, and at the end ofthe study). In patients who did not have a VTE during the study, mean D-dimer levels weresignificantly reduced at Month 12 relative to Baseline across all treatment arms. However, D-dimerlevels ≥2× ULN at Month 12 were observed in approximately 30% of patients without subsequent

VTE events, indicating limited specificity of D-Dimer testing in this study.

In patients with cardiovascular or malignancy risk factors (see also section 4.4 “Major adversecardiovascular events (including myocardial infarction)” and “Malignancies and lymphoproliferativedisorders”) tofacitinib should only be used if no suitable treatment alternatives are available.

In patients with VTE risk factors other than MACE or malignancy risk factors, tofacitinib should beused with caution. VTE risk factors other than MACE or malignancy risk factors include previous

VTE, patients undergoing major surgery, immobilisation, use of combined hormonal contraceptives orhormone replacement therapy, inherited coagulation disorder. Patients should be re-evaluatedperiodically during tofacitinib treatment to assess for changes in VTE risk.

For patients with RA with known risk factors for VTE, consider testing D-dimer levelsafter approximately 12 months of treatment. If D-dimer test result is ≥ 2× ULN, confirm that clinicalbenefits outweigh risks prior to a decision on treatment continuation with tofacitinib.

Promptly evaluate patients with signs and symptoms of VTE and discontinue tofacitinib in patientswith suspected VTE, regardless of dose or indication.

Retinal venous thrombosis

Retinal venous thrombosis (RVT) has been reported in patients treated with tofacitinib (see section4.8). The patients should be advised to promptly seek medical care in case they experience symptomssuggestive of RVT.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or otheropportunistic pathogens have been reported in patients receiving tofacitinib (see section 4.8). The riskof opportunistic infections is higher in Asian geographic regions (see section 4.8). Rheumatoidarthritis 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.

Patients should be closely monitored for the development of signs and symptoms of infection duringand after treatment with tofacitinib. Treatment should be interrupted if a patient develops a seriousinfection, an opportunistic infection, or sepsis. A patient who develops a new infection duringtreatment with tofacitinib should undergo prompt and complete diagnostic testing appropriate for animmunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patientshould 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). Inpatients 65 years of age and older, tofacitinib should only be used if no suitable treatment alternativesare available (see section 5.1).

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should begiven to lymphocyte counts when assessing individual patient risk of infection. Discontinuation andmonitoring criteria for lymphopenia are discussed in section 4.2.

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 applicableguidelines during administration of tofacitinib.

Patients with latent TB, who test positive, should be treated with standard antimycobacterial therapybefore administering tofacitinib.

Antituberculosis therapy should also be considered prior to administration of tofacitinib in patientswho test negative for TB but who have a past history of latent or active TB and where an adequatecourse of treatment cannot be confirmed; or those who test negative but who have risk factors for TBinfection. Consultation with a healthcare professional with expertise in the treatment of TB isrecommended to aid in the decision about whether initiating antituberculosis therapy is appropriate foran individual patient. Patients should be closely monitored for the development of signs and symptomsof TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral reactivation and cases of herpes virus reactivation (e.g., herpes zoster) have been observed inpatients receiving tofacitinib (see section 4.8).

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 biologicaldisease modifying antirheumatic drugs (DMARDs).

- Patients treated with 10 mg twice daily.

The impact of tofacitinib on chronic viral hepatitis reactivation is unknown. Patients screened positivefor hepatitis B or C were excluded from clinical studies. Screening for viral hepatitis should beperformed in accordance with clinical guidelines before starting therapy with tofacitinib.

At least one confirmed case of progressive multifocal leukoencephalopathy (PML) has been reportedin RA patients receiving tofacitinib in the post marketing setting. PML can be fatal and should beconsidered in the differential diagnosis in immunosuppressed patients with new onset or worseningneurological symptoms.

Major adverse cardiovascular events (MACE) have been observed in patients taking tofacitinib.

In a randomised post authorisation safety study in patients with RA who were 50 years of age or olderwith at least one additional cardiovascular risk factor, an increased incidence of myocardial infarctionswas observed with tofacitinib compared to TNF inhibitors (see sections 4.8 and 5.1). In patients65 years of age and older, patients who are current or past long-time smokers, and patients withhistory of atherosclerotic cardiovascular disease or other cardiovascular risk factors, tofacitinib shouldonly be used if no suitable treatment alternatives are available (see section 5.1).

Malignancies and lymphoproliferative disorder

Tofacitinib may affect host defences against malignancies.

In a randomised post authorisation safety study in patients with RA who were 50 years of age or olderwith at least one additional cardiovascular risk factor, an increased incidence of malignanciesparticularly NMSC, lung cancer and lymphoma, was observed with tofacitinib compared to TNFinhibitors (see sections 4.8 and 5.1).

NMSC lung cancers and lymphoma in patients treated with tofacitinib have also been observed inother clinical studies and in the post-marketing setting.

Other malignancies in patients treated with tofacitinib were observed in clinical studies and thepost-marketing setting, including, but not limited to, breast cancer, melanoma, prostate cancer, andpancreatic cancer.

In patients 65 years of age and older, patients who are current or past long-time smokers, and patientswith other malignancy risk factors (e.g. current malignancy or history of malignancy other than asuccessfully treated non-melanoma skin cancer) tofacitinib should only be used if no suitabletreatment alternatives are available (see section 5.1). Periodic skin examination is recommended for allpatients, particularly those who are at increased risk for skin cancer (see Table 7 in section 4.8).

Caution is also recommended in patients with a history of chronic lung disease as they may be moreprone to infections. Events of interstitial lung disease (some of which had a fatal outcome) have beenreported in patients treated with tofacitinib in RA clinical studies and in the post-marketing settingalthough the role of Janus kinase (JAK) inhibition in these events is not known. Asian RA patients areknown to be at higher risk of interstitial lung disease, thus caution should be exercised in treating thesepatients.

Events of gastrointestinal perforation have been reported in clinical studies although the role of JAKinhibition in these events is not known. Tofacitinib should be used with caution in patients who maybe 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). Patientspresenting with new onset abdominal signs and symptoms should be evaluated promptly for earlyidentification of gastrointestinal perforation.

Fractures

Fractures have been observed in patients treated with tofacitinib.

Tofacitinib should be used with caution in patients with known risk factors for fractures such aselderly patients, female patients and patients with corticosteroid use, regardless of indication anddosage.

Treatment with tofacitinib was associated with an increased incidence of liver enzyme elevation insome patients (see section 4.8 liver enzyme tests). Caution should be exercised when consideringinitiation of tofacitinib treatment in patients with elevated alanine aminotransferase (ALT) or aspartateaminotransferase (AST), particularly when initiated in combination with potentially hepatotoxicmedicinal products such as MTX. Following initiation, routine monitoring of liver tests and promptinvestigation of the causes of any observed liver enzyme elevations are recommended to identifypotential cases of drug-induced liver injury. If drug-induced liver injury is suspected, theadministration of tofacitinib should be interrupted until this diagnosis has been excluded.

In post-marketing experience, cases of hypersensitivity associated with tofacitinib administration havebeen reported. Allergic reactions included angioedema and urticaria; serious reactions have occurred.

If any serious allergic or anaphylactic reaction occurs, tofacitinib should be discontinued immediately.

Treatment with tofacitinib was associated with an increased incidence of lymphopenia compared toplacebo. Lymphocyte counts less than 750 cells/mm3 were associated with an increased incidence ofserious infections. It is not recommended to initiate or continue tofacitinib treatment in patients with aconfirmed lymphocyte count less than 750 cells/mm3. Lymphocytes should be monitored at baselineand every 3 months thereafter. For recommended modifications based on lymphocyte counts (seesection 4.2).

Treatment with tofacitinib was associated with an increased incidence of neutropenia (less than2,000 cells/mm3) compared to placebo. It is not recommended to initiate tofacitinib treatment inpatients with an ANC less than 1,000 cells/mm3. ANC should be monitored at baseline and after 4 to8 weeks of treatment and every 3 months thereafter. For recommended modifications based on ANC(see section 4.2).

Treatment with tofacitinib has been associated with decreases in haemoglobin levels. It is notrecommended 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 monthsthereafter. For recommended modifications based on haemoglobin level (see section 4.2).

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. Maximumeffects were generally observed within 6 weeks. Assessment of lipid parameters should be performedafter 8 weeks following initiation of tofacitinib therapy. Patients should be managed according toclinical guidelines for the management of hyperlipidaemia. Increases in total and LDL cholesterolassociated with tofacitinib may be decreased to pretreatment levels with statin therapy.

Hypoglycaemia in patients treated for diabetes

There have been reports of hypoglycaemia following initiation of tofacitinib in patients receivingmedication for diabetes. Dose adjustment of anti-diabetic medication may be necessary in the eventthat hypoglycaemia occurs.

Prior to initiating tofacitinib, it is recommended that all patients be brought up to date with allimmunisations in agreement with current immunisation guidelines. It is recommended that livevaccines not be given concurrently with tofacitinib. The decision to use live vaccines prior totofacitinib 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 previouslyreceived two or more biological DMARDs. If live zoster vaccine is administered; it should only beadministered to patients with a known history of chickenpox or those that are seropositive for varicellazoster virus (VZV). If the history of chickenpox is considered doubtful or unreliable it isrecommended to test for antibodies against VZV.

Vaccination with live vaccines should occur at least 2 weeks but preferably 4 weeks prior to initiationof tofacitinib or in accordance with current vaccination guidelines regarding immunomodulatorymedicinal products. No data are available on the secondary transmission of infection by live vaccinesto patients receiving tofacitinib.

Gastrointestinal obstruction with a non-deformable prolonged-release formulation

Caution should be used when administering tofacitinib prolonged-release tablets to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports ofobstructive symptoms in patients with known strictures in association with the ingestion of othermedicinal products utilising a non-deformable prolonged-release formulation.

Tofacitinib prolonged-release tablets contain sorbitol. The additive effect of concomitantlyadministered 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 othermedicinal products for oral use administered concomitantly.

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 productsresults 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 andpotent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporin (moderate CYP3A4inhibitor) 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 lossof or reduced clinical response (see Figure 1). Coadministration of potent inducers of CYP3A4 withtofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increasedtofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitantadministration 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

Coadministered PK Ratio and 90% CI Recommendation

Medicinal Product

CYP3A Inhibitor

Ketoconazole AUC Tofacitinib dose should be reduced a

Cmax

CYP3A & CYP2C19 Inhibitor

Fluconazole AUC Tofacitinib dose should be reduced a

Cmax

CYP Inducer

Rifampicin AUC Efficacy may be decreased

Cmax

Methotrexate AUC No dose adjustment

Cmax

Tacrolimus AUC Combined use of tofacitinib with

Cmax tacrolimus should be avoided

Ciclosporin AUC Combined use of tofacitinib with

Cmax ciclosporin should be avoided0 0.5 1 1.5 2 2.5

Ratio relative to reference

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 (asprolonged-release tablet) once daily (see section 4.2).

Coadministration of tofacitinib did not have an effect on the PK of oral contraceptives, levonorgestreland ethinyl estradiol, in healthy female volunteers.

In RA patients, coadministration of tofacitinib with MTX 15-25 mg once weekly decreased the AUCand Cmax of MTX by 10% and 13%, respectively. The extent of decrease in MTX exposure does notwarrant modifications to the individualised dosing of MTX.

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 andperi/postnatal development (see section 5.3).

As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (seesection 4.3).

Women of childbearing potential should be advised to use effective contraception during treatmentwith tofacitinib and for at least 4 weeks after the last dose.

Based on published data, tofacitinib is excreted in human milk. The effects of tofacitinib on thebreast-fed infant from published literature and post-marketing data is unknown and is limited to asmall number of cases with no causally related adverse events. A risk to the breast-fed child cannot beexcluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated(see section 4.3).

Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impairedfemale fertility but not male fertility in rats (see section 5.3).

Tofacitinib has no or negligible influence on the ability to drive and use machines.

The most common serious adverse reactions were serious infections (see section 4.4). In the long-termsafety all exposure population, the most common serious infections reported with tofacitinib werepneumonia (1.7%), herpes zoster (0.6%), urinary tract infection (0.4%), cellulitis (0.4%), diverticulitis(0.3%), and appendicitis (0.2%). Among opportunistic infections, TB and other mycobacterialinfections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster,cytomegalovirus infection, BK virus infections and listeriosis were reported with tofacitinib. Somepatients have presented with disseminated rather than localised disease. Other serious infections thatwere not reported in clinical studies may also occur (e.g., coccidioidomycosis).

The most commonly reported adverse reactions during the first 3 months of the double-blind, placeboor MTX controlled clinical studies were headache (3.9%), upper respiratory tract infections (3.8%),viral upper respiratory tract infection (3.3%), diarrhoea (2.9%), nausea (2.7%), and hypertension(2.2%).

The proportion of patients who discontinued treatment due to adverse reactions during first 3 monthsof the double-blind, placebo or MTX controlled studies was 3.8% for patients taking tofacitinib. Themost common infections resulting in discontinuation of therapy during the first 3 months in controlledclinical studies were herpes zoster (0.19%) and pneumonia (0.15%).

Overall, the safety profile observed in patients with active PsA treated with tofacitinib was consistentwith the safety profile observed in patients with RA treated with tofacitinib.

Overall, the safety profile observed in patients with active AS treated with tofacitinib was consistentwith the safety profile observed in patients with RA treated with tofacitinib.

The adverse reactions listed in the table below are from clinical studies in patients with RA, PsA, AS,and UC and are presented by System Organ Class (SOC) and frequency categories, defined using thefollowing 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 estimatedfrom the available data). Within each frequency grouping, adverse reactions are presented in the orderof decreasing seriousness.

Table 7: Adverse reactions

System organ Common Uncommon Rare Very rare Not knownclass ≥1/100 to <1/10 ≥1/1,000 to ≥1/10,000 to <1/10,000 (cannot be<1/100 <1/1,000 estimated fromthe availabledata)

Infections and Pneumonia Tuberculosis Sepsis Tuberculosisinfestations Influenza Diverticulitis Urosepsis of central

Herpes zoster Pyelonephritis Disseminated nervous

Urinary tract Cellulitis TB systeminfection Herpes simplex Bacteraemia Meningitis

Sinusitis Gastroenteritis viral Pneumocystis cryptococcal

Bronchitis Viral infection jirovecii Necrotizing

Nasopharyngitis pneumonia fasciitis

Pharyngitis Pneumonia Encephalitispneumococcal Staphylococca

Pneumonia l bacteraemiabacterial Mycobacteriu

Cytomegalovir m aviumus infection complex

Arthritis infectionbacterial Atypicalmycobacterialinfection

Neoplasms Lung cancer Lymphomabenign, Non-melanoma skinmalignant and cancersunspecified (inclcysts and polyps)

Blood and Lymphopenia Leukopenialymphatic system Anaemia Neutropeniadisorders

Immune system Hypersensitivitydisorders *

Angioedema*

Urticaria*

Metabolism and Dyslipidaemianutrition Hyperlipidaemiadisorders Dehydration

Psychiatric Insomniadisorders

Nervous system Headache Paraesthesiadisorders

Cardiac disorders Myocardialinfarction

Vascular Hypertension Venousdisorders thromboembolism**

Respiratory, Cough Dyspnoeathoracic and Sinus congestionmediastinaldisorders

Gastrointestinal Abdominal paindisorders Vomiting

Nausea

Gastritis

Dyspepsia

System organ Common Uncommon Rare Very rare Not knownclass ≥1/100 to <1/10 ≥1/1,000 to ≥1/10,000 to <1/10,000 (cannot be<1/100 <1/1,000 estimated fromthe availabledata)

Hepatobiliary Hepatic steatosis Liver functiondisorders Hepatic enzyme test abnormalincreased

Transaminasesincreased

Gamma glutamyl-transferase increased

Skin and Rash Erythemasubcutaneous Acne Pruritustissue disorders

Musculoskeletal Arthralgia Joint swelling Musculoskeletand connective Tendonitis al paintissue disorders

General disorders Oedema Pyrexiaand peripheral Fatigueadministrationsite conditions

Investigations Blood creatine Blood creatininephosphokinase increasedincreased Blood cholesterolincreased

Low densitylipoprotein increased

Weight increased

Injury, poisoning Ligament sprainand procedural Muscle straincomplications

*Spontaneous reporting data

**Venous thromboembolism includes PE, DVT, and Retinal Venous Thrombosis

In a large (N=4,362), randomised post-authorisation safety study of rheumatoid arthritis patients whowere 50 years of age and older and had at least one additional cardiovascular (CV) risk factor, VTEwas observed at an increased and dose-dependent incidence in patients treated with tofacitinibcompared to TNF inhibitors (see section 5.1). The majority of these events were serious and someresulted in death. The incidence rates (95% CI) for PE for tofacitinib 5 mg twice daily, tofacitinib10 mg twice daily, and TNF inhibitors were 0.17 (0.08-0.33), 0.50 (0.32-0.74), and 0.06(0.01-0.17) patients with events per 100 patient-years, respectively. Compared with TNF inhibitors,the hazard ratio (HR) for PE was 2.93 (0.79-10.83) and 8.26 (2.49, 27.43) for tofacitinib 5 mg twicedaily and tofacitinib 10 mg twice daily, respectively (see section 5.1). In tofacitinib-treated patientswhere PE was observed, the majority (97%) had VTE risk factors.

In the combined Phase 2 and Phase 3 randomised controlled clinical trials, there were no VTE eventsin 420 patients (233 patient-years of observation) receiving tofacitinib up to 48 weeks.

In controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg film-coatedtablets twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) tofacitinibmonotherapy groups were 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to18.9% (23 patients) in the placebo group (total 122 patients). In controlled phase 3 clinical studieswith background DMARDs, the rates of infections over 0-3 months in the 5 mg twice daily (total973 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 placeboplus 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 withevents for 5 mg and 10 mg twice daily, respectively). For patients (total 1,750) on monotherapy, therates 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 patientswith events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.

In the combined Phase 2 and Phase 3 clinical trials, during the placebo-controlled period of up to16 weeks, the frequency of infections in the tofacitinib 5 mg twice daily group (185 patients) was27.6% and the frequency in the placebo group (187 patients) was 23.0%. In the combined Phase 2 and

Phase 3 clinical trials, among the 316 patients treated with tofacitinib 5 mg twice daily for up to48 weeks, the frequency of infections was 35.1%.

In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mgtwice daily tofacitinib monotherapy group was 1.7 patients with events per 100 patient-years. In the10 mg twice daily tofacitinib monotherapy group the rate was 1.6 patients with events per100 patient-years, the rate was 0 events per 100 patient-years for the placebo group, and the rate was1.9 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 and10 mg twice daily tofacitinib plus DMARD groups were 3.6 and 3.4 patients with events per100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in theplacebo plus DMARD group.

In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and3.0 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 tractinfection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have beenreported (see section 4.4).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years or older with at least one additional cardiovascular risk factor, a dose-dependent increase inserious infections was observed with tofacitinib compared to TNF inhibitors (see section 4.4).

The incidence rates (95% CI) for serious infections for tofacitinib 5 mg twice daily, tofacitinib 10 mgtwice daily, and TNF inhibitors were 2.86 (2.41, 3.37), 3.64 (3.11, 4.23), and 2.44 (2.02, 2.92) patientswith events per 100 patient-years, respectively. Compared with TNF inhibitors, the hazard ratio (HR)for serious infections was 1.17 (0.92, 1.50) and 1.48 (1.17, 1.87) for tofacitinib 10 mg twice daily andtofacitinib 5 mg twice daily, respectively.

In the combined Phase 2 and Phase 3 clinical trials, among the 316 patients treated with tofacitinib5 mg twice daily for up to 48 weeks, there was one serious infection (aseptic meningitis) yielding arate of 0.43 patients with events per 100 patient-years.

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 patientswere 65 years of age and older, including 85 patients 75 years and older. The frequency of seriousinfection among tofacitinib-treated patients 65 years of age and older was higher than those under theage of 65 (4.8 per 100 patient-years versus 2.4 per 100 patient-years, respectively).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years or older with at least one additional cardiovascular risk factor, an increase in seriousinfections was observed in patients 65 years of age and older for tofacitinib 10 mg twice dailycompared to TNF inhibitors and to tofacitinib 5 mg twice daily (see section 4.4). The incidence rates(95% CI) for serious infections in patients ≥65 years were 4.03 (3.02, pct. 5.27), 5.85 (4.64, 7.30), and 3.73(2.81, pct. 4.85) patients with events per 100 patient-years for tofacitinib 5 mg twice daily, tofacitinib 10mg twice daily, and TNF inhibitors, respectively.

Compared with TNF inhibitors, the hazard ratio (HR) for serious infections in patients ≥65 years ofage was 1.08 (0.74, 1.58) and 1.55 (1.10, 2.19) for tofacitinib 5 mg twice daily and tofacitinib 10 mgtwice daily, respectively.

Serious infections from non-interventional post approval safety study

Data from a non-interventional post approval safety study that evaluated tofacitinib in RA patientsfrom a registry (US Corrona) showed that a numerically higher incidence rate of serious infection wasobserved for the 11 mg prolonged-release tablet administered once daily than the 5 mg film-coatedtablet administered twice daily. Crude incidence rates (95% CI) (i.e., not adjusted for age or sex) fromavailability of each formulation at 12 months following initiation of treatment were 3.45 (1.93, 5.69)and 2.78 (1.74, 4.21) and at 36 months were 4.71 (3.08, 6.91) and 2.79 (2.01, 3.77) patients withevents per 100 patient-years in the 11 mg prolonged-release tablet once daily and 5 mg film-coatedtablet twice daily groups, respectively. The unadjusted hazard ratio was 1.30 (95% CI: 0.67, 2.50) at12 months and 1.93 (95% CI: 1.15, 3.24) at 36 months for the 11 mg prolonged-release once dailydose compared to the 5 mg film-coated twice daily dose. Data is based on a small number of patientswith events observed with relatively large confidence intervals and limited follow up time.

Patients treated with tofacitinib who are Japanese or Korean, or patients with long standing RA whohave previously received two or more biological DMARDs, or patients with an ALC lessthan 1,000 cells/mm3, or patients treated with 10 mg twice daily may have an increased risk of herpeszoster (see section 4.4).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years or older with at least one additional cardiovascular risk factor, an increase in herpes zosterevents was observed in patients treated with tofacitinib compared to TNF inhibitors. The incidencerates (95% CI) for herpes zoster for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and

TNF inhibitors were 3.75 (3.22, pct. 4.34), 3.94 (3.38, 4.57), and 1.18 (0.90, 1.52) patients with events per100 patient-years, respectively.

In the controlled RA clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in0.3% of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twicedaily and 10 mg twice daily doses combined.

In the RA long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twicedaily and 10 mg twice daily doses combined.

Confirmed ALC less than 750 cells/mm3 were associated with an increased incidence of seriousinfections (see section 4.4).

In the controlled RA clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were noconfirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was noclear relationship between neutropenia and the occurrence of serious infections.

In the RA long-term safety population, the pattern and incidence of confirmed decreases in ANCremained consistent with what was seen in the controlled clinical studies (see section 4.4).

Platelets

Patients in the Phase 3 controlled clinical studies (RA, PsA, AS) were required to have a platelet count≥ 100,000 cells/mm3 to be eligible for enrolment, therefore, there is no information available forpatients with a platelet count < 100,000 cells/mm3 before starting treatment with tofacitinib.

Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) wereuncommonly 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 ofliver 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 receivingplacebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greaterthan 3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, tofacitinib 5 mgand 10 mg twice daily, respectively.

In the RA phase 3 monotherapy study (0-24 months) (study VI, see section 5.1), ALT elevationsgreater than 3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving MTX, tofacitinib5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN wereobserved 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 thesestudies, AST elevations greater than 3x ULN were observed in 0.72%, 0.5% and 0.31% of patientsreceiving 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 wereobserved 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 mgtwice daily groups.

In the RA long-term extension studies, on background DMARDs, ALT elevations greater than3x 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 tofacitinib5 mg and 10 mg twice daily groups.

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years or older with at least one additional cardiovascular risk factor, ALT elevations greater than orequal to 3x ULN were observed in 6.01%, 6.54% and 3.77% of patients receiving tofacitinib 5 mgtwice daily, tofacitinib 10 mg twice daily, and TNF inhibitors respectively. AST elevations greaterthan or equal to 3x ULN were observed in 3.21%, 4.57% and 2.38% of patients receiving tofacitinib5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors respectively.

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 clinicalstudies 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 controlledclinical studies in RA are summarised below:

- Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 20% inthe tofacitinib 10 mg twice daily arm at month 12, and increased by 16% in the tofacitinib5 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% inthe tofacitinib 10 mg twice daily arm at month 12, and increased by 19% in the tofacitinib5 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 wereessentially unchanged in tofacitinib-treated patients.

In an RA controlled clinical study, elevations in LDL cholesterol and ApoB decreased to pretreatmentlevels in response to statin therapy.

In the RA long-term safety populations, elevations in the lipid parameters remained consistent withwhat was seen in the controlled clinical studies.

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years or older with at least one additional cardiovascular risk factor, changes in lipid parametersfrom baseline through 24 months are summarised below:

- Mean LDL cholesterol increased by 13.80%, 17.04%, and 5.50% in patients receiving tofacitinib5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor, respectively, at month 12. Atmonth 24, the increase was 12.71%, 18.14%, and 3.64%, respectively,

- Mean HDL cholesterol increased by 11.71%, 13.63%, and 2.82% in patients receiving tofacitinib5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor, respectively, at month 12. Atmonth 24, the increase was 11.58%, 13.54%, and 1.42%, respectively.

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years of age or older with at least one additional cardiovascular risk factor, the incidence rates(95% CI) for non-fatal myocardial infarction for tofacitinib 5 mg twice daily, tofacitinib 10 mg twicedaily, and TNF inhibitors were 0.37 (0.22, 0.57), 0.33 (0.19, 0.53), and 0.16 (0.07, 0.31) patients withevents per 100 patient-years, respectively. Few fatal myocardial infarctions were reported with ratessimilar in patients treated with tofacitinib compared to TNF inhibitors (see sections 4.4 and 5.1). Thestudy required at least 1500 patients to be followed for 3 years.

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were50 years of age or older with at least one additional cardiovascular risk factor, the incidence rates(95% CI) for lung cancer for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNFinhibitors were 0.23 (0.12, 0.40), 0.32 (0.18, 0.51), and 0.13 (0.05, 0.26) patients with events per100 patient-years, respectively (see sections 4.4 and 5.1). The study required at least 1500 patients tobe followed for 3 years.

The incidence rates (95% CI) for lymphoma for tofacitinib 5 mg twice daily, tofacitinib 10 mg twicedaily, and TNF inhibitors were 0.07 (0.02, 0.18), 0.11 (0.04, 0.24), and 0.02 (0.00, 0.10) patients withevents per 100 patient-years, respectively (see sections 4.4 and 5.1).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms ofadverse reactions. There is no specific antidote for overdose with tofacitinib. Treatment should besymptomatic and supportive.

Pharmacokinetic data up to and including a single dose of 100 mg in healthy volunteers indicate thatmore than 95% of the administered dose is expected to be eliminated within 24 hours.

Pharmacotherapeutic groups: Immunosuppressants, Janus-associated kinase (JAK) inhibitors; ATCcode: L04AF01

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 ofselectivity against other kinases in the human genome. In human cells, tofacitinib preferentiallyinhibits signalling by heterodimeric cytokine receptors that associate with JAK3 and/or JAK1 withfunctional 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 andtype II interferons, which will result in modulation of the immune and inflammatory response.

In patients with RA, treatment up to 6 months with tofacitinib was associated with dose-dependentreductions of circulating CD16/56+ natural killer (NK) cells, with estimated maximum reductionsoccurring at approximately 8-10 weeks after initiation of therapy. These changes generally resolvedwithin 2-6 weeks after discontinuation of treatment. Treatment with tofacitinib was associated withdose-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. Incontrast to the observed decrease after short-term dosing, CD16/56+ natural killer cell counts showeda median increase of 73% from baseline. CD19+ B cell counts showed no further increases afterlong-term tofacitinib treatment. All these lymphocyte subset changes returned toward baseline aftertemporary discontinuation of treatment. There was no evidence of a relationship between serious oropportunistic infections or herpes zoster and lymphocyte subset counts (see section 4.2 for absolutelymphocyte count monitoring).

Changes in total serum IgG, IgM, and IgA levels over 6-month tofacitinib dosing in patients with RAwere small, not dose-dependent and similar to those seen on placebo, indicating a lack of systemichumoral 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 treatmentdo not reverse fully within 2 weeks after discontinuation, indicating a longer duration ofpharmacodynamic activity compared to the half-life.

In a controlled clinical study 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%) andplacebo (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 MTXmonotherapy; and 77% for placebo. The clinical significance of this is unknown, however, similarresults were obtained in a separate vaccine study with influenza and pneumococcal polysaccharidevaccines 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 liveattenuated herpes virus vaccine 2 to 3 weeks before initiating a 12-week treatment with tofacitinib5 mg twice daily or placebo. Evidence of humoral and cell-mediated responses to VZV was observedin both tofacitinib and placebo-treated patients at 6 weeks. These responses were similar to thoseobserved in healthy volunteers aged 50 years and older. A patient with no previous history of varicellainfection and no anti-varicella antibodies at baseline experienced dissemination of the vaccine strainof varicella 16 days after vaccination. Tofacitinib was discontinued and the patient recovered aftertreatment with standard doses of antiviral medicinal product. This patient subsequently made a robust,though delayed, humoral and cellular response to the vaccine (see section 4.4).

The efficacy and safety of tofacitinib film-coated tablets were assessed in 6 randomised, double-blind,controlled multicentre studies in patients greater than 18 years of age with active RA diagnosedaccording to American College of Rheumatology (ACR) criteria. Table 8 provides informationregarding the pertinent study design and population characteristics.

Table 8: Phase 3 clinical studies of tofacitinib 5 mg and 10 mg twice daily doses in patients with

RA

Studies Study I Study II Study III Study IV Study V Study VI Study VII(ORAL (ORAL (ORAL (ORAL (ORAL (ORAL (ORAL

Solo) Sync) Standard) Scan) Step) Start) Strategy)

Population DMARD-IR DMARD- MTX-IR MTX-IR TNFi-IR MTX-naïvea MTX-IR

IR

Control Placebo Placebo Placebo Placebo Placebo MTX MTX,

ADA

Background Noneb csDMARDs MTX MTX MTX Noneb 3 Parallel arms:treatment - Tofacitinibmonotherapy

- Tofacitinib+MTX

- ADA+MTX

Key features Monotherapy Various Active X-Ray TNFi-IR Monotherapy, Tofacitinib with andcsDMARDs control Active without MTX in(ADA) comparator comparison to ADA(MTX), with MTX

X-Ray

Studies Study I Study II Study III Study IV Study V Study VI Study VII(ORAL (ORAL (ORAL (ORAL (ORAL (ORAL (ORAL

Solo) Sync) Standard) Scan) Step) Start) Strategy)

Number of 610 792 717 797 399 956 1,146patientstreated

Total study 6 months 1 year 1 year 2 years 6 months 2 years 1 yearduration

Co-primary Month 3: Month 6: Month 6: Month 6: Month 3: Month 6: Month 6:efficacy ACR20 ACR20 ACR20 ACR20 ACR20 mTSS ACR50endpointsc HAQ-DI DAS28- DAS28- mTSS HAQ-DI ACR70

DAS28- 4(ESR)<2.6 4(ESR)<2.6 DAS28- DAS28-4(ESR)<2.6 Month 3: Month 3: 4(ESR)<2.6 4(ESR)<2.6

HAQ-DI HAQ-DI Month 3:

HAQ-DI

Time of Month 3 Month 6 (placebo subjects with < 20% Month 3 NA NAmandatory improvement in swollen and tender jointplacebo counts advanced to tofacitinib atrescue to month 3)tofacitinib5 mg or10 mg twicedaily

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 ACR70responses; 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.

The percentages of tofacitinib-treated patients achieving ACR20, ACR50 and ACR70 responses instudies ORAL Solo, ORAL Sync, ORAL Standard, ORAL Scan, ORAL Step, ORAL Start, and

ORAL Strategy are shown in Table 9. In all studies, patients treated with either 5 mg or 10 mg twicedaily tofacitinib had statistically significant ACR20, ACR50 and ACR70 response rates at month 3and 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 werenumerically similar compared to adalimumab 40 mg + MTX and both were numerically higher thantofacitinib 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 withthe overall ACR response in patients treated with 5 mg or 10 mg twice daily tofacitinib, each of thecomponents of the ACR response was consistently improved from baseline including: tender andswollen joint counts; patient and physician global assessment; disability index scores; pain assessmentand CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.

Table 9: Proportion (%) of patients with an ACR response

ORAL Solo: DMARD inadequate responders

Tofacitinib 5 mg Tofacitinib 10 mg

Placebo twice daily twice daily

Endpoint Time

N=122 monotherapy monotherapy

N=241 N=243

Month 3 26 60*** 65***

ACR20

Month 6 NA 69 71

Month 3 12 31*** 37***

ACR50

Month 6 NA 42 47

Month 3 6 15* 20***

ACR70

Month 6 NA 22 29

ORAL Sync: DMARD inadequate responders

Placebo + Tofacitinib 5 mg Tofacitinib 10 mg

DMARD(s) twice daily + twice daily +

Endpoint Time

DMARD(s) DMARD(s)

N=158 N=312 N=315

Month 3 27 56*** 63***

ACR20 Month 6 31 53*** 57***

Month 12 NA 51 56

Month 3 9 27*** 33***

ACR50 Month 6 13 34*** 36***

Month 12 NA 33 42

Month 3 2 8** 14***

ACR70 Month 6 3 13*** 16***

Month 12 NA 19 25

ORAL Standard: MTX inadequate responders

Tofacitinib Adalimumab 40 mg

Endpoint Time Placebo twice daily + MTX QOW+ MTX5 mg 10 mg

N=105 N=198 N=197 N=199

ACR20 Month 3 26 59*** 57*** 56***

Month 6 28 51*** 51*** 46**

Month 12 NA 48 49 48

Month 3 7 33*** 27*** 24***

ACR50 Month 6 12 36*** 34*** 27**

Month 12 NA 36 36 33

Month 3 2 12** 15*** 9*

ACR70 Month 6 2 19*** 21*** 9*

Month 12 NA 22 23 17

ORAL Scan: MTX inadequate responders

Tofacitinib 5 mg Tofacitinib 10 mg

Placebo + MTX twice daily twice daily

Endpoint Time

N=156 + MTX + MTX

N=316 N=309

Month 3 27 55*** 66***

Month 6 25 50*** 62***

ACR20

Month 12 NA 47 55

Month 24 NA 40 50

Month 3 8 28*** 36***

Month 6 8 32*** 44***

ACR50

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

Tofacitinib 5 mg Tofacitinib 10 mg

Placebo + MTX twice daily twice daily

Endpoint Time

N=132 + MTX + MTX

N=133 N=134

Month 3 24 41* 48***

ACR20

Month 6 NA 51 54

Month 3 8 26*** 28***

ACR50

Month 6 NA 37 30

Month 3 2 14*** 10*

ACR70

Month 6 NA 16 16

ORAL Start: MTX-naïve

Tofacitinib 5 mg Tofacitinib 10 mg

MTX twice daily twice daily

Endpoint Time

N=184 monotherapy monotherapy

N=370 N=394

Month 3 52 69*** 77***

Month 6 51 71*** 75***

ACR20

Month 12 51 67** 71***

Month 24 42 63*** 64***

Month 3 20 40*** 49***

Month 6 27 46*** 56***

ACR50

Month 12 33 49** 55***

Month 24 28 48*** 49***

Month 3 5 20*** 26***

Month 6 12 25*** 37***

ACR70

Month 12 15 28** 38***

Month 24 15 34*** 37***

ORAL Strategy: MTX inadequate responders

Tofacitinib 5 mg Tofacitinib 5 mg

Adalimumabtwice daily twice daily

Endpoint Time + MTX

N=384 + MTX

N=386

N=376

Month 3 62.50 70.48ǂ 69.17

ACR20 Month 6 62.84 73.14ǂ 70.98

Month 12 61.72 70.21ǂ 67.62

Month 3 31.51 40.96ǂ 37.31

ACR50 Month 6 38.28 46.01ǂ 43.78

Month 12 39.31 47.61ǂ 45.85

Month 3 13.54 19.41ǂ 14.51

ACR70 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 multiplecomparison 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 atbaseline. Significant reductions in DAS28-4(ESR) from baseline (mean improvement) of 1.8-2.0 and1.9-2.2 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 isshown in Table 10.

Table 10: 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.

In ORAL Scan and ORAL Start, inhibition of progression of structural joint damage was assessedradiographically and expressed as mean change from baseline in mTSS and its components, theerosion 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 greaterinhibition 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 meanprogression of structural damage (not statistically significant). Analysis of erosion and JSN scoreswere consistent with overall results.

In the placebo plus MTX group, 78% of patients experienced no radiographic progression (mTSSchange less than or equal to 0.5) at month 6 compared to 89% and 87% of patients treated withtofacitinib 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 progressionof structural damage compared to MTX at months 6 and 12 as shown in Table 11, which was alsomaintained 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 to83% and 90% of patients treated with tofacitinib 5 mg or 10 mg twice daily respectively, bothsignificant versus MTX.

Table 11: Radiographic changes at months 6 and 12

ORAL Scan: MTX inadequate responders

Placebo + Tofacitinib Tofacitinib Tofacitinib Tofacitinib

MTX 5 mg 5 mg 10 mg 10 mg

N=139 twice daily + twice daily + MTX twice daily + twice daily +

Mean MTX Mean difference MTX MTX(SD)a N=277 from placebob (CI) N=290 Mean difference

Mean (SD)a Mean (SD)a from placebob(CI)mTSSc

Baseline 33 (42) 31 (48) - 37 (54) -

Month 6 0.5 (2.0) 0.1 (1.7) -0.3 (-0.7, 0.0) 0.1 (2.0) -0.4 (-0.8, 0.0)

Month 12 1.0 (3.9) 0.3 (3.0) -0.6 (-1.3, 0.0) 0.1 (2.9) -0.9 (-1.5, -0.2)

ORAL Start: MTX-naïve

MTX Tofacitinib Tofacitinib Tofacitinib Tofacitinib

N=168 5 mg 5 mg 10 mg 10 mg

Mean twice daily twice daily twice daily twice daily(SD)a N=344 Mean difference N=368 Mean difference

Mean (SD)a from MTXd (CI) Mean (SD)a from MTXd (CI)mTSSc

Baseline 16 (29) 20 (41) - 19 (39) -

Month 6 0.9 (2.7) 0.2 (2.3) -0.7 (-1.0, -0.3) 0.0 (1.2) -0.8 (-1.2, -0.4)

Month 12 1.3 (3.7) 0.4 (3.0) -0.9 (-1.4, -0.4) 0.0 (1.5) -1.3 (-1.8, -0.8)a SD = Standard Deviationb Difference between least squares means tofacitinib minus placebo (95% CI = 95% confidence interval)c Month 6 and month 12 data are mean change from baselined 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, asmeasured by the HAQ-DI. Patients receiving tofacitinib 5 mg or 10 mg twice daily demonstratedsignificantly greater improvement from baseline in physical functioning compared to placebo atmonth 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 patientsdemonstrated significantly greater improvement in physical functioning compared to placebo as earlyas 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 12.

Table 12: LS Mean change from baseline in HAQ-DI at month 3

Placebo + Tofacitinib Tofacitinib Adalimumab

MTX 5 mg twice daily 10 mg twice 40 mg QOW+ MTX daily + MTX+ 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 Tofacitinib5 mg twice daily + 10 mg twice

DMARD(s) 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 otherweek, 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). Patientsreceiving either 5 mg or 10 mg tofacitinib twice daily experienced significantly greater improvementfrom 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 or10 mg twice daily demonstrated significantly greater improvement from baseline in fatigue comparedto placebo in all 5 studies. In ORAL Standard and ORAL Scan, mean FACIT-F improvements weremaintained 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 receivingtofacitinib 5 mg or 10 mg twice daily demonstrated significantly greater improvement from baseline inboth 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 intofacitinib-treated patients.

Durability of clinical responses

Durability of effect was assessed by ACR20, ACR50, ACR70 response rates in studies of duration ofup to two years. Changes in mean HAQ-DI and DAS28-4(ESR) were maintained in both tofacitinibtreatment groups through to the end of the studies.

Evidence of persistence of efficacy with tofacitinib treatment for up to 5 years is also provided fromdata in a randomised post-authorisation safety study in patients with RA who were 50 years of age orolder with at least one additional cardiovascular risk factor, as well as in completed open-label,long-term follow-up studies up to 8 years.

Long-term controlled safety data

Study ORAL Surveillance (A3921133) was a large (N=4362), randomised active-controlledpost-authorisation safety surveillance study of rheumatoid arthritis patients who were 50 years of ageand older and had at least one additional cardiovascular risk factor (CV risk factors defined as: currentcigarette smoker, diagnosis of hypertension, diabetes mellitus, family history of premature coronaryheart disease, history of coronary artery disease including a history of revascularization procedure,coronary artery bypass grafting, myocardial infarction, cardiac arrest, unstable angina, acute coronarysyndrome, and presence of extra-articular disease associated with RA, e.g. nodules, Sjögren’ssyndrome, anaemia of chronic disease, pulmonary manifestations). The majority (more than 90%) oftofacitinib patients who were current or past smokers had a smoking duration of more than 10 yearsand a median of 35.0 and 39.0 smoking years, respectively. Patients were required to be on a stabledose of methotrexate at study entry; dose adjustment was permitted during the study.

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 everyother week) in a 1:1:1 ratio. The co-primary endpoints were adjudicated malignancies excluding

NMSC and adjudicated major adverse cardiovascular events (MACE); cumulative incidence andstatistical assessment of endpoints were blinded. The study was an event-powered study that alsorequired at least 1500 patients to be followed for 3 years. The study treatment of tofacitinib 10 mgtwice daily was stopped and patients were switched to 5 mg twice daily because of a dose-dependentsignal of venous thromboembolic events (VTE). For patients in the tofacitinib 10 mg twice dailytreatment arm, the data collected before and after the dose switch were analysed in their originallyrandomised treatment group.

The study did not meet the non-inferiority criterion for the primary comparison of the combinedtofacitinib doses to TNF inhibitor since the upper limit of the 95% CI for HR exceeded thepre-specified non-inferiority criterion of 1.8 for adjudicated MACE and adjudicated malignanciesexcluding NMSC.

The results for adjudicated MACE, adjudicated malignancies excluding NMSC, and selected otherevents are provided below.

MACE (including myocardial infarction) and venous thromboembolism (VTE)

An increase in non-fatal myocardial infarction was observed in patients treated with tofacitinibcompared to TNF inhibitor. A dose-dependent increase in VTE events was observed in patients treatedwith tofacitinib compared to TNF inhibitor (see sections 4.4 and 4.8).

Table 13: Incidence rate and hazard ratio for MACE, myocardial infarction and venousthromboembolism

Tofacitinib 5 mg Tofacitinib 10 mg All Tofacitinibb TNF inhibitortwice daily twice dailya (TNFi)

MACEc

IR (95% CI) per 100 0.91 (0.67, 1.21) 1.05 (0.78, 1.38) 0.98 (0.79, 1.19) 0.73 (0.52, 1.01)

PY

HR (95% CI) vs TNFi 1.24 (0.81, 1.91) 1.43 (0.94, 2.18) 1.33 (0.91, 1.94)

Fatal MIc

IR (95% CI) per 100 0.00 (0.00, 0.07) 0.06 (0.01, 0.18) 0.03 (0.01, 0.09) 0.06 (0.01, 0.17)

PY

HR (95% CI) vs TNFi 0.00 (0.00, Inf) 1.03 (0.21, 5.11) 0.50 (0.10, 2.49)

Non-fatal MIc

IR (95% CI) per 100 0.37 (0.22, 0.57) 0.33 (0.19, 0.53) 0.35 (0.24, 0.48) 0.16 (0.07, 0.31)

PY

HR (95% CI) vs TNFi 2.32 (1.02, 5.30) 2.08 (0.89, pct. 4.86) 2.20 (1.02, 4.75)

VTEd

IR (95% CI) per 100 0.33 (0.19, 0.53) 0.70 (0.49, 0.99) 0.51 (0.38, 0.67) 0.20 (0.10, 0.37)

PY

HR (95% CI) vs TNFi 1.66 (0.76, 3.63) 3.52 (1.74, 7.12) 2.56 (1.30, 5.05)

PEd

IR (95% CI) per 100 0.17 (0.08, 0.33) 0.50 (0.32, 0.74) 0.33 (0.23, 0.46) 0.06 (0.01, 0.17)

PY

HR (95% CI) vs TNFi 2.93 (0.79, 10.83) 8.26 (2.49, 27.43) 5.53 (1.70, 18.02)

DVTd

IR (95% CI) per 100 0.21 (0.11, 0.38) 0.31 (0.17, 0.51) 0.26 (0.17, 0.38) 0.14 (0.06, 0.29)

PY

HR (95% CI) vs TNFi 1.54 (0.60, 3.97) 2.21 (0.90, 5.43) 1.87 (0.81, pct. 4.30)a The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mg twice dailyto tofacitinib 5 mg twice daily as a result of a study modification.b Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.c Based on events occurring on treatment or within 60 days of treatment discontinuation.d Based on events occurring on treatment or within 28 days of treatment discontinuation.

Abbreviations: MACE = major adverse cardiovascular events, MI = myocardial infarction, VTE = venous thromboembolism, PE =pulmonary embolism, DVT = deep vein thrombosis, TNF = tumour necrosis factor, IR = incidence rate, HR = hazard ratio, CI =confidence interval, PY = patient years, Inf = infinity

The following predictive factors for development of MI (fatal and non-fatal) were identified using amultivariate Cox model with backward selection: age ≥65 years, male, current or past smoking,history of diabetes, and history of coronary artery disease (which includes myocardial infarction,coronary heart disease, stable angina pectoris, or coronary artery procedures) (see sections 4.4 and4.8).

An increase in malignancies excluding NMSC, particularly lung cancer, lymphoma and an increase in

NMSC was observed in patients treated with tofacitinib compared to TNF inhibitor.

Table 14: Incidence rate and hazard ratio for malignanciesa

Tofacitinib 5 mg Tofacitinib 10 mg All Tofacitinibc TNF inhibitortwice daily twice dailyb (TNFi)

IR (95% CI) per 100 1.13 (0.87, 1.45) 1.13 (0.86, 1.45) 1.13 (0.94, 1.35) 0.77 (0.55, 1.04)

PY

HR (95% CI) vs TNFi 1.47 (1.00, 2.18) 1.48 (1.00, 2.19) 1.48 (1.04, 2.09)

Lung cancer

IR (95% CI) per 100 0.23 (0.12, 0.40) 0.32 (0.18, 0.51) 0.28 (0.19, 0.39) 0.13 (0.05, 0.26)

PY

HR (95% CI) vs TNFi 1.84 (0.74, pct. 4.62) 2.50 (1.04, 6.02) 2.17 (0.95, 4.93)

Lymphoma

IR (95% CI) per 100 0.07 (0.02, 0.18) 0.11 (0.04, 0.24) 0.09 (0.04, 0.17) 0.02 (0.00, 0.10)

PY

HR (95% CI) vs TNFi 3.99 (0.45, 35.70) 6.24 (0.75, 51.86) 5.09 (0.65, 39.78)

NMSC

IR (95% CI) per 100 0.61 (0.41, 0.86) 0.69 (0.47, 0.96) 0.64 (0.50, 0.82) 0.32 (0.18, 0.52)

PY

HR (95% CI) vs TNFi 1.90 (1.04, 3.47) 2.16 (1.19, 3.92) 2.02 (1.17, 3.50)a For malignancies excluding NMSC, lung cancer, and lymphoma, based on events occurring on treatment or after treatmentdiscontinuation up to the end of the study. For NMSC based on events occurring on treatment or within 28 days of treatmentdiscontinuation.b The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mg twice dailyto tofacitinib 5 mg twice daily as a result of a study modification.c Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.

Abbreviations: NMSC = non melanoma skin cancer, TNF = tumour necrosis factor, IR = incidence rate, HR = hazard ratio, CI =confidence interval, PY = patient years

The following predictive factors for development of malignancies excluding NMSC were identifiedusing a Multivariate Cox model with backward selection: age ≥65 years and current or past smoking(see section 4.4 and 4.8).

Increased mortality was observed in patients treated with tofacitinib compared to TNF inhibitors.

Mortality was mainly due to cardiovascular events, infections and malignancies.

Table 15: Incidence rate and hazard ratio for mortalitya

Tofacitinib 5 mg Tofacitinib 10 mg All Tofacitinibc TNF inhibitortwice daily twice dailyb (TNFi)

Mortality (all cause)

IR (95% CI) per 100 PY 0.50 (0.33, 0.74) 0.80 (0.57, 1.09) 0.65 (0.50, 0.82) 0.34 (0.20, 0.54)

HR (95% CI) vs TNFi 1.49 (0.81, 2.74) 2.37 (1.34, 4.18) 1.91 (1.12, 3.27)

Fatal infections

IR (95% CI) per 100 PY 0.08 (0.02, 0.20) 0.18 (0.08, 0.35) 0.13 (0.07, 0.22) 0.06 (0.01, 0.17)

HR (95% CI) vs TNFi 1.30 (0.29, 5.79) 3.10 (0.84, 11.45) 2.17 (0.62, 7.62)

Fatal CV events

IR (95% CI) per 100 PY 0.25 (0.13, 0.43) 0.41 (0.25, 0.63) 0.33 (0.23, 0.46) 0.20 (0.10, 0.36)

HR (95% CI) vs TNFi 1.26 (0.55, 2.88) 2.05 (0.96, pct. 4.39) 1.65 (0.81, 3.34)

Fatal Malignancies

IR (95% CI) per 100 PY 0.10 (0.03, 0.23) 0.00 (0.00, 0.08) 0.05 (0.02, 0.12) 0.02 (0.00, 0.11)

HR (95% CI) vs TNFi 4.88 (0.57, 41.74) 0 (0.00, Inf) 2.53 (0.30, 21.64)a Based on events occurring on treatment or within 28 days of treatment discontinuation.b The tofacitinib 10 mg twice daily treatment group includes data from patients that were switched from tofacitinib 10 mgtwice daily to tofacitinib 5 mg twice daily as a result of a study modification.c Combined tofacitinib 5 mg twice daily and tofacitinib 10 mg twice daily.

Abbreviations: TNF = tumor necrosis factor, IR = incidence rate, HR = hazard ratio, CI = confidence interval, PY = patientyears, CV = cardiovascular, Inf = infinity

The efficacy and safety of tofacitinib film-coated tablets were assessed in 2 randomised, double-blind,placebo-controlled Phase 3 studies in adult patients with active PsA (≥ 3 swollen and ≥ 3 tenderjoints). Patients were 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 (dueto lack of efficacy or intolerance) to a csDMARD (MTX for 92.7% of patients); 32.7% of the patientsin this study had a previous inadequate response to > 1 csDMARD or 1 csDMARD and a targetedsynthetic DMARD (tsDMARD). In OPAL BROADEN, previous treatment with TNF inhibitor wasnot allowed. All patients were required to have 1 concomitant csDMARD; 83.9% of patients receivedconcomitant MTX, 9.5% of patients received concomitant sulfasalazine, and 5.7% of patients receivedconcomitant leflunomide. The median PsA disease duration was 3.8 years. At baseline, 79.9% and56.2% of patients had enthesitis and dactylitis, respectively. Patients randomised to tofacitinibreceived 5 mg twice daily or tofacitinib 10 mg twice daily for 12 months. Patients randomised toplacebo were advanced in a blinded manner at month 3 to either tofacitinib 5 mg twice daily ortofacitinib 10 mg twice daily and received treatment until month 12. Patients randomised toadalimumab (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 tolack 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 receivedconcomitant leflunomide. The median PsA disease duration was 7.5 years. At baseline, 80.7% and49.2% of patients had enthesitis and dactylitis, respectively. Patients randomised to tofacitinibreceived 5 mg twice daily or tofacitinib 10 mg twice daily for 6 months. Patients randomised toplacebo were advanced in a blinded manner at month 3 to either tofacitinib 5 mg twice daily ortofacitinib 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 forimportant endpoints assessed are shown in Table 16.

Table 16: Proportion (%) of PsA patients who achieved clinical response and mean changefrom baseline in OPAL BROADEN and OPAL BEYOND studies

Conventional synthetic DMARD TNFiinadequate respondersa (TNFi-Naïve) inadequate respondersb

OPAL BROADEN OPAL BEYONDc

Treatment Placebo Tofacitinib 5 Adalimumab 40 mg Placebo Tofacitinib 5group mg twice daily SC q2W mg twice daily

N 105 107 106 131 131

ACR20

Month 3 33% 50%d,* 52%* 24% 50%d,***

Month 6 NA 59% 64% NA 60%

Month 12 NA 68% 60% - -

ACR50

Month 3 10% 28%e,** 33%*** 15% 30%e,*

Month 6 NA 38% 42% NA 38%

Month 12 NA 45% 41% - -

ACR70

Month 3 5% 17%e,* 19%* 10% 17%

Month 6 NA 18% 30% NA 21%

Month 12 NA 23% 29% - -∆LEIf

Month 3 -0.4 -0.8 -1.1* -0.5 -1.3*

Month 6 NA -1.3 -1.3 NA -1.5

Month 12 NA -1.7 -1.6 - -∆DSSf

Month 3 -2.0 -3.5 -4.0 -1.9 -5.2*

Month 6 NA -5.2 -5.4 NA -6.0

Month 12 NA -7.4 -6.1 - -

PASI75g

Month 3 15% 43%d,*** 39%** 14% 21%

Month 6 NA 46% 55% NA 34%

Month 12 NA 56% 56% - -

*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 frombaseline 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 andtreated patients; NA=Not applicable, as data for placebo treatment is not available beyond month 3 due to placeboadvanced 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-specifiedstep-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 twice daily-treatedpatients had significantly higher ACR20 response rates compared to placebo at month 3. Examinationof age, sex, race, baseline disease activity and PsA subtype did not identify differences in response totofacitinib. The number of patients with arthritis mutilans or axial involvement was too small to allowmeaningful assessment. Statistically significant ACR20 response rates were observed with tofacitinib5 mg twice daily in both studies as early as week 2 (first post-baseline assessment) in comparison toplacebo.

In OPAL BROADEN, Minimal Disease Activity (MDA) response was achieved by 26.2%, 25.5% and6.7% of tofacitinib 5 mg twice daily, adalimumab and placebo treated patients, respectively(tofacitinib 5 mg twice daily treatment difference from placebo 19.5% [95% CI: 9.9, 29.1]) at month3. In OPAL BEYOND, MDA was achieved by 22.9% and 14.5% of tofacitinib 5 mg twice daily andplacebo treated patients, respectively, however tofacitinib 5 mg twice daily did not achieve nominalstatistical significance (treatment difference from placebo 8.4% [95% CI: -1.0, 17.8] at month 3).

In study OPAL BROADEN, the progression of structural joint damage was assessed radiographicallyutilising the van der Heijde modified Total Sharp Score (mTSS) and the proportion of patients withradiographic progression (mTSS increase from baseline greater than 0.5) was assessed at month 12. Atmonth 12, 96% and 98% of patients receiving tofacitinib 5 mg twice daily, and adalimumab 40 mgsubcutaneously every 2 weeks, respectively, did not have radiographic progression (mTSS increasefrom baseline less than or equal to 0.5).

Improvement in physical functioning was measured by the HAQ-DI. Patients receiving tofacitinib5 mg twice daily demonstrated greater improvement (p≤ 0.05) from baseline in physical functioningcompared to placebo at month 3 (see Table 17).

Table 17: 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 TNFiinadequate respondersa (TNFi-naïve) inadequate respondersb

OPAL BROADEN OPAL BEYOND

Treatment Placebo Tofacitinib 5 mg Adalimumab 40 mg Placebo Tofacitinib 5 mggroup twice daily SC q2W 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=tumournecrosis factor inhibitor.a Inadequate response to at least one conventional synthetic DMARD (csDMARD) due to lack of efficacy and/orintolerability.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 3in studies OPAL BROADEN and OPAL BEYOND was 53% and 50%, respectively in patientsreceiving tofacitinib 5 mg twice daily, 31% and 28%, respectively in patients receiving placebo, and53% in patients receiving adalimumab 40 mg subcutaneously once every 2 weeks (OPAL BROADENonly).

Health-related quality of life was assessed by SF-36v2, fatigue was assessed by the FACIT-F. Patientsreceiving tofacitinib 5 mg twice daily demonstrated greater improvement from baseline compared toplacebo in the SF-36v2 physical functioning domain, the SF-36v2 physical component summaryscore, and FACIT-F scores at month 3 in studies OPAL BROADEN and OPAL BEYOND (nominalp≤ 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-baselineassessment) through month 3 compared to placebo in studies OPAL BROADEN and OPAL

BEYOND (nominal p≤ 0.05).

The tofacitinib clinical development program to assess the efficacy and safety included oneplacebo-controlled confirmatory trial (Study AS-I). Study AS-I was a randomised, double-blind,placebo-controlled, 48-week treatment clinical trial in 269 adult patients who had an inadequateresponse (inadequate clinical response or intolerance) to at least 2 NSAIDs. Patients were randomisedand treated with tofacitinib 5 mg twice daily or placebo for 16 weeks of blinded treatment and then allwere advanced to tofacitinib 5 mg twice daily for an additional 32 weeks. Patients had active diseaseas defined by both Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and back painscore (BASDAI question 2) of greater or equal to 4 despite non-steroidal anti-inflammatory drug(NSAID), corticosteroid or DMARD therapy.

Approximately 7% and 21% of patients used concomitant methotrexate or sulfasalazine, respectively,from baseline to Week 16. Patients were allowed to receive a stable low dose of oral corticosteroids(8.6% received) and/or NSAIDs (81.8% received) from baseline to Week 48. Twenty-two percent ofpatients had an inadequate response to 1 or 2 TNF blockers. The primary endpoint was to evaluate theproportion of patients who achieved an ASAS20 response at Week 16.

Patients treated with tofacitinib 5 mg twice daily achieved greater improvements in ASAS20 and

ASAS40 responses compared to placebo at Week 16 (Table 18). The responses were maintained from

Week 16 through to Week 48 in patients receiving tofacitinib 5 mg twice daily.

Table 18: ASAS20 and ASAS40 Responses at Week 16, Study AS-I

Placebo Tofacitinib 5 mg Difference from Placebo(N=136) Twice Daily (95% CI)(N=133)

ASAS20 response*, % 29 56 27 (16, 38)**

ASAS40 response*, % 13 41 28 (18, 38)**

* type I error-controlled.

** p<0.0001.

The efficacy of tofacitinib was demonstrated in bDMARD naïve and TNF-inadequate responders(IR)/bDMARD experienced (non-IR) patients (Table 19).

Table 19: ASAS20 and ASAS40 Responses (%) by Treatment History at Week 16, Study AS-I

Prior Treatment Efficacy Endpoint

History ASAS20 ASAS40

Placebo Tofacitinib Difference Placebo Tofacitinib Difference

N 5 mg from Placebo N 5 mg Twice from

Twice (95% CI) Daily Placebo

Daily N (95% CI)

NbDMARD-Naïve 105 102 28 105 102 31(15, 41) (19, 43)

TNFi-IR or 31 31 23 31 31 19bDMARD Use (1, 44) (2, 37)(Non-IR)

ASAS20 = An improvement from Baseline ≥ 20% and ≥ 1 unit increase in at least 3 domains on a scale of 0 to 10, and noworsening of ≥ 20% and ≥ 1 unit in the remaining domain; ASAS40 = An improvement from Baseline ≥ 40% and≥ 2 units in at least 3 domains on a scale of 0 to 10 and no worsening at all in the remaining domain; bDMARD = biologicdisease-modifying anti-rheumatic drug; CI = confidence interval; Non-IR = non-inadequate response; TNFi-IR = tumournecrosis factor inhibitor inadequate response.

The improvements in the components of the ASAS response and other measures of disease activitywere higher in tofacitinib 5 mg twice daily compared to placebo at Week 16 as shown in Table 20.

The improvements were maintained from Week 16 through to Week 48 in patients receivingtofacitinib 5 mg twice daily.

Table 20: ASAS Components and Other Measures of Disease Activity at Week 16, Study AS-I

Placebo Tofacitinib 5 mg Twice Daily(N=136) (N=133)

Baseline Week 16 Baseline Week 16 Difference(mean) (LSM (mean) (LSM from Placebochange from change from (95% CI)

Baseline) Baseline)

ASAS Components Patient Global 7.0 -0.9 6.9 -2.5 -1.6

Assessment of (-2.07, -1.05)**

Disease Activity(0-10)a,* Total spinal pain 6.9 -1.0 6.9 -2.6 -1.6(0-10)a,* (-2.10, -1.14)** BASFI 5.9 -0.8 5.8 -2.0 -1.2(0-10)b,* (-1.66, -0.80)** Inflammation 6.8 -1.0 6.6 -2.7 -1.7(0-10)c,* (-2.18, -1.25)**

BASDAI Scored 6.5 -1.1 6.4 -2.6 -1.4(-1.88, -1.00)**

BASMIe,* 4.4 -0.1 4.5 -0.6 -0.5(-0.67, -0.37)**hsCRPf,* (mg/dL) 1.8 -0.1 1.6 -1.1 -1.0(-1.20, -0.72)**

ASDAScrpg,* 3.9 -0.4 3.8 -1.4 -1.0(-1.16, -0.79)**

* type I error-controlled.

** p<0.0001.a Measured on a numerical rating scale with 0 = not active or no pain, 10 = very active or most severe pain.b Bath Ankylosing Spondylitis Functional Index measured on a numerical rating scale with 0 = easy and 10 = impossible.c Inflammation is the mean of two patient-reported stiffness self-assessments in BASDAI.d Bath Ankylosing Spondylitis Disease Activity Index total score.e Bath Ankylosing Spondylitis Metrology Index.f High sensitivity C-reactive protein.g Ankylosing Spondylitis Disease Activity Score with C-reactive protein.

LSM = least squares mean.

Other health-related outcomes

Patients treated with tofacitinib 5 mg twice daily achieved greater improvements from baseline in

Ankylosing Spondylitis Quality of Life (ASQoL) (-4.0 vs -2.0) and Functional Assessment of Chronic

Illness Therapy - Fatigue (FACIT-F) Total score (6.5 vs 3.1) compared to placebo-treated patients at

Week 16 (p<0.001). Patients treated with tofacitinib 5 mg twice daily achieved consistently greaterimprovements from baseline in the Short Form health survey version 2 (SF-36v2), Physical

Component Summary (PCS) compared to placebo-treated patients at Week 16.

The European Medicines Agency has deferred the obligation to submit results of studies withtofacitinib in one or more subsets of the paediatric population in juvenile idiopathic arthritis and inulcerative colitis (see section 4.2 for information on paediatric use).

Following oral administration of tofacitinib 11 mg prolonged-release tablet, peak plasmaconcentrations are reached at 4 hours and half-life is ~6 hours. Steady state concentrations areachieved 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 areequivalent to those of tofacitinib 5 mg film-coated tablets administered twice daily.

Coadministration of tofacitinib 11 mg prolonged-release tablet with a high-fat meal resulted in nochanges in AUC while Cmax was increased by 27%.

After intravenous administration, the volume of distribution is 87 L. Approximately 40% ofcirculating tofacitinib is bound to plasma proteins. Tofacitinib binds predominantly to albumin anddoes not appear to bind to 1-acid glycoprotein. Tofacitinib distributes equally between red bloodcells and plasma.

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renalexcretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 withminor contribution from CYP2C19. In a human radiolabelled study, more than 65% of the totalcirculating 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 metaboliteshave been observed in animal species and are predicted to have less than 10-fold potency thantofacitinib 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 asubstrate 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 RApatients, the oral clearance of tofacitinib does not vary with time, indicating that treatment withtofacitinib does not normalise CYP enzyme activity.

Population PK analysis in RA patients indicated that systemic exposure (AUC) of tofacitinib in theextremes of body weight (40 kg, 140 kg) were similar (within 5%) to that of a 70 kg patient. Elderlypatients 80 years of age were estimated to have less than 5% higher AUC relative to the mean age of55 years. Women were estimated to have 7% lower AUC compared to men. The available data havealso shown that there are no major differences in tofacitinib AUC between White, Black and Asianpatients. An approximate linear relationship between body weight and volume of distribution wasobserved, 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 AS were consistent with those inpatients with RA.

Subjects with mild (creatinine clearance 50-80 mL/min), moderate (creatinine clearance30-49 mL/min), and severe (creatinine clearance < 30 mL/min) renal impairment had 37%, 43% and123% higher AUC, respectively, compared to subjects with normal renal function (see section 4.2). Insubjects with end-stage renal disease (ESRD), contribution of dialysis to the total clearance oftofacitinib was relatively small. Following a single dose of 10 mg, mean AUC in subjects with ESRDbased on concentrations measured on a non-dialysis day was approximately 40% (90% confidenceintervals: 1.5-95%) higher compared to subjects with normal renal function. In clinical studies,tofacitinib was not evaluated in patients with baseline creatinine clearance values (estimated by

Cockcroft-Gault equation) less than 40 mL/min (see section 4.2).

Subjects with mild (Child Pugh A) and moderate (Child Pugh B) hepatic impairment had 3%, and65% higher AUC, respectively, compared to subjects with normal hepatic function. In clinical studies,tofacitinib was not evaluated in subjects with severe (Child Pugh C) hepatic impairment (seesections 4.2 and 4.4), or in patients screened positive for hepatitis B or C.

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 atclinically meaningful concentrations.

Comparison of PK of prolonged-release and film-coated tablet formulations

Tofacitinib 11 mg prolonged-release tablets once daily have demonstrated PK equivalence (AUC and

Cmax) to tofacitinib 5 mg film-coated tablets twice daily.

In non-clinical studies, effects were observed on the immune and haematopoietic systems that wereattributed to the pharmacological properties (JAK inhibition) of tofacitinib. Secondary effects fromimmunosuppression, such as bacterial and viral infections and lymphoma were observed at clinicallyrelevant doses. Lymphoma was observed in 3 of 8 adult monkeys at 6 or 3 times the clinical tofacitinibexposure level (unbound AUC in humans at a dose of 5 mg or 10 mg twice daily), and 0 of 14 juvenilemonkeys at 5 or 2.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Exposure inmonkeys at the no observed adverse effect level (NOAEL) for the lymphomas was approximately 1 or0.5 times the clinical exposure level of 5 mg or 10 mg twice daily. Other findings at doses exceedinghuman 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 testsfor gene mutations and chromosomal aberrations.

The carcinogenic potential of tofacitinib was assessed in 6-month rasH2 transgenic mousecarcinogenicity and 2-year rat carcinogenicity studies. Tofacitinib was not carcinogenic in mice atexposures up to 38 or 19 times the clinical exposure level at 5 mg or 10 mg twice daily. Benigntesticular interstitial (Leydig) cell tumours were observed in rats: benign Leydig cell tumours in ratsare not associated with a risk of Leydig cell tumours in humans. Hibernomas (malignancy of brownadipose tissue) were observed in female rats at exposures greater than or equal to 83 or 41 times theclinical exposure level at 5 mg or 10 mg twice daily. Benign thymomas were observed in female ratsat 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 viablefoetuses; and an increase in early resorptions), parturition, and peri/postnatal development. Tofacitinibhad no effects on male fertility, sperm motility or sperm concentration. Tofacitinib was secreted inmilk of lactating rats at concentrations approximately 2-fold those in serum from 1 to 8 hourspostdose. In studies conducted in juvenile rats and monkeys, there were no tofacitinib-related effectson bone development in males or females, at exposures similar to those achieved at approved doses inhumans.

No tofacitinib-related findings were observed in juvenile animal studies that indicate a highersensitivity of paediatric populations compared with adults. In the juvenile rat fertility study, there wasno evidence of developmental toxicity, no effects on sexual maturation, and no evidence ofreproductive toxicity (mating and fertility) was noted after sexual maturity. In 1-month juvenile ratand 39-week juvenile monkey studies tofacitinib-related effects on immune and haematologyparameters consistent with JAK1/3 and JAK2 inhibition were observed. These effects were reversibleand consistent with those also observed in adult animals at similar exposures.

Tablet coresorbitol (E420)hydroxyethyl cellulosecopovidonemagnesium stearate

Film coatcellulose acetatehydroxypropyl cellulose (E463)hypromellose (E464)titanium dioxide (E171)triacetinred iron oxide (E172)

Printing inkshellac (E904)ammonium hydroxide (E527)propylene glycol (E1520)black iron oxide (E172)

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

HDPE bottles with 2 silica gel desiccants and child-resistant, polypropylene closure containing 30 or90 prolonged-release tablets.

Aluminium foil/PVC backed aluminium foil blisters containing 7 prolonged-release tablets. Each packcontains 28 or 91 prolonged-release tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

EU/1/17/1178/010

EU/1/17/1178/011

EU/1/17/1178/012

EU/1/17/1178/013

Date of first authorisation: 22 March 2017

Date of renewal of the authorisation: 04 March 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.