XELJANZ 1mg / ml oral solution medication leaflet

XELJANZ 1 mg/mL oral solution

Each mL of oral solution contains tofacitinib citrate, equivalent to 1 mg tofacitinib.

Each mL of oral solution contains 2.39 mg propylene glycol.

Each mL of oral solution contains 0.9 mg of sodium benzoate.

For the full list of excipients, see section 6.1.

Oral solution

Clear, colourless solution.

Tofacitinib is indicated for the treatment of active polyarticular juvenile idiopathic arthritis(rheumatoid factor positive [RF+] or negative [RF-] polyarthritis and extended oligoarthritis), andjuvenile psoriatic arthritis (PsA) in patients 2 years of age and older, who have responded inadequatelyto previous therapy with disease modifying antirheumatic drugs (DMARDs).

Tofacitinib can be given in combination with methotrexate (MTX) or as monotherapy in case ofintolerance to MTX or where continued treatment with MTX is inappropriate.

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

Tofacitinib may be used as monotherapy or in combination with methotrexate (MTX).

The recommended dose in patients 2 years of age and older is based upon the following weightcategories:

Table 1: Tofacitinib dose for patients with polyarticular juvenile idiopathic arthritis andjuvenile PsA two years of age and older

Body weight (kg) Dose regimen10 - < 20 3.2 mg (3.2 mL of oral solution) twice daily20 - < 40 4 mg (4 mL of oral solution) twice daily 40 5 mg (5 mL of oral solution or 5 mg film-coated tablet) twice daily

Patients  40 kg treated with tofacitinib 5 mL oral solution twice daily may be switched to tofacitinib5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oralsolution.

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

Available data suggest that clinical improvement is observed within 18 weeks of initiation of treatmentwith tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibiting noimprovement within this timeframe.

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 paediatric patients with an absolute lymphocyte count(ALC) less than 750 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, dosing should be reduced or interrupted until

ALC is greater than 750.

For patients receiving tofacitinib 5 mg twice daily, dosing should beinterrupted.

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 paediatric patients with an absolute neutrophil count (ANC)less than 1,200 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, dosing should be reduced or interrupted until

ANC is greater than 1,000.

For patients receiving tofacitinib 5 mg twice daily, dosing should beinterrupted.

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 paediatric patients with haemoglobin less than 10 g/dL.

Table 4: Low haemoglobin value

Low haemoglobin value (see 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 to 5 mg film-coated tablet once daily or weight-basedequivalent once daily in patients receiving 5 mg film-coated tablets or weight-based equivalent twicedaily in patients receiving potent inhibitors of cytochrome P450 (CYP) 3A4 (e.g., ketoconazole) andin patients receiving 1 or more concomitant medicinal products that result in both moderate inhibitionof CYP3A4 as well as potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.5).

The safety and efficacy of tofacitinib oral solution has not been established in the elderly.

Table 5: Dose adjustment for hepatic impairment

Hepatic Classification Dose adjustment in hepatic impairment for oralimpairment solutioncategory

Mild Child Pugh A No dose adjustment required.

Moderate Child Pugh B Dose should be reduced to 5 mg or weight-basedequivalent once daily when the indicated dose in thepresence of normal hepatic function is 5 mg orweight-based equivalent twice daily (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 oralimpairment clearance solutioncategory

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 or weight-basedpatients equivalent once daily when the indicated dose in theundergoing presence of normal renal function is 5 mg orhaemodialysis) weight-based equivalent twice daily.

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

The safety and efficacy of tofacitinib in children below 2 years of age has not been established. Nodata are available.

Oral use.

Tofacitinib oral solution should be administered using the included press-in bottle adapter and oraldosing syringe.

Tofacitinib is given orally with or without food.

- 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)

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 biological diseasemodifying antirheumatic drugs (DMARDs).

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 in adultpatients with an ANC less than 1,000 cells/mm3 and in paediatric patients with an ANC less than1,200 cells/mm3. ANC should be monitored at baseline and after 4 to 8 weeks of treatment and every3 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 adult patients with a haemoglobin value less than9 g/dL and in paediatric patients with haemoglobin value less than 10 g/dL. Haemoglobin should bemonitored at baseline and after 4 to 8 weeks of treatment and every 3 months thereafter. Forrecommended 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, particularly pJIA and jPsA patients,be brought up to date with all immunisations in agreement with current immunisation guidelines. It isrecommended that live vaccines not be given concurrently with tofacitinib. The decision to use livevaccines prior to tofacitinib treatment should take into account the pre-existing immunosuppression ina 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.

This medicinal product contains 2.39 mg propylene glycol in each mL.

Examples of propylene glycol exposures based on daily doses (see section 4.2) are as follows:

- A dose of 3.2 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a childweighing 10 kg to < 20 kg would result in a propylene glycol exposure of 1.53 mg/kg/day.

- A dose of 4 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a child weighing20 kg to <40 kg would result in a propylene glycol exposure of 0.96 mg/kg/day.

- A dose of 5 mg twice daily of XELJANZ 1 mg/mL oral solution administered to a child weighing≥40 kg would result in a propylene glycol exposure of 0.60 mg/kg/day.

This medicinal product contains 0.9 mg sodium benzoate in each mL.

This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially‘sodium-free’.

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 film-coated tablet once daily or oral solution weight-based equivalent inpatients receiving 5 mg or weight-based equivalent twice 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.

Interaction studies have only been performed in adults.

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%).

The adverse reactions listed in the table below are from clinical studies in adult patients with RA, PsA,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

Hepatobiliary Hepatic steatosis Liver functiondisorders Hepatic enzyme test abnormalincreased

Transaminasesincreased

Gamma glutamyl-transferase increased

Skin and Rash Erythemasubcutaneous Acne Pruritustissue disorders

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)

Musculoskeletal Arthralgia Musculoskeletand connective Joint swelling al paintissue disorders Tendonitis

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 controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg twice daily(total 616 patients) and 10 mg twice daily (total 642 patients) tofacitinib monotherapy groups were16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in theplacebo group (total 122 patients). In controlled phase 3 clinical studies with background DMARDs,the rates of infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twicedaily (total 969 patients) tofacitinib plus DMARD group were 21.3% (207 patients) and21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARDgroup (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 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.

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).

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

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

The adverse reactions in JIA patients in the clinical development program were consistent in type andfrequency with those seen in adult RA patients, with the exception of some infections (influenza,pharyngitis, sinusitis, viral infection) and gastrointestinal or general disorders (abdominal pain,nausea, vomiting, pyrexia, headache, cough), which were more common in JIA paediatric population.

MTX was the most frequent concomitant csDMARD used (on Day 1, 156 of 157 patients oncsDMARDs took MTX). There are insufficient data regarding the safety profile of tofacitinib usedconcomitantly with any other csDMARDs.

In the double-blind portion of the pivotal Phase 3 trial (Study JIA-I), infection was the mostcommonly reported adverse reaction (44.3%). The infections were generally mild to moderate inseverity.

In the integrated safety population, 7 patients had serious infections during treatment with tofacitinibwithin the reporting period (up to 28 days after the last dose of study medication), representing anincidence rate of 1.92 patients with events per 100 patient-years: pneumonia, epidural empyema (withsinusitis and subperiosteal abscess), pilonidal cyst, appendicitis, escherichia pyelonephritis, abscesslimb, and UTI.

In the integrated safety population, 3 patients had non-serious events of herpes zoster within thereporting window representing an incidence rate of 0.82 patients with events per 100 patient-years.

One (1) additional patient had an event of serious HZ outside the reporting window.

Patients in the JIA pivotal study were required to have AST and ALT levels less than 1.5 times theupper limit of normal to be eligible for enrolment. In the integrated safety population, there were2 patients with ALT elevations ≥3 times the ULN at 2 consecutive visits. Neither event met Hy’s Lawcriteria. Both patients were on background MTX therapy and each event resolved after discontinuationof MTX and permanent discontinuation of tofacitinib.

Changes in laboratory tests in JIA patients in the clinical development program were consistent withthose seen in adult RA patients. Patients in the JIA pivotal study were required to have a platelet count≥100,000 cells/mm3 to be eligible for enrolment, therefore, there is no information available for JIApatients with a platelet count <100,000 cells/mm3 before starting treatment with tofacitinib.

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 tofacitinib Phase 3 program for JIA consisted of one completed Phase 3 trial (Study JIA-I[A3921104]) and one ongoing long-term extension (LTE) (A3921145) trial. In these studies thefollowing JIA subgroups were included: patients with either RF+ or RF- polyarthritis, extendedoligoarthritis, systemic JIA with active arthritis and no current systemic symptoms (referred as pJIAdataset) and two separate subgroups of patients with juvenile PsA and enthesitis-related arthritis(ERA). However, the pJIA efficacy population only includes the subgroups with either RF+ or RF-polyarthritis or extended oligoarthritis; inconclusive results have been seen in the subgroup of patientswith systemic JIA with active arthritis and no current systemic symptoms. Patients with juvenile PsAare included as separate efficacy subgroup. ERA patients are not included in the efficacy analysis.

All eligible patients in Study JIA-I received open-label tofacitinib 5 mg film-coated tablets twice dailyor tofacitinib oral solution weight-based equivalent twice daily for 18 weeks (run-in phase); patientswho achieved at least a JIA ACR30 response at the end of the open-label phase were randomised (1:1)to either active tofacitinib 5 mg film-coated tablets or tofacitinib oral solution, or placebo in the26-week double-blind, placebo-controlled phase. Patients who did not achieve a JIA ACR30 responseat the end of the open-label run-in phase or experienced a single episode of disease flare at any timewere discontinued from the study. A total of 225 patients were enrolled in the open-label run-in phase.

Of these, 173 (76.9%) patients were eligible to be randomised into the double-blind phase to eitheractive tofacitinib 5 mg film-coated tablets or tofacitinib oral solution weight-based equivalent twicedaily (n=88) or placebo (n=85). There were 58 (65.9%) patients in the tofacitinib group and58 (68.2%) patients in the placebo group taking MTX during the double-blind phase, which waspermitted but not required per the protocol.

There were 133 patients with pJIA [RF+ or RF- polyarthritis and extended oligoarthritis] and 15 withjuvenile PsA randomised into the double-blind phase of the study and included in the efficacy analysespresented below.

Signs and symptoms

A significantly smaller proportion of patients with pJIA in Study JIA-I treated with tofacitinib 5 mgfilm-coated tablets twice daily or tofacitinib oral solution weight-based equivalent twice daily flared at

Week 44 compared with patients treated with placebo. A significantly greater proportion of patientswith pJIA treated with tofacitinib 5 mg film-coated tablets or tofacitinib oral solution achieved JIA

ACR30, 50, and 70 responses compared to patients treated with placebo at Week 44 (Table 8).

The occurrence of disease flare and JIA ACR30/50/70 results were favourable to tofacitinib 5 mgtwice daily in comparison to placebo across the RF+ polyarthritis, RF- polyarthritis, extendedoligoarthritis, and jPsA JIA subtypes and were consistent with those for the overall population.

The occurrence of disease flare and JIA ACR30/50/70 results were favourable to tofacitinib 5 mgtwice daily in comparison to placebo for pJIA patients who received tofacitinib 5 mg twice daily withconcomitant MTX use on Day 1 [n=101 (76%)] and those who were on tofacitinib monotherapy [n=32(24%)]. In addition, the occurrence of disease flare and JIA ACR30/50/70 results were also favourableto tofacitinib 5 mg twice daily compared to placebo for pJIA patients who had prior bDMARDexperience [n=39 (29%)] and those who were bDMARD naïve [n=94 (71%)].

In Study JIA-I, at Week 2 of the open-label run-in phase, the JIA ACR30 response in patients withpJIA was 45.03%.

Table 8: Primary and secondary efficacy endpoints in patients with pJIA at Week 44* in Study

JIA-I (all p-values<0.05)

Primary endpoint Difference (%)(Type I error Occurrence from placebocontrolled) Treatment group rate (95% CI)

Occurrence of disease Tofacitinib 5 mg 28% -24.7 (-40.8, -8.5)flare Twice Daily(N=67)

Placebo 53%(N=66)

Secondary endpoints Difference (%)(Type I error Response from placebocontrolled) Treatment group rate (95% CI)

JIA ACR30 Tofacitinib 5 mg 72% 24.7 (8.50, 40.8)

Twice Daily(N=67)

Placebo 47%(N=66)

JIA ACR50 Tofacitinib 5 mg 67% 20.2 (3.72, 36.7)

Twice Daily(N=67)

Placebo 47%(N=66)

JIA ACR70 Tofacitinib 5 mg 55% 17.4 (0.65, 34.0)

Twice Daily(N=67)

Placebo 38%(N=66)

Secondary endpoint Difference from(Type I error LS mean placebo (95% CI)controlled) Treatment group (SEM)

Change from Double- Tofacitinib 5 mg -0.11 (0.04) -0.11 (-0.22, -0.01)

Blind Baseline in Twice Daily

CHAQ Disability (N=67; n=46)

Index Placebo 0.00 (0.04)(N=66; n=31)

ACR = American College of Rheumatology; CHAQ = childhood health assessment questionnaire; CI =confidence interval; JIA = juvenile idiopathic arthritis; LS = least squares; n = number of patients withobservations at the visit; N = total number of patients; SEM = standard error of the mean

* The 26-week double-blind phase is from Week 18 through Week 44 on and after randomisation day.

The Type-I error-controlled endpoints are tested in this order: Disease Flare, JIA ACR50, JIA ACR30,

JIA ACR70, CHAQ Disability Index.

In the double-blind phase, each of the components of the JIA ACR response showed greaterimprovement from the open-label baseline (Day 1) at Week 24 and Week 44 for patients with pJIAtreated with tofacitinib oral solution dosed as 5 mg twice daily or weight-based equivalent twice dailycompared with those receiving placebo in Study JIA-I.

Changes in physical function in Study JIA-I were measured by the CHAQ Disability Index. The meanchange from the double-blind baseline in CHAQ-Disability Index in patients with pJIA wassignificantly lower in the tofacitinib 5 mg film-coated tablets twice daily or tofacitinib oral solutionweight-based equivalent twice daily compared to placebo at Week 44 (Table 8). The mean changefrom the double-blind baseline in CHAQ Disability Index results were favourable to tofacitinib 5 mgtwice daily in comparison to placebo across the RF+ polyarthritis, RF- polyarthritis, extendedoligoarthritis, and jPsA JIA subtypes and were consistent with those for the overall study population.

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 9: 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 10: 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 11: 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 PK profile of tofacitinib is characterised by rapid absorption (peak plasma concentrations arereached within 0.5-1 hour), rapid elimination (half-life of ~3 hours) and dose-proportional increases insystemic exposure. Steady state concentrations are achieved in 24-48 hours with negligibleaccumulation after twice daily administration.

Tofacitinib is well-absorbed, with an oral bioavailability of 74%. Coadministration of tofacitinib witha high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical studies,tofacitinib was administered without regard to meal.

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.

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.

Population PK analysis based on results from both tofacitinib 5 mg film-coated tablets twice daily andtofacitinib oral solution weight-based equivalent twice daily indicated that tofacitinib clearance andvolume of distribution both decreased with decreasing body weight in JIA patients. The available dataindicated that there were no clinically relevant differences in tofacitinib exposure (AUC), based onage, race, gender, patient type or baseline disease severity. The between-subject variability(% coefficient of variation) in (AUC) was estimated to be approximately 24%.

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.

Grape flavour [containing propylene glycol (E1520), glycerin (E422), and natural flavours]

Hydrochloric acid

Lactic acid (E270)

Purified water

Sodium benzoate (E211)

Sucralose (E955)

Xylitol (E967)

Not applicable.

2 years.

Should be discarded after 60 days of first opening.

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

Store in the original bottle and package in order to protect from light.

For storage conditions after first opening of the medicinal product, see section 6.3.

White coloured HDPE 250 mL bottles containing 240 mL of oral solution with a child resistant,polypropylene cap with PP liner sealed by aluminium-foil heat-induction seal and a 5 mL oral dosingsyringe with 3.2 mL, 4 mL, and 5 mL graduations.

The container closure system also includes a low-density polyethylene (LDPE) press-in bottle adapter(PIBA).

Pack size: each pack contains one bottle, one press-in bottle adapter, and one oral dosing syringe.

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/1/17/1178/015

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.