4.1 Therapeutic indication

Applies to: XELJANZ 5 mg film-coated tablets / XELJANZ 10 mg film-coated tablets

Rheumatoid arthritis

Tofacitinib in combination with methotrexate (MTX) is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs) (see section 5.1).
Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see sections 4.4 and 4.5).

Psoriatic arthritis

Tofacitinib in combination with MTX is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy (see section 5.1).

Ankylosing spondylitis

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

Ulcerative colitis

Tofacitinib is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent (see section 5.1).

Juvenile idiopathic arthritis (JIA)

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

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

Applies to: XELJANZ 11 mg prolonged-release tablets

Rheumatoid arthritis

Tofacitinib in combination with methotrexate (MTX) is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have responded inadequately to, or who are intolerant to one or more disease-modifying antirheumatic drugs (DMARDs) (see section 5.1).
Tofacitinib can be given as monotherapy in case of intolerance to MTX or when treatment with MTX is inappropriate (see sections 4.4 and 4.5).

Psoriatic arthritis

Tofacitinib in combination with MTX is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior disease-modifying antirheumatic drug (DMARD) therapy (see section 5.1).

Ankylosing spondylitis

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

Applies to: XELJANZ 1 mg/mL oral solution

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

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

4.2 Posology and method of administration

Applies to: XELJANZ 5 mg film-coated tablets / XELJANZ 10 mg film-coated tablets

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

Posology

Rheumatoid arthritis and psoriatic arthritis

The recommended dose is 5 mg film-coated tablets administered twice daily, which should not 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-release tablets see Table 1.

Table 1: Switching between tofacitinib film-coated tablets and tofacitinib prolonged-release tablets Switching between tofacitinib 5 mg film-coated tablets and tofacitinib 11 mg prolonged-release tableta Treatment with tofacitinib 5 mg film-coated tablets twice daily and tofacitinib 11 mg prolonged-release tablet once daily may be switched between each other on the day following the last dose of either tablet.
a See section 5.2 for comparison of pharmacokinetics of prolonged-release and film-coated formulations.

Ankylosing spondylitis

The recommended dose of tofacitinib is 5 mg administered twice daily.

Ulcerative colitis

Induction treatment
The recommended dose is 10 mg given orally twice daily for induction for 8 weeks.

For patients who do not achieve adequate therapeutic benefit by week 8, the induction dose of 10 mg twice daily can be extended for an additional 8 weeks (16 weeks total), followed by 5 mg twice daily

for maintenance. Tofacitinib induction therapy should be discontinued in any patient who shows no evidence of therapeutic benefit by week 16.

Maintenance treatment
The recommended dose for maintenance treatment is tofacitinib 5 mg given orally twice daily.

Tofacitinib 10 mg twice daily for maintenance treatment is not recommended in patients with UC who have known venous thromboembolism (VTE), major adverse cardiovascular events (MACE) and malignancy risk factors, unless there is no suitable alternative treatment available (see section 4.4 and 4.8).

For patients with UC who are not at increased risk for VTE, MACE and malignancy (see section 4.4), tofacitinib 10 mg orally twice daily may be considered if the patient experiences a decrease in response on tofacitinib 5 mg twice daily and failed to respond to alternative treatment options for ulcerative colitis such as tumour necrosis factor inhibitor (TNF inhibitor) treatment. Tofacitinib 10 mg twice daily for maintenance treatment should be used for the shortest duration possible. The lowest effective dose needed to maintain response should be used.

In patients who have responded to treatment with tofacitinib, corticosteroids may be reduced and/or discontinued in accordance with standard of care.

Retreatment in UC
If therapy is interrupted, restarting treatment with tofacitinib can be considered. If there has been a loss of response, reinduction with tofacitinib 10 mg twice daily may be considered. The treatment interruption period in clinical studies extended up to 1 year. Efficacy may be regained by 8 weeks of 10 mg twice daily therapy (see section 5.1).

Polyarticular JIA and juvenile PsA (children between 2 and 18 years of age)

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

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

Table 2: Tofacitinib dose for patients with polyarticular juvenile idiopathic arthritis and juvenile PsA two years of age and older Body weight (kg) Dose regimen 10 - < 20 3.2 mg (3.2 mL of oral solution) twice daily 20 - < 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 tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution.

Dose interruption and discontinuation in adults and paediatric patients

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

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. As described in Tables 3, 4 and 5 below, recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities (see section 4.4).

It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.

Table 3: Low absolute lymphocyte count
Low absolute lymphocyte count (ALC) (see section 4.4)
Laboratory value
(cells/mm3)
Recommendation
ALC greater than or equal to 750
Dose should be maintained.
ALC 500-750
For persistent (2 sequential values in this range on routine testing) decrease in this range, dosing should be reduced or interrupted.

For patients receiving tofacitinib 10 mg twice daily, dosing should be reduced to tofacitinib 5 mg twice daily.

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

When ALC is greater than 750, treatment should be resumed as clinically appropriate.
ALC less than 500

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

It is recommended not to initiate dosing in adult patients with an absolute neutrophil count (ANC) less than 1,000 cells/mm3. It is recommended not to initiate dosing in paediatric patients with an absolute neutrophil count (ANC) less than 1,200 cells/mm3.

Table 4: Low absolute neutrophil count
Low absolute neutrophil count (ANC) (see section 4.4)
Laboratory Value
(cells/mm3)
Recommendation
ANC greater than 1,000
Dose should be maintained.
ANC 500-1,000
For persistent (2 sequential values in this range on routine testing) decreases in this range, dosing should be reduced or interrupted.

For patients receiving tofacitinib 10 mg twice daily, dosing should be reduced to tofacitinib 5 mg twice daily.

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

When ANC is greater than 1,000, treatment should be resumed as clinically appropriate.
ANC less than 500

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

It is recommended not to initiate dosing in adult patients with haemoglobin less than 9 g/dL. It is recommended not to initiate dosing in paediatric patients with haemoglobin less than 10 g/dL.

Table 5: Low haemoglobin value
Low haemoglobin value (see section 4.4)
Laboratory value
(g/dL)
Recommendation
Less than or equal to
2 g/dL decrease and greater than or equal to 9.0 g/dL
Dose should be maintained.
Greater than 2 g/dL decrease or less than

Applies to: XELJANZ 11 mg prolonged-release tablets

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

Posology

Rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis

The recommended dose is one 11 mg prolonged-release tablet administered once daily, which should not 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-release tablets see Table 1.

Table 1: Switching between tofacitinib film-coated tablets and tofacitinib prolonged-release tablets Switching between tofacitinib 5 mg film-coated tablets and tofacitinib 11 mg prolonged-release tableta Treatment with tofacitinib 5 mg film-coated tablets twice daily and tofacitinib 11 mg prolonged-release tablet once daily may be switched between each other on the day following the last dose of either tablet.
a See section 5.2 for comparison of pharmacokinetics of prolonged-release and film-coated formulations.

Dose interruption and discontinuation

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

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. As described in Tables 2, 3 and 4 below, recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities (see section 4.4).

It is recommended not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3.

Table 2: Low absolute lymphocyte count
Low absolute lymphocyte count (ALC) (see section 4.4)
Laboratory value
(cells/mm3)
Recommendation
ALC greater than or equal to 750
Dose should be maintained.
ALC 500-750
For persistent (2 sequential values in this range on routine testing) decrease in this range, tofacitinib 11 mg prolonged-release dosing should be interrupted.

When ALC is greater than 750, treatment should be resumed as clinically appropriate.
ALC less than 500

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

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

Table 3: Low absolute neutrophil count
Low absolute neutrophil count (ANC) (see section 4.4)
Laboratory Value
(cells/mm3)
Recommendation
ANC greater than 1,000
Dose should be maintained.
ANC 500-1,000
For persistent (2 sequential values in this range on routine testing) decreases in this range, tofacitinib 11 mg prolonged-release dosing should be interrupted.

When ANC is greater than 1,000, treatment should be resumed as clinically appropriate.
ANC less than 500

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

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

Table 4: Low haemoglobin value
Low haemoglobin value (Section 4.4)
Laboratory Value
(g/dL)
Recommendation
Less than or equal to
2 g/dL decrease and greater than or equal to 9.0 g/dL
Dose should be maintained.
Greater than 2 g/dL decrease or less than

Applies to: XELJANZ 1 mg/mL oral solution

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

Posology

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 weight categories:

Table 1: Tofacitinib dose for patients with polyarticular juvenile idiopathic arthritis and juvenile PsA two years of age and older Body weight (kg) Dose regimen 10 - < 20 3.2 mg (3.2 mL of oral solution) twice daily 20 - < 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 tofacitinib 5 mg film-coated tablets twice daily. Patients < 40 kg cannot be switched from tofacitinib oral solution.

Dose adjustment

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

Dose interruption and discontinuation

Available data suggest that clinical improvement is observed within 18 weeks of initiation of treatment with tofacitinib. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

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

Interruption of dosing may be needed for management of dose-related laboratory abnormalities including lymphopenia, neutropenia, and anaemia. As described in Tables 2, 3 and 4 below, recommendations for temporary dose interruption or permanent discontinuation of treatment are made according to the severity of laboratory abnormalities (see section 4.4).

It is recommended not to initiate dosing in 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
(cells/mm3)
Recommendation
ALC greater than or equal to 750
Dose should be maintained.
ALC 500-750
For persistent (2 sequential values in this range on routine testing) decrease in this range, dosing should be reduced or interrupted until ALC is greater than 750.

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

When ALC is greater than 750, treatment should be resumed as clinically appropriate.
ALC less than 500

If laboratory value confirmed by repeat testing within 7 days, dosing should 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
(cells/mm3)
Recommendation
ANC greater than 1,000
Dose should be maintained.
ANC 500-1,000
For persistent (2 sequential values in this range on routine testing) decreases in this range, dosing should be reduced or interrupted until ANC is greater than 1,000.

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

When ANC is greater than 1,000, treatment should be resumed as clinically appropriate.
ANC less than 500

If laboratory value confirmed by repeat testing within 7 days, dosing should 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
(g/dL)
Recommendation
Less than or equal to
2 g/dL decrease and greater than or equal to 9.0 g/dL
Dose should be maintained.
Greater than 2 g/dL decrease or less than

4.3 Contraindications

Applies to: XELJANZ 5 mg film-coated tablets / XELJANZ 10 mg film-coated tablets · XELJANZ 11 mg prolonged-release tablets · XELJANZ 1 mg/mL oral solution

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active tuberculosis (TB), serious infections such as sepsis, or opportunistic infections (see section 4.4).
Severe hepatic impairment (see section 4.2).
Pregnancy and lactation (see section 4.6).

4.8 Undesirable effects

Applies to: XELJANZ 5 mg film-coated tablets / XELJANZ 10 mg film-coated tablets

Summary of the safety profile

Rheumatoid arthritis
The most common serious adverse reactions were serious infections (see section 4.4). In the long-term safety all exposure population, the most common serious infections reported with tofacitinib were pneumonia (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 mycobacterial infections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localised disease. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

The most commonly reported adverse reactions during the first 3 months of the double-blind, placebo or 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 months of the double-blind, placebo or MTX controlled studies was 3.8% for patients taking tofacitinib. The most common infections resulting in discontinuation of therapy during the first 3 months in controlled clinical studies were herpes zoster (0.19%) and pneumonia (0.15%).

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

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

Ulcerative colitis
The most commonly reported adverse reactions in patients receiving tofacitinib 10 mg twice daily in the induction studies were headache, nasopharyngitis, nausea, and arthralgia.

In the induction and maintenance studies, across tofacitinib and placebo treatment groups, the most common categories of serious adverse reactions were gastrointestinal disorders and infections, and the most common serious adverse reaction was worsening of UC.

Overall, the safety profile observed in patients with UC treated with tofacitinib was consistent with the safety profile of tofacitinib in the RA indication.

Tabulated list of adverse reactions

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

Table 8: Adverse reactions
System organ class
Common
≥1/100 to <1/10

Uncommon
≥1/1,000 to
<1/100
Rare
≥1/10,000 to
<1/1,000
Very rare
<1/10,000
Not known
(cannot be estimated from the available data)
Infections and infestations
Pneumonia
Influenza
Herpes zoster
Urinary tract infection
Sinusitis
Bronchitis
Nasopharyngitis
Pharyngitis
Tuberculosis
Diverticulitis
Pyelonephritis
Cellulitis
Herpes simplex
Gastroenteritis viral
Viral infection

Sepsis
Urosepsis
Disseminated
TB
Bacteraemia
Pneumocystis jirovecii pneumonia
Pneumonia pneumococcal
Pneumonia bacterial
Cytomegalovir us infection
Arthritis bacterial
Tuberculosis of central nervous system
Meningitis cryptococcal
Necrotizing fasciitis
Encephalitis
Staphylococc al bacteraemia
Mycobacteriu m avium complex infection
Atypical mycobacteria l infection

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

Lung cancer
Non-melanoma skin cancers
Lymphoma

Blood and lymphatic system disorders
Lymphopenia
Anaemia
Leukopenia
Neutropenia

Immune system disorders

Hypersensitivity
*
Angioedema*
Urticaria*
Metabolism and nutrition disorders

Dyslipidaemia
Hyperlipidaemia
Dehydration

Psychiatric disorders

Insomnia

Nervous system disorders
Headache
Paraesthesia

Cardiac disorders

Myocardial infarction

Vascular disorders
Hypertension
Venous thromboembolism**

Respiratory, thoracic and mediastinal disorders
Cough
Dyspnoea
Sinus congestion

System organ class
Common
≥1/100 to <1/10

Uncommon
≥1/1,000 to
<1/100
Rare
≥1/10,000 to
<1/1,000
Very rare
<1/10,000
Not known
(cannot be estimated from the available data)
Gastrointestinal disorders
Abdominal pain
Vomiting
Diarrhoea
Nausea
Gastritis
Dyspepsia

Hepatobiliary disorders

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

Skin and subcutaneous tissue disorders
Rash
Acne
Erythema
Pruritus

Musculoskeletal and connective tissue disorders
Arthralgia
Joint swelling
Tendonitis
Musculoskelet al pain

General disorders and administration site conditions
Oedema peripheral

Pyrexia
Fatigue

Investigations

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

Injury, poisoning and procedural complications

Ligament sprain
Muscle strain

*Spontaneous reporting data
**Venous thromboembolism includes PE, DVT, Retinal Venous Thrombosis, and Cerebral Venous Sinus Thrombosis

Description of selected adverse reactions

Venous thromboembolism

Rheumatoid arthritis
In a large (N=4,362), randomised post-authorisation safety study of rheumatoid arthritis patients who were 50 years of age and older and had at least one additional cardiovascular (CV) risk factor, VTE was observed at an increased and dose-dependent incidence in patients treated with tofacitinib compared to TNF inhibitors (see section 5.1). The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE for tofacitinib 5 mg twice daily, tofacitinib 10 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 twice daily and tofacitinib 10 mg twice daily, respectively (see section 5.1). In tofacitinib-treated patients where PE was observed, the majority (97%) had VTE risk factors.

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

Ulcerative colitis (UC)
In the UC ongoing extension trial, cases of PE and DVT have been observed in patients using tofacitinib 10 mg twice daily and with underlying VTE risk factor(s).

Overall infections

Rheumatoid arthritis
In controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) tofacitinib monotherapy groups were 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In controlled phase 3 clinical studies with background DMARDs, the rates of infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 969 patients) tofacitinib plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients).

The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% and 3.2%, respectively).

The overall incidence rate of infections with tofacitinib in the long-term safety all exposure population (total 4,867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with events for 5 mg and 10 mg twice daily, respectively). For patients (total 1,750) on monotherapy, the rates were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients (total 3,117) on background DMARDs, the rates were 41.0 and 50.3 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.

Ankylosing spondylitis
In the combined Phase 2 and Phase 3 clinical studies, during the placebo-controlled period of up to 16 weeks, the frequency of infections in the tofacitinib 5 mg twice daily group (185 patients) was 27.6% and the frequency in the placebo group (187 patients) was 23.0%. In the combined Phase 2 and Phase 3 clinical studies, among the 316 patients treated with tofacitinib 5 mg twice daily for up to 48 weeks, the frequency of infections was 35.1%.

Ulcerative colitis
In the randomised 8-week Phase 2/3 induction studies, the proportions of patients with infections were 21.1% (198 patients) in the tofacitinib 10 mg twice daily group compared to 15.2% (43 patients) in the placebo group. In the randomised 52-week phase 3 maintenance study, the proportion of patients with infections were 35.9% (71 patients) in the 5 mg twice daily and 39.8% (78 patients) in the 10 mg twice daily tofacitinib groups, compared to 24.2% (48 patients) in the placebo group.

In the entire treatment experience with tofacitinib, the most commonly reported infection was nasopharyngitis, occurring in 18.2% of patients (211 patients).

In the entire treatment experience with tofacitinib, the overall incidence rate of infections was 60.3 events per 100 patient-years (involving 49.4% of patients; total 572 patients).

Serious infections

Rheumatoid arthritis
In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice daily tofacitinib monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice daily tofacitinib monotherapy group the rate was 1.6 patients with events per 100 patient-years, the rate was 0 events per 100 patient-years for the placebo group, and the rate was 1.9 patients with events per 100 patient-years for the MTX group.

In studies of 6-, 12-, or 24-month duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily tofacitinib plus DMARD groups were 3.6 and 3.4 patients with events per

100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily tofacitinib groups, respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract infection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have been reported (see section 4.4).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, a dose-dependent increase in serious 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 mg twice daily, and TNF inhibitors were 2.86 (2.41, 3.37), 3.64 (3.11, 4.23), and 2.44 (2.02, 2.92) patients with 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 and tofacitinib 5 mg twice daily, respectively.

Ankylosing spondylitis
In the combined Phase 2 and Phase 3 clinical studies, among the 316 patients treated with tofacitinib 5 mg twice daily for up to 48 weeks, there was one serious infection (aseptic meningitis) yielding a rate of 0.43 patients with events per 100 patient-years.

Ulcerative colitis
The incidence rates and types of serious infections in the UC clinical studies were generally similar to those reported in RA clinical studies with tofacitinib monotherapy treatment groups.

Serious infections in the elderly
Of the 4,271 patients who enrolled in RA studies I-VI (see section 5.1), a total of 608 RA patients were 65 years of age and older, including 85 patients 75 years and older. The frequency of serious infection among tofacitinib-treated patients 65 years of age and older was higher than those under the age of 65 (4.8 per 100 patient-years versus 2.4 per 100 patient-years, respectively).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, an increase in serious infections was observed in patients 65 years of age and older for tofacitinib 10 mg twice daily compared 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, 5.27), 5.85 (4.64, 7.30), and 3.73 (2.81, 4.85) patients with events per 100 patient-years for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively.

Compared with TNF inhibitors, the hazard ratio (HR) for serious infections in patients ≥65 years of age was 1.08 (0.74, 1.58) and 1.55 (1.10, 2.19) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice 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 patients from a registry (US Corrona) showed that a numerically higher incidence rate of serious infection was observed for the 11 mg prolonged-release tablet administered once daily than the 5 mg film-coated tablet administered twice daily. Crude incidence rates (95% CI) (i.e., not adjusted for age or sex) from availability 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 with events per 100 patient-years in the 11 mg prolonged-release tablet once daily and 5 mg film-coated tablet twice daily groups, respectively. The unadjusted hazard ratio was 1.30 (95% CI: 0.67, 2.50) at 12 months and 1.93 (95% CI: 1.15, 3.24) at 36 months for the 11 mg prolonged-release once daily

dose compared to the 5 mg film-coated twice daily dose. Data is based on a small number of patients with events observed with relatively large confidence intervals and limited follow up time.

Viral reactivation

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

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, an increase in herpes zoster events was observed in patients treated with tofacitinib compared to TNF inhibitors. The incidence rates (95% CI) for herpes zoster for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors were 3.75 (3.22, 4.34), 3.94 (3.38, 4.57), and 1.18 (0.90, 1.52) patients with events per 100 patient-years, respectively.

Laboratory tests

Lymphocytes
In the controlled RA clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in 0.3% of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

In the RA long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in 1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

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

In the clinical studies in UC, changes in ALC observed with tofacitinib treatment were similar to the changes observed in clinical studies in RA.

Neutrophils
In the controlled RA clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.

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

In the clinical studies in UC, changes in ANC observed with tofacitinib treatment were similar to the changes observed in clinical studies in RA.

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

Liver enzyme tests
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were uncommonly observed in RA patients. In those patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD,

interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalisation of liver enzymes.

In the controlled portion of the RA phase 3 monotherapy study (0-3 months) (study I, see section 5.1), ALT elevations greater than 3x ULN were observed in 1.65%, 0.41%, and 0% of patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 1.65%, 0.41% and 0% of patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively.

In the RA phase 3 monotherapy study (0-24 months) (study VI, see section 5.1), ALT elevations greater than 3x ULN were observed in 7.1%, 3.0%, and 3.0% of patients receiving MTX, tofacitinib 5 mg and 10 mg twice daily, respectively. In this study, AST elevations greater than 3x ULN were observed in 3.3%, 1.6% and 1.5% of patients receiving MTX, tofacitinib 5 mg and 10 mg twice daily, respectively.

In the controlled portion of the RA phase 3 studies on background DMARDs (0-3 months) (studies II-V, see section 5.1), ALT elevations greater than 3x ULN were observed in 0.9%, 1.24% and 1.14% of patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively. In these studies, AST elevations greater than 3x ULN were observed in 0.72%, 0.5% and 0.31% of patients receiving placebo, tofacitinib 5 mg and 10 mg twice daily, respectively.

In the RA long-term extension studies, on monotherapy, ALT elevations greater than 3x ULN were observed in 1.1% and 1.4% of patients receiving tofacitinib 5 mg and 10 mg twice daily, respectively.
AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg and 10 mg twice daily groups.

In the RA long-term extension studies, on background DMARDs, ALT elevations greater than 3x ULN were observed in 1.8% and 1.6% of patients receiving tofacitinib 5 mg and 10 mg twice daily, respectively. AST elevations greater than 3x ULN were observed in < 1.0% in both the tofacitinib 5 mg and 10 mg twice daily groups.

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, ALT elevations greater than or equal to 3x ULN were observed in 6.01%, 6.54% and 3.77% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors respectively. AST elevations greater than or equal to 3x ULN were observed in 3.21%, 4.57% and 2.38% of patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors respectively.

In the clinical studies in UC, changes in liver enzyme tests observed with tofacitinib treatment were similar to the changes observed in clinical studies in RA.

Lipids
Elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were first assessed at 1 month following initiation of tofacitinib in the controlled double-blind clinical studies of RA. Increases were observed at this time point and remained stable thereafter.

Changes in lipid parameters from baseline through the end of the study (6-24 months) in the controlled clinical studies in RA are summarised below:

Mean LDL cholesterol increased by 15% in the tofacitinib 5 mg twice daily arm and 20% in the tofacitinib 10 mg twice daily arm at month 12, and increased by 16% in the tofacitinib 5 mg twice daily arm and 19% in the tofacitinib 10 mg twice daily arm at month 24.
Mean HDL cholesterol increased by 17% in the tofacitinib 5 mg twice daily arm and 18% in the tofacitinib 10 mg twice daily arm at month 12, and increased by 19% in the tofacitinib 5 mg twice daily arm and 20% in the tofacitinib 10 mg twice daily arm at month 24.

Upon withdrawal of tofacitinib treatment, lipid levels returned to baseline.

Mean LDL cholesterol/HDL cholesterol ratios and Apolipoprotein B (ApoB)/ApoA1 ratios were essentially unchanged in tofacitinib-treated patients.

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

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

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, changes in lipid parameters from baseline through 24 months are summarised below:

Mean LDL cholesterol increased by 13.80%, 17.04%, and 5.50% in patients receiving tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor, respectively, at month 12. At month 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 tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitor, respectively, at month 12. At month 24, the increase was 11.58%, 13.54%, and 1.42%, respectively.

In the clinical studies in UC, changes in lipids observed with tofacitinib treatment were similar to the changes observed in clinical studies in RA.

Myocardial infarction

Rheumatoid arthritis
In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 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 twice daily, and TNF inhibitors were 0.37 (0.22, 0.57), 0.33 (0.19, 0.53), and 0.16 (0.07, 0.31) patients with events per 100 patient-years, respectively. Few fatal myocardial infarctions were reported with rates similar in patients treated with tofacitinib compared to TNF inhibitors (see sections 4.4 and 5.1). The study required at least 1500 patients to be followed for 3 years.

Malignancies excluding NMSC

Rheumatoid arthritis
In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 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 TNF inhibitors were 0.23 (0.12, 0.40), 0.32 (0.18, 0.51), and 0.13 (0.05, 0.26) patients with events per 100 patient-years, respectively (see sections 4.4 and 5.1). The study required at least 1500 patients to be followed for 3 years.

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

Paediatric population

Polyarticular juvenile idiopathic arthritis and juvenile PsA
The adverse reactions in JIA patients in the Phase 3 pivotal trial (Study JIA-I) and long-term extension study, which included paediatric patients with pJIA, jPsA, ERA, and sJIA, were generally consistent in type and frequency with those seen in adult RA patients, with the exception of some infections

(upper respiratory tract infection and viral infection) and gastrointestinal or general disorders (abdominal pain and pyrexia), which were more common in the JIA paediatric population. MTX was the most frequent concomitant csDMARD used (on Day 1, 156 of 157 patients on csDMARDs took MTX). There are insufficient data regarding the safety profile of tofacitinib used concomitantly with any other csDMARDs.

Infections
In the double-blind portion of Study JIA-I, infection was the most commonly reported adverse reaction (44.3%). The infections were generally mild to moderate in severity.

In Study JIA-I, serious infections were reported in 3 patients (1.3%) who received tofacitinib, corresponding to an incidence rate of 2.43 patients with events per 100 patient-years. Herpes zoster was reported in 2 patients (0.9%), with an incidence rate of 1.63 patients with events per 100 patient-years. Both events involved a single dermatome and were non-serious.

In the long-term extension study, serious infections occurred in 14 patients (4.6%) receiving tofacitinib, corresponding to an incidence rate of 1.50 patients with events per 100 patient-years. The most frequent serious infections were herpes zoster and pneumonia. Herpes zoster events were reported in 6 patients (2.0%) corresponding to an incidence rate of 0.64 patients with events per 100 patient-years. Of these, 2 patients (0.7%) experienced serious events of multidermatomal herpes zoster with an incidence rate of 0.21 events per 100 patient-years. In addition, there were 3 herpes zoster events (2 serious and 1 non-serious) confined to a single dermatome. The remaining herpes zoster event was non-serious, involved 2 adjacent dermatomes, and occurred in a patient with a prior non-serious varicella event reported 5.8 years earlier in the study.

Hepatic events
Patients in the JIA pivotal study were required to have AST and ALT levels less than 1.5 times the upper limit of normal to be eligible for enrolment. In Study JIA-I, ALT elevations > 5 × ULN at 2 consecutive visits were reported in 1 patient (0.4%) receiving tofacitinib who was receiving background methotrexate; the event was adjudicated as related to tofacitinib and resolved following discontinuation of methotrexate and tofacitinib. In the long-term extension study, AST or ALT elevations > 5 × ULN at 2 consecutive visits were reported in 2 patients (0.66%); both events were adjudicated as unrelated to tofacitinib. None of the events in either study met Hy’s Law criteria.

Laboratory tests
Changes in laboratory tests in JIA patients in the clinical development program were consistent with those 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 JIA patients with a platelet count <100,000 cells/mm3 before starting treatment with tofacitinib.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: XELJANZ 11 mg prolonged-release tablets

Summary of the safety profile

Rheumatoid arthritis
The most common serious adverse reactions were serious infections (see section 4.4). In the long-term safety all exposure population, the most common serious infections reported with tofacitinib were pneumonia (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 mycobacterial infections, cryptococcus, histoplasmosis, oesophageal candidiasis, multidermatomal herpes zoster, cytomegalovirus infection, BK virus infections and listeriosis were reported with tofacitinib. Some patients have presented with disseminated rather than localised disease. Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

The most commonly reported adverse reactions during the first 3 months of the double-blind, placebo or 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 months of the double-blind, placebo or MTX controlled studies was 3.8% for patients taking tofacitinib. The most common infections resulting in discontinuation of therapy during the first 3 months in controlled clinical studies were herpes zoster (0.19%) and pneumonia (0.15%).

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

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

Tabulated list of adverse reactions

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

Table 7: Adverse reactions
System organ class
Common
≥1/100 to <1/10

Uncommon
≥1/1,000 to
<1/100
Rare
≥1/10,000 to
<1/1,000
Very rare
<1/10,000
Not known
(cannot be estimated from the available data)
Infections and infestations
Pneumonia
Influenza
Herpes zoster
Urinary tract infection
Sinusitis
Bronchitis
Nasopharyngitis
Pharyngitis
Tuberculosis
Diverticulitis
Pyelonephritis
Cellulitis
Herpes simplex
Gastroenteritis viral
Viral infection

Sepsis
Urosepsis
Disseminated
TB
Bacteraemia
Pneumocystis jirovecii pneumonia
Pneumonia pneumococcal
Pneumonia bacterial
Cytomegalovir us infection
Arthritis bacterial
Tuberculosis of central nervous system
Meningitis cryptococcal
Necrotizing fasciitis
Encephalitis
Staphylococca l bacteraemia
Mycobacteriu m avium complex infection
Atypical mycobacterial infection

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

Lung cancer
Non-melanoma skin cancers
Lymphoma

Blood and lymphatic system disorders
Lymphopenia
Anaemia
Leukopenia
Neutropenia

Immune system disorders

Hypersensitivity
*
Angioedema*
Urticaria*
Metabolism and nutrition disorders

Dyslipidaemia
Hyperlipidaemia
Dehydration

Psychiatric disorders

Insomnia

Nervous system disorders
Headache
Paraesthesia

Cardiac disorders

Myocardial infarction

Vascular disorders
Hypertension
Venous thromboembolism**

Respiratory, thoracic and mediastinal disorders
Cough
Dyspnoea
Sinus congestion

Gastrointestinal disorders
Abdominal pain
Vomiting
Diarrhoea
Nausea
Gastritis
Dyspepsia

Hepatobiliary disorders

Hepatic steatosis
Hepatic enzyme increased
Transaminases increased
Gamma glutamyl- transferase increased

Liver function test abnormal

Skin and subcutaneous tissue disorders
Rash
Acne
Erythema
Pruritus

System organ class
Common
≥1/100 to <1/10

Uncommon
≥1/1,000 to
<1/100
Rare
≥1/10,000 to
<1/1,000
Very rare
<1/10,000
Not known
(cannot be estimated from the available data)
Musculoskeletal and connective tissue disorders
Arthralgia
Joint swelling
Tendonitis
Musculoskelet al pain

General disorders and administration site conditions
Oedema peripheral

Pyrexia
Fatigue

Investigations

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

Injury, poisoning and procedural complications

Ligament sprain
Muscle strain

*Spontaneous reporting data
**Venous thromboembolism includes PE, DVT, Retinal Venous Thrombosis, and Cerebral Venous Sinus Thrombosis

Description of selected adverse reactions

Venous thromboembolism

Rheumatoid arthritis
In a large (N=4,362), randomised post-authorisation safety study of rheumatoid arthritis patients who were 50 years of age and older and had at least one additional cardiovascular (CV) risk factor, VTE was observed at an increased and dose-dependent incidence in patients treated with tofacitinib compared to TNF inhibitors (see section 5.1). The majority of these events were serious and some resulted in death. The incidence rates (95% CI) for PE for tofacitinib 5 mg twice daily, tofacitinib 10 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 twice daily and tofacitinib 10 mg twice daily, respectively (see section 5.1). In tofacitinib-treated patients where PE was observed, the majority (97%) had VTE risk factors.

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

Overall infections

Rheumatoid arthritis
In controlled phase 3 clinical studies, the rates of infections over 0-3 months in the 5 mg film-coated tablets twice daily (total 616 patients) and 10 mg twice daily (total 642 patients) tofacitinib monotherapy groups were 16.2% (100 patients) and 17.9% (115 patients), respectively, compared to 18.9% (23 patients) in the placebo group (total 122 patients). In controlled phase 3 clinical studies with background DMARDs, the rates of infections over 0-3 months in the 5 mg twice daily (total 973 patients) and 10 mg twice daily (total 969 patients) tofacitinib plus DMARD group were 21.3% (207 patients) and 21.8% (211 patients), respectively, compared to 18.4% (103 patients) in the placebo plus DMARD group (total 559 patients).

The most commonly reported infections were upper respiratory tract infections and nasopharyngitis (3.7% and 3.2%, respectively).

The overall incidence rate of infections with tofacitinib in the long-term safety all exposure population (total 4,867 patients) was 46.1 patients with events per 100 patient-years (43.8 and 47.2 patients with events for 5 mg and 10 mg twice daily, respectively). For patients (total 1,750) on monotherapy, the rates were 48.9 and 41.9 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively. For patients (total 3,117) on background DMARDs, the rates were 41.0 and 50.3 patients with events per 100 patient-years for 5 mg and 10 mg twice daily, respectively.

Ankylosing spondylitis
In the combined Phase 2 and Phase 3 clinical trials, during the placebo-controlled period of up to 16 weeks, the frequency of infections in the tofacitinib 5 mg twice daily group (185 patients) was 27.6% 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 to 48 weeks, the frequency of infections was 35.1%.

Serious infections

Rheumatoid arthritis
In the 6-month and 24-month, controlled clinical studies, the rate of serious infections in the 5 mg twice daily tofacitinib monotherapy group was 1.7 patients with events per 100 patient-years. In the 10 mg twice daily tofacitinib monotherapy group the rate was 1.6 patients with events per 100 patient-years, the rate was 0 events per 100 patient-years for the placebo group, and the rate was 1.9 patients with events per 100 patient-years for the MTX group.

In studies of 6-, 12-, or 24-month duration, the rates of serious infections in the 5 mg twice daily and 10 mg twice daily tofacitinib plus DMARD groups were 3.6 and 3.4 patients with events per 100 patient-years, respectively, compared to 1.7 patients with events per 100 patient-years in the placebo plus DMARD group.
In the long-term safety all exposure population, the overall rates of serious infections were 2.4 and 3.0 patients with events per 100 patient-years for 5 mg and 10 mg twice daily tofacitinib groups, respectively. The most common serious infections included pneumonia, herpes zoster, urinary tract infection, cellulitis, gastroenteritis and diverticulitis. Cases of opportunistic infections have been reported (see section 4.4).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, a dose-dependent increase in serious 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 mg twice daily, and TNF inhibitors were 2.86 (2.41, 3.37), 3.64 (3.11, 4.23), and 2.44 (2.02, 2.92) patients with 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 and tofacitinib 5 mg twice daily, respectively.

Ankylosing spondylitis
In the combined Phase 2 and Phase 3 clinical trials, among the 316 patients treated with tofacitinib 5 mg twice daily for up to 48 weeks, there was one serious infection (aseptic meningitis) yielding a rate 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 patients were 65 years of age and older, including 85 patients 75 years and older. The frequency of serious infection among tofacitinib-treated patients 65 years of age and older was higher than those under the age of 65 (4.8 per 100 patient-years versus 2.4 per 100 patient-years, respectively).

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, an increase in serious

infections was observed in patients 65 years of age and older for tofacitinib 10 mg twice daily compared 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, 5.27), 5.85 (4.64, 7.30), and 3.73 (2.81, 4.85) patients with events per 100 patient-years for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors, respectively.

Compared with TNF inhibitors, the hazard ratio (HR) for serious infections in patients ≥65 years of age was 1.08 (0.74, 1.58) and 1.55 (1.10, 2.19) for tofacitinib 5 mg twice daily and tofacitinib 10 mg twice 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 patients from a registry (US Corrona) showed that a numerically higher incidence rate of serious infection was observed for the 11 mg prolonged-release tablet administered once daily than the 5 mg film-coated tablet administered twice daily. Crude incidence rates (95% CI) (i.e., not adjusted for age or sex) from availability 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 with events per 100 patient-years in the 11 mg prolonged-release tablet once daily and 5 mg film-coated tablet twice daily groups, respectively. The unadjusted hazard ratio was 1.30 (95% CI: 0.67, 2.50) at 12 months and 1.93 (95% CI: 1.15, 3.24) at 36 months for the 11 mg prolonged-release once daily dose compared to the 5 mg film-coated twice daily dose. Data is based on a small number of patients with events observed with relatively large confidence intervals and limited follow up time.

Viral reactivation

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

In a large (N=4,362) randomised post-authorisation safety study in patients with RA who were 50 years or older with at least one additional cardiovascular risk factor, an increase in herpes zoster events was observed in patients treated with tofacitinib compared to TNF inhibitors. The incidence rates (95% CI) for herpes zoster for tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and TNF inhibitors were 3.75 (3.22, 4.34), 3.94 (3.38, 4.57), and 1.18 (0.90, 1.52) patients with events per 100 patient-years, respectively.

Laboratory tests

Lymphocytes
In the controlled RA clinical studies, confirmed decreases in ALC below 500 cells/mm3 occurred in 0.3% of patients and for ALC between 500 and 750 cells/mm3 in 1.9% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

In the RA long-term safety population, confirmed decreases in ALC below 500 cells/mm3 occurred in 1.3% of patients and for ALC between 500 and 750 cells/mm3 in 8.4% of patients for the 5 mg twice daily and 10 mg twice daily doses combined.

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

Neutrophils
In the controlled RA clinical studies, confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.08% of patients for the 5 mg twice daily and 10 mg twice daily doses combined. There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group. There was no clear relationship between neutropenia and the occurrence of serious infections.

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

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 for patients with a platelet count < 100,000 cells/mm3 before starting treatment with tofacitinib.

Liver enzyme tests
Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were uncommonly observed in RA patients. In those patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of tofacitinib, or reduction in tofacitinib dose, resulted in decrease or normalisation of liver enzymes.