Xeljanz · 4.3 Contraindications · 3

HOS-097887 · has-adverse-reaction-information · PDF-Seite 100

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%). Tabulated list of adverse reactions 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 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. 100 Table 7: Adverse reactions System organ Common Uncommon Rare Very rare Not known class ≥1/100 to <1/10 ≥1/1,000 to ≥1/10,000 to <1/10,000 (cannot be <1/100 <1/1,000 estimated from

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HOS-097875 · has-adverse-reaction-information · PDF-Seite 15

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. 15 Overall, the safety profile observed in patients with UC tre

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HOS-097881 · has-adverse-reaction-information · PDF-Seite 63

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.

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HOS-097883 · has-contraindication-information · PDF-Seite 92

• 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). 92

HOS-097877 · has-contraindication-information · PDF-Seite 55

• 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). 55

HOS-097871 · has-contraindication-information · PDF-Seite 7

• 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).

HOS-097882 · has-indication-information · PDF-Seite 89

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.

HOS-097870 · has-indication-information · PDF-Seite 2

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). 2 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.

HOS-097876 · has-indication-information · PDF-Seite 52

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.

HOS-097873 · has-interaction-information · PDF-Seite 13

Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.2). Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib. Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporin (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC. Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response (see Figure 1). Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitant administration with MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1). 13 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

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HOS-097885 · has-interaction-information · PDF-Seite 98

Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.2). Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib. Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporin (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC. Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response (see Figure 1). Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitant administration with MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1). 98 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 Co

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HOS-097879 · has-interaction-information · PDF-Seite 61

Potential for other medicinal products to influence the pharmacokinetics (PK) of tofacitinib Since tofacitinib is metabolised by CYP3A4, interaction with medicinal products that inhibit or induce CYP3A4 is likely. Tofacitinib exposure is increased when coadministered with potent inhibitors of CYP3A4 (e.g., ketoconazole) or when administration of one or more concomitant medicinal products results in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g., fluconazole) (see section 4.2). Tofacitinib exposure is decreased when coadministered with potent CYP inducers (e.g., rifampicin). Inhibitors of CYP2C19 alone or P-glycoprotein are unlikely to significantly alter the PK of tofacitinib. Coadministration with ketoconazole (strong CYP3A4 inhibitor), fluconazole (moderate CYP3A4 and potent CYP2C19 inhibitor), tacrolimus (mild CYP3A4 inhibitor) and ciclosporin (moderate CYP3A4 inhibitor) increased tofacitinib AUC, while rifampicin (potent CYP inducer) decreased tofacitinib AUC. Coadministration of tofacitinib with potent CYP inducers (e.g., rifampicin) may result in a loss of or reduced clinical response (see Figure 1). Coadministration of potent inducers of CYP3A4 with tofacitinib is not recommended. Coadministration with ketoconazole and fluconazole increased tofacitinib Cmax, while tacrolimus, ciclosporin and rifampicin decreased tofacitinib Cmax. Concomitant administration with MTX 15-25 mg once weekly had no effect on the PK of tofacitinib in RA patients (see Figure 1). 61 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

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HOS-097874 · has-pregnancy-information · PDF-Seite 14

Pregnancy There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development (see section 5.3). As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (see section 4.3). Women of childbearing potential/contraception in females Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose. 14 Breast-feeding Based on published data, tofacitinib is excreted in human milk. The effects of tofacitinib on the breast-fed infant from published literature and post-marketing data is unknown and is limited to a small number of cases with no causally related adverse events. A risk to the breast-fed child cannot be excluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated (see section 4.3). Fertility Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats (see section 5.3).

HOS-097880 · has-pregnancy-information · PDF-Seite 62

Pregnancy There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development (see section 5.3). As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (see section 4.3). Women of childbearing potential/contraception in females Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose. Breast-feeding Based on published data, tofacitinib is excreted in human milk. The effects of tofacitinib on the breast-fed infant from published literature and post-marketing data is unknown and is limited to a 62 small number of cases with no causally related adverse events. A risk to the breast-fed child cannot be excluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated (see section 4.3). Fertility Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats (see section 5.3).

HOS-097886 · has-pregnancy-information · PDF-Seite 99

Pregnancy There are no adequate and well-controlled studies on the use of tofacitinib in pregnant women. Tofacitinib has been shown to be teratogenic in rats and rabbits, and to affect parturition and peri/postnatal development (see section 5.3). As a precautionary measure, the use of tofacitinib during pregnancy is contraindicated (see section 4.3). Women of childbearing potential/contraception in females Women of childbearing potential should be advised to use effective contraception during treatment with tofacitinib and for at least 4 weeks after the last dose. 99 Breast-feeding Based on published data, tofacitinib is excreted in human milk. The effects of tofacitinib on the breast-fed infant from published literature and post-marketing data is unknown and is limited to a small number of cases with no causally related adverse events. A risk to the breast-fed child cannot be excluded. As a precautionary measure, the use of tofacitinib during breast-feeding is contraindicated (see section 4.3). Fertility Formal studies of the potential effect on human fertility have not been conducted. Tofacitinib impaired female fertility but not male fertility in rats (see section 5.3).

HOS-097878 · has-warning-information · PDF-Seite 56

Tofacitinib should only be used if no suitable treatment alternatives are available in patients: -65 years of age and older; -patients with history of atherosclerotic cardiovascular disease or other cardiovascular risk factors (such as current or past long-time smokers); -patients with malignancy risk factors (e.g. current malignancy or history of malignancy) Use in patients 65 years of age and older Considering the increased risk of serious infections, myocardial infarction, malignancies and all cause mortality with tofacitinib in patients 65 years of age and older, tofacitinib should only be used in these patients if no suitable treatment alternatives are available (see further details below in section 4.4 and section 5.1). Combination with other therapies Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection. There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies. Venous thromboembolism (VTE) Serious VTE events including pulmonary embolism (PE), some of which were fatal, cerebral venous sinus thrombosis (CVST), and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib (see Table 7 in section 4.8). In a randomised post-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed 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, at 12 months treatment, had D-dimer level ≥2× ULN versus those with D-dimer level <2×ULN; this was not evident in TNF inhibitor-treated patients. Interpretation is limited by the low number of VTE

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HOS-097884 · has-warning-information · PDF-Seite 93

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) Combination with other therapies Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection. There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies. Venous thromboembolism (VTE) Serious VTE events including pulmonary embolism (PE), some of which were fatal, cerebral venous sinus thrombosis (CVST), and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib (see Table 7 in section 4.8). In a randomised post-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed 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, at 12 months treatment, had D-dimer level ≥2× ULN versus those with D-dimer level <2×ULN; this was not evident in TNF inhibitor-treated patients. Interpretation is limited by the low number of VTE events and restricted D-dimer test availability (only assessed at Baseline, Month 12, and at the end of the study). In patients who did not have a VTE during the study, mean D-dimer levels were significantly reduced at Month 12 relative to Baseline across all treatment arms. However, D-dimer levels ≥2× ULN at Month 12 were observed in approximately 30% of patients without

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HOS-097872 · has-warning-information · PDF-Seite 7

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) 7 Use in patients 65 years of age and older Considering the increased risk of serious infections, myocardial infarction, malignancies and all cause mortality with tofacitinib in patients 65 years of age and older, tofacitinib should only be used in these patients if no suitable treatment alternatives are available (see further details below in section 4.4 and section 5.1). Combination with other therapies Tofacitinib has not been studied and its use should be avoided in combination with biologics such as TNF antagonists, interleukin (IL)-1R antagonists, IL-6R antagonists, anti-CD20 monoclonal antibodies, IL-17 antagonists, IL-12/IL-23 antagonists, anti-integrins, selective co-stimulation modulators and potent immunosuppressants such as azathioprine, 6-mercaptopurine, ciclosporin and tacrolimus because of the possibility of increased immunosuppression and increased risk of infection. There was a higher incidence of adverse events for the combination of tofacitinib with MTX versus tofacitinib as monotherapy in RA clinical studies. The use of tofacitinib in combination with phosphodiesterase 4 inhibitors has not been studied in tofacitinib clinical studies. Venous thromboembolism (VTE) Serious VTE events including pulmonary embolism (PE), some of which were fatal, cerebral venous sinus thrombosis (CVST), and deep vein thrombosis (DVT), have been observed in patients taking tofacitinib (see Table 8 in section 4.8). In a randomised post-authorisation safety study in patients with rheumatoid arthritis who were 50 years of age or older with at least one additional cardiovascular risk factor, a dose dependent increased risk for VTE was observed 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, at 12 months treatment, had D-dimer level ≥2× ULN versus those with D-dimer level <2× ULN; this was not evident in TNF inhibitor-treated p

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