Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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.

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 the available data)
Infections and      Pneumonia         Tuberculosis            Sepsis          Tuberculosis infestations        Influenza         Diverticulitis          Urosepsis       of central Herpes zoster     Pyelonephritis          Disseminated    nervous
Urinary tract     Cellulitis              TB              system infection         Herpes simplex          Bacteraemia     Meningitis
Sinusitis         Gastroenteritis viral   Pneumocystis    cryptococcal Bronchitis        Viral infection         jirovecii       Necrotizing Nasopharyngitis                           pneumonia       fasciitis
Pharyngitis                               Pneumonia       Encephalitis pneumococcal    Staphylococca
Pneumonia       l bacteraemia bacterial       Mycobacteriu
Cytomegalovir   m avium us infection    complex
Arthritis       infection bacterial       Atypical mycobacterial infection

Neoplasms                             Lung cancer             Lymphoma benign,                               Non-melanoma skin malignant and                         cancers unspecified (incl cysts and polyps)
Blood and           Lymphopenia       Leukopenia lymphatic system    Anaemia           Neutropenia disorders
Immune system                                                                                 Hypersensitivity disorders                                                                                     * Angioedema*
Urticaria*
Metabolism and                        Dyslipidaemia nutrition                             Hyperlipidaemia disorders                             Dehydration
Psychiatric                           Insomnia disorders
Nervous system      Headache          Paraesthesia disorders
Cardiac disorders                     Myocardial infarction


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 the available data)
Vascular            Hypertension      Venous disorders                             thromboembolism**
Respiratory,        Cough             Dyspnoea thoracic and                          Sinus congestion mediastinal disorders
Gastrointestinal    Abdominal pain disorders           Vomiting
Diarrhoea
Nausea
Gastritis
Dyspepsia
Hepatobiliary                         Hepatic steatosis       Liver function disorders                             Hepatic enzyme          test abnormal increased
Transaminases increased
Gamma glutamyl- transferase increased
Skin and            Rash              Erythema subcutaneous        Acne              Pruritus tissue disorders
Musculoskeletal     Arthralgia                                Musculoskelet and connective                        Joint swelling          al pain tissue disorders                      Tendonitis
General disorders   Oedema            Pyrexia and                 peripheral        Fatigue administration site conditions
Investigations      Blood creatine    Blood creatinine phosphokinase     increased increased         Blood cholesterol increased
Low density lipoprotein increased
Weight increased
Injury, poisoning                     Ligament sprain and procedural                        Muscle strain complications
*Spontaneous reporting data
**Venous thromboembolism includes PE, DVT, and Retinal Venous 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

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.

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.

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).

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.

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.

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 clinical development program were consistent in type and frequency 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 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 the pivotal Phase 3 trial (Study JIA-I), infection was the most commonly reported adverse reaction (44.3%). The infections were generally mild to moderate in severity.

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




In the integrated safety population, 3 patients had non-serious events of herpes zoster within the reporting 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.

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 the integrated safety population, there were 2 patients with ALT elevations ≥3 times the ULN at 2 consecutive visits. Neither event met Hy’s Law criteria. Both patients were on background MTX therapy and each event resolved after discontinuation of MTX and permanent discontinuation of tofacitinib.

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. Any suspected adverse event should be reported to the Ministry of Health according to the National Regulation by using an online form
 https://sideeffects.health.gov.il/