Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity reactions.

RA Patients
The safety profile of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV and V), 1 MTX-controlled study (study I) and their extension periods (see section 5.1).

The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up to 2 years in one study (study II). In the double-blind controlled studies, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in combination with MTX or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

The long-term exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in the studies. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year, 2806 received treatment for at least 2 years and 1222 for 3 years.

ADRs from clinical trials and/or post marketing experience with Actemra based on spontaneous case reports, literature cases and cases from non-interventional study programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category for each ADR is based on 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) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. List of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period or during postmarketing experience

MedDRA                                     Frequency categories with preferred terms System Organ            Very Common                Common              Uncommon                            Rare Class
Infections and         Upper respiratory        Cellulitis,               Diverticulitis infestations           tract infections         Pneumonia, Oral
herpes simplex,
Herpes zoster
Gastrointestinal                                Abdominal pain,           Stomatitis, Gastric disorders                                       Mouth ulceration,         ulcer Gastritis
Skin and                                        Rash, Pruritus,                                     Stevens-Johnson- subcutaneous                                    Urticaria                                           Syndrome3 tissue disorders
Nervous system                                  Headache,
disorders                                       Dizziness
Investigations                                  Hepatic
transaminases
increased, Weight
increased, Total
bilirubin increased*
Vascular                                        Hypertension
disorders
Blood and                                       Leukopenia,
lymphatic                                       Neutropenia,
system disorders                                Hypofibrinogenaem
ia
Immune system                                                                                       Anaphylaxis disorders                                                                                           (fatal)1, 2 ,3 Metabolism and         Hypercholesterolae                                 Hypertriglyceridae nutrition              mia*                                               mia disorders
General                                         Peripheral oedema,
disorders and                                   Hypersensitivity
administration                                  reactions
site conditions
Eye disorders                                   Conjunctivitis
Respiratory,                                    Cough, Dyspnoea
thoracic and
mediastinal
disorders
Renal disorders                                                           Nephrolithiasis Endocrine                                                                 Hypothyroidism disorders
Hepatobiliary                                                                                       Drug-induced liver disorders                                                                                           injury, Hepatitis, Jaundice,
Very rare: Hepatic
failure
* Includes elevations collected as part of routine laboratory monitoring (see text below) 1
See section 4.3
2
See section 4.4
3
This adverse reaction was identified through post marketing surveillance but not observed in controlled clinical trials.
The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to TCZ in clinical trials.
Infections
In the 6-month controlled studies the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with Actemra was 108 events per 100 patient years exposure.

In 6-month controlled clinical studies, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.

In the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

Interstitial Lung Disease
Impaired lung function may increase the risk for developing infections. There have been post- marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.

Gastrointestinal Perforation
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion reactions
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.

The rate of anaphylactic reactions (occurring in a total of 8/4,009 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4,009 patients (1.4%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab (see section 4.4).

Immunogenicity
A total of 2,876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1%) developed neutralising antibodies.
Haematological abnormalities:
Neutrophils
In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ l occurred in 3.4% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 x 109/ l did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/ l were reported in 0.3% patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.

Platelets
In the 6-month controlled trials decreases in platelet counts below 100 x 103/ μL occurred in 1.7% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.

Very rare reports of pancytopenia have occurred in the post marketing setting.

Hepatic transaminase elevations
During the 6-month controlled trials transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of
patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.

Lipid parameters
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving Actemra in clinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/ l, with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/ l. Elevations in lipid parameters responded to treatment with lipid-lowering agents.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.

Malignancies
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Skin Reactions
Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.

sJIA and pJIA Patients

The safety profile of toclizumab in the pediatric population is summarized in the sections on pJIA and sJIA below. In general, the ADRs in pJIA and sJIA patients were similar in type to those seen in RA patients, see section 4.8.

ADRs in the pJIA and sJIA patients treated with tocilizumab are listed in the Table 2 and presented by MedDRA system organ class. The corresponding frequency category for each ADR is based on the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10) or uncommon (≥ 1/1,000 to <1/100).

Table 2: List of ADRs occurring in clinical trial patients with sJIA or pJIA receiving tocilizumab as monotherapy or in combination with MTX.

MedDRA SOC           Preferrred term (PT)                                       Frequency Infections and Infestations                             Very Common              Common              Uncommon Upper Respiratory                  pJIA, sJIA
Tract Infections
Nasopharyngitis                    pJIA, sJIA
Gastrointestinal Disorders
Nausea                                                       pJIA
Diarrhea                                                     pJIA, sJIA General disorders and administration site
conditions
Infusion related                                             pJIA1, sJIA2 reactions
Nervous system disorders
Headache                           pJIA                      sJIA
Investigations
Hepatic transaminases                                        pJIA
increased
Decrease in neutrophil             sJIA                      pJIA
count
Platelet count decreased                                     sJIA               pJIA Cholesterol increased                                        sJIA               pJIA 1. Infusion related reaction events in pJIA patients included but were not limited to headache, nausea and hypotension 2. Infusion related reaction events in sJIA patients included but were not limited to rash, urticaria, diarrhoea, epigastric
discomfort, arthralgia and headache

pJIA Patients
The safety profile of intravenous Actemra in pJIA has been studied in 188 patients from 2 to 17 years of age. The total patient exposure was 184.4 patient years. The frequency of ADRs in pJIA patients can be found in Table 2. The types of ADRs in pJIA patients were similar to those seen in RA and sJIA patients, see section 4.8. When compared to the adult RA population, events of nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in the pJIA population. Events of cholesterol increased were less frequently reported in the pJIA population than in the adult RA population.

Infections
The rate of infections in the tocilizumab all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing <30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing ≥30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing <30 kg treated with 10 mg/kg tocilizumab (21.4%) compared to patients weighing ≥30 kg, treated with 8 mg/kg tocilizumab (7.6%).
Infusion Reactions
In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9%) experienced infusion reactions during the infusion and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients, see section 4.8.

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

Immunogenicity
One patient in the 10 mg/kg < 30kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
Neutrophils
During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7% of patients.

Platelets
During routine laboratory monitoring in the tocilizumab all exposure population, 1% of patients had a decrease in platelet count to ≤ 50 × 103/µL without associated bleeding events.

Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥ 3xULN occurred in 3.7% and <1% of patients, respectively.

Lipid parameters
During routine laboratory monitoring in the intravenous Actemra study WA19977 3.4% and 10.4% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during the study treatment, respectively.

sJIA Patients
The safety profile of intravenous Actemra in sJIA has been studied in 112 patients from 2 to 17 years of age. In the 12 week double-blind, controlled phase, 75 patients received treatment with tocilizumab (8 mg/kg or 12 mg/kg based upon body weight). After 12 weeks or at the time of switching to Actemra, due to disease worsening, patients were treated in the open label extension phase.

In general, the ADRs in sJIA patients were similar in type to those seen in RA patients, see section 4.8. The frequency of ADRs in sJIA patients can be found in Table 2. When compared to the adult RA
population, patients with sJIA experienced a higher frequency of nasopharyngitis, decrease in neutrophil counts, hepatic transaminases increased, and diarrhea. Events of cholesterol increased were less frequently reported in the sJIA population than in the adult RA population.

Infections
In the 12 week controlled phase, the rate of all infections in the intravenous Actemra group was 344.7 per 100 patient years and 287.0 per 100 patient years in the placebo group. In the open label extension phase (Part II), the overall rate of infections remained similar at 306.6 per 100 patient years.

In the 12 week controlled phase, the rate of serious infections in the intravenous Actemra group was 11.5 per 100 patient years. At one year in the open label extension phase the overall rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.

Infusion Reactions
Infusion related reactions are defined as all events occurring during or within 24 hours of an infusion.
In the 12 week controlled phase, 4% of patients from the tocilizumab group experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

In the 12 week controlled phase, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the events included, but were not limited to rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in 1 out of 112 patients (< 1%) treated with tocilizumab during the controlled and up to and including the open label clinical trial.

Immunogenicity
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reaction leading to withdrawal. The incidence of anti-tocilizumab antibody formation might be underestimated because of interference of tocilizumab with the assay and higher drug concentration observed in children compared to adults.

Neutrophils
During routine laboratory monitoring in the 12 week controlled phase, a decrease in neutrophil counts below 1 x 109/l occurred in 7% of patients in the tocilizumab group, and no decreases in the placebo group.

In the open label extension phase, decreases in neutrophil counts below 1 x 109/l, occurred in 15% of the tocilizumab group.

Platelets
During routine laboratory monitoring in the 12 week controlled phase, 3% of patients in the placebo group and 1% in the tocilizumab group had a decrease in platelet count to ≤ 100 x 103/µl.

In the open label extension phase, decreases in platelet counts below 100 x 103/µl, occurred in 3% of patients in the tocilizumab group, without associated bleeding events.

Hepatic transaminase elevations
During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST ≥ 3 x ULN occurred in 5% and 3% of patients, respectively, in the tocilizumab group, and 0% in the placebo group.

In the open label extension phase, elevation in ALT or AST ≥ 3 x ULN occurred in 12% and 4% of patients, respectively, in the tocilizumab group.

Immunoglobulin G
IgG levels decrease during therapy. A decrease to the lower limit of normal occurred in 15 patients at some point in the study.

Lipid parameters
During routine laboratory monitoring in the 12 week controlled phase (study WA18221), 13.4% and 33.3% of patients experienced a post-baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during study treatment, respectively.

In the open label extension phase (study WA18221), 13.2% and 27.7% of patients experienced a post- baseline elevation of their LDL-cholesterol value to ≥ 130 mg/dL and total cholesterol value to ≥ 200 mg/dL at any time during study treatment, respectively.

CRS Patients
The safety of tocilizumab in CRS has been evaluated in a retrospective analysis of data from clinical trials, where 51 patients were treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T- cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered.

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