Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The safety profile comes from 4510 patients exposed to Actemra in clinical trials; the majority of these patients were participating in adult RA studies (n=4009), while the remaining experience comes from 

GCA (n=149), pJIA (n=240) and sJIA (n=112) studies. The safety profile of Actemra across these indications remains similar and undifferentiated.

The most commonly reported Adverse Drug Reactions (ADRs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

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

Tabulated list of adverse reactions
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 AR 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 treated with Actemra

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
Blood and                                Leukopenia,
lymphatic                                Neutropenia,
system disorders                         Hypofibrinogenae mia
Immune system                                                                        Anaphylaxis (fatal)1, disorders                                                                            2 ,3 
Endocrine                                                      Hypothyroidism disorders
Metabolism and     Hypercholesterolae                          Hypertriglyceridae nutrition          mia*                                        mia disorders
Nervous system                           Headache,
disorders                                Dizziness
Eye disorders                            Conjunctivitis
Vascular                                 Hypertension disorders
Respiratory,                             Cough, Dyspnoea thoracic and mediastinal disorders
Gastrointestinal                         Abdominal pain,       Stomatitis, Gastric disorders                                Mouth ulceration,     ulcer
Gastritis
Hepatobiliary                                                                        Drug-induced liver disorders                                                                            injury, Hepatitis, Jaundice,
Very rare: Hepatic failure
Skin and                                 Rash, Pruritus,                             Stevens-Johnson- subcutaneous                             Urticaria                                   Syndrome3 tissue disorders


MedDRA                                     Frequency categories with preferred terms System Organ            Very Common                Common              Uncommon                            Rare Class
Renal and                                                                 Nephrolithiasis urinary disorders
General                 Injection site          Peripheral oedema disorders and          reaction                 Hypersensitivity administration                                  reaction,
site conditions
Investigations                                  Hepatic transaminases increased, Weight increased, Total bilirubin increased*
* 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.

Subcutaneous use

RA
The safety of subcutaneous Actemra in RA includes a double-blind, controlled, multicenter study, SC-I.
SC-I was a non-inferiority study that compared the efficacy and safety of Actemra 162 mg administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received background non-biologic DMARD(s). The safety and immunogenicity observed for Actemra administered subcutaneous was consistent with the known safety profile of intravenous Actemra and no new or unexpected adverse drug reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.

Injection site reactions
During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the subcutaneous Actemra and the subcutaneous placebo (intravenous group) weekly injections, respectively. These injection site reactions (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved without any treatment and none necessitated drug discontinuation.

Immunogenicity
In SC-I, a total of 625 patients treated with Actemra 162mg weekly were tested for anti- Actemra antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti- Actemra antibodies; of these, all developed neutralizing anti- Actemra antibodies. One patient was tested positive for IgE isotype (0.2%).

In SC-II, a total of 434 patients treated with Actemra 162mg every other week were tested for anti- Actemra antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive anti Actemra antibodies; of these, six (1.4%) developed neutralizing anti- Actemra antibodies. Four patients were tested positive for IgE isotype (0.9%).

No correlation of antibody development to clinical response or adverse events was observed.

Haematological abnormalities:
Neutrophils
During routine laboratory monitoring in the Actemra 6 month controlled clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on the subcutaneous weekly dose.


There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.

Platelets
During routine laboratory monitoring in the Actemra 6-month clinical trial SC-I, none of the patients on the SC weekly dose had a decrease in platelet count to ≤50 × 103 / μL.

Hepatic transaminase elevations
During routine laboratory monitoring in the Actemra 6-month controlled clinical trial SC-I, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on the subcutaneous weekly dose.

Lipid parameters
During routine laboratory monitoring in the Actemra 6 month controlled clinical trial SC-I, 19% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dl), with 9% experiencing a sustained increase in LDL to  4.1 mmol/L(160 mg/dL) on the subcutaneous weekly dose.
 sJIA (SC)
The safety profile of subcutaneous Actemra was evaluated in 51 paediatric patients (1 to 17 years of age) with sJIA. In general, the adverse drug reactions in patients with sJIA were similar in type to those seen in RA patients (see Undesirable Effects section above).

In addition, a higher frequency of serious adverse events and infections (severe and not severe) was observed in sJIA patients who weigh less than 30 kg.

Infections
The rate of infection in sJIA patients treated with SC Actemra was comparable to sJIA patients treated with IV Actemra.

Injection Site Reactions (ISRs)
In the SC Study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs to Actemra SC.
The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.

Immunogenicity
In the SC Study (WA28118), 46 of the 51 (90.2%) patients tested for anti-tocilizumab antibodies at baseline had at least one post-baseline screening assay result. No patient developed positive anti- tocilizumab antibodies post baseline.

Laboratory Abnormalities
In the 52-week open-label SC Study (WA28118), neutrophil count decrease to below 1 × 109/L occurred in 23.5% of patients treated with Actemra SC. Decreases in platelet counts to below 100 × 103/μL occurred in 2% of the patients treated with Actemra SC. An elevation in ALT or AST to ≥3 x ULN occurred in 9.8% and 4.0% patients treated with Actemra SC, respectively.

Lipid parameters
In the 52-week open-label SC Study (WA28118), 23.4% and 35.4% 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 study treatment, respectively.


pJIA (SC)
The safety profile of subcutaneous Actemra was also evaluated in 52 paediatric patients with pJIA.
The total patient exposure to Actemra in the pJIA all exposure population was 184.4 patient years for IV and 50.4 patient years for SC tocilizumab. In general, the safety profile observed in patients with pJIA was consistent with the known safety profile of Actemra with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following SC Actemra injections compared to adult RA.

Infections
In the SC Actemra study, the rate of infection in pJIA patients treated with SC Actemra was comparable with pJIA patients treated with IV Actemra.

Injection Site Reactions
A total of 28.8% (15/52) pJIA patients experienced ISRs to Actemra SC. These ISRs occurred in a 44% of patients ≥30 kg compared to 14.8% of patients below 30 kg. The most common ISRs were injection site erythema, swelling, hematoma, pain and pruritis. All ISRs reported were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or dose interruption.

Immunogenicity
In the SC Study 5.8% [3/52] developed positive neutralizing anti-tocilizumab antibodies without developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 subsequently withdrew from the study. No correlation between antibody development and clinical response or adverse events was observed

Laboratory Abnormalities
During routine laboratory monitoring in the Actemra all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with SC Actemra. An elevation in ALT or AST ≥3 x ULN occurred in 9.6% and 3.8% patients treated with Actemra SC, respectively. No patients treated with SC Actemra experienced a decrease in platelet count to 50 × 103 / μL.

Lipid parameters
In the SC Study, 14.3% and 12.8% 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.

GCA (SC)
The safety of subcutaneous Actemra has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the Actemra all exposure population was 138.5 patient years during the 12 month double blind, placebo controlled phase of the study. The overall safety profile observed in the Actemra treatment groups was consistent with the known safety profile of Actemra (see Table 1).

Infections
The rate of infection/serious infection events was balanced between the Actemra weekly group (200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 events per 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years) groups.

Injection site reactions
In the Actemra subcutaneous weekly group, a total of 6% (6/100) patients reported an adverse reaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as a serious adverse event or required treatment discontinuation.

Immunogenicity
In the Actemra subcutaneous weekly group, one patient (1.1%, 1/95) developed positive neutralizing anti-Actemra antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.

Haematological abnormalities:
Neutrophils
During routine laboratory monitoring in the Actemra 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 109/L occurred in 4% of patients in the Actemra subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.

Platelets
During routine laboratory monitoring in the Actemra 12 month controlled clinical trial, one patient (1%, 1/100) in the Actemra subcutaneous weekly group had a single transient occurence of decrease in platelet count to <100 × 103 / μL without associated bleeding events. A decrease in platelet count below 100 × 103 / μL was not observed in either of the placebo plus prednisone taper groups.

Hepatic transaminase elevations
During routine laboratory monitoring in the Actemra 12 month controlled clinical trial, elevation in ALT ≥3 x ULN occurred in 3% of patients in the Actemra subcutaneous weekly group compared to 2% in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1% of patients in the Actemra subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.

Lipid parameters
During routine laboratory monitoring in the Actemra 12 month controlled clinical trial, 34% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dL), with 15% experiencing a sustained increase in LDL to  4.1 mmol/L (160 mg/dL) in the Actemra subcutaneous weekly group.

Intravenous use
RA
The safety of Actemra has been studied in 5 Phase III, double-blind controlled trials and their extension periods.

The all control population includes all patients from the double-blind phases of each core study from randomization until either the first change in the treatment regimen, or two years is reached. The control period in 4 of the studies was 6 months and in 1 study was up to 2 years. In the double-blind controlled studies 774 patients received Actemra 4 mg/kg in combination with MTX, 1870 patients received tocilizumab 8 mg/kg in combination with MTX/other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.

The all exposure population includes all patients who received at least one dose of Actemra either in the double-blind control period or open label extension phase in 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.

Description of selected adverse reactions

Infections
In the 6-month controlled studies the rate of all infections reported with Actemra 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 Actemra 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 Actemra group and 1.5 events per 100 patient years of exposure in the MTX group.


In the all exposure population the overall rate of serious infections was 4.7 events per 100 pt years.
Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis. Cases of opportunistic infections have also 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 Actemra 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 Actemra were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.

Infusion Related 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 6/3778patients, 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 Actemra and requiring treatment discontinuation were reported in a total of 13 out of 3778 patients (0.3%) treated with Actemra 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 intravenous Actemra (see section 4.4).

Immunogenicity
A total of 2,876 patients have been tested for anti-Actemra antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-Actemra 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 Actemra 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 Actemra 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 Actemra 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 Actemra 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg Actemra plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to Actemra monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of Actemra monotherapy patients and 1.4% of Actemra 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 Actemra + 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 Actemra. Long-term safety evaluations are ongoing.

Skin Reactions
Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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/