Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639, Grenzach-Wyhlen, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including RoActemra (see section 4.8, undesirable effects). RoActemra treatment must not be initiated in patients with active infections (see section 4.3). Administration of RoActemra should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of RoActemra in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments for moderate to severe RA, sJIA or pJIA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.
As recommended for other biological treatments, RA, sJIA and pJIA patients should be screened for latent tuberculosis (TB) infection prior to starting RoActemra therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating RoActemra. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.
Patients should be instructed to seek medical advice if signs/symptoms (e.g. persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with RoActemra.
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded.
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with RoActemra in RA patients (see section 4.8). RoActemra should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.
Serious hypersensitivity reactions have been reported in association with infusion of RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions even if they have received premedication with steroids and antihistamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with RoActemra. If an anaphylactic reaction or other serious hypersensitivity/serious infusion related reaction occurs, administration of RoActemra should be stopped immediately and RoActemra should be permanently discontinued.
Treatment with RoActemra, particularly when administered concomitantly with MTX, may be associated with elevations in hepatic transaminases, therefore, caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment (see sections 4.2 and 4.8).
Transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with RoActemra treatment (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with RoActemra. When clinically indicated, other liver function tests including bilirubin should be considered.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with RoActemra (see section 4.8). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of RoActemra. Cases of liver failure resulting in liver transplantation have been reported. Patients should be advised to immediately seek medical help if they experience signs and symptoms of hepatic injury.
Caution should be exercised when considering initiation of RoActemra treatment in patients with elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST >5 x ULN, treatment is not recommended.
In RA, pJIA and sJIA patients, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications, including RoActemra discontinuation, based on transaminases levels see section 4.2. For ALT or AST elevations >3–5 x ULN, confirmed by repeat testing, RoActemra treatment should be interrupted.
Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.
In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 × 109/l. Caution should be exercised when considering initiation of RoActemra treatment in patients with a low platelet count (i.e. platelet count below 100 × 103/μL). In patients who develop an ANC <0.5 × 109/l or a platelet count <50 × 103/μL, continued treatment is not recommended.
Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with RoActemra to date.
In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.
In sJIA and pJIA patients, neutrophils and platelets should be monitored at the time of second infusion and thereafter according to good clinical practice, see section 4.2.
Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). In the majority of patients, there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid lowering agents.
In sJIA, pJIA and RA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of RoActemra therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with RoActemra is currently unknown.
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.
Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with RoActemra and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only. It is recommended that all patients, particularly sJIA and pJIA patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.
There is no experience with the use of RoActemra with TNF antagonists or other biological treatments for RA, sJIA or pJIA patients. RoActemra is not recommended for use with other biological agents.
This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium free’.
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.
Interaction studies have only been performed in adults.
Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.
Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance.
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.
In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects.
When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
Women of childbearing potential must use effective contraception during and up to 3 months after treatment.
There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown.
RoActemra should not be used during pregnancy unless clearly necessary.
It is unknown whether tocilizumab is excreted in human breast milk. The excretion of tocilizumab in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with RoActemra should be made taking into account the benefit of breast-feeding to the child and the benefit of RoActemra therapy to the woman.
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.
RoActemra has minor influence on the ability to drive and use machines (see section 4.8, dizziness).
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.
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 RoActemra 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:
Very Common: Upper respiratory tract infections
Common: Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster
Uncommon: Diverticulitis
Common: Abdominal pain, Mouth ulceration, Gastritis
Uncommon: Stomatitis, Gastric ulcer
Common: Rash, Pruritus, Urticaria
Rare: Stevens-Johnson Syndrome3
Common: Headache, Dizziness
Common: Hepatic transaminases increased, Weight increased, Total bilirubin increased*
Common: Hypertension
Common: Leukopenia, Neutropenia, Hypofibrinogenaem ia Immune system disorders
Rare: Anaphylaxis (fatal)1,2,3
Very Common: Hypercholesterolaemia*
Uncommon: Hypertriglyceridaemia
Common: Peripheral oedema, Hypersensitivity reactions
Common: Conjunctivitis
Common: Cough, Dyspnoea
Uncommon: Nephrolithiasis
Uncommon: Hypothyroidism
Rare: Drug-induced liver 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.
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 RoActemra 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.
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.
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.
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).
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.
In the 6-month controlled trials decreases in neutrophil counts below 1 × 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 × 109/l did so within 8 weeks after starting therapy. Decreases below 0.5 × 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.
In the 6-month controlled trials decreases in platelet counts below 100 × 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.
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.
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 RoActemra 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.
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.
The safety profile of tocilizumab 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:
Upper Respiratory Tract Infections:
Very Common: pJIA, sJIA
Nasopharyngitis:
Very Common: pJIA, sJIA
Nausea:
Common: pJIA
Diarrhea:
Common: pJIA, sJIA
Infusion related reactions:
Common: pJIA1, sJIA2
Headache:
Very Common: pJIA
Common: sJIA
Hepatic transaminases increased:
Common: pJIA
Decrease in neutrophil count:
Very Common: sJIA
Common: pJIA
Platelet count decreased:
Common: sJIA
Uncommon: pJIA
Cholesterol increased:
Common: sJIA
Uncommon: pJIA
The safety profile of intravenous RoActemra 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.
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%).
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.
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.
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.
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.
During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥3 x ULN occurred in 3.7% and <1% of patients, respectively.
During routine laboratory monitoring in the intravenous RoActemra 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.
The safety profile of intravenous RoActemra 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 RoActemra, 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.
In the 12 week controlled phase, the rate of all infections in the intravenous RoActemra 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 RoActemra 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 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.
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.
During routine laboratory monitoring in the 12 week controlled phase, a decrease in neutrophil counts below 1 × 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 × 109/l, occurred in 15% of the tocilizumab group.
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 × 103/μl.
In the open label extension phase, decreases in platelet counts below 100 × 103/μl, occurred in 3% of patients in the tocilizumab group, without associated bleeding events.
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.
IgG levels decrease during therapy. A decrease to the lower limit of normal occurred in 15 patients at some point in the study.
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.
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 suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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