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).
RoActemra subcutaneous formulation is not intended for intravenous administration.
RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg.
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.
RoActemra monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Glucocorticoids should be given according to medical judgement and practice guidelines.
Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients. In clinical trials, RoActemra 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 RoActemra 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 RoActemra clearance in RA patients. In GCA patients, no effect of cumulative corticosteroid dose on RoActemra exposure was observed.
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 RoActemra, is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. RoActemra 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 RoActemra 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 RoActemra 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 RoActemra treatment.
RoActemra has a minor influence on the ability to drive and use machines (see section 4.8, dizziness).
The safety profile comes from 4510 patients exposed to RoActemra 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 RoActemra 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.
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 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 RoActemra:
Common: Leukopenia, Neutropenia, Hypofibrinogenae mia
Uncommon: Hypothyroidism
Common: Conjunctivitis
Common: Abdominal pain, Mouth ulceration, Gastritis
Uncommon: Stomatitis, Gastric ulcer
Very Common: Injection site reaction
Common: Peripheral oedema, Hypersensitivity reaction
Rare: Drug-induced liver injury, Hepatitis, Jaundice, Very rare: Hepatic failure
Rare: Anaphylaxis (fatal)1,2,3
Very Common: Upper respiratory tract infections
Common: Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster
Uncommon: Diverticulitis
Common: Hepatic transaminases increased, Weight increased, Total bilirubin increased*
Very Common: Hypercholesterolaemia*
Uncommon: Hypertriglyceridaemia
Common: Headache, Dizziness
Uncommon: Nephrolithiasis
Common: Cough, Dyspnoea
Common: Rash, Pruritus, Urticaria
Rare: Stevens-Johnson Syndrome3
Common: Hypertension
The safety of subcutaneous RoActemra 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 RoActemra 162 mg administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received background non-biologic DMARD. The safety and immunogenicity observed for RoActemra administered subcutaneous was consistent with the known safety profile of intravenous RoActemra 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.
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 RoActemra 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.
In SC-I, a total of 625 patients treated with RoActemra 162mg weekly were tested for anti-RoActemra antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-RoActemra antibodies; of these, all developed neutralizing anti-RoActemra antibodies. One patient was tested positive for IgE isotype (0.2%).
In SC-II, a total of 434 patients treated with RoActemra 162mg every other week were tested for anti-RoActemra antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive antiRoActemra antibodies; of these, six (1.4%) developed neutralizing anti-RoActemra antibodies. Four patients were tested positive for IgE isotype (0.9%).
No correlation of antibody development to clinical response or adverse events was observed.
Neutrophils: During routine laboratory monitoring in the RoActemra 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 × 109/L and the occurrence of serious infections.
Platelets: During routine laboratory monitoring in the RoActemra 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 RoActemra 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 RoActemra 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.
The safety profile of subcutaneous RoActemra 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).
The rate of infection in sJIA patients treated with SC RoActemra was comparable to sJIA patients treated with IV RoActemra.
In the SC Study (WA28118), a total of 41.2% (21/51) sJIA patients experienced ISRs to RoActemra 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.
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.
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 RoActemra SC. Decreases in platelet counts to below 100 × 103/μL occurred in 2% of the patients treated with RoActemra SC. An elevation in ALT or AST to ≥3 x ULN occurred in 9.8% and 4.0% patients treated with RoActemra SC, respectively.
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.
The safety profile of subcutaneous RoActemra was also evaluated in 52 paediatric patients with pJIA. The total patient exposure to RoActemra 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 RoActemra with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following SC RoActemra injections compared to adult RA.
In the SC RoActemra study, the rate of infection in pJIA patients treated with SC RoActemra was comparable with pJIA patients treated with IV RoActemra.
A total of 28.8% (15/52) pJIA patients experienced ISRs to RoActemra 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.
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
During routine laboratory monitoring in the RoActemra all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with SC RoActemra. An elevation in ALT or AST ≥3 x ULN occurred in 9.6% and 3.8% patients treated with RoActemra SC, respectively. No patients treated with SC RoActemra experienced a decrease in platelet count to ≤50 × 103/μL.
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.
The safety of subcutaneous RoActemra has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the RoActemra 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 RoActemra treatment groups was consistent with the known safety profile of RoActemra (see Table 1).
The rate of infection/serious infection events was balanced between the RoActemra 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.
In the RoActemra 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.
In the RoActemra subcutaneous weekly group, one patient (1.1%, 1/95) developed positive neutralizing anti-RoActemra antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.
Neutrophils: During routine laboratory monitoring in the Roactemra 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 109/L occurred in 4% of patients in the RoActemra subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.
Platelets: During routine laboratory monitoring in the RoActemra 12 month controlled clinical trial, one patient (1%, 1/100) in the RoActemra 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 RoActemra 12 month controlled clinical trial, elevation in ALT ≥3 x ULN occurred in 3% of patients in the RoActemra 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 RoActemra subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.
Lipid parameters: During routine laboratory monitoring in the RoActemra 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 RoActemra subcutaneous weekly group.
The safety of RoActemra 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 RoActemra 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 RoActemra 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.
In the 6-month controlled studies the rate of all infections reported with RoActemra 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 RoActemra 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 RoActemra 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.
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 RoActemra 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 RoActemra 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 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 RoActemra and requiring treatment discontinuation were reported in a total of 13 out of 3778 patients (0.3%) treated with RoActemra 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 RoActemra (see section 4.4).
A total of 2,876 patients have been tested for anti-RoActemra antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-RoActemra 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.
Neutrophils: In the 6-month controlled trials decreases in neutrophil counts below 1 × 109/L occurred in 3.4% of patients on RoActemra 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 × 10^9/L did so within 8 weeks after starting therapy. Decreases below 0.5 × 10^9/L were reported in 0.3% patients receiving RoActemra 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 × 103/μL occurred in 1.7% of patients on RoActemra 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 RoActemra 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg RoActemra plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic drugs (e.g. MTX) to RoActemra monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST >5 x ULN were observed in 0.7% of RoActemra monotherapy patients and 1.4% of RoActemra 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 RoActemra + 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 RoActemra. Long-term safety evaluations are ongoing.
Rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.
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.
In the absence of compatability studies, this medicinal product must not be mixed with other medicinal products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
