Actemra

Actemra Adverse Reactions

tocilizumab

Manufacturer:

Roche

Marketer:

DKSH
Full Prescribing Info
Adverse Reactions
Clinical Trials: The safety profile in this section comes from 4510 patients exposed to Actemra in clinical trials; the majority of these patients were participating in RA studies (n=4009), while the remaining experience comes from pJIA (n=240), sJIA (n=112), and GCA (n=149) studies.
The safety profile of Actemra across these indications remains similar and undifferentiated.
Adverse Drug Reactions (ADRs) from clinical trials (Table 14) are listed by MedDRA system organ class according to clinical importance to the patient. 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 (≥1/1000 to < 1/100). (See Table 14.)

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Description of selected adverse drug reactions from clinical trials: Rheumatoid Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra has been studied in 5 Phase III, double-blind controlled trials and their extension periods.
The double-blind controlled 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 Actemra 8 mg/kg in combination with MTX/other DMARDs and 288 patients received Actemra 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.
Infections: In the 6-month controlled trials, the rate of all infections reported with Actemra 8 mg/kg+DMARD treatment was 127 events per 100 patient (pt) years compared to 112 events per 100 pt years in the placebo+DMARD group. In the long-term exposure population the overall rate of infections with Actemra was 108 events per 100 pt years exposure.
In 6-month controlled clinical trials rate of serious infections (bacterial, viral and fungal) with Actemra 8 mg/kg+DMARD was 5.3 events per 100 pt years exposure compared to 3.9 events per 100 pt years exposure in the placebo+DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 pt years of exposure in the Actemra group and 1.5 events per 100 pt years of exposure in the MTX group.
In the long-term 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 pt years with Actemra therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 pt years. Reports of gastrointestinal perforation on Actemra were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula 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 Actemra 8 mg/kg+DMARD and 5.1% of patients in the placebo+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 anaphylaxis (occurring in a total of 6/3778 patients) was several-fold higher in the 4 mg/kg arm in comparison 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 trials. These reactions were generally observed during the second to fifth infusions of Actemra (see General under Precautions).
Immunogenicity: A total of 2876 patients have been tested for anti-Actemra antibodies in the 6-month controlled clinical trials. Forty six patients (1.6%) developed positive anti-Actemra antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralizing antibodies.
Early Rheumatoid Arthritis: Study VI (WA19926) evaluated 1162 patients with early, moderate to severe RA who were naive to treatment with both MTX and a biologic agent. The overall safety profile observed in the Actemra treatment groups was consistent with the known safety profile of Actemra (see Table 14).
Monotherapy: Actemra versus adalimumab: In a 24 week double-blinded, parallel study (monotherapy with Actemra 8 mg/kg IV q4w (N=162) compared to adalimumab 40 mg SC q2w (N=162)), the overall clinical adverse event profile was similar between Actemra and adalimumab. The proportion of patients with serious adverse events was balanced between the treatment groups (Actemra 11.7% vs. adalimumab 9.9%) with the most common event being infections (3.1% each). Both study treatments induced the same pattern of changes in laboratory safety parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, the magnitude of change and the frequency of marked abnormalities was higher with Actemra compared with adalimumab. Four (2.5%) patients in the Actemra arm and two (1.2%) patients in the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients in the Actemra arm and five (3.1%) patients in the adalimumab arm experienced ALT increases of CTC grade 2 or higher. The mean LDL increase from baseline was 0.64 mmol/l (25 mg/dL) for patients in the Actemra arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The safety observed in the Actemra arm was consistent with the known safety profile of Actemra and no new or unexpected adverse drug reactions were observed (see Table 14) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Patients Treated with Subcutaneous Actemra: The safety of subcutaneous Actemra in RA was studied in SC-I. The study compared the efficacy and safety of Actemra 162 mg administered every week SC versus 8 mg/kg IV in 1262 subjects with adult RA. All patients in the study received background non-biologic DMARD(s). The safety and immunogenicity observed for Actemra administered SC was consistent with the known safety profile of IV Actemra and no new or unexpected adverse drug reactions were observed (see Table 14). A higher frequency of injection site reactions (ISRs) was observed in the SC arms compared with placebo SC injections in the IV arms (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Injection Site Reactions (ISRs): During the 6-month controlled period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the SC Actemra and the SC placebo (IV group) weekly injections, respectively. These ISRs (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 162 mg weekly were tested for anti-tocilizumab antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-tocilizumab antibodies; of these, all developed neutralizing anti-tocilizumab antibodies. A total of 1454 SC Actemra all exposure patients have been tested for anti-tocilizumab antibodies, thirteen patients (0.9%) developed positive anti-tocilizumab antibodies, and of these 12 patients (0.8%) developed neutralizing anti-tocilizumab antibodies. No correlation of antibody development to clinical response or adverse events was observed.
Polyarticular Juvenile Idiopathic Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra was studied in 188 pediatric patients, 2 to 17 years of age, with pJIA. The total patient exposure in the Actemra all exposure population was 184.4 patient years. In general, the types of adverse drug reactions in patients with pJIA were similar to those seen in RA and sJIA patients (see Adverse Reactions).
Infections: The rate of infections in the Actemra 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 below30 kg treated with 10 mg/kg Actemra (12.2 per 100 patient years) compared to patients weighing ≥30 kg, treated with 8 mg/kg Actemra (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing below 30 kg treated with 10 mg/kg Actemra (21.4%) compared to patients weighing ≥30 kg, treated with 8 mg/kg Actemra (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 Actemra 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 Adverse Reactions).
No clinically significant hypersensitivity reactions associated with Actemra and requiring treatment discontinuation were reported.
Immunogenicity: One patient in the 10 mg/kg below 30 kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
Systemic Juvenile Idiopathic Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra in sJIA has been studied in 112 pediatric patients 2 to 17 years of age. In the 12 week double-blind, controlled portion of the clinical trial 75 patients received treatment with Actemra (8 or 12 mg/kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated in the on-going open-label extension phase.
In general, the adverse drug reactions in patients with sJIA were similar in type to those seen in RA patients (see Adverse Reactions previously mentioned).
Infections: In the 12 week controlled trial the rate of all infections in the Actemra group was 344.7 per 100 patient-years and 287.0 per 100 patient-years in the placebo group. In the on-going open label extension study (Part II) the overall rate of infections remained similar at 306.6 per 100 patient-years.
In the 12 week controlled trial the rate of serious infections in the Actemra group was 11.5 per 100 patient years. In the on-going open label extension study 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: For sJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the 12 week controlled trial, four percent (4.0%) of patients from the Actemra 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 trial experience, 16% of patients in the Actemra group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the Actemra group, the events included, but 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 Actemra and requiring treatment discontinuation, were reported in 1 out of 112 patients (below 1%) treated with Actemra during the controlled and open-label parts of the 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.
Laboratory Abnormalities: Haematology abnormalities: Neutrophils: There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections in any of the indications.
Rheumatoid Arthritis: Intravenous Administration: 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+DMARD compared to below 0.1% of patients on placebo+DMARD. Approximately half of the instances of ANC below 1 x 109/l occurred within 8 weeks of starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receiving Actemra 8 mg/kg +DMARD (see Dosage & Administration and Precautions).
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.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on Actemra 162 mg SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7% of patients.
Systemic juvenile idiopathic arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, a decrease in neutrophil counts below 1 × 109/L occurred in 7% of patients in the Actemra group, and in none in the placebo group.
In the ongoing open-label extension study decreases in neutrophil counts below 1 x 109/L, occurred in 15% of the Actemra group.
Platelets: Rheumatoid Arthritis: Intravenous Administration: 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 traditional DMARDs compared to below 1% of patients on placebo plus traditional DMARDs, without associated bleeding events (see Dosage & Administration and Precautions).
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.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, none of the patients had a decrease in platelet count to ≤50 × 103/μL.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, 1% of patients had a decrease in platelet count to ≤ 50 × 103/μL without associated bleeding events.
Systemic juvenile idiopathic arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, 3% of patients in the placebo group and 1% in the Actemra group had a decrease in platelet count to ≤100 × 103/μL.
In the ongoing open-label extension study decreases in platelet counts below 100 x 103/μL occurred in 3% of patients of the Actemra group, without associated bleeding events.
Liver enzyme elevations: Rheumatoid Arthritis: Intravenous Administration: During the 6-month controlled trials transient elevations in ALT/AST above 3xULN 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 Actemra 8 mg/kg + DMARD compared to 1.5% of patients on placebo+DMARD. The addition of potentially hepatotoxic drugs (e.g. MTX) to Actemra monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST above 5xULN were observed in 0.7% of Actemra monotherapy patients and 1.4% of Actemra+DMARD patients, the majority of whom were discontinued from Actemra treatment (see Dosage & Administration and Precautions). During routine laboratory monitoring, the incidence of indirect bilirubin greater than the upper limit of normal was 6.2% in patients treated with 8 mg/kg Actemra + DMARD in the double-blind controlled population.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
In Study WA25204, of the 1538 patients with moderate to severe RA (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions) and treated with Actemra, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with Actemra treatment (see Precautions).
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, elevation in ALT or AST ≥3 x ULN occurred in 3.7% and below 1% of patients, respectively.
Systemic Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, elevation in ALT or AST ≥ 3xULN occurred in 5% and 3% of patients, respectively, in the Actemra group, and in 0% of placebo patients.
In the ongoing open-label extension study, elevation in ALT or AST ≥ 3xULN occurred in 12% and 4% of patients, respectively, in the Actemra group.
Elevations in lipid parameters: Rheumatoid Arthritis: Intravenous Administration: During routine laboratory monitoring in the 6-month controlled trials elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were observed in patients treated with Actemra. Approximately 24% of patients receiving Actemra in clinical trials experienced sustained elevations in total cholesterol above 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 majority of patients there was no increase in atherogenic indices, and elevations in total cholesterol 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 clinical trials.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, 19% of patients on SC weekly experienced sustained elevations in total cholesterol above 6.2 mmol/L (240 mg/dL), with 9% experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) on SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, elevation in total cholesterol above 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL above 1.5-2 x ULN in one patient (0.5%).
Systemic Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, elevation in total cholesterol above 1.5 x ULN to 2 x ULN occurred in 1.5% of the Actemra group and in 0% of placebo patients. Elevation in LDL above 1.5 x ULN to 2 x ULN occurred in 1.9% of patients in the Actemra group and 0% of the placebo group.
In the ongoing open-label extension study the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled trial data.
Post Marketing Experience: The following adverse drug reactions have been identified from post marketing experience with Actemra (Table 15) based on spontaneous case reports, literature cases and cases from non-interventional study programs. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction 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); very rare (<1/10,000). (See Table 15.)

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