8) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.
Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen MA Inc. 1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The tocilizumab-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies.
In these studies, patients received doses of tocilizumab-IV 8 mg per kg monotherapy (288 patients), tocilizumab-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or tocilizumab-IV 4 mg per kg in combination with methotrexate (774 patients).
The all exposure population includes all patients in registration studies who received at least one dose of tocilizumab-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.
All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian. 1) ]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with tocilizumab-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking tocilizumab-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of tocilizumab-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.
Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the tocilizumab-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group.
The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis. The overall rate of infections with tocilizumab-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.
5 per 100 patient-years in the methotrexate group. 9 events per 100 patient-years in the placebo plus DMARD group. In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies.
The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. 1) ]. 1) ]. 26 events per 100 patient-years with tocilizumab-IV therapy.
In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess.
2) ]. The relative contribution of these concomitant medications versus tocilizumab-IV to the development of GI perforations is not known. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg tocilizumab-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group.
The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria.
These events were not treatment limiting. 2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of tocilizumab-IV. 6) ]. 1% of patients in the placebo plus DMARD group.
Approximately half of the instances of ANC below 1000 per mm 3 occurred within 8 weeks of starting therapy. 1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm 3 and the occurrence of serious infections.
4) ]. 5% of patients on placebo plus DMARD, without associated bleeding events. 4) ]. Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. 8) ]. 4) ]. Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V For a description of these studies, see Section 14, Clinical Studies.
3 In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials. 2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab.
Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of tocilizumab-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter.
Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below: Mean LDL increased by 13 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 20 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 25 mg per dL in tocilizumab 8 mg per kg monotherapy.
Mean HDL increased by 3 mg per dL in the tocilizumab 4 mg per kg+DMARD arm, 5 mg per dL in the tocilizumab 8 mg per kg+DMARD, and 4 mg per dL in tocilizumab 8 mg per kg monotherapy. 26 in tocilizumab 8 mg per kg monotherapy. ApoB/ApoA1 ratios were essentially unchanged in tocilizumab-treated patients.
Elevated lipids responded to lipid lowering agents. In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials. Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay.
Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of tocilizumab or of other tocilizumab products.
In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal.
Thirty patients (1%) developed neutralizing antibodies. Malignancies During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving tocilizumab-IV, compared to 8 malignancies in patients in the control groups.
37 events per 100 patient-years). 5) ]. Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg tocilizumab-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2 .
2 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in an open label PK-PD and safety study in 24 patients with GCA who were in remission on tocilizumab-IV at time of enrollment.
Patients received tocilizumab 7 mg/kg every 4 weeks for 20 weeks, followed by 6 mg/kg every 4 weeks for 20 weeks. 5 years. The safety of tocilizumab by another route of administration has been studied in one Phase III study with 251 GCA patients.
5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed was generally consistent with the known safety profile of tocilizumab. There was an overall higher incidence of infections in GCA patients relative to RA patients.
The overall safety profile observed for tocilizumab administered intravenously in GCA patients was consistent with the known safety profile of tocilizumab. 3 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate.
4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. 4) ]. 7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections.
0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).
Infusion Reactions In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. 2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension.
4) ]. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Immunogenicity One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
7% of patients. There was no clear relationship between decreases in neutrophils below 1 × 10 9 per L and the occurrence of serious infections. Thrombocytopenia During routine laboratory monitoring in the tocilizumab-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm 3 without associated bleeding events.
Elevated Liver Enzymes During routine laboratory monitoring in the tocilizumab-IV all exposure population, elevation in ALT or AST at or greater than 3 × ULN occurred in 4% and less than 1% of patients, respectively. 5%). 4 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The data described below reflect exposure to tocilizumab-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy.
3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with tocilizumab-IV (8 or 12 mg per kg based upon body weight).
After 12 weeks or at the time of escape, due to disease worsening, patients were treated with tocilizumab-IV in the open-label extension phase. The most common adverse events (at least 5%) seen in tocilizumab-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.
Infections In the 12 week controlled phase, the rate of all infections in the tocilizumab-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.
5 per 100 patient years. 4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media. Macrophage Activation Syndrome In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with tocilizumab-IV.
One patient in the placebo group escaped to tocilizumab-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had tocilizumab-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae.
Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the tocilizumab-IV SJIA clinical development experience; however no definitive conclusions can be made. Infusion Reactions Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA.
Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of tocilizumab-IV and 0% of placebo treated patients experienced events occurring during infusion.
One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment. Within 24 hours after infusion, 16% of patients in the tocilizumab-IV treatment group and 5% of patients in the placebo group experienced an event.
In the tocilizumab-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious. 6) ]. Immunogenicity All 112 patients were tested for anti-tocilizumab antibodies at baseline.
Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.
Laboratory Abnormalities Neutropenia During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 × 10 9 per L occurred in 7% of patients in the tocilizumab-IV group, and in no patients in the placebo group.
In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the tocilizumab-IV group. There was no clear relationship between decrease in neutrophils below 1 × 10 9 per L and the occurrence of serious infections.
Thrombocytopenia During routine monitoring in the 12 week controlled phase, 1% of patients in the tocilizumab-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm 3 . In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the tocilizumab-IV group, with no associated bleeding.
Elevated Liver Enzymes During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3× ULN occurred in 5% and 3% of patients, respectively in the tocilizumab-IV group and in 0% of placebo patients.
In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3× ULN occurred in 13% and 5% of tocilizumab-IV treated patients, respectively. 5% of the tocilizumab-IV group and in 0% of placebo patients.
9% of patients in the tocilizumab-IV group and 0% of the placebo group. In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.
5 Clinical Trials Experience in COVID-19 Patients Treated with Intravenous Tocilizumab (Tocilizumab-IV) The safety of tocilizumab in hospitalized COVID-19 patients was evaluated in a pooled safety population that includes patients enrolled in EMPACTA, COVACTA, AND REMDACTA.
The analysis of adverse reactions included a total of 974 patients exposed to tocilizumab. Patients received a single, 60-minute infusion of intravenous tocilizumab 8 mg/kg (maximum dose of 800 mg). If clinical signs or symptoms worsened or did not improve, one additional dose of tocilizumab 8 mg/kg could be administered between 8- 24 hours after the initial dose.
Adverse reactions summarized in Table 3 occurred in at least 3% of tocilizumab -treated patients and more commonly than in patients on placebo in the pooled safety population. Table 3 Adverse Reactions Patients are counted once for each category regardless of the number of reactions Identified From the Pooled COVID-19 Safety Population Adverse Reaction Tocilizumab 8mg per kg Placebo N = 974 (%) N = 483 (%) Hepatic Transaminases increased 10% 8% Constipation 9% 8% Urinary tract infection 5% 4% Hypertension 4% 1% Hypokalaemia 4% 3% Anxiety 4% 2% Diarrhea 4% 2% Insomnia 4% 3% Nausea 3% 2% In the pooled safety population, the rates of infection/serious infection events were 30%/19% in patients receiving tocilizumab versus 32%/23% receiving placebo.
5% of patients who received placebo. 5% of patients who received placebo. 9% of patients who received placebo. 6 Postmarketing Experience The following adverse reactions have been identified during post-approval use of tocilizumab products.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. 3) ]