What is Actemra (tocilizumab)?
Actemra (tocilizumab) is an interleukin-6 (IL-6) receptor inhibitor used to treat:
- moderate to severe active rheumatoid arthritis in adults,
- giant cell arthritis, polyarticular juvenile idiopathic arthritis in patients 2 years of age and older with active disease,
- systemic juvenile idiopathic arthritis in patients 2 years of age and older with active disease, and
- cytokine release syndrome in patients 2 years of age and older with active disease.
Inflammation is the body's reaction to injury and is a necessary process for injury repair. IL-6 is a protein the body produces when there is inflammation. IL-6 promotes inflammation which, in the case of arthritis, includes fever as well as pain, tenderness, and joint swelling.
The unchecked inflammation of rheumatoid arthritis eventually leads to destruction of the joints. Actemra binds to IL-6 in the body and blocks the effects of IL-6. As a result, inflammation and its consequences in the joints are reduced, and the progressive destruction of the joints is slowed or prevented.
Common side effects of Actemra include:
- respiratory tract infections,
- headaches,
- high blood pressure (hypertension),
- elevations in liver tests suggesting liver injury, and
- injection site reactions (rash, redness, swelling, itching).
Serious side effects of Actemra include:
- serious infections (such as tuberculosis, sepsis, and fungal infections),
- worsening or new diseases of the nervous system,
- cancer,
- reduced levels of white blood cells or platelets,
- reactivation of herpes zoster infection (shingles),
- gastrointestinal perforation in patients with diverticulitis, and
- hypersensitivity (allergic) reactions.
Drug interactions of Actemra include:
- anakinra,
- abatacept, and
- rituximab, which can result in a reduction in white blood cells and serious infections.
Actemra may interfere with the effectiveness of vaccines. Actemra has not been studied in combination with other similar drugs that block other chemicals that promote inflammation such as TNF blockers.
There are no adequate studies of Actemra in pregnant women. It is unknown if Actemra is excreted in breast milk. Consult your doctor before breastfeeding.
What are the important side effects of Actemra (tocilizumab)?
The most common adverse effects of tocilizumab in clinical studies were:
- respiratory tract infections,
- headaches,
- hypertension (high blood pressure), and
- elevations in liver tests suggesting liver injury.
Injection site reactions (rash, redness, swelling, itching) may also occur. Use of tocilizumab has been associated with serious infections such as:
- tuberculosis,
- sepsis (bacteria in the blood) and
- fungal infections.
Individuals with active infections should not be treated with tocilizumab. Tocilizumab may worsen or cause new diseases of the nervous system. In studies, some patients who used tocilizumab developed cancer. Other side effects include:
- reduced levels of white blood cells or platelets,
- reactivation of herpes zoster infection (shingles), and
- hypersensitivity (allergic) reactions.
In studies, gastrointestinal perforation was observed in patients with diverticulitis.
Actemra (tocilizumab) side effects list for healthcare professionals
The following serious adverse reactions are described elsewhere in labeling:
- Serious Infections
- Gastrointestinal Perforations
- Laboratory Parameters
- Immunosuppression
- Hypersensitivity Reactions, Including Anaphylaxis
- Demyelinating Disorders
- Active Hepatic Disease and Hepatic Impairment
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.
Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Intravenous Actemra (Actemra-IV)
The Actemra-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Actemra-IV 8 mg per kg monotherapy (288 patients), ActemraIV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Actemra-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 Actemra-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.
The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Actemra-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 Actemra-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Actemra-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 Actemra-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 Actemra-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 Actemra-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.
Serious Infections
In the 24 week, controlled clinical studies, the rate of serious infections in the Actemra-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Actemra-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 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. Cases of opportunistic infections have been reported.
In the cardiovascular outcomes Study WA25204, the rate of serious infections in the Actemra 8 mg/kg IV every 4 weeks group, with or without DMARD, was 4.5 per 100 patient-years, and the rate in the etanercept 50 mg weekly SC group, with or without DMARD, was 3.2 per 100 patient-years.
Gastrointestinal Perforations
During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Actemra-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. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The relative contribution of these concomitant medications versus Actemra-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 Actemra-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.
Anaphylaxis
Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Actemra-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Actemra-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.
Laboratory Abnormalities
Neutropenia
In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Actemra-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Actemra-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of serious infections.
In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.
Thrombocytopenia
In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Actemra-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.
In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies.
Elevated Liver Enzymes
Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Actemra-IV, or reduction in Actemra-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.
Table 1 - Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V
Actemra 8 mg per kg Monotherapy N = 288 (%) | Methotrexate N = 284 (%) | Actemra 4 mg per kg + DMARDs N = 774 (%) | Actemra 8 mg per kg + DMARDs N = 1582 (%) | Placebo + DMARDs N = 1170 (%) | |
AST (U/L) | |||||
> ULN to 3x ULN | 22 | 26 | 34 | 41 | 17 |
> 3x ULN to 5x ULN | 0.3 | 2 | 1 | 2 | 0.3 |
> 5x ULN | 0.7 | 0.4 | 0.1 | 0.2 | < 0.1 |
ALT (U/L) | |||||
> ULN to 3x ULN | 36 | 33 | 45 | 48 | 23 |
> 3x ULN to 5x ULN | 1 | 4 | 5 | 5 | 1 |
> 5x ULN | 0.7 | 1 | 1.3 | 1.5 | 0.3 |
ULN = Upper Limit of Normal |
In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials.
In Study WA25204, of the 1538 patients with moderate to severe RA and treated with tocilizumab, 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 tocilizumab.
Lipids
Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Actemra-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 Actemra 4 mg per kg+DMARD arm, 20 mg per dL in the Actemra 8 mg per kg+DMARD, and 25 mg per dL in Actemra 8 mg per kg monotherapy.
- Mean HDL increased by 3 mg per dL in the Actemra 4 mg per kg+DMARD arm, 5 mg per dL in the Actemra 8 mg per kg+DMARD, and 4 mg per dL in Actemra 8 mg per kg monotherapy.
- Mean LDL/HDL ratio increased by an average of 0.14 in the Actemra 4 mg per kg+DMARD arm, 0.15 in the Actemra 8 mg per kg+DMARD, and 0.26 in Actemra 8 mg per kg monotherapy.
- ApoB/ApoA1 ratios were essentially unchanged in Actemra-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
As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.
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 Actemra-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Actemra-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).
In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.
Other Adverse Reactions
Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Actemra-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.
Table 2 - Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Actemra plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD
24 Week Phase 3 Controlled Study Population | |||||
Preferred Term | Actemra 8 mg per kg Monotherapy N = 288 (%) | Methotrexate N = 284 (%) | Actemra 4 mg per kg + DMARDs N = 774 (%) | Actemra 8 mg per kg + DMARDs N = 1582 (%) | Placebo + DMARDs N = 1170 (%) |
Upper Respiratory Tract Infection | 7 | 5 | 6 | 8 | 6 |
Nasopharyngitis | 7 | 6 | 4 | 6 | 4 |
Headache | 7 | 2 | 6 | 5 | 3 |
Hypertension | 6 | 2 | 4 | 4 | 3 |
ALT increased | 6 | 4 | 3 | 3 | 1 |
Dizziness | 3 | 1 | 2 | 3 | 2 |
Bronchitis | 3 | 2 | 4 | 3 | 3 |
Rash | 2 | 1 | 4 | 3 | 1 |
Mouth Ulceration | 2 | 2 | 1 | 2 | 1 |
Abdominal Pain Upper | 2 | 2 | 3 | 3 | 2 |
Gastritis | 1 | 2 | 1 | 2 | 1 |
Transaminase increased | 1 | 5 | 2 | 2 | 1 |
Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Actemra-IV in controlled trials were:
Infections and Infestations: oral herpes simplex
Gastrointestinal disorders: stomatitis, gastric ulcer
Investigations: weight increased, total bilirubin increased
Blood and lymphatic system disorders: leukopenia
General disorders and administration site conditions: edema peripheral
Respiratory, thoracic, and mediastinal disorders: dyspnea, cough
Eye disorders: conjunctivitis
Renal disorders: nephrolithiasis
Endocrine disorders: hypothyroidism
Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Subcutaneous Actemra (Actemra-SC)
The Actemra-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously and 8 mg/kg intravenously every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week subcutaneously or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.
The safety observed for Actemra-SC administered subcutaneously was consistent with the known safety profile of intravenous Actemra, with the exception of injection site reactions (ISRs), which were more common with Actemra-SC compared with placebo SC injections (IV arm).
Injection Site Reactions
In the 6-month control period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the weekly Actemra-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of ISRs was 7.1% (31/437) and 4.1% (9/218) for the every other week Actemra-SC and placebo groups, respectively. These ISRs (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.
Immunogenicity
In the 6-month control period in SC-I, 0.8% (5/625) in the Actemra-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Actemra-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti-tocilizumab antibodies; of these, 1.4% (6/434) in the Actemra-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.
A total of 1454 (>99%) patients who received Actemra-SC in the all exposure group have been tested for antitocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.
The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.
Laboratory Abnormalities
Neutropenia
During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving Actemra-SC weekly and every other week, respectively.
There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.
Thrombocytopenia
During routine laboratory monitoring in the Actemra-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm3.
Elevated Liver Enzymes
During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Actemra-SC weekly and 3.4% and 0.7% receiving Actemra-SC every other week.
Lipid Parameters Elevations
During routine laboratory monitoring in the Actemra-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Actemra-SC weekly, every other week and placebo, respectively.
Clinical Trials Experience In Giant Cell Arteritis Patients Treated With Subcutaneous Actemra (Actemra-SC)
The safety of subcutaneous Actemra (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the Actemra GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the Actemra treatment groups was generally consistent with the known safety profile of Actemra. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the Actemra weekly group and 160.2/4.4 events per 100 patient years in the Actemra every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups.
Clinical Trials Experience In Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous Actemra (Actemra-IV)
The safety of Actemra-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. The total patient exposure in the Actemra-IV all exposure population (defined as patients who received at least one dose of Actemra-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients.
Infections
The rate of infections in the Actemra-IV 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 less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 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 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. In the Actemra-IV all exposure population, 11 patients (6%) experienced an event 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 occurring 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.
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.
Laboratory Abnormalities
Neutropenia
During routine laboratory monitoring in the Actemra-IV all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 3.7% of patients.
There was no clear relationship between decreases in neutrophils below 1 × 109 per L and the occurrence of serious infections.
Thrombocytopenia
During routine laboratory monitoring in the Actemra-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm3 without associated bleeding events.
Elevated Liver Enzymes
During routine laboratory monitoring in the Actemra-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively.
Lipids
During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%).
Clinical Trials Experience In Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Actemra (Actemra-SC)
The safety of Actemra-SC was studied in 52 pediatric patients 1 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the PJIA Actemra-SC population (defined as patients who received at least one dose of Actemra-SC and accounting for treatment discontinuation) was 49.5 patient years. In general, the safety observed for Actemra administered subcutaneously was consistent with the known safety profile of intravenous Actemra, with the exception of injection site reactions (ISRs), and neutropenia.
Injection Site Reactions
During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in Actemra-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption. A higher frequency of ISRs was observed in Actemra-SC treated PJIA patients compared to what was seen in adult RA or GCA patients.
Immunogenicity
Three patients, 1 patient below 30 kg and 2 patients at or above 30 kg, developed positive anti-tocilizumab antibodies with neutralizing potential without developing a serious or clinically significant hypersensitivity reaction. One patient subsequently withdrew from the study.
Neutropenia
During routine laboratory monitoring in the Actemra-SC all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 × 109 per L and the occurrence of serious infections.
Clinical Trials Experience In Systemic Juvenile Idiopathic Arthritis Patients Treated With Intravenous Actemra (Actemra-IV)
The data described below reflect exposure to Actemra-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. At baseline, approximately half of the patients were taking 0.3 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 ActemraIV (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 Actemra-IV in the open-label extension phase.
The most common adverse events (at least 5%) seen in Actemra-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 Actemra-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.
In the 12 week controlled phase, the rate of serious infections in the Actemra-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 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 Actemra-IV. One patient in the placebo group escaped to Actemra-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 Actemra-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 Actemra-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 Actemra-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 Actemra-IV treatment group and 5% of patients in the placebo group experienced an event. In the Actemra-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.
Anaphylaxis
Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Actemra-IV during the controlled and open label extension study.
Immunogenicity
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive antitocilizumab 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 × 109 per L occurred in 7% of patients in the Actemra-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 Actemra-IV group. There was no clear relationship between decrease in neutrophils below 1 × 109 per L and the occurrence of serious infections.
Thrombocytopenia
During routine monitoring in the 12 week controlled phase, 1% of patients in the Actemra-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm3.
In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Actemra-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 3x ULN occurred in 5% and 3% of patients, respectively in the Actemra-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 3x ULN occurred in 13% and 5% of Actemra-IV treated patients, respectively.
Lipids
During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN – 2x ULN occurred in 1.5% of the Actemra-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN – 2x ULN occurred in 1.9% of patients in the Actemra-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.
Clinical Trials Experience In Systemic Juvenile Idiopathic Arthritis Patients Treated With Subcutaneous Actemra (Actemra-SC)
The safety profile of Actemra-SC was studied in 51 pediatric patients 1 to 17 years of age with SJIA who had an inadequate clinical response to NSAIDs and corticosteroids. In general, the safety observed for Actemra administered subcutaneously was consistent with the known safety profile of intravenous Actemra, with the exception of ISRs where a higher frequency was observed in Actemra-SC treated SJIA patients compared to PJIA patients and adult RA or GCA patients [see Clinical Trials Experience In Rheumatoid Arthritis Patients Treated With Subcutaneous Actemra (Actemra-SC) and Clinical Trials Experience In Giant Cell Arteritis Patients Treated With Subcutaneous Actemra (Actemra-SC)].
Injection Site Reactions (ISRs)
A total of 41.2% (21/51) SJIA patients experienced ISRs to Actemra-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.
Immunogenicity
Forty-six of the 51 (90.2%) patients who were 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.
Clinical Trials Experience In Patients With Cytokine Release Syndrome Treated With Intravenous Actemra (Actemra-IV)
In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with 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. No adverse reactions related to tocilizumab were reported.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of Actemra. 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.
- Fatal anaphylaxis
- Stevens-Johnson Syndrome
- Pancreatitis
- Drug-induced liver injury, Hepatitis, Hepatic failure, Jaundice
What drugs interact with Actemra (tocilizumab)?
Concomitant Drugs For Treatment Of Adult Indications
In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Concomitant administration of a single intravenous dose of 10 mg/kg Actemra with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Actemra has not been studied in combination with biological DMARDs such as TNF antagonists.
In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed.
Interactions With CYP450 Substrates
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure one week following a single dose of Actemra, respectively. The effect of tocilizumab on CYP enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where the dose is individually adjusted. Upon initiation or discontinuation of Actemra, in patients being treated with these types of medicinal products, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual dose of the medicinal product adjusted as needed. Exercise caution when coadministering Actemra with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.
Live Vaccines
Avoid use of live vaccines concurrently with Actemra.
Drug Abuse And Dependence
No studies on the potential for Actemra to cause dependence have been performed. However, there is no evidence from the available data that Actemra treatment results in dependence.
Summary
Actemra (tocilizumab) is an interleukin-6 (IL-6) receptor inhibitor used to treat moderate to severe active rheumatoid arthritis in adults, giant cell arthritis, polyarticular juvenile idiopathic arthritis in patients 2 years of age and older with active disease, systemic juvenile idiopathic arthritis in patients 2 years of age and older with active disease, and cytokine release syndrome in patients 2 years of age and older with active disease. Common side effects of Actemra include respiratory tract infections, headaches, high blood pressure (hypertension), elevations in liver tests suggesting liver injury, and injection site reactions (rash, redness, swelling, itching). There are no adequate studies of Actemra in pregnant women. It is unknown if Actemra is excreted in breast milk. Consult your doctor before breastfeeding.
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Related Disease Conditions
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Gout
Buildup of uric acid crystals in a joint causes gouty arthritis. Symptoms and signs include joint pain, swelling, heat, and redness, typically of a single joint. Gout may be treated with diet and lifestyle changes, as well as medication.
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Rheumatoid Arthritis (RA)
Rheumatoid arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints, the tissue around the joints, as well as other organs in the body. Early RA signs and symptoms include anemia, both sides of the body affected (symmetric), depression, fatigue, fever, joint deformity, joint pain, joint redness, joint stiffness, joint swelling, joint tenderness, joint warmth, limping, loss of joint function, loss of joint range of motion, and polyarthritis.
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Pain Management and Rheumatoid Arthritis
Second Source article from WebMD
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Osteoarthritis (OA)
Osteoarthritis is a type of arthritis caused by inflammation, breakdown, and eventual loss of cartilage in the joints. Also known as degenerative arthritis, osteoarthritis can be caused by aging, heredity, and injury from trauma or disease.
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Arthritis (Joint Inflammation)
Arthritis is inflammation of one or more joints. When joints are inflamed they can develop stiffness, warmth, swelling, redness and pain. There are over 100 types of arthritis, including osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, lupus, gout, and pseudogout.
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Psoriatic Arthritis
Psoriatic arthritis is a disease that causes skin and joint inflammation. Symptoms and signs include painful, stiff, and swollen joints, tendinitis, and organ inflammation. Treatment involves anti-inflammatory medications and exercise.
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16 Early Rheumatoid Arthritis (RA) Signs & Symptoms
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Osteoarthritis vs. Osteoporosis Differences and Similarities
Arthritis is defined as painful inflammation and joint stiffness. Osteoarthritis is a type of arthritis and the most common cause of chronic joint pain, affecting over 25 million Americans. Osteoarthritis is a type of arthritis that involves the entire joint. Osteoporosis is not a type of arthritis. It is a disease that mainly is caused by a loss of bone tissue that is not limited to the joint areas. It is possible for one person to have both osteoarthritis and osteoporosis. The differences in the signs and symptoms of osteoarthritis and osteoporosis include; pain, stiffness, and joint swelling, joint deformity, crackle sounds when the joint is moving, and walking with a limp. Osteoporosis is called the "silent disease" because it can progress for years without signs and symptoms before it is diagnosed, severe back pain, bone fractures, height loss, and difficulty or inability to walk. The differences in the causes of osteoarthritis and osteoporosis are that osteoarthritis usually is caused by wear and tear on the joints. Osteoporosis usually is caused by one or more underlying problems, for example, calcium and vitamin D deficiencies. Treatment for osteoarthritis and osteoporosis are not the same. There is no cure for osteoarthritis or osteoporosis.
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Fungal Arthritis
Fungal arthritis is inflammation of a joint by a fungus that has invaded the body and is growing in the normally sterile joint. Fungal arthritis symptoms and signs include pain, redness, loss of range of motion, and swelling. Fungal arthritis treatment includes antibiotics, adequate drainage of the joint, and sometimes surgery.
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Septic Arthritis
Septic arthritis, or infectious arthritis, is infection of one or more joints by bacteria, viruses, or fungi. Symptoms and signs of septic arthritis include fever, joint pain, chills, swelling, redness, warmth, and stiffness. Treatment involves antibiotics and the drainage of the infected joint.
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Reactive Arthritis
Reactive arthritis is a chronic, systemic rheumatic disease characterized by three conditions, including conjunctivitis, joint inflammation, and genital, urinary, or gastrointestinal system inflammation. Inflammation leads to pain, swelling, warmth, redness, and stiffness of the affected joints. Non-joint areas may experience irritation and pain. Treatment for reactive arthritis depends on which area of the body is affected. Joint inflammation is treated with anti-inflammatory medications.
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Rheumatoid Arthritis vs. Fibromyalgia
Though rheumatoid arthritis (RA) and fibromyalgia have similar symptoms, RA is an autoimmune disease and fibromyalgia is a chronic pain syndrome. RA symptoms include joint redness, swelling, and pain that lasts more than 6 weeks. Fibromyalgia symptoms include widespread pain, tingling feet or hands, depression, and bowel irritability. Home remedies for both include stress reduction, exercise, and getting enough sleep.
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Rheumatoid Arthritis vs. Arthritis
Arthritis is a general term used to describe joint disease. Rheumatoid arthritis (RA) is a type of arthritis in which the body’s immune system mistakenly attacks the joints, causing chronic inflammation.
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Juvenile Rheumatoid Arthritis (JRA)
Juvenile rheumatoid arthritis (JRA) annually affects one child in every thousand. There are six types of JRA. Treatment of juvenile arthritis depends upon the type the child has and should focus on treating the symptoms that manifest.
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Osteoarthritis vs. Rheumatoid Arthritis
Osteoarthritis (OA) and rheumatoid arthritis (RA) are chronic joint disorders. RA is also an autoimmune disease. OA and RA symptoms and signs include joint pain, warmth, and tenderness. Over-the-counter pain relievers treat both diseases. There are several prescription medications that treat RA.
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Non-Radiographic Axial Spondyloarthritis (nr-axSpA)
Non-radiographic spondyloarthritis (nr-axSpA) is an inflammatory arthritis that mainly affects the joints of the spine. Morning stiffness and back pain are the usual symptoms of nr-axSpA. Nonsteroidal anti-inflammatory drugs, exercise, and biologics are treatments for nr-axSpA.
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Quackery of Arthritis
Arthritis patients are sometimes vulnerable to quackery (the business of promoting unproven remedies). These "quick fix" treatments are promoted as cure-alls, but they really have no right to such claims. Consumers should be wary of products that have marketing claims like "will cure," "ancient remedy," "has no side effects," and "revolutionary new scientific breakthrough." Read about arthritis remedies and tests that have no scientific proof of benefits.
Treatment & Diagnosis
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Medications & Supplements

Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Professional side effects and drug interactions sections courtesy of the U.S. Food and Drug Administration.