Actemra IV

Actemra IV

tocilizumab

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Tocilizumab.
Description
Excipients/Inactive Ingredients: Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and water for injections.
Action
Therapeutic/Pharmacologic Class of Drug: Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. ATC Code: L04AC07.
Pharmacology: Pharmacodynamics: In clinical studies with tocilizumab, rapid decreases in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and serum amyloid A and fibrinogen were observed. Increases in hemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability.
In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration (see General under Precautions).
Mechanism of Action:
Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit sIL-6R and mIL-6R-mediated signaling. IL-6 is a multi-functional cytokine, produced by a variety of cell types involved in local paracrine function as well as regulation of systemic physiological and pathological processes such as induction of immunoglobulin secretion, T-cell activation, induction of hepatic acute phase proteins and stimulation of hematopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis, and neoplasia.
The possibility exists for tocilizumab to affect host defences against infections and malignancies. The role of IL-6 receptor inhibition in the development of malignancies is not known.
Clinical/Efficacy Studies: Rheumatoid Arthritis: The efficacy of intravenously administered tocilizumab in alleviating the signs and symptoms of rheumatoid arthritis was assessed in five randomized, double-blind, multicenter studies. Studies I-V required patients ≥ age 18 with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria who had at least 8 tender and 6 swollen joints at baseline. Tocilizumab was administered intravenously every 4 weeks as monotherapy (Study I), in combination with MTX (Studies II, III, V) or with other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV).
Study I evaluated 673 patients who had not been treated with MTX within 6 months prior to randomization, and who had not discontinued previous MTX treatment as a result of clinically important toxic effects or lack of response. The majority (67%) of patients were MTX naïve. Doses of 8 mg/kg of tocilizumab were given every four weeks as monotherapy. The comparator group was weekly MTX (dose titrated from 7.5 to a maximum of 20 mg weekly over an 8 week period). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.
Study II, a 2 year study evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks as blinded therapy for 52 weeks, in combination with stable MTX (10 - 25 mg weekly). The primary endpoint at week 24 was the proportion of patients who achieved ACR20 response criteria. At week 52 the co-primary endpoints were prevention of joint damage and improvement in physical function.
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 - 25 mg weekly). Study IV evaluated 1220 patients who had an inadequate response to their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg tocilizumab or placebo were given every four weeks, in combination with the stable DMARD. Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or more anti-TNF therapies. The anti-TNF agent was discontinued prior to randomization. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 - 25 mg weekly). The primary endpoint for studies III-V was the proportion of patients who achieved an ACR20 response at week 24.
The percent of patients achieving ACR 20, 50 and 70 responses in Studies I to V are shown in Table 1. (See Table 1.)

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In all studies, 8 mg/kg tocilizumab-treated patients had statistically significant higher ACR20, 50, 70 response rates at 6 months compared to control. The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the magnitude of response continued to improve with duration of treatment. Continued durable responses were seen for over 3 years in the ongoing open label extension studies of Studies I-V.
In the 8 mg/kg tocilizumab-treated patients significant improvements were noted on all individual components of the ACR response (tender and swollen joint counts, patients and physician global assessment, disability index scores (HAQ), pain assessment and CRP compared to patients receiving placebo+MTX/DMARDS in all studies.
Tocilizumab 8 mg/kg treated patients had a statistically significantly greater reduction in disease activity score (DAS28) than patients treated with placebo+DMARD. A good to moderate EULAR response was achieved by significantly more tocilizumab treated patients compared to patients treated with placebo+DMARD (Table 2). (See Table 2.)

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Major Clinical Response: After 2 years of treatment with tocilizumab/MTX, 14% of patients achieved a major clinical response (maintenance of an ACR70 response for 24 weeks or more).
Radiographic response: In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was assessed radiographically and expressed as change in modified Sharp score and its components, the erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with significantly less radiographic progression in patients receiving tocilizumab compared to control.
In the open-label extension of Study II the inhibition of progression of structural damage in tocilizumab/MTX-treated patients was maintained in the second year of treatment. (See Table 3.)

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Following 1 year of treatment with tocilizumab/MTX, 83% of patients had no progression of structural damage, as defined by a change in the TSS score of zero or less, compared with 67% of placebo/MTX-treated patients. This remained consistent following 2 years of treatment (83%). Ninety three percent (93%) of patients had no progression between week 52 and week 104.
Quality of Life Outcomes: Clinically significant improvements in disability index (HAQ-DI, Health Assessment Questionnaire Disability Index), fatigue (FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy Fatigue) and improvement in both the physical (PCS, Physical Component Summary) and mental health (MCS, Mental Component Summary) domains of the SF-36 (Short Form 36) were observed in patients treated with 8 mg/kg tocilizumab (monotherapy or combination with DMARDs) compared to patients treated with MTX/DMARDs (Table 4).
At week 24, the proportion of 8 mg/kg tocilizumab treated patients showing a clinically relevant improvement in HAQ-DI (defined as an individual total score decrease of >0.25), was significantly higher than among patients receiving placebo + MTX/DMARDs in all studies. During the open-label period of Study II the improvement in physical function has been maintained for up to 2 years. (See Table 4.)

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In study II, changes in PCS, MCS and FACIT-Fatigue at 52 weeks were 10.1***, 5.4 and 8.4**, respectively, in the TCZ 8 mg/kg + MTX group compared to 5.6, 3.8 and 5.5, respectively, in the Placebo plus MTX group. At week 52, the mean change in HAQ-DI was -0.58 in TCZ 8mg/kg + MTX group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was maintained at Week 104 in the TCZ 8 mg/kg + MTX group (-0.61).
Laboratory Evaluations: Treatment with 8 mg/kg tocilizumab in combination with DMARD/MTX or as monotherapy resulted in a highly statistically significant improvement in hemoglobin levels compared with placebo + MTX/DMARD (p<0.0001) at week 24. The greatest improvement was observed in patients with chronic anemia associated with RA; mean hemoglobin levels increased by week 2 and remained within normal range through week 24.
A marked decrease in mean levels of acute phase reactants, CRP, ESR, and serum amyloid A occurred rapidly after tocilizumab administration. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range.
MTX naïve, Early RA: Study VI, a 2 year study with the planned primary analysis at week 52 evaluated 1162 MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months). This study evaluated the efficacy of IV tocilizumab 4 or 8 mg/kg every 4 weeks/MTX combination therapy, IV tocilizumab 8 mg/kg monotherapy and MTX monotherapy in reducing the signs and symptoms and rate of progression of joint damage for 104 weeks. The primary endpoint was the proportion of patients achieving DAS28 remission (DAS28 < 2.6) at week 24. A significantly higher proportion of patients in the tocilizumab 8 mg/kg + MTX and tocilizumab monotherapy groups met the primary endpoint compared with MTX alone. The tocilizumab 8 mg/kg + MTX group also showed statistically significant results across the key secondary endpoints. Numerically greater responses compared with MTX alone were observed in the tocilizumab 8 mg/kg monotherapy group in all secondary endpoints, including radiographic endpoints. In this study, ACR/EULAR remission (Boolean and Index) were also analyzed as pre-specified exploratory endpoints, with higher responses observed in the tocilizumab groups. The results from study VI are shown in Table 5. (See Table 5.)

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Monotherapy: tocilizumab versus adalimumab: Study WA19924 evaluated 326 patients with RA who were intolerant of MTX or where continued treatment with MTX was considered inappropriate (including MTX inadequate responders). Patients in the tocilizumab arm received an intravenous (IV) infusion of tocilizumab (8 mg/kg) every 4 weeks (q4w) and a subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo infusion q4w.
A statistically significant superior treatment effect was seen in favour of tocilizumab over adalimumab in control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28 and for all secondary endpoints (Table 6). (See Table 6.)

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Cardiovascular Outcomes: Study WA25204 was a randomized, open-label (sponsor-blinded), 2-arm parallel-group, multi center, non-inferiority, cardiovascular (CV) outcomes trial in patients with a diagnosis of moderate to severe RA [100]. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with TCZ compared with a TNF inhibitor standard of care (etanercept [ETA]).
The study included 3,080 seropositive RA patients with active disease and an inadequate response to non-biologic disease-modifying anti-rheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV TCZ 8 mg/kg Q4W or SC ETA 50 mg QW and followed for an average of 3.2 years. The primary endpoint was the comparison of the time-to-first occurrence of any component of a composite of major adverse CV events (MACE; non-fatal myocardial infarction, non-fatal stroke, or CV death), with the final intent-to-treat analysis based on a total of 161 confirmed CV events reviewed by an independent and blinded adjudication committee.
Non-inferiority of TCZ to ETA for cardiovascular risk was determined by excluding a >80% relative increase in the risk of MACE. The primary endpoint was met such that a >43% increase in the risk of MACE could be excluded (hazard ratio [HR] comparing TCZ to ETA = 1.05; 95% CI = 0.77, 1.43).
Polyarticular Juvenile Idiopathic Arthritis: The efficacy of tocilizumab was assessed in a three-part study including an open-label extension in children with active polyarticular juvenile idiopathic arthritis (pJIA). Part I consisted of a 16-week active tocilizumab treatment lead-in period (n=188) followed by Part II, a 24-week randomized double-blind placebo-controlled withdrawal period (ITT, n=163), followed by Part III, a 64-week open-label period. Eligible patients ≥ 30 kg received tocilizumab at 8 mg/kg for 4 doses. Patients < 30 kg were randomized 1:1 to receive either tocilizumab 8 mg/kg or 10 mg/kg IV every 4 weeks for 4 doses. Patients who completed Part I of the study and achieved at least a JIA ACR30 response at week 16 compared to baseline entered the blinded withdrawal period (Part II) of the study. In Part II, patients were randomized to tocilizumab (same dose received in Part I) or placebo in a 1:1 ratio was stratified by concurrent methotrexate use and concurrent corticosteroid use. Each patient continued in Part II of the study until Week 40 or until the patient satisfied JIA ACR30 flare criteria (relative to Week 16) and qualified for escape.
The primary endpoint was the proportion of patients with a JIA ACR30 flare at week 40 relative to week 16. Forty eight percent (48.1%, 39/81) of the patients treated with placebo flared compared with 25.6% (21/82) of TCZ-treated patients. These proportions were statistically significantly different (p=0.0024).
At the conclusion of Part I, JIA ACR 30/50/70/90 responses were 89.4%, 83.0%, 62.2%, and 26.1%, respectively.
During the withdrawal phase (Part II), the percent of patients achieving JIA ACR 30, 50, and 70 responses at Week 40 relative to baseline are shown in the Table 7 as follows.

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Systemic Juvenile Idiopathic Arthritis: The efficacy of tocilizumab for the treatment of active sJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients (treated with or without MTX) were randomized (TCZ:placebo = 2:1) to one of two treatment groups, 75 patients received tocilizumab infusions every two weeks either 8 mg/kg for patients ≥30kg or 12 mg/kg for patients < 30 kg and 37 patients were assigned to receiving placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated in the open-label extension phase at weight appropriate dosing.
The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR30 response) at Week 12 and absence of fever (no temperature recording ≥ 37.5°C in the preceding 7 days). Eighty five percent (64/75) of the patients treated with TCZ and 24.3% (9/37) of placebo patients achieved this endpoint. These proportions were highly significantly different (p<0.0001).
The percent of patients achieving JIA ACR 30, 50, 70 and 90 responses are shown in the table as follows. Responses are maintained in the open label extension. (See Table 8.)

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Systemic Features: In those patients treated with tocilizumab, 85% who had fever due to sJIA at baseline were free of fever (no temperature recording ≥ 37.5°C in the preceding 14 days) at week 12 versus only 21% of placebo patients (p<0.0001) and 64% of tocilizumab treated patients with rash characteristic of sJIA at baseline were free of rash at week 12 versus 11% of placebo patients (p=0.0008).
There was a highly statistically significant reduction in pain for tocilizumab treated patients at week 12 in comparison to placebo patients. The adjusted mean change in the pain VAS after 12 weeks of tocilizumab treatment was a reduction of 41 points on a scale of 0 -100 compared to a reduction of 1 for placebo patients (p<0.0001).
The responses for systemic features are maintained in the on-going open label extension.
Corticosteroid Tapering: Of the 31 placebo and 70 tocilizumab patients receiving oral corticosteroids at baseline, 8 placebo and 48 tocilizumab patients achieved a JIA ACR70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) tocilizumab patients versus 1 (3%) placebo patient were able to reduce the dose of corticosteroid by at least 20% without experiencing a subsequent JIA ACR30 flare or occurrence of systemic symptoms to week 12 (p=0.028). Reductions in corticosteroids continued, with 44 patients off oral corticosteroids, at week 44, while maintaining ACR responses.
Quality of Life: At week 12, the proportion of tocilizumab treated patients showing a minimally clinically important improvement in CHAQ-DI (defined as an individual total score decrease of ≥0.13) was significantly higher than in patients receiving placebo, 77% versus 19% (p<0.0001).
Laboratory Parameters: Fifty out of seventy five (67%) patients treated with tocilizumab had a haemoglobin < LLN at baseline. Forty (80%) of these patients with decreased haemoglobin had an increase in their haemoglobin to within the normal range at week 12, in comparison to only 2 out of 29 (7%) of placebo patients with haemoglobin < LLN at baseline (p<0.0001). Forty four (88%) tocilizumab patients with decreased haemoglobin at baseline had an increase in their haemoglobin by ≥10 g/L at week 6 versus 1 (3%) placebo patient (p<0.0001).
The proportion of tocilizumab treated patients with thrombocytosis at baseline who had a normal platelet count at week 12 was significantly higher than in the placebo patients, 90% versus 4%, (p<0.0001).
A marked decrease in mean levels of acute phase reactants, CRP, ESR, and serum amyloid A occurred rapidly after tocilizumab administration.
A Phase I, multi-centre, open-label, single arm study (NP25737) to evaluate the PK, safety and exploratory PD and efficacy of tocilizumab over 12 weeks in paediatric sJIA patients (N=11) under 2 years of age was conducted. Patients (treated with stable background therapy of corticosteroids, MTX, or non-steroidal anti-inflammatory drugs) received intravenous tocilizumab 12 mg/kg every two weeks. Patients who completed the 12-week period could continue to the optional extension period (a total of 52-weeks or until the age of 2 years, whichever was longer).
The primary PK endpoints (Cmax, Cmin and AUC2weeks) of TCZ at steady-state in this study are within the ranges of these parameters observed in paediatric patients aged 2 to 17 years in Study WA18221.
The types of AEs observed during the 12-week evaluation period of Study NP25737 were consistent with the safety profile observed in the pivotal Phase III study (WA18221). Of the 11 patients aged under 2 years, three experienced serious hypersensitivity reactions, and three developed treatment induced anti-tocilizumab antibodies after the event. However, due to the small sample size, the low number of events and confounding factors, conclusions could not be drawn.
Exploratory efficacy results showed that tocilizumab improved the median JADAS-71 score over the course of the study for all patients. The observed PD responses in sIL6R, CRP, and ESR were also consistent with the pivotal Phase III study.
Pharmacokinetics: Rheumatoid Arthritis: The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 1793 rheumatoid arthritis patients treated with a one hour infusion of 4 and 8 mg/kg every 4 weeks for 24 weeks.
The pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in area under the curve (AUC) and trough concentration (Cmin) was observed for doses of 4 and 8 mg/kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, predicted AUC and Cmin were 2.7 and 6.5 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.
The following parameters are valid for a dose of 8 mg/kg tocilizumab given every 4 weeks. Predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg·h/mL, 9.74 ± 10.5 mcg/mL, and 183 ± 85.6 mcg/mL, respectively. The accumulation ratios for AUC and Cmax were small; 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35), which was expected based on the nonlinear clearance contribution at lower concentrations. Steady-state was reached following the first administration and after 8 and 20 weeks for Cmax, AUC, and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg·h/mL, 19.0 ± 12.0 mcg/mL, and 269 ± 57 mcg/mL, respectively, which are higher than mean exposure values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients ≥ 100 kg (see Dosage & Administration).
The following parameters are valid for a dose of 4 mg/kg tocilizumab given every 4 weeks. Predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg·h/mL, 1.49 ± 2.13 mcg/mL, and 88.3 ± 41.4 mcg/mL, respectively. The accumulation ratios for AUC and Cmax were small; 1.11 and 1.02, respectively. The accumulation ratio was higher for Cmin (1.96). Steady-state was reached following the first administration for Cmax and AUC, respectively, and after 16 weeks for Cmin.
Polyarticular Juvenile Idiopathic Arthritis: The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.
The following parameters are valid for a dose of 8 mg/kg tocilizumab (patients with a body weight ≥ 30 kg) given every 4 weeks. The predicted mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 μg⋅hr/mL, 182 ± 37 μg/mL and 7.49 ± 8.2μg/mL, respectively.
The following parameters are valid for a dose of 10 mg/kg tocilizumab (patients with a body weight < 30 kg) given every 4 weeks. The predicted mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 μg·hr/mL, 175 ± 32 μg/mL and 2.35 ± 3.59 μg/mL, respectively. The accumulation ratios were 1.05 and 1.16 for AUC4weeks, and 1.43 and 2.22 for Cmin for 10 mg/kg (BW < 30 kg) and 8 mg/kg (BW ≥ 30 kg) doses, respectively. No accumulation for Cmax was observed.
Systemic Juvenile Idiopathic Arthritis: The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with systemic juvenile idiopathic arthritis treated with 8 mg/kg (patients with a body weight ≥ 30 kg) or 12 mg/kg (patients with a body weight < 30 kg), given every 2 weeks. The predicted mean (± SD) AUC2weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg·h/mL, 245 ± 57.2 mcg/mL and 57.5 ± 23.3 mcg/mL, respectively. The accumulation ratio for Cmin (week12/week2) was 3.2 ± 1.3. The tocilizumab Cmin was stabilized after week 12. Mean predicted tocilizumab exposure parameters were similar between the two body weight groups.
The pharmacokinetics of tocilizumab were similar in paediatric patients under 2 years compared to patients over 2 years of age with a body weight below 30 kg from a regimen of 12 mg/kg IV tocilizumab given every 2 weeks.
Distribution: Following IV dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5L, the peripheral volume of distribution was 2.9 L resulting in a volume of distribution at steady state of 6.4 L.
In pediatric patients with pJIA, the central volume of distribution was 1.98 L, the peripheral volume of distribution was 2.1 L, resulting in a volume of distribution at steady state of 4.08 L.
In pediatric patients with sJIA, the central volume of distribution was 0.94 L, the peripheral volume of distribution was 1.60 L resulting in a volume of distribution at steady state of 2.54 L.
Elimination: The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 12.5 mL/h in rheumatoid arthritis patients, 5.8 mL/h in pediatric patients with polyarticular juvenile idiopathic arthritis and 7.1 mL/h in pediatric patients with systemic juvenile idiopathic arthritis. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
The t½ of tocilizumab is concentration-dependent in rheumatoid arthritis, the concentration-dependent apparent t½ is up to 11 days for 4 mg/kg and 13 days for 8 mg/kg every 4 weeks in patients with RA at steady-state.
The t½ of tocilizumab in children with pJIA is up to 16 days for the two body weight categories (8 mg/kg for body weight ≥ 30 kg or 10 mg/kg for body weight < 30 kg) during a dosing interval at steady state.
The t½ of tocilizumab in children with sJIA is up to 23 days for the two body weight categories (8 mg/kg for body weight ≥ 30 kg or 12 mg/kg for body weight <30 kg) at Week 12.
Pharmacokinetics in Special Populations: Hepatic Impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.
Renal Impairment: No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab was conducted.
Most of the patients in the rheumatoid arthritis population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance based on Cockcroft-Gault < 80 mL/min and ≥ 50 mL/min) did not impact the pharmacokinetics of tocilizumab. No dose adjustment is required in patients with mild renal impairment.
Other special populations: Population pharmacokinetics analyses in adult rheumatoid arthritis patients showed that age, gender and race did not affect pharmacokinetics of tocilizumab. No dose adjustment is necessary for these demographic factors.
Toxicology: Nonclinical Safety: Carcinogenicity: A carcinogenicity study of tocilizumab has not been conducted. Available preclinical data, showed the contribution of the pleiotropic cytokine IL-6 to malignant progression and apoptosis resistance of various cancer types. These data do not suggest a relevant risk for cancer initiation and progression under therapy with tocilizumab. Accordingly, proliferate lesions have not been observed in a chronic cynomolgus monkey 6-month toxicity study nor were they described in IL-6 knock-out mice under chronic IL-6 depletion.
Genotoxicity: Standard genotoxicity studies with tocilizumab in both prokaryotic and eukaryotic cells were all negative.
Impairment of Fertility: Preclinical data do not suggest an effect on fertility under treatment with an analogue of tocilizumab. Effects on endocrine active organs or on organs of the reproductive system were not seen in a chronic cynomolgus monkey toxicity study, nor was the reproductive performance affected in IL-6 deficient male and female mice.
Reproductive Toxicity: When tocilizumab was administered intravenously to cynomolgus monkeys during early gestation, no direct or indirect harmful effects on pregnancy or embryo-fetal development were observed.
Other: In an embryo-fetal toxicity study conducted in cynomolgus monkeys a slight increase of abortion/embryo-fetal death was observed with high systemic cumulative exposure (>100 times human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. The abortion incidence was within the historical background for the cynomolgus monkey in captivity and the individual cases of abortions/embryo-foetal death did not show any consistent relationship to dosing or duration of dosing with tocilizumab. Although IL-6 does not seem to be a critical cytokine for either fetal growth or the immunological control of the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.
Transfer of a murine analogue of tocilizumab into the milk of lactating mice has been observed.
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
Indications/Uses
Rheumatoid Arthritis (RA): Tocilizumab is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients. Tocilizumab can be used alone or in combination with methotrexate (MTX) and/or other disease-modifying anti-rheumatic drugs (DMARDs). Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-Ray and to improve physical function when given in combination with methotrexate (MTX).
Polyarticular Juvenile Idiopathic Arthritis (pJIA): Tocilizumab in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX.
Tocilizumab can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
Systemic Juvenile Idiopathic Arthritis (sJIA): Tocilizumab is indicated for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. Tocilizumab can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX.
Dosage/Direction for Use
General: Tocilizumab should be diluted by a healthcare professional with sterile 0.9% w/v sodium chloride solution using aseptic technique (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
Tocilizumab is recommended for IV infusion over 1 hour.
Rheumatoid Arthritis: The recommended dose of tocilizumab for adult patients is 8 mg/kg given once every four weeks as an i.v. infusion. Tocilizumab can be used alone or in combination with MTX and/or other DMARDs.
For individuals whose body weight is more than 100 kg, doses exceeding 800 mg per infusion are not recommended (see Pharmacology: Pharmacokinetics under Actions). (See Table 9.)

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Polyarticular Juvenile Idiopathic Arthritis (pJIA): The recommended dose of tocilizumab for patients with pJIA is: 10 mg/kg for patients < 30 kilograms (kgs), 8 mg/kg for patients ≥ 30 kilograms (kgs), given once every four weeks as an IV infusion. A change in dose should only be based on a consistent change in the patient's body weight over time. Tocilizumab can be used alone or in combination with MTX.
Dose Modification Recommendations for pJIA: Dose interruptions of tocilizumab for the following laboratory abnormalities are recommended in pJIA patients in the tables as follows. If appropriate, the dose of concomitant MTX and/or other medications should be modified or dosing stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co- morbid conditions that may affect laboratory values in pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient. (See Table 10.)

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Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in pJIA patients.
Available data suggest that clinical improvement is observed within 12 weeks of initiation of treatment with tocilizumab. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.
Systemic Juvenile Idiopathic Arthritis (sJIA): The recommended dose of tocilizumab for patients with sJIA is: 12 mg/kg for patients < 30 kilograms (kgs), 8 mg/kg for patients ≥ 30 kilograms (kgs), given once every two weeks as an IV infusion. A change in dose should only be based on a consistent change in the patient's body weight over time. Tocilizumab can be used alone or in combination with MTX.
Dose Modification Recommendation for sJIA: Dose reduction of tocilizumab has not been studied in the sJIA population.
Dose interruptions of tocilizumab for laboratory abnormalities are recommended in sJIA patients as specified in the tables as follows. If appropriate, the dose of concomitant MTX and/or other medications should be modified or dosing be stopped and tocilizumab dosing interrupted until the clinical situation has been evaluated. As there are many co-morbidity conditions that may affect laboratory values in sJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient. (See Table 11.)

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Reduction of tocilizumab dose due to laboratory abnormalities has not been studied in sJIA patients.
Available data suggest that clinical improvement is observed within 6 weeks of initiation of treatment with Actemra. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.
Special Dosage Instructions: Pediatric use: The safety and efficacy of tocilizumab in children with conditions other than pJIA or sJIA have not been established. Children under the age of two have not been studied.
Geriatric use: No dose adjustment is required in elderly patients > 65 years of age.
Renal impairment: No dose adjustment is required in patients with mild renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Tocilizumab has not been studied in patients with moderate to severe renal impairment.
Hepatic impairment: The safety and efficacy of tocilizumab has not been studied in patients with hepatic impairment (see General under Precautions).
Route of Administration: Intravenous (i.v.) infusion.
Overdosage
There are limited data available on overdosage with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose-limiting neutropenia was observed.
Contraindications
Actemra is contraindicated in patients with a known hypersensitivity to tocilizumab or to any of the excipients.
Special Precautions
General: In order to improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded (or stated) in the patient file.
All Indications: Infections: Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see Adverse Reactions). Tocilizumab treatment should not be initiated in patients with active infections. Administration of tocilizumab should be interrupted if a patient develops a serious infection until the infection is controlled. Healthcare professionals should exercise caution when considering the use of tocilizumab in patients with a history of recurring infection or with underlying conditions (e.g. diverticulitis, diabetes) which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving biologic treatments for moderate to severe RA, pJIA or sJIA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reactants. Patients and parents/guardians of minors with pJIA or sJIA should be instructed to contact a healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.
Complications of diverticulitis: Events of diverticular perforation as complications of diverticulitis have been reported in RA patients. Tocilizumab 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, should be evaluated promptly for early identification of gastrointestinal perforation.
Tuberculosis: As recommended for other biologic therapies in rheumatoid arthritis, pJIA or sJIA, patients should be screened for latent tuberculosis infection prior to starting tocilizumab therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating tocilizumab.
Vaccinations: Live and live attenuated vaccines should not be given concurrently with tocilizumab as clinical safety has not been established.
No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab.
In a randomized open-label study, adult RA patients treated with tocilizumab 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 pJIA or sJIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis with fatal outcome, have been reported in association with infusion of tocilizumab (see Clinical Trials under Adverse Reactions). In the post marketing setting, events of serious hypersensitivity and anaphylaxis, including in some cases with a fatal outcome, have occurred in patients treated with a range of doses of tocilizumab, with or without concomitant arthritis therapies, premedication, and/ or a previous hypersensitivity reaction. In the post marketing setting, cases with a fatal outcome have been reported with intravenous tocilizumab. These events have occurred as early as the first infusion of tocilizumab (see Contraindications, Post Marketing under Adverse Reactions). Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during infusion with tocilizumab. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of tocilizumab should be stopped immediately and tocilizumab should be permanently discontinued (see Dosage & Administration).
Active Hepatic Disease and Hepatic Impairment: Treatment with tocilizumab particularly when administered concomitantly with methotrexate, 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 Special Dosage Instructions under Dosage & Administration, Laboratory abnormalities under Adverse Reactions).
Hepatotoxicity: Mild and moderate elevations of hepatic transaminases have been observed with tocilizumab treatment (see Clinical Trials under Adverse Reactions). Increased frequency of these elevations was observed when drugs, which are known to cause hepatotoxicity (e.g. methotrexate (MTX)), were used in combination with tocilizumab.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see Post Marketing Experience under Adverse Reactions). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of tocilizumab. Cases of liver failure resulting in liver transplantation have been reported.
Caution should be exercised when considering initiation of tocilizumab treatment in patients with elevated transaminases ALT or AST above 1.5x ULN. In patients with elevated ALT or AST above 5x ULN treatment is not recommended.
In RA, GCA, pJIA /sJIA , ALT and AST should be monitored every 4 to 8 weeks for the first 6 months of treatment following by every 12 weeks thereafter. For recommended dose modifications, including tocilizumab discontinuation based on transaminases levels, see Dosage & Administration.
Viral reactivation: Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for rheumatoid arthritis. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded.
Demyelinating disorders: Physicians should be vigilant for symptoms potentially indicative of new onset central demyelinating disorders. The potential for central demyelination with tocilizumab is currently unknown.
Neutropenia: Treatment with tocilizumab was associated with a higher incidence of neutropenia. Treatment-related neutropenia was not associated with serious infection in clinical trials (see Clinical Trials under Adverse Reactions).
Caution should be exercised when considering initiation of tocilizumab treatment in patients with a low neutrophil count i.e. absolute neutrophil count (ANC) below 2 x 109/L. In patients with an absolute neutrophil count below 0.5 x 109/L treatment is not recommended.
In RA, the neutrophil count should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended dose modifications based on ANC results, see Dosage & Administration.
In pJIA and sJIA, the neutrophil count should be monitored at the time of the second administration and thereafter according to good clinical practice (see Dose modifications under Dosage & Administration).
Thrombocytopenia: Treatment with tocilizumab was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials (see Clinical Trials under Adverse Reactions).
Caution should be exercised when considering initiation of tocilizumab treatment in patients with a platelet count below 100 x 103/μL. In patients with a platelet count below 50 x 103/μL treatment is not recommended.
In RA, platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended dose modifications based on platelet counts, see Dosage & Administration.
In pJIA and sJIA, platelets should be monitored at the time of the second administration and thereafter according to good clinical practice (see Dose modifications under Dosage & Administration).
Lipids parameters: Elevations of lipid parameters such as total cholesterol, triglycerides and/or low density lipoprotein (LDL) cholesterol have been observed (see Clinical Trials under Adverse Reactions).
In patients treated with tocilizumab, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of tocilizumab therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Systemic Juvenile Idiopathic Arthritis: Macrophage activation syndrome (MAS): MAS is a serious life-threatening disorder that may develop in patients with sJIA. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.
Drug Abuse and Dependence: No studies on the effects on the potential for tocilizumab to cause dependence have been performed. However, there is no evidence from the available data that tocilizumab treatment results in dependence.
Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, there is no evidence from the available data that tocilizumab treatment affects the ability to drive and use machines.
Renal Impairment: (See Special Dosage Instructions under Dosage & Administration, Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Hepatic Impairment: (See Special Dosage Instructions under Dosage & Administration, Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Use in Children: (See Special Dosage Instructions under Dosage & Administration.)
Use in Elderly: (See Special Dosage Instructions under Dosage & Administration, Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.)
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data from the use of tocilizumab in pregnant women. A study in monkeys did not indicate any dysmorphogenic potential but has yielded a higher number of spontaneous abortion /embryo-fetal death at a high dose (see Pharmacology: Toxicology: Nonclinical Safety: Other under Actions). The relevance of these data for humans is unknown.
Tocilizumab should not be used during pregnancy unless clearly indicated by medical need.
Nursing Mothers: It is unknown whether tocilizumab is excreted in human breast milk. Although endogenous immunoglobulins of the IgG isotope are secreted into human milk, a systemic absorption of tocilizumab via breast feeding is unlikely due to the rapid proteolytic degradation of such proteins in the digestive system. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with tocilizumab should be made taking into account the benefit of breast-feeding to the child and the benefit of tocilizumab therapy to the woman.
Adverse Reactions
Clinical Trials: Rheumatoid Arthritis: The safety of tocilizumab 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 tocilizumab 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 mg/kg monotherapy.
The all exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in 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.
Adverse Drug Reactions (ADRs) from clinical trials (Table 12) 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 12.)

Click on icon to see table/diagram/image

Infections: In the 6 month controlled trials, the rate of all infections reported with tocilizumab 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 all exposure population the overall rate of infections with tocilizumab was 108 events per 100 pt years exposure.
In 6 month controlled clinical trials rate of serious infections (bacterial, viral and fungal) with tocilizumab 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 tocilizumab group and 1.5 events per 100 pt 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.
Gastrointestinal Perforation: During the 6 month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 pt years with tocilizumab therapy. In the all exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 pt years. Reports of gastrointestinal perforation on tocilizumab 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 tocilizumab 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 tocilizumab and requiring treatment discontinuation, were reported in a total of 13 out of 3778 patients (0.3%) treated with tocilizumab during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of tocilizumab (see General under Precautions).
Immunogenicity: A total of 2876 patients have been tested for anti-tocilizumab antibodies in the 6 month controlled clinical trials. Forty six patients (1.6%) developed positive anti-tocilizumab 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 naïve to treatment with both MTX and a biologic agent. The overall safety profile observed in the tocilizumab treatment groups was consistent with the known safety profile of tocilizumab (see Table 12) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Monotherapy: tocilizumab versus adalimumab: In a 24 week double-blinded, parallel study (monotherapy with tocilizumab 8 mg/kg IV q4w (N=162) compared to adalizumab 40 mg SC q2w (N=162)), the overall clinical adverse event profile was similar between tocilizumab and adalimumab. The proportion of patients with serious adverse events was balanced between the treatment groups (tocilizumab 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 tocilizumab compared with adalimumab. Four (2.5%) patients in the tocilizumab 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 tocilizumab 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 tocilizumab arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The safety observed in the tocilizumab arm was consistent with the known safety profile of tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 12) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Polyarticular Juvenile Idiopathic Arthritis: The safety of tocilizumab was studied in 188 pediatric patients, 2 to 17 years of age, with pJIA. The total patient exposure in the tocilizumab 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 tocilizumab all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing: <30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing ≥30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing <30 kg treated with 10 mg/kg tocilizumab (21.4%) compared to patients weighing ≥30 kg, treated with 8 mg/kg tocilizumab (7.6%).
Infusion Reactions: In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9%) experienced infusion reactions during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients (see Adverse Reactions). No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.
Immunogenicity: One patient in the 10 mg/kg <30 kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
Systemic Juvenile Idiopathic Arthritis: The safety of tocilizumab 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 tocilizumab (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 previously mentioned).
Infections: In the 12 weeks controlled trial the rate of all infections in the tocilizumab 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 patients-years.
In the 12 week controlled trial the rate of serious infections in the tocilizumab 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 tocilizumab group experienced events occurring during infusion, one event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
In the 12 week controlled trial experience, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the events included, but not limited to rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. On of these events, (urticaria) was considered serious.
Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in 1 out of 112 patients (<1%) treated with tocilizumab during the controlled and 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: Hematology abnormalities: Neutrophils: Rheumatoid Arthritis: In the 6 month controlled trials decreases in neutrophil counts below 1 x 109/L occurred in 3.4% of patients on tocilizumab 8 mg/kg+DMARD compared to <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 tocilizumab 8 mg/kg +DMARD (see Dosage & Administration, General under Precautions). There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.
In the all control and all exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6 month controlled clinical trials.
Polyarticular Juvenile Idiopathic Arthritis: During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 x 109/L occurred in 3.7% of patients.
There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.
Systemic juvenile idiopathic arthritis: During routine laboratory monitoring in the 12 week controlled trial, a decrease in neutrophil counts below 1 x 109/L occurred in 7% of patients in the tocilizumab group, and no decreases 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 tocilizumab group. There was no clear relationship between decreases in neutrophils below 1 x 109/L and occurrence of serious infections.
Platelets: Rheumatoid Arthritis: In the 6 month controlled trials decreases in platelet counts below 100 x 103 / μL occurred in 1.7% of patients on tocilizumab 8 mg/kg plus traditional DMARDs compared to <1% of patients on placebo plus traditional DMARDs, without associated bleeding events (see Dosage & Administration, General under Precautions).
In the all control and all exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6 month controlled clinical trials.
Polyarticular Juvenile Idiopathic Arthritis: During routine laboratory monitoring in the tocilizumab all exposure population, 1% of patients had a decrease in platelet count to ≤50 x 103/μL without associated bleeding events.
Systemic juvenile idiopathic arthritis: During routine laboratory monitoring in the 12 week controlled trial, 3% of patients in the placebo group and 1% in the tocilizumab group had a decrease in platelet count to ≤100 x 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 tocilizumab group, without associated bleeding events.
Liver enzyme elevations: Rheumatoid Arthritis: During the 6 month controlled trials transient elevations in ALT/AST > 3xULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX, and in 6.5% of patients who received tocilizumab 8 mg/kg + DMARD compared to 1.5% of patients on placebo+DMARD. The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST >5xULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab+DMARD patients, the majority of whom were discontinued from tocilizumab treatment (see Dosage & Administration, General under 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 tocilizumab + DMARD in the all control population.
In the all control and all exposure population, the pattern and incidence of elevations in ALT/AST remained consistent with what was seen in the 6 month controlled clinical trials.
In Study VI, MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months) experienced more transient elevations in ALT > 3xULN compared with the all control population. This was observed in both tocilizumab treated patients and MTX monotherapy patients.
In Study WA25204, of the 1538 patients with moderate to severe RA (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions) 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 treatment (see General under Precautions).
Polyarticular Juvenile Idiopathic Arthritis: During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥3 x ULN occurred in 3.7% and <1% of patients, respectively.
Systemic juvenile idiopathic arthritis: 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 tocilizumab 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 tocilizumab group.
Elevations in lipid parameters: Rheumatoid Arthritis: 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 tocilizumab. Approximately 24% of patients receiving tocilizumab in clinical trials 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 majority of patients there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid-lowering agents.
In the all control and all exposure population, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6 month controlled clinical trials.
Polyarticular Juvenile Idiopathic Arthritis: During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol >1.5-2 xULN occurred in one patient (0.5%) and elevation in LDL >1.5-2 xULN in one patient (0.5%).
Systemic juvenile idiopathic arthritis: During routine laboratory monitoring in the 12 week controlled trial, elevation in total cholesterol >1.5 xULN to 2 xULN occurred in 1.5% of the tocilizumab group and in 0% of placebo patients. Elevation in LDL >1.5 xULN to 2 xULN occurred in 1.9% of patients in the tocilizumab 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: The following adverse drug reactions have been identified from post marketing experience with tocilizumab (Table 13) 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 13.)

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Drug Interactions
Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.
Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25mg MTX once weekly had no clinically significant effect on MTX exposure.
Tocilizumab has not been studied in combination with other biological DMARDs.
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalizes expression of these enzymes.
The effect of tocilizumab on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index, and/or where the dose is individually adjusted.
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 or slightly higher than those observed in healthy subjects.
When starting or stopping therapy with tocilizumab, patients taking medicinal products, which are individually dose-adjusted and are metabolized via CYP450 3A4, 1A2, or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, cyclosporine, or benzodiazepines) should be monitored as doses of these products may need to be adjusted to maintain their 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.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Parenteral medications should be inspected visually for particulate matter or discoloration prior to administration.
Only solutions which are clear to opalescent, colourless to pale yellow and free of visible particles must be infused.
Rheumatoid Arthritis: From a 100 mL infusion bag, withdraw a volume of 0.9% sodium chloride solution equal to the volume of the tocilizumab solution required for the patient's dose. Withdraw the required amount of tocilizumab (0.4 mL/kg) under aseptic conditions and dilute to a calculated tocilizumab concentration in a 100 mL infusion bag containing sterile, non- pyrogenic 0.9% sodium chloride solution. To mix the solution, gently invert the bag to avoid foaming.
pJIA and sJIA Patients ≥ 30 kg: From a 100 mL infusion bag, withdraw a volume of 0.9% Sodium Chloride solution equal to the volume of the tocilizumab solution required for the patient's dose. Withdraw the required amount of tocilizumab (0.4 mL/kg) under aseptic conditions and dilute to a calculated tocilizumab concentration in a 100 mL infusion bag containing sterile, non- pyrogenic 0.9% Sodium Chloride solution. To mix the solution, gently invert the bag to avoid foaming.
pJIA Patients < 30 kg: From a 50 mL infusion bag, withdraw a volume of 0.9% Sodium Chloride solution equal to 0.5 mL/kg of the patient's body weight and discard. This volume should be replaced in the saline bag with an equal volume of tocilizumab under aseptic conditions. To mix the solution, gently invert the bag to avoid foaming.
sJIA Patients < 30 kg: From a 50 mL infusion bag, withdraw a volume of 0.9% Sodium Chloride solution equal to 0.6 mL/kg of the patient's body weight and discard. This volume should be replaced in the saline bag with an equal volume of tocilizumab under aseptic conditions. To mix the solution, gently invert the bag to avoid foaming.
Disposal of unused/expired medicines: The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater, and disposal through household waste should be avoided. Use established 'collection systems' if available in the location.
Storage
For vials: Store between 2°C - 8°C, do not freeze. Keep the container in the outer carton in order to protect from light.
For prepared infusion solution: The prepared infusion solution of tocilizumab is physically and chemically stable in 0.9% w/v sodium chloride solution at 30°C for 24 hours.
From a microbiological point of view, the prepared infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
ATC Classification
L04AC07 - tocilizumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.
Presentation/Packing
Infusion conc (clear to opalescent, colourless to pale yellow liquid, in preservative-free, non-pyrogenic single-use vial) 80 mg/4 mL x 1's. 400 mg/20 mL x 1's.
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