Actemra

Actemra

tocilizumab

Manufacturer:

Roche

Marketer:

DKSH
Full Prescribing Info
Contents
Tocilizumab.
Description
Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass.
Concentrate solution: Tocilizumab is supplied in 10 ml and 20 ml vials containing 4 ml, 10 ml or 20 ml of tocilizumab (20 mg/ml).
Subcutaneous injection: Each pre-filled syringe delivers 0.9 mL (162 mg) of tocilizumab.
Excipients/Inactive Ingredients: Concentrate solution: Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate and water for injections.
Subcutaneous injection: L-histidine, L-histidine hydrochloride monohydrate, L-arginine, L-arginine hydrochloride, L-methionine, polysorbate 80, water for injection.
Action
ATC Code: L04AC07.
Pharmacology: Pharmacodynamics: In clinical studies with Actemra in RA, rapid decreases in C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), serum amyloid A and fibrinogen were observed. Increases in hemoglobin levels were observed, through Actemra decreasing the IL-6 driven effects on hepcidin production to increase iron availability.
In study WA28119, similar rapid decreases in CRP and ESR were observed along with slight increases in mean corpuscular haemoglobin concentration.
In healthy subjects administered Actemra 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 Actemra administration (see General under Precautions).
Mechanism of Action: Actemra is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Actemra binds to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit sIL-6R and mIL-6Rmediated 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 Actemra 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 Actemra 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.
Actemra 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 Actemra 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 two year study evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of Actemra 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 Actemra 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 Actemra 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 Actemra 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.
The efficacy of subcutaneously administered Actemra was assessed in a double-blind, controlled, multicenter study in patients with active RA. The study (SC-I) required patients to be above 18 years of age with active rheumatoid arthritis diagnosed according to ACR criteria and who had at least 4 tender and 4 swollen joints at baseline. All patients received background non-biologic DMARD(s).
Study SC-I evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to their existing rheumatologic therapy, including one or more DMARD(s). Approximately 20% had a history of inadequate response to at least one TNF inhibitor. In SC-I, 1262 patients were randomized 1:1 to receive Actemra SC 162 mg every week or Actemra IV 8 mg/kg every four weeks in combination with nonbiologic DMARD(s). The primary endpoint in the study was the difference in the proportion of patients who achieved an ACR20 response at week 24. The results from study SC-I is shown in Table 3. (See Table 1.)

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In all studies, 8 mg/kg Actemra-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 18 months in the on going open label extension studies of Studies I, III-V.
In the 8 mg/kg Actemra-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.
Actemra 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 Actemra treated patients compared to patients treated with placebo+DMARD (Table 2). (See Tables 2 and 3.)

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Major clinical response: After 2 years of treatment with Actemra plus MTX, 14% of patients achieved a major clinical response (maintenance of an ACR70 response for 24 weeks or more).
Radiographic Response: Intravenous Administration: 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 Actemra compared to control (see table as follows).
In the open-label extension of Study II the inhibition of progression of structural damage in Actemra/MTX-treated patients was maintained in the second year of treatment. (See Table 4.)

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Following 1 year of treatment with Actemra/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.
Radiographic Response: Subcutaneous Administration: The radiographic response of subcutaneously administered Actemra was assessed in a double-blind, controlled, multicentre study in patients with active RA. This study (SC-II) evaluated patients with moderate to severe active rheumatoid arthritis who had an inadequate clinical response to their existing rheumatologic therapy, including one or more DMARD(s) where approximately 20% had a history of inadequate response to at least one TNF inhibitor. Patients were required to be above 18 years of age with active rheumatoid arthritis diagnosed according to ACR criteria and who had at least 8 tender and 6 swollen joints at baseline. In SC-II, 656 patients were randomized 2:1 to Actemra SC 162 mg every other week or placebo, in combination with non-biologic DMARD(s).
In study SC-II, inhibition of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week 24, inhibition of structural damage was shown, with significantly less radiographic progression in patients receiving Actemra SC compared with placebo (mTSS of 0.62 vs. 1.23, p=0.0149 (van Elteren). These results are consistent with those observed in patients treated with intravenous Actemra.
Quality of Life Outcomes: Intravenous Administration: Clinically significant improvements in disability index (HAQ-DI, Health Assessment Questionnaire Disability Index), fatigue (FACITFatigue, 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 Actemra (monotherapy or combination with DMARDs) compared to patients treated with MTX/DMARDs (Table 5).
At week 24, the proportion of 8 mg/kg Actemra treated patients showing a clinically relevant improvement in HAQ-DI (defined as an individual total score decrease of above 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 5.)

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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 ACT 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 the ACT 8 mg/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 ACT 8 mg/kg + MTX group (-0.61).
Quality of Life Outcomes - Subcutaneous Administration: In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 for both Actemra SC 162 mg weekly and Actemra IV 8 mg/kg every 4 weeks. The proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was comparable in the Actemra SC every week group (65.2%) versus the Actemra IV 8 mg/kg group (67.4%), with a weighted difference in proportions of -2.3% (95% CI -8.1, 3.4). The SF-36 summary was split into mental and physical components. The mental component scores were similar between the groups, with a mean change from baseline at week 24 of 6.22 for the SC group and 6.54 for the IV group. The physical component scores were also similar between the groups, with mean change from baseline at week 24 of 9.49 for the SC group and 9.65 for the IV group.
Laboratory Evaluations: Treatment with 8 mg/kg Actemra 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 Actemra administration. Consistent with the effect on acute phase reactants, treatment with Actemra was associated with reduction in platelet count within the normal range.
Monotherapy: Actemra 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 Actemra arm received an intravenous (IV) infusion of Actemra (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 Actemra 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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MTX naive, Early RA: Study VI (WA19926), a 2 year study with the planned primary analysis at week 52 evaluated 1162 MTX-naive adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months). Approximately 20% of patients had received prior treatment with DMARDs other than MTX. This study evaluated the efficacy of IV Actemra 4 or 8 mg/kg every 4 weeks/MTX combination therapy, IV Actemra 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 below 2.6) at week 24. A significantly higher proportion of patients in the Actemra 8 mg/kg + MTX and Actemra monotherapy groups met the primary endpoint compared with MTX alone. The Actemra 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 Actemra 8 mg/kg monotherapy group in all secondary endpoints, including radiographic endpoints. In this study, ACR/EULAR remission (Boolean and Index) were also analysed as pre-specified exploratory endpoints, with higher responses observed in the Actemra groups. The results from study VI are shown in Table 7. (See Table 7.)

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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. This CV safety study was designed to exclude a moderate increase in CV risk in patients treated with ACT 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 antirheumatic drugs, who were aged ≥50 years with at least one additional CV risk factor beyond RA. Patients were randomized 1:1 to IV ACT 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 ACT 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 ACT to ETA = 1.05; 95% CI = 0.77, 1.43).
Polyarticular Juvenile Idiopathic Arthritis: The efficacy of intravenous Actemra 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 Actemra 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 Actemra at 8 mg/kg for 4 doses. Patients below 30 kg were randomized 1:1 to receive either Actemra 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 Actemra (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 ACT-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 as follows. (See Table 8.)

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Systemic Juvenile Idiopathic Arthritis: The efficacy of intravenous Actemra 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 (ACT:placebo = 2:1) to one of two treatment groups, 75 patients received Actemra infusions every two weeks either 8 mg/kg for patients ≥30kg or 12 mg/kg for patients below 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 ACT 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 9.)

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Systemic Features: In those patients treated with Actemra, 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 Actemra 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 Actemra treated patients at week 12 in comparison to placebo patients. The adjusted mean change in the pain VAS after 12 weeks of Actemra 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 Actemra patients receiving oral corticosteroids at baseline, 8 placebo and 48 Actemra patients achieved a JIA ACR70 response at week 6 or 8 enabling corticosteroid dose reduction. Seventeen (24%) Actemra 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 Actemra 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). Responses are maintained in the on-going open label extension.
Laboratory Parameters: Fifty out of seventy five (67%) patients treated with Actemra had a haemoglobin below 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 below LLN at baseline (p<0.0001). Forty four (88%) Actemra 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 Actemra 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 Actemra administration. A Phase I, multi-centre, open-label, single arm study (NP25737) to evaluate the PK, safety and exploratory PD and efficacy of Actemra 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 Actemra 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 ACT 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-Actemra antibodies after the event. However, due to the small sample size, the low number of events and confounding factors, conclusions could not be drawn.
Pharmacokinetics: PK of Actemra is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of Actemra elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of Actemra do not change with time. Due to the dependence of total clearance on Actemra serum concentrations, the half-life of Actemra is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.
Rheumatoid Arthritis: The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations.
The table as follows shows model predicted secondary PK parameters at each of the four approved dose regimens. The population PK (popPK) model was developed from an analysis dataset composed of an IV dataset of 1793 patients from studies WA17822, WA17824, WA18062 and WA18063 and IV and SC dataset of 1759 patients from studies WA22762 and NA25220. Cmean is included in the table since for dosing regimens with different inter-dose interval, the mean concentration over the dosing period characterizes the comparative exposure better than AUCτ. (See Table 10.)

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At high serum concentrations, when total clearance of Actemra is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates.
While after IV administration maximum concentration (Cmax) increased doseproportionally between doses of 4 and 8 mg/kg IV every 4 weeks, a greater than doseproportional increase was observed in the average concentration (Cmean) and trough concentration (Ctrough). At steady-state, Cmean and Ctrough were 3.2 and 32 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively. Exposures after the 162 mg SC QW regimen were greater by 4.6 (Cmean) to 7.5 fold (Ctrough) compared to the 162 SC Q2W regimen.
The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg Q4W are low, while the accumulation ratios are higher for Ctrough (2.62 and 2.47). Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations.
For Cmax, more than 90% of the steady-state was reached after the 1st IV infusion, and after the 12th SC and the 5th SC injection in QW and Q2W regimens respectively. For AUCτ and Cmean, 90% of the steady-state was reached after the 1st and 3rd infusion for the 4 mg/kg and 8 mg/kg IV, respectively, and after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens respectively. For Ctrough, approximately 90% of the steady-state was reached after the 4th IV infusion, the 6th and 12th injections for the respective SC regimens.
Population PK analysis identified body weight as a significant covariate impacting pharmacokinetics of Actemra. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, Actemra doses exceeding 800 mg per infusion are not recommended in patients ≥ 100 kg (see Dosage & Administration). Due to the flat dosing employed for SC administration of Actemra, no modifications are necessary by this dosing route.
Polyarticular Juvenile Idiopathic Arthritis: The pharmacokinetics of intravenous Actemra 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 Actemra (patients with a body weight ≥ 30 kg) given every 4 weeks. The predicted mean (± SD) AUC4weeks, Cmax and Ctrough of Actemra were 29500 ± 8660 μg·hr/mL, 182 ± 37 μg/mL and 7.49 ± 8.2 μg/mL, respectively.
The following parameters are valid for a dose of 10 mg/kg Actemra (patients with a body weight below 30 kg) given every 4 weeks. The predicted mean (± SD) AUC4weeks, Cmax and Ctrough of Actemra 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 Ctrough for 10 mg/kg (BW below 30 kg) and 8 mg/kg (BW ≥ 30 kg) doses, respectively. No accumulation for Cmax was observed.
Systemic Juvenile Idiopathic Arthritis: The pharmacokinetics of intravenous Actemra 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 below 30 kg), given every 2 weeks. The predicted mean (± SD) AUC2weeks, Cmax and Ctrough of Actemra were 32200 ± 9960 μg·hr/mL, 245 ±57.2 μg/mL and 57.5 ± 23.3 μg/mL, respectively. The accumulation ratio for Ctrough (week12/week2) was 3.2 ± 1.3. The Actemra Ctrough was stabilized after week 12. Mean predicted Actemra exposure parameters were similar between the two body weight groups. The pharmacokinetics of Actemra 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 Actemra given every 2 weeks.
Absorption: Following SC dosing in RA patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 80%.
Distribution: Following IV dosing, Actemra undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L, 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 Actemra 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 RA 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 Actemra concentrations. Once the nonlinear clearance pathway is saturated, at higher Actemra concentrations, clearance is mainly determined by the linear clearance. Due to dependence of total clearance on Actemra serum concentrations, t1/2 of Actemra is also concentration-dependent and can only be calculated at a given serum concentration level. In RA patients, for intravenous administration, the concentration-dependent apparent t1/2 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. For subcutaneous administration, the concentration-dependent apparent t1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state. At high serum concentrations, when total clearance of Actemra is dominated by linear clearance, a terminal t1/2 of approximately 21.5 days was derived from the population parameter estimates.
In children with pJIA, the t1/2 of IV Actemra 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 below 30 kg) during a dosing interval at steady state.
In children with sJIA, the t1/2 of IV Actemra 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 below 30 kg) at Week 12.
Pharmacokinetics in Special Populations: Hepatic Impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of Actemra was conducted.
Renal Impairment: No formal study of the effect of renal impairment on the pharmacokinetics of Actemra was conducted.
Most of the patients in the RA population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance based on Cockcroft-Gault formula < 80 ml/min and ≥ 50 ml/min) did not impact the pharmacokinetics of Actemra.
Approximately one-third of the patients in the study WA28119 had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on Actemra exposure was noted in these patients.
No dose adjustment is required in patients with mild or moderate renal impairment.
Other special populations: Population pharmacokinetics analyses in adult RA patients showed that age, sex and race did not affect pharmacokinetics of Actemra. No dose adjustment is necessary for these demographic factors.
Toxicology: Nonclinical Safety: Carcinogenicity: A carcinogenicity study of Actemra 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 Actemra. 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 Actemra in both prokaryotic and eukaryotic cells were all negative.
Impairment of Fertility: Nonclinical data do not suggest an effect on fertility under treatment with an analogue of Actemra. 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 Actemra 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 (above 100 times human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other lowdose 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 Actemra. Although IL-6 does not seem to be a critical cytokine for either fetal growth or the immunological control of the maternal/fetal interface, a relation of this finding to Actemra cannot be excluded.
Transfer of a murine analogue of Actemra 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.
The non-clinical safety profile of Actemra in the cynomolgus monkey does not suggest a difference between IV and SC routes of administration.
Indications/Uses
Rheumatoid Arthritis [IV and SC formulations]: Actemra, in combination with methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs), is indicated for: the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX [IV formulation only]; the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists [IV and SC formulations].
In these patients, Actemra can be used alone in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
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.
Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]: Actemra is indicated in combination with methotrexate (MTX) for the treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. Actemra can be given alone in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
Systemic Juvenile Idiopathic Arthritis (sJIA) [IV formulation only]: Actemra is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older, who have responded inadequately to previous therapy with NSAIDS and systemic corticosteroids. Actemra can be given alone or in combination with MTX.
Dosage/Direction for Use
Substitution by any other biological medicinal product requires the consent of the prescribing physician.
The safety and efficacy of alternating or switching between Actemra and products that are biosimilar but not deemed interchangeable to Actemra has not been established. Therefore, the benefit/risk of alternating or switching need to be carefully considered.
Intravenous Administration: Actemra IV formulation is not intended for subcutaneous administration.
Actemra IV formulation 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).
Actemra is recommended for IV infusion over 1 hour.
Subcutaneous Administration: Actemra SC formulation is not intended for intravenous administration.
Actemra SC formulation is administered with a single-use PFS+NSD. The first injection should be performed under the supervision of a qualified health care professional. A patient can self-inject ACTEMRA only if the physician determines that it is appropriate and the patient agrees to medical follow-up as necessary and has been trained in proper injection technique. The recommended injection sites (abdomen, thigh and upper arm) should be rotated and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
Patients who transition from Actemra IV therapy to SC administration should administer the first SC dose at the time of the next scheduled IV dose under the supervision of a qualified health care professional.
Assess suitability of patient or parent/guardian for SC home administration and instruct the patient or parent/guardian to inform a healthcare professional before administering the next dose, if any symptoms of allergic reaction are experienced. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions (see General under Precautions and Adverse Reactions).
Rheumatoid Arthritis (RA) [IV and SC formulations]: Intravenous Dosing Regimen: The recommended dose of Actemra for adult patients is 8 mg/kg, but no lower than 480 mg, given once every four weeks.
Doses above 1.2 g have not been evaluated in clinical studies.
Actemra should be diluted to 100 ml 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).
Actemra is recommended for IV infusion over 1 hour.
For individuals whose body weight is more than 100 kilograms (kg), doses exceeding 800 mg per infusion are not recommended (see Pharmacology: Pharmacokinetics under Actions).
Subcutaneous Dosing Regimen: The recommended dose of Actemra for adult patients is 162 mg given once every week as a subcutaneous injection. Actemra can be used alone or in combination with MTX and/or other DMARDs.
Dose Modification Recommendations for RA: (See General under Precautions.) (See Tables 11, 12 and 13.)

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Polyarticular Juvenile Idiopathic Arthritis (pJIA) [IV formulation only]: The recommended dose of Actemra for patients with pJIA is: 10 mg/kg for patients below 30 kg, 8 mg/kg for patients ≥ 30 kg, 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. Actemra can be used alone or in combination with MTX.
Systemic juvenile idiopathic arthritis (sJIA) [IV formulation only]: The recommended dose of Actemra for patients with sJIA is: 12 mg/kg for patients below 30 kg, 8 mg/kg for patients ≥ 30 kg, 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. Actemra can be used alone or in combination with MTX.
Actemra 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).
Actemra is recommended for IV infusion over 1 hour.
Dose Modification Recommendations for pJIA and sJIA: Dose reduction of Actemra has not been studied in the pJIA or sJIA population. Dose interruptions of Actemra for laboratory abnormalities are recommended in patients with pJIA or sJIA and are similar to what is outlined above for patients with RA (see General under Precautions). If appropriate, concomitant methotrexate and/or other medications should be dose modified or stopped and Actemra dosing interrupted until the clinical situation has been evaluated. In pJIA or sJIA the decision to discontinue Actemra for a laboratory abnormality should be based upon the medical assessment of the individual patient.
Special Dosage Instructions: Pediatric use: The safety and efficacy of Actemra intravenous formulation in paediatric patients below the age of 2 years old have not been established. The safety and efficacy of Actemra subcutaneous formulation in children from birth to less than 18 years have not been established. No data are available.
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 or moderate renal impairment (see Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Actemra has not been studied in patients with severe renal impairment.
Hepatic impairment: The safety and efficacy of Actemra has not been studied in patients with hepatic impairment (see General under Precautions).
Overdosage
There are limited data available on overdosage with Actemra. 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 the active substance or to any of the excipients.
Active, severe infections.
Special Precautions
General: In order to improve the traceability of biological medicinal products, the trade name and batch number 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 Actemra (see Adverse Reactions). Actemra treatment should not be initiated in patients with active infections. Administration of Actemra 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 Actemra 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 immunosuppressive agents, such as Actemra, as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. Patients (which include younger children who may be less able to communicate their symptoms) and parents/guardians of minors 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 patients treated with Actemra. Actemra 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 all patients should be screened for latent tuberculosis infection prior to starting Actemra therapy. Patients with latent tuberculosis should be treated with standard anti-mycobacterial therapy before initiating Actemra.
Vaccinations: Live and live attenuated vaccines should not be given concurrently with Actemra 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 Actemra. In a randomized open-label study, adult RA patients treated with Actemra 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. The data demonstrated a small attenuation in the immune response to the 23-valent pneumococcal polysaccharide with ACT + MTX compared with MTX alone, but the response to tetanus toxoid vaccine in each treatment group was similar.
It is recommended that all patients, particularly pediatric or elderly patients, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Actemra therapy. The interval between live vaccinations and initiation of Actemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Hypersensitivity Reactions:
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with Actemra (see Clinical Trials under Adverse Reactions). In the post marketing setting, events of serious hypersensitivity and anaphylaxis have occurred in patients treated with a range of doses of Actemra, with or without concomitant therapies, premedication, and / or a previous hypersensitivity reaction. In the post marketing setting, cases with a fatal outcome have been reported with intravenous Actemra. These events have occurred as early as the first infusion of Actemra (see Contraindications and Post Marketing Experience under Adverse Reactions). Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during infusion with Actemra. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of Actemra should be stopped immediately and Actemra should be permanently discontinued (see Dosage & Administration).
Active Hepatic Disease and Hepatic Impairment: Treatment with Actemra particularly when administered concomitantly with methotrexate, may be associated with elevations in hepatic transaminases (see Clinical Trials under Adverse Reactions). Therefore caution should be exercised when considering treatment of patients with active hepatic disease or hepatic impairment, as the safety of Actemra in these patients has not been adequately studied (see Special Dosage Instructions under Dosage & Administration).
Hepatotoxicity: Mild and moderate elevations of hepatic transaminases have been observed with Actemra 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 Actemra.
Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with Actemra (see Post Marketing Experience under Adverse Reactions). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of Actemra. Cases of liver failure resulting in liver transplantation have been reported.
Caution should be exercised when considering initiation of Actemra 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, pJIA and SJIA, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended dose modifications, including Actemra 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 Actemra, 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 Actemra is currently unknown.
Neutropenia: Treatment with Actemra 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 Actemra 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 infusion and thereafter according to good clinical practice (see Dose modifications under Dosage & Administration).
Thrombocytopenia: Treatment with Actemra 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 Actemra treatment in patients with a platelet count below 100 x 103/mL. In patients with a platelet count below 50 x 103/mL 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 and Administration. In pJIA and sJIA: Platelets should be monitored at the time of the second infusion 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 Actemra, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of Actemra therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Cardiovascular risk: RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.
Combination with TNF antagonists: There is no experience with the use of Actemra with TNF antagonists or other biological treatments for RA. Actemra is not recommended for use with other biological agents.
Neurological disorders: Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with Actemra is currently unknown.
Malignancy: The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.
Infusion reactions: Infusion reactions have been observed during and within 24 hours of treatment with Actemra.
Sodium:
This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially 'sodium free'.
Systemic juvenile idiopathic arthritis [IV formulation only]: Macrophage activation syndrome (MAS): MAS is a serious life-threatening disorder that may develop in patients with sJIA. In clinical trials, Actemra 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 Actemra to cause dependence have been performed. However, there is no evidence from the available data that Actemra treatment results in dependence.
Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machine have been performed. However, there is no evidence from the available data that Actemra treatment affects the ability to drive and use machines.
Renal Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Hepatic Impairment: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use in Children: See Special Dosage Instructions under Dosage & Administration.
Use in the Elderly: See Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions.
Use In Pregnancy & Lactation
Pregnancy: There are no adequate data from the use of Actemra in pregnant women. A study in monkeys did not indicate any dysmorphogenic potential but has yielded higher number of spontaneous abortion /embryo-fetal death at a high dose (see Pharmacology: Toxicology: Other under Actions). The relevance of these data for humans is unknown. Women of childbearing potential must use effective contraception during and up to 6 months after treatment. Actemra should not be used during pregnancy unless clearly indicated by medical need.
Nursing Mothers: It is unknown whether Actemra is excreted in human breast milk. Although endogenous immunoglobulins of the IgG isotope are secreted into human milk, a systemic absorption of Actemra 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 Actemra should be made taking into account the benefit of breast-feeding to the child and the benefit of Actemra therapy to the woman.
Adverse Reactions
Clinical Trials: The safety profile in this section comes from 4510 patients exposed to Actemra in clinical trials; the majority of these patients were participating in RA studies (n=4009), while the remaining experience comes from pJIA (n=240), sJIA (n=112), and GCA (n=149) studies.
The safety profile of Actemra across these indications remains similar and undifferentiated.
Adverse Drug Reactions (ADRs) from clinical trials (Table 14) are listed by MedDRA system organ class according to clinical importance to the patient. The corresponding frequency category for each ADR is based on the following convention: very common (≥1/10), common (≥1/100 to < 1/10) or uncommon (≥1/1000 to < 1/100). (See Table 14.)

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Description of selected adverse drug reactions from clinical trials: Rheumatoid Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra has been studied in 5 Phase III, double-blind controlled trials and their extension periods.
The double-blind controlled population includes all patients from the double-blind phases of each core study from randomization until either the first change in the treatment regimen, or two years is reached. The control period in 4 of the studies was 6 months and in 1 study was up to 2 years. In the double-blind controlled studies 774 patients received Actemra 4 mg/kg in combination with MTX, 1870 patients received Actemra 8 mg/kg in combination with MTX/other DMARDs and 288 patients received Actemra 8 mg/kg monotherapy.
The all exposure population includes all patients who received at least one dose of Actemra either in the double-blind control period or open label extension phase in studies. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year; 2806 received treatment for at least 2 years and 1222 for 3 years.
Infections: In the 6-month controlled trials, the rate of all infections reported with Actemra 8 mg/kg+DMARD treatment was 127 events per 100 patient (pt) years compared to 112 events per 100 pt years in the placebo+DMARD group. In the long-term exposure population the overall rate of infections with Actemra was 108 events per 100 pt years exposure.
In 6-month controlled clinical trials rate of serious infections (bacterial, viral and fungal) with Actemra 8 mg/kg+DMARD was 5.3 events per 100 pt years exposure compared to 3.9 events per 100 pt years exposure in the placebo+DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 pt years of exposure in the Actemra group and 1.5 events per 100 pt years of exposure in the MTX group.
In the long-term exposure population the overall rate of serious infections was 4.7 events per 100 pt years. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis. Cases of opportunistic infections have also been reported.
Interstitial Lung Disease: Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes.
Gastrointestinal Perforation: During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 pt years with Actemra therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 pt years. Reports of gastrointestinal perforation on Actemra were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess.
Infusion Reactions: In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the Actemra 8 mg/kg+DMARD and 5.1% of patients in the placebo+DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylaxis (occurring in a total of 6/3778 patients) was several-fold higher in the 4 mg/kg arm in comparison to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with Actemra and requiring treatment discontinuation, were reported in a total of 13 out of 3778 patients (0.3%) treated with Actemra during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of Actemra (see General under Precautions).
Immunogenicity: A total of 2876 patients have been tested for anti-Actemra antibodies in the 6-month controlled clinical trials. Forty six patients (1.6%) developed positive anti-Actemra antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralizing antibodies.
Early Rheumatoid Arthritis: Study VI (WA19926) evaluated 1162 patients with early, moderate to severe RA who were naive to treatment with both MTX and a biologic agent. The overall safety profile observed in the Actemra treatment groups was consistent with the known safety profile of Actemra (see Table 14).
Monotherapy: Actemra versus adalimumab: In a 24 week double-blinded, parallel study (monotherapy with Actemra 8 mg/kg IV q4w (N=162) compared to adalimumab 40 mg SC q2w (N=162)), the overall clinical adverse event profile was similar between Actemra and adalimumab. The proportion of patients with serious adverse events was balanced between the treatment groups (Actemra 11.7% vs. adalimumab 9.9%) with the most common event being infections (3.1% each). Both study treatments induced the same pattern of changes in laboratory safety parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, the magnitude of change and the frequency of marked abnormalities was higher with Actemra compared with adalimumab. Four (2.5%) patients in the Actemra arm and two (1.2%) patients in the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients in the Actemra arm and five (3.1%) patients in the adalimumab arm experienced ALT increases of CTC grade 2 or higher. The mean LDL increase from baseline was 0.64 mmol/l (25 mg/dL) for patients in the Actemra arm and 0.19 mmol/L (7 mg/dL) for patients in the adalimumab arm. The safety observed in the Actemra arm was consistent with the known safety profile of Actemra and no new or unexpected adverse drug reactions were observed (see Table 14) (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Patients Treated with Subcutaneous Actemra: The safety of subcutaneous Actemra in RA was studied in SC-I. The study compared the efficacy and safety of Actemra 162 mg administered every week SC versus 8 mg/kg IV in 1262 subjects with adult RA. All patients in the study received background non-biologic DMARD(s). The safety and immunogenicity observed for Actemra administered SC was consistent with the known safety profile of IV Actemra and no new or unexpected adverse drug reactions were observed (see Table 14). A higher frequency of injection site reactions (ISRs) was observed in the SC arms compared with placebo SC injections in the IV arms (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Injection Site Reactions (ISRs): During the 6-month controlled period, in SC-I, the frequency of ISRs was 10.1% (64/631) and 2.4% (15/631) for the SC Actemra and the SC placebo (IV group) weekly injections, respectively. These ISRs (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved without any treatment and none necessitated drug discontinuation.
Immunogenicity: In SC-I, a total of 625 patients treated with Actemra 162 mg weekly were tested for anti-tocilizumab antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-tocilizumab antibodies; of these, all developed neutralizing anti-tocilizumab antibodies. A total of 1454 SC Actemra all exposure patients have been tested for anti-tocilizumab antibodies, thirteen patients (0.9%) developed positive anti-tocilizumab antibodies, and of these 12 patients (0.8%) developed neutralizing anti-tocilizumab antibodies. No correlation of antibody development to clinical response or adverse events was observed.
Polyarticular Juvenile Idiopathic Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra was studied in 188 pediatric patients, 2 to 17 years of age, with pJIA. The total patient exposure in the Actemra all exposure population was 184.4 patient years. In general, the types of adverse drug reactions in patients with pJIA were similar to those seen in RA and sJIA patients (see Adverse Reactions).
Infections: The rate of infections in the Actemra all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing below30 kg treated with 10 mg/kg Actemra (12.2 per 100 patient years) compared to patients weighing ≥30 kg, treated with 8 mg/kg Actemra (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing below 30 kg treated with 10 mg/kg Actemra (21.4%) compared to patients weighing ≥30 kg, treated with 8 mg/kg Actemra (7.6%).
Infusion Reactions: In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Actemra all exposure population, 11 patients (5.9%) experienced infusion reactions during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients (see Adverse Reactions).
No clinically significant hypersensitivity reactions associated with Actemra and requiring treatment discontinuation were reported.
Immunogenicity: One patient in the 10 mg/kg below 30 kg group developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.
Systemic Juvenile Idiopathic Arthritis: Patients Treated with Intravenous Actemra: The safety of Actemra in sJIA has been studied in 112 pediatric patients 2 to 17 years of age. In the 12 week double-blind, controlled portion of the clinical trial 75 patients received treatment with Actemra (8 or 12 mg/kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated in the on-going open-label extension phase.
In general, the adverse drug reactions in patients with sJIA were similar in type to those seen in RA patients (see Adverse Reactions previously mentioned).
Infections: In the 12 week controlled trial the rate of all infections in the Actemra group was 344.7 per 100 patient-years and 287.0 per 100 patient-years in the placebo group. In the on-going open label extension study (Part II) the overall rate of infections remained similar at 306.6 per 100 patient-years.
In the 12 week controlled trial the rate of serious infections in the Actemra group was 11.5 per 100 patient years. In the on-going open label extension study the overall rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.
Infusion Reactions: For sJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the 12 week controlled trial, four percent (4.0%) of patients from the Actemra group experienced events occurring during infusion, one event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.
In the 12 week controlled trial experience, 16% of patients in the Actemra group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the Actemra group, the events included, but not limited to rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, (urticaria) was considered serious.
Clinically significant hypersensitivity reactions associated with Actemra and requiring treatment discontinuation, were reported in 1 out of 112 patients (below 1%) treated with Actemra during the controlled and open-label parts of the clinical trial.
Immunogenicity: All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reaction leading to withdrawal.
Laboratory Abnormalities: Haematology abnormalities: Neutrophils: There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections in any of the indications.
Rheumatoid Arthritis: Intravenous Administration: In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/L occurred in 3.4% of patients on Actemra 8 mg/kg+DMARD compared to below 0.1% of patients on placebo+DMARD. Approximately half of the instances of ANC below 1 x 109/l occurred within 8 weeks of starting therapy. Decreases below 0.5 x 109/L were reported in 0.3% patients receiving Actemra 8 mg/kg +DMARD (see Dosage & Administration and Precautions).
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on Actemra 162 mg SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7% of patients.
Systemic juvenile idiopathic arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, a decrease in neutrophil counts below 1 × 109/L occurred in 7% of patients in the Actemra group, and in none in the placebo group.
In the ongoing open-label extension study decreases in neutrophil counts below 1 x 109/L, occurred in 15% of the Actemra group.
Platelets: Rheumatoid Arthritis: Intravenous Administration: In the 6-month controlled trials decreases in platelet counts below 100 x 103/μL occurred in 1.7% of patients on Actemra 8 mg/kg plus traditional DMARDs compared to below 1% of patients on placebo plus traditional DMARDs, without associated bleeding events (see Dosage & Administration and Precautions).
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, none of the patients had a decrease in platelet count to ≤50 × 103/μL.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, 1% of patients had a decrease in platelet count to ≤ 50 × 103/μL without associated bleeding events.
Systemic juvenile idiopathic arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, 3% of patients in the placebo group and 1% in the Actemra group had a decrease in platelet count to ≤100 × 103/μL.
In the ongoing open-label extension study decreases in platelet counts below 100 x 103/μL occurred in 3% of patients of the Actemra group, without associated bleeding events.
Liver enzyme elevations: Rheumatoid Arthritis: Intravenous Administration: During the 6-month controlled trials transient elevations in ALT/AST above 3xULN were observed in 2.1% of patients on Actemra 8 mg/kg compared to 4.9% of patients on MTX, and in 6.5% of patients who received Actemra 8 mg/kg + DMARD compared to 1.5% of patients on placebo+DMARD. The addition of potentially hepatotoxic drugs (e.g. MTX) to Actemra monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST above 5xULN were observed in 0.7% of Actemra monotherapy patients and 1.4% of Actemra+DMARD patients, the majority of whom were discontinued from Actemra treatment (see Dosage & Administration and Precautions). During routine laboratory monitoring, the incidence of indirect bilirubin greater than the upper limit of normal was 6.2% in patients treated with 8 mg/kg Actemra + DMARD in the double-blind controlled population.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
In Study WA25204, of the 1538 patients with moderate to severe RA (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions) and treated with Actemra, elevations in ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively. One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with Actemra treatment (see Precautions).
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, elevation in ALT or AST ≥3 x ULN occurred in 3.7% and below 1% of patients, respectively.
Systemic Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, elevation in ALT or AST ≥ 3xULN occurred in 5% and 3% of patients, respectively, in the Actemra group, and in 0% of placebo patients.
In the ongoing open-label extension study, elevation in ALT or AST ≥ 3xULN occurred in 12% and 4% of patients, respectively, in the Actemra group.
Elevations in lipid parameters: Rheumatoid Arthritis: Intravenous Administration: During routine laboratory monitoring in the 6-month controlled trials elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were observed in patients treated with Actemra. Approximately 24% of patients receiving Actemra in clinical trials experienced sustained elevations in total cholesterol above 6.2 mmol/L (240 mg/dL), with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL).
In the majority of patients there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled clinical trials.
Subcutaneous Administration: During routine laboratory monitoring in the Actemra 6-month controlled period of clinical trial SC-I, 19% of patients on SC weekly experienced sustained elevations in total cholesterol above 6.2 mmol/L (240 mg/dL), with 9% experiencing a sustained increase in LDL to ≥ 4.1 mmol/L (160 mg/dL) on SC weekly.
Polyarticular Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the Actemra all exposure population, elevation in total cholesterol above 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL above 1.5-2 x ULN in one patient (0.5%).
Systemic Juvenile Idiopathic Arthritis: Intravenous Administration: During routine laboratory monitoring in the 12 week controlled trial, elevation in total cholesterol above 1.5 x ULN to 2 x ULN occurred in 1.5% of the Actemra group and in 0% of placebo patients. Elevation in LDL above 1.5 x ULN to 2 x ULN occurred in 1.9% of patients in the Actemra group and 0% of the placebo group.
In the ongoing open-label extension study the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled trial data.
Post Marketing Experience: The following adverse drug reactions have been identified from post marketing experience with Actemra (Table 15) based on spontaneous case reports, literature cases and cases from non-interventional study programs. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000). (See Table 15.)

Click on icon to see table/diagram/image
Drug Interactions
Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs or corticosteroids on Actemra clearance in RA patients.
Concomitant administration of a single 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 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 Actemra is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Actemra normalizes expression of these enzymes.
The effect of Actemra on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index, 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 Actemra, to the level similar or slightly higher than those observed in healthy subjects.
When starting or stopping therapy with Actemra, patients taking medicinal products, which are individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, 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 Actemra on CYP450 enzyme activity may persist for several weeks after stopping therapy.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Intravenous Actemra: 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 Actemra solution required for the patient's dose. Withdraw the required amount of Actemra (0.4 ml/kg) under aseptic conditions and dilute to a calculated Actemra 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 Actemra solution required for the patient's dose. Withdraw the required amount of Actemra (0.4 mL/kg) under aseptic conditions and dilute to a calculated Actemra 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 below 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 Actemra under aseptic conditions. To mix the solution, gently invert the bag to avoid foaming.
sJIA Patients below 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 Actemra under aseptic conditions. To mix the solution, gently invert the bag to avoid foaming.
Subcutaneous Actemra: Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to yellowish, or any part of the PFS+NSD appears to be damaged.
Disposal of syringes/sharps: The following points should be strictly adhered to regarding the use and disposal of the PFS+NSD and pre-filled pen: Syringes and pre-filled pens should never be reused.
Place all used syringes and pre-filled pens into a sharps container (puncture-proof disposable container).
Keep this container out of the reach of children.
Placing used sharps containers in the household waste should be avoided.
Dispose of the full container according to local requirements or as instructed by your healthcare provider.
For home use, patients should procure a puncture resistant container for the disposal of used syringes and pre-filled pens.
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
Intravenous Actemra: For vials: Store between 2ºC - 8ºC, 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 Actemra is physically and chemically stable in 0.9% w/v sodium chloride solution at 30ºC 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 should not be longer than 24 hours at 2ºC - 8ºC, unless dilution has taken place in controlled and validated aseptic conditions.
Subcutaneous Actemra: Store the pre-filled syringe in a refrigerator at a temperature of 2-8°C. Do not freeze, keep in carton to protect from light, and keep dry.
Once removed from the refrigerator, Actemra solution for injection must be administered within 8 hours and should not be kept above 30°C.
ATC Classification
L04AC07 - tocilizumab ; Belongs to the class of interleukin inhibitors. Used as immunosuppressants.
Presentation/Packing
Conc soln for infusion (vial) (clear to opalescent, colourless to pale yellow liquid) 80 mg/4 mL x 1's, 4's. 200 mg/10 mL x 1's, 4's. 400 mg/20 mL x 1's, 4's. Soln for inj (pre-filled syringe) (yellowish, preservative-free liquid) 162 mg/0.9 mL x 1's, 4's.
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