Aktempa

Overdose

There are limited data available on overdoses with Aktempa. One case of accidental overdose was reported with intravenous Aktempa in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia.

In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

There are limited data available on overdose with Aktempa. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg administered intravenously. No adverse reactions were observed.

No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose limiting neutropenia was observed.

Contraindications

Aktempa is contraindicated in patients with known hypersensitivity to Aktempa.

Active, severe infections.

Incompatibilities

In the absence of compatability studies, this medicinal product must not be mixed with other medicinal products.

Undesirable effects

The following serious adverse reactions are described elsewhere in labeling:

• Serious Infections
• Gastrointestinal Perforations
• Laboratory Parameters
• Immunosuppression
• Hypersensitivity Reactions, Including Anaphylaxis
• Demyelinating Disorders
• Active Hepatic Disease and Hepatic Impairment

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

The Aktempa-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter studies. In these studies, patients received doses of Aktempa-IV 8 mg per kg monotherapy (288 patients), Aktempa-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 patients), or Aktempa-IV 4 mg per kg in combination with methotrexate (774 patients).

The all exposure population includes all patients in registration studies who received at least one dose of Aktempa-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years.

All patients in these studies had moderately to severely active rheumatoid arthritis. The study population had a mean age of 52 years, 82% were female and 74% were Caucasian.

The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring in at least 5% of patients treated with Aktempa-IV monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The proportion of patients who discontinued treatment due to any adverse reactions during the double-blind, placebo-controlled studies was 5% for patients taking Aktempa-IV and 3% for placebo-treated patients. The most common adverse reactions that required discontinuation of Aktempa-IV were increased hepatic transaminase values (per protocol requirement) and serious infections.

In the 24 week, controlled clinical studies, the rate of infections in the Aktempa-IV monotherapy group was 119 events per 100 patient-years and was similar in the methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and nasopharyngitis.

The overall rate of infections with Aktempa-IV in the all exposure population remained consistent with rates in the controlled periods of the studies.

In the 24 week, controlled clinical studies, the rate of serious infections in the Aktempa-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.

In the all-exposure population, the overall rate of serious infections remained consistent with rates in the controlled periods of the studies. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.

During the 24 week, controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient-years with Aktempa-IV therapy.

In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroids, or methotrexate. The relative contribution of these concomitant medications versus Aktempa-IV to the development of GI perforations is not known.

In the 24 week, controlled clinical studies, adverse events associated with the infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% of patients in the 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD group, respectively, compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for both doses), while the most frequently reported event occurring within 24 hours of finishing an infusion were headache (1% for both doses) and skin reactions (1% for both doses), including rash, pruritus and urticaria. These events were not treatment limiting.

Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, associated with Aktempa-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally observed during the second to fourth infusion of Aktempa-IV. Appropriate medical treatment should be available for immediate use in the event of a serious hypersensitivity reaction.

Neutropenia

In the 24 week, controlled clinical studies, decreases in neutrophil counts below 1000 per mm³ occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo plus DMARD group. Approximately half of the instances of ANC below 1000 per mm³ occurred within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm³ occurred in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD, respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no clear relationship between decreases in neutrophils below 1000 per mm³ and the occurrence of serious infections.

In the all-exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 24 week controlled clinical studies.

Thrombocytopenia

In the 24 week, controlled clinical studies, decreases in platelet counts below 100,000 per mm³ occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg per kg Aktempa-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus DMARD, without associated bleeding events.

In the all-exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 24 week controlled clinical studies.

Elevated Liver Enzymes

Liver enzyme abnormalities are summarized in Table 1. In patients experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of Aktempa-IV, or reduction in Aktempa-IV dose, resulted in decrease or normalization of liver enzymes. These elevations were not associated with clinically relevant increases in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic insufficiency.

Table 1 : Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Studies I to V*

In the all-exposure population, the elevations in ALT and AST remained consistent with what was seen in the 24 week, controlled clinical trials

Lipids

Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed at 6 weeks following initiation of Aktempa-IV in the controlled 24 week clinical trials. Increases were observed at this time point and remained stable thereafter. Increases in triglycerides to levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from baseline to week 24 were evaluated and are summarized below:

• Mean LDL increased by 13 mg per dL in the Aktempa 4 mg per kg+DMARD arm, 20 mg per dL in the Aktempa 8 mg per kg+DMARD, and 25 mg per dL in Aktempa 8 mg per kg monotherapy.
• Mean HDL increased by 3 mg per dL in the Aktempa 4 mg per kg+DMARD arm, 5 mg per dL in the Aktempa 8 mg per kg+DMARD, and 4 mg per dL in Aktempa 8 mg per kg monotherapy.
• Mean LDL/HDL ratio increased by an average of 0.14 in the Aktempa 4 mg per kg+DMARD arm, 0.15 in the Aktempa 8 mg per kg+DMARD, and 0.26 in Aktempa 8 mg per kg monotherapy.
• ApoB/ApoA1 ratios were essentially unchanged in Aktempa-treated patients.

Elevated lipids responded to lipid lowering agents.

In the all-exposure population, the elevations in lipid parameters remained consistent with what was seen in the 24 week, controlled clinical trials.

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tocilizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In the 24 week, controlled clinical studies, a total of 2876 patients have been tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading to withdrawal. Thirty patients (1%) developed neutralizing antibodies.

During the 24 week, controlled period of the studies, 15 malignancies were diagnosed in patients receiving Aktempa-IV, compared to 8 malignancies in patients in the control groups. Exposure-adjusted incidence was similar in the Aktempa-IV groups (1.32 events per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years).

In the all-exposure population, the rate of malignancies remained consistent with the rate observed in the 24 week, controlled period.

Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per kg Aktempa-IV plus DMARD and at least 1% greater than that observed in patients on placebo plus DMARD are summarized in Table 2.

Table 2 : Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per kg Aktempa plus DMARD and at Least 1% Greater Than That Observed in Patients on Placebo plus DMARD

Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% in rheumatoid arthritis patients treated with Aktempa-IV in controlled trials were:

Infections and Infestations: oral herpes simplex

Gastrointestinal disorders: stomatitis, gastric ulcer

Investigations: weight increased, total bilirubin increased

Blood and lymphatic system disorders: leucopenia

General disorders and administration site conditions: edema peripheral

Respiratory, thoracic, and mediastinal disorders: dyspnea, cough

Eye disorders: conjunctivitis

Renal disorders: nephrolithiasis

Endocrine disorders: hypothyroidism

The Aktempa-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies received background non-biologic DMARDs.

The safety observed for Aktempa administered subcutaneously was consistent with the known safety profile of intravenous Aktempa, with the exception of injection site reactions, which were more common with Aktempa-SC compared with placebo SC injections (IV arm).

In the 6-month control period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly Aktempa-SC and placebo SC (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC Aktempa and placebo groups, respectively. These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.

In the 6-month control period in SC-I, 0.8% (5/625) in the Aktempa-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed neutralizing antibodies. In SC-II, 1.6% (7/434) in the Aktempa-SC arm compared with 1.4 % (3/217) in the placebo arm developed anti-tocilizumab antibodies; of these, 1.4% (6/434) in the Aktempa-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies.

A total of 1454 (>99%) patients who received Aktempa-SC in the all exposure group have been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies.

The rate is consistent with previous intravenous experience. No correlation of antibody development to adverse events or loss of clinical response was observed.

Neutropenia

During routine laboratory monitoring in the 6-month controlled clinical trials, a decrease in neutrophil count below 1 x 109/L occurred in 2.9% and 3.7% of patients receiving Aktempa-SC weekly and every other week, respectively.

There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Aktempa-SC 6-month controlled clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm³.

Elevated Liver Enzymes

During routine laboratory monitoring in the 6-month controlled clinical trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, receiving Aktempa-SC weekly and 3.4% and 0.7% receiving Aktempa SC every other week.

Lipid Parameters Elevations

During routine laboratory monitoring in the Aktempa-SC 6-month clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l (160 mg/dL) receiving Aktempa-SC weekly, every other week and placebo, respectively.

The safety of subcutaneous Aktempa (tocilizumab) has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the Aktempa GCA all exposure population was 138.5 patient years during the 12-month double blind, placebo-controlled phase of the study. The overall safety profile observed in the Aktempa treatment groups was generally consistent with the known safety profile of Aktempa. There was an overall higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious infection events was 200.2/9.7 events per 100 patient years in the Aktempa weekly group and 160.2/4.4 events per 100 patient years in the Aktempa every other week group as compared to 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 events per 100 patient years in the placebo + 52 week taper groups.

The safety of Aktempa-IV was studied in 188 pediatric patients 2 to 17 years of age with PJIA who had an inadequate clinical response or were intolerant to methotrexate. The total patient exposure in the AktempaIV all exposure population (defined as patients who received at least one dose of Aktempa-IV) was 184.4 patient years. At baseline, approximately half of the patients were taking oral corticosteroids and almost 80% were taking methotrexate. In general, the types of adverse drug reactions in patients with PJIA were consistent with those seen in RA and SJIA patients.

The rate of infections in the Aktempa-IV all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg tocilizumab (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg tocilizumab (8%).

In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the Aktempa-IV all exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and SJIA patients.

No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported.

One patient, in the 10 mg/kg less than 30 kg group, developed positive anti-tocilizumab antibodies without developing a hypersensitivity reaction and subsequently withdrew from the study.

Neutropenia

During routine laboratory monitoring in the Aktempa-IV all exposure population, a decrease in neutrophil counts below 1 x 109 per L occurred in 3.7% of patients.

There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine laboratory monitoring in the Aktempa-IV all exposure population, 1% of patients had a decrease in platelet count at or less than 50,000 per mm³ without associated bleeding events.

Elevated Liver Enzymes

During routine laboratory monitoring in the Aktempa-IV all exposure population, elevation in ALT or AST at or greater than 3 x ULN occurred in 4% and less than 1% of patients, respectively.

Lipids

During routine laboratory monitoring in the tocilizumab all exposure population, elevation in total cholesterol greater than 1.5-2 x ULN occurred in one patient (0.5%) and elevation in LDL greater than 1.5-2 x ULN occurred in one patient (0.5%).

The data described below reflect exposure to Aktempa-IV in one randomized, double-blind, placebo-controlled trial of 112 pediatric patients with SJIA 2 to 17 years of age who had an inadequate clinical response to nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids due to toxicity or lack of efficacy. At baseline, approximately half of the patients were taking 0.3 mg/kg/day corticosteroids or more, and almost 70% were taking methotrexate. The trial included a 12 week controlled phase followed by an open-label extension. In the 12 week double-blind, controlled portion of the clinical study 75 patients received treatment with Aktempa-IV (8 or 12 mg per kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Aktempa-IV in the open-label extension phase.

The most common adverse events (at least 5%) seen in Aktempa-IV treated patients in the 12 week controlled portion of the study were: upper respiratory tract infection, headache, nasopharyngitis and diarrhea.

In the 12 week controlled phase, the rate of all infections in the Aktempa-IV group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.

In the 12 week controlled phase, the rate of serious infections in the Aktempa-IV group was 11.5 per 100 patient years. In the open label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.

In the 12 week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with Aktempa-IV. One patient in the placebo group escaped to Aktempa-IV 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had Aktempa-IV dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the Aktempa-IV SJIA clinical development experience; however no definitive conclusions can be made.

Patients were not premedicated, however most patients were on concomitant corticosteroids as part of their background treatment for SJIA. Infusion related reactions were defined as all events occurring during or within 24 hours after an infusion. In the 12 week controlled phase, 4% of Aktempa-IV and 0% of placebo treated patients experienced events occurring during infusion. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

Within 24 hours after infusion, 16% of patients in the Aktempa-IV treatment group and 5% of patients in the placebo group experienced an event. In the Aktempa-IV group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia and headache. One of these events, urticaria, was considered serious.

Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with Aktempa-IV during the controlled and open label extension study.

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive antitocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed macrophage activation syndrome while on escape therapy and was discontinued from the study.

Neutropenia

During routine monitoring in the 12 week controlled phase, a decrease in neutrophil below 1 x 109 per L occurred in 7% of patients in the Aktempa-IV group, and in no patients in the placebo group. In the open label extension over an average duration of 73 weeks of treatment, a decreased neutrophil count occurred in 17% of the Aktempa-IV group. There was no clear relationship between decrease in neutrophils below 1 x 109 per L and the occurrence of serious infections.

Thrombocytopenia

During routine monitoring in the 12 week controlled phase, 1% of patients in the Aktempa-IV group and 3% in the placebo group had a decrease in platelet count to no more than 100,000 per mm³.

In the open label extension over an average duration of 73 weeks of treatment, decreased platelet count occurred in 4% of patients in the Aktempa-IV group, with no associated bleeding.

Elevated Liver Enzymes

During routine laboratory monitoring in the 12 week controlled phase, elevation in ALT or AST at or above 3x ULN occurred in 5% and 3% of patients, respectively in the Aktempa-IV group and in 0% of placebo patients.

In the open label extension over an average duration of 73 weeks of treatment, the elevation in ALT or AST at or above 3x ULN occurred in 13% and 5% of Aktempa-IV treated patients, respectively.

Lipids

During routine laboratory monitoring in the 12 week controlled phase, elevation in total cholesterol greater than 1.5x ULN - 2x ULN occurred in 1.5% of the Aktempa-IV group and in 0% of placebo patients. Elevation in LDL greater than 1.5x ULN - 2x ULN occurred in 1.9% of patients in the Aktempa-IV group and 0% of the placebo group.

In the open label extension study over an average duration of 73 weeks of treatment, the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled study data.

In a retrospective analysis of pooled outcome data from multiple clinical trials 45 patients were treated with tocilizumab 8 mg/kg (12 mg/kg for patients less than 30 kg) with or without additional high-dose corticosteroids for severe or life-threatening CAR T-cell-induced CRS. A median of 1 dose of tocilizumab (range, 1-4 doses) was administered. No adverse reactions related to tocilizumab were reported.

The following adverse reactions have been identified during post-approval use of Aktempa. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Fatal anaphylaxis
• Stevens-Johnson Syndrome
• Pancreatitis

Summary of the safety profile

The safety profile comes from 4510 patients exposed to Aktempa in clinical trials; the majority of these patients were participating in RA studies (n=4009), while the remaining experience comes from GCA (n=149), pJIA (n=240) and sJIA (n=112) studies. The safety profile of Aktempa across these indications remains similar and undifferentiated.

The most commonly reported Adverse Drug Reactions (ADRs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.

The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity reactions.

Tabulated summary of adverse reactions

The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using 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) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1. Summary of ADRs occurring in patients treated with Aktempa.

* Includes elevations collected as part of routine laboratory monitoring (see text below)

RA

Intravenous use

The safety of Aktempa 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 Aktempa 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 8 mg/kg monotherapy.

The all exposure population includes all patients who received at least one dose of Aktempa 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.

Description of selected adverse reactions

Infections

In the 6-month controlled studies the rate of all infections reported with Aktempa 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with Aktempa was 108 events per 100 patient years exposure.

In 6-month controlled clinical studies, the rate of serious infections with Aktempa 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the Aktempa group and 1.5 events per 100 patient 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.

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 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on Aktempa were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae 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 plus DMARD group and 5.1% of patients in the placebo plus 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 anaphylactic reactions (occurring in a total of 6/3778patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with Aktempa and requiring treatment discontinuation were reported in a total of 13 out of 3778 patients (0.3%) treated with Aktempa during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab. Fatal anaphylaxis has been reported after marketing authorisation during treatment with intravenous Aktempa.

Immunogenicity

A total of 2,876 patients have been tested for anti-Aktempa antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-Aktempa antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1%) developed neutralising antibodies.

Haematological abnormalities:

Neutrophils

In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ L occurred in 3.4% of patients on Aktempa 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 x 109/ L did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/ L were reported in 0.3% patients receiving Aktempa 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.

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.

Platelets

In the 6-month controlled trials decreases in platelet counts below 100 x 103/ μL occurred in 1.7% of patients on Aktempa 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.

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.

Very rare reports of pancytopenia have occurred in the post marketing setting.

Hepatic transaminase elevations

During the 6-month controlled trials transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on Aktempa 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg Aktempa plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.

The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of Aktempa monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. These elevations were not associated with clinically relevant increase in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg Aktempa + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN.

During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.

Lipid parameters

During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving Aktempa in clinical trials experienced sustained elevations in total cholesterol > 6.2 mmol/ L, with 15% experiencing a sustained increase in LDL to > 4.1 mmol/ L. Elevations in lipid parameters 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 trials.

Malignancies

The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.

Skin Reactions

Very rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.

Subcutaneous use

RA

The safety of subcutaneous Aktempa in RA includes a double-blind, controlled, multicenter study, SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of Aktempa 162 mg administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received background non-biologic DMARD(s). The safety and immunogenicity observed for Aktempa administered subcutaneous was consistent with the known safety profile of intravenous Aktempa and no new or unexpected adverse drug reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.

Injection site reactions

During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo ( intravenous group) weekly injections, respectively. These injection site reactions (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 Aktempa 162mg weekly were tested for anti-Aktempa antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-Aktempa antibodies; of these, all developed neutralizing anti-Aktempa antibodies. One patient was tested positive for IgE isotype (0.2%).

In SC-II, a total of 434 patients treated with tocilizumab 162mg every other week were tested for anti-Aktempa antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive antiAktempa antibodies; of these, six (1.4%) developed neutralizing anti-Aktempa antibodies. Four patients were tested positive for IgE isotype (0.9%).

No correlation of antibody development to clinical response or adverse events was observed.

Haematological abnormalities:

Neutrophils

During routine laboratory monitoring in the tocilizumab 6 month controlled clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on the subcutaneous weekly dose.

There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.

Platelets

During routine laboratory monitoring in the tocilizumab 6 month clinical trial SC-I, none of the patients on the SC weekly dose had a decrease in platelet count to ≤50 × 103 / μL.

Hepatic transaminase elevations

During routine laboratory monitoring in the tocilizumab 6-month controlled clinical trial SC-I, elevation in ALT or AST >3 x ULN occurred in 6.5% and 1.4% of patients, respectively on the subcutaneous weekly dose.

Lipid parameters

During routine laboratory monitoring in the Aktempa 6 month controlled clinical trial SC-I, 19% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/L (240 mg/dl), with 9% experiencing a sustained increase in LDL to > 4.1 mmol/L(160 mg/dL) on the subcutaneous weekly dose.

Subcutaneous use

GCA

The safety of subcutaneous Aktempa has been studied in one Phase III study (WA28119) with 251 GCA patients. The total patient years duration in the Aktempa all exposure population was 138.5 patient years during the 12 month double blind, placebo controlled phase of the study. The overall safety profile observed in the Aktempa treatment groups was consistent with the known safety profile of Aktempa (see Table 1).

Infections

The rate of infection/serious infection events was balanced between the Aktempa weekly group (200.2/9.7 events per 100 patient years) vs. placebo plus 26 weeks prednisone taper (156.0/4.2 events per 100 patient years) and placebo plus 52 weeks taper (210.2/12.5 events per 100 patient years) groups.

Injection site reactions

In the Aktempa subcutaneous weekly group, a total of 6% (6/100) patients reported an adverse reaction occurring at the site of a subcutaneous injection. No injection site reaction was reported as a serious adverse event or required treatment discontinuation.

Immunogenicity

In the Aktempa subcutaneous weekly group, one patient (1.1%, 1/95) developed positive neutralizing anti-Aktempa antibodies, though not of the IgE isotype. This patient did not develop a hypersensitivity reaction or injection site reaction.

Haematological abnormalities:

Neutrophils

During routine laboratory monitoring in the Aktempa 12 month controlled clinical trial, a decrease in neutrophil count below 1 × 109/L occurred in 4% of patients in the Aktempa subcutaneous weekly group. This was not observed in either of the placebo plus prednisone taper groups.

Platelets

During routine laboratory monitoring in the Aktempa 12 month controlled clinical trial, one patient (1%, 1/100) in the Aktempa subcutaneous weekly group had a single transient occurence of decrease in platelet count to <100 × 103 / μL without associated bleeding events. A decrease in platelet count below 100 × 103 / μL was not observed in either of the placebo plus prednisone taper groups.

Hepatic transaminase elevations

During routine laboratory monitoring in the Aktempa 12 month controlled clinical trial, elevation in ALT >3 x ULN occurred in 3% of patients in the Aktempa subcutaneous weekly group compared to 2% in the placebo plus 52 week prednisone taper group and none in the placebo plus 26 week prednisone taper group. An elevation in AST > 3 ULN occurred in 1% of patients in the Aktempa subcutaneous weekly group, compared to no patients in either of the placebo plus prednisone taper groups.

Lipid parameters

During routine laboratory monitoring in the Aktempa 12 month controlled clinical trial, 34% of patients 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 Aktempa subcutaneous weekly group.

Subcutaneous Aktempa

pJIA

The safety profile of subcutaneous Aktempa was also evaluated in 52 paediatric patients with pJIA. The total patient exposure to Aktempa in the pJIA all exposure population was 184.4 patient years for IV and 50.4 patient years for SC tocilizumab. In general, the safety profile observed in patients with pJIA was consistent with the known safety profile of Aktempa with the exception of ISRs (see Table 1). A higher frequency of pJIA patients experienced ISRs following SC Aktempa injections compared to adult RA.

Infections

In the SC Aktempa study, the rate of infection in pJIA patients treated with SC Aktempa was comparable with pJIA patients treated with IV Aktempa.

Injection Site Reactions

A total of 28.8% (15/52) pJIA patients experienced ISRs to Aktempa SC. These ISRs occurred in a 44% of patients >30 kg compared to 14.8% of patients below 30 kg. The most common ISRs were injection site erythema, swelling, hematoma, pain and pruritis. All ISRs reported were non-serious Grade 1 events, and none of the ISRs required patient withdrawal from treatment or dose interruption.

Immunogenicity

In the SC Study 5.8% [3/52] developed positive neutralizing anti-tocilizumab antibodies without developing a serious or clinically significant hypersensitivity reaction. Of these 3 patients, 1 subsequently withdrew from the study. No correlation between antibody development and clinical response or adverse events was observed

Laboratory Abnormalities

During routine laboratory monitoring in the Aktempa all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 15.4% of patients treated with SC Aktempa. An elevation in ALT or AST >3 x ULN occurred in 9.6% and 3.8% patients treated with Aktempa SC, respectively. No patients treated with SC Aktempa experienced a decrease in platelet count to ≤50 × 103 / μL.

Lipid parameters

In the SC Study, 14.3% and 12.8% of patients experienced a post-baseline elevation of their LDL-cholesterol value to > 130 mg/dL and total cholesterol value to > 200 mg/dL at any time during study treatment, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.

Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to have intrinsic carcinogenic potential.

Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and progression under Aktempa treatment. Additionally, proliferative lesions were not observed in a 6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.

Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment. Effects on endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey toxicity study and reproductive performance was not affected in IL-6 deficient mice. Aktempa administered to cynomolgus monkeys during early gestation, was observed to have no direct or indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in abortion/embryonal-foetal death was observed with high systemic exposure (> 100 x human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 does not seem to be a critical cytokine for foetal growth or the immunological control of the maternal/foetal interface, a relation of this finding to Aktempa cannot be excluded.

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 Aktempa in the cynomolgus monkey does not suggest a difference between intravenous and subcutaneous routes of administration.

Therapeutic indications

Aktempa® (tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).

Aktempa® (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult patients.

Aktempa® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.

Aktempa® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

Aktempa® (tocilizumab) is indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome in adults and pediatric patients 2 years of age and older.

Aktempa, in combination with methotrexate (MTX), is indicated for

- the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX.

- the treatment of moderate to severe active 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.

In these patients, Aktempa can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Aktempa 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.

Aktempa in combination with methotrexate (MTX) is indicated for the treatment of juvenile idiopathic polyarthritis (pJIA; 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.

Aktempa can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.

Aktempa is indicated for the treatment of Giant Cell Arteritis (GCA) in adult patients.

Pharmacotherapeutic group

Pharmacodynamic properties

In clinical studies in RA patients with the 4 mg per kg and 8 mg per kg IV doses or the 162 mg weekly and every other weekly SC doses of Aktempa, decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with doses, however the greatest improvements were observed with 8 mg per kg Aktempa. Pharmacodynamic changes were also observed to occur after Aktempa administration in GCA, PJIA, and SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered Aktempa in doses from 2 to 28 mg per kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to the nadir 3 to 5 days following Aktempa administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis and GCA patients demonstrated a similar pattern of absolute neutrophil counts following Aktempa administration.

Pharmacotherapeutic group: Immunosuppressants, Interleukin inhibitors; ATC code: L04AC07.

Mechanism of action

Aktempa binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.

Pharmacodynamic effects

In clinical studies with Aktempa , rapid decreases in CRP, erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) were observed. Consistent with the effect on acute phase reactants, treatment with Aktempa was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through Aktempa decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In Aktempa -treated patients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintained while on treatment.

In GCA clinical study WA28119, similar rapid decreases in CRP and ESR were observed along with slight increases in mean corpuscular haemoglobin concentration. In healthy subjects administered Aktempa in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner.

Patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts following Aktempa administration.

RA

Intravenous use

Clinical efficacy

The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in five randomised, double-blind, multi-centre studies. Studies I-V enrolled patients > 18 years of age with active RA diagnosed according to the American College of Rheumatology (ACR) criteria and who had at least eight tender and six swollen joints at baseline.

In Study I, Aktempa was administered intravenously every four weeks as monotherapy. In Studies II, III and V, Aktempa was administered intravenously every four weeks in combination with MTX vs. placebo and MTX. In Study IV, Aktempa was administered intravenously every 4 weeks in combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of the five studies was the proportion of patients who achieved an ACR 20 response at week 24.

Study I evaluated 673 patients who had not been treated with MTX within six months prior to randomisation 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 Aktempa were given every four weeks as monotherapy. The comparator group was weekly MTX (dose titrated from 7.5 mg to a maximum of 20 mg weekly over an eight week period).

Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of Aktempa or placebo were given every four weeks as blinded therapy for 52 weeks in combination with stable MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label treatment with Aktempa 8 mg/kg. Of the patients who completed the study who were originally randomised to placebo + MTX, 86% received open-label Aktempa 8 mg/kg in year 2. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104 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 Aktempa or placebo were given every four weeks, in combination with stable MTX (10 mg to 25 mg weekly).

Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg Aktempa or placebo were given every four weeks in combination with stable DMARDs.

Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomisation. Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks in combination with stable MTX (10 mg to 25 mg weekly).

Clinical response

In all studies, patients treated with Aktempa 8 mg/kg had statistically significant higher ACR 20, 50, 70 response rates at 6 months compared to control (Table 2). In study I, superiority of Aktempa 8 mg/kg was demonstrated against the active comparator MTX.

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 I-V.

In patients treated with Aktempa 8 mg/kg, significant improvements were noted on all individual components of the ACR response including: tender and swollen joint counts; patients and physician global assessment; disability index scores; pain assessment and CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.

Patients in studies I - V had a mean Disease Activity Score (DAS28) of 6.5-6.8 at baseline. Significant reduction in DAS28 from baseline (mean improvement) of 3.1-3.4 were observed in tocilizumab-treated patients compared to control patients (1.3-2.1). The proportion of patients achieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receiving tocilizumab (28-34%) compared to 1-12% of control patients at 24 weeks. In study II, 65% of patients achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients at week 24.

In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the tocilizumab 8 mg/kg plus DMARD vs. the tocilizumab 4 mg/kg plus DMARD group (p< 0.03). Similarly the proportion of patients achieving a DAS 28 remission (DAS28 < 2.6) was significantly higher (31% vs. 16% respectively) in patients receiving Aktempa 8 mg/kg plus DMARD than in patients receiving Aktempa 4 mg/kg plus DMARD (p< 0.0001).

Table 2. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients)

TCZ - Tocilizumab

MTX - Methotrexate

PBO - Placebo

DMARD - Disease modifying anti-rheumatic drug

** - p< 0.01, TCZ vs. PBO + MTX/DMARD

*** - p< 0.0001, TCZ vs. PBO + MTX/DMARD

Major clinical response

After 2 years of treatment with tocilizumab plus 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 Aktempa compared to control (Table 3).

In the open-label extension of Study II the inhibition of progression of structural joint damage in tocilizumab plus MTX-treated patients was maintained in the second year of treatment. The mean change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients randomised to Aktempa 8 mg/kg plus MTX (p<0.0001) compared with patients who were randomised to placebo plus MTX.

Table 3. Radiographic mean changes over 52 weeks in Study II

PBO - Placebo

MTX - Methotrexate

TCZ - Tocilizumab

JSN - Joint space narrowing

* - p≤ 0.0001, TCZ vs. PBO + MTX

** - p< 0.005, TCZ vs. PBO + MTX

Following 1 year of treatment with tocilizumab plus MTX, 85% of patients(n=348) had no progression of structural joint damage, as defined by a change in the Total Sharp Score of zero or less, compared with 67% of placebo plus MTX-treated patients(n=290) (p ≤ 0.001). This remained consistent following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patients had no progression between week 52 and week 104.

Health-related and quality of life outcomes

Aktempa -treated patients reported an improvement in all patient-reported outcomes (Health Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were observed in patients treated with Aktempa compared with patients treated with DMARDs. During the open-label period of Study II, the improvement in physical function has been maintained for up to 2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the Aktempa 8 mg/kg plus MTX group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was maintained at Week 104 in the Aktempa 8 mg/kg plus MTX group (-0.61).

Haemoglobin levels

Statistically significant improvements in haemoglobin levels were observed with Aktempa compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2 and remained within normal range through to week 24.

Tocilizumab versus adalimumab in monotherapy

Study VI (WA19924), a 24 week double-blinded study that compared Aktempa monotherapy with adalimumab monotherapy, 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 Aktempa arm received an intravenous (IV) infusion of Aktempa (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 Aktempa 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 4).

Table 4: Efficacy Results for Study VI (WA19924)

ap value is adjusted for region and duration of RA for all endpoints and additionally baseline value for all continuous endpoints.

b Non-responder Imputation used for missing data. Multiplicity controlled using Bonferroni-Holm Procedure

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 (Aktempa 11.7% vs. adalimumab 9.9%). The types of adverse drug reactions in the tocilizumab arm were consistent with the known safety profile of Aktempa and adverse drug reactions were reported at a similar frequency compared with Table 1. A higher incidence of infections and infestations was reported in the Aktempa arm (48% vs. 42%), with no difference in the incidence of serious infections (3.1%). 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 Aktempa compared with adalimumab. Four (2.5%) patients in the Aktempa 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 Aktempa 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 Aktempa 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 Aktempa and no new or unexpected adverse drug reactions were observed (see Table 1).

Subcutaneous use

Clinical efficacy

The efficacy of subcutaneous administered Aktempa in alleviating the signs and symptoms of RA and radiographic response, was assessed in two randomised, double-blind, controlled, multi-center studies. For study I (SC-I), patients were required to be >18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline. All patients received background non-biologic DMARD(s). For study II (SC-II), patients were required to be > 18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline.

Switching from 8 mg/kg intravenous once every 4 weeks to 162 mg subcutaneous once every week, will alter exposure in the patient. The extent varies with the patient's body weight (increased in light body weight patients and decreased in heavy body weight patients) but clinical outcome is consistent with that observed in intravenous treated patients.

Clinical response

Study SC-I evaluated patients with moderate to severe active RA 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. In SC-I, 1262 patients were randomized 1:1 to receive Aktempa subcutaneous 162 mg every week or Aktempa intravenous 8 mg/kg every four weeks in combination with non-biologic 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 5.

Table 5. ACR responses in study SC-I (% patients) at Week 24

TCZ = tocilizumab

a = Per Protocol Population

Patients in study SC-I had a mean Disease Activity Score (DAS28) at baseline of 6.6 and 6.7 on the subcutaneous and intravenous arms, respectively. At week 24, a significant reduction in DAS28 from baseline (mean improvement) of 3.5 was observed on both treatment arms, and a comparable proportion of patients had achieved DAS28 clinical remission (DAS28 < 2.6) on the subcutaneous (38.4%) and IV (36.9%) arms.

Radiographic response

The radiographic response of subcutaneous administered Aktempa was assessed in a double-blind, controlled, multicenter study in patients with active RA (SC-II). Study SC-II evaluated patients with moderate to severe active RA 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 >18 years of age with active RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-II, 656 patients were randomized 2:1 to Aktempa subcutaneous 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 Aktempa subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van Elteren). These results are consistent with those observed in patients treated with intravenous tocilizumab.

In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% for patients treated with Aktempa subcutaneous every other week versus placebo ACR20 of 31.5%, ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneous and 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 was observed on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed on subcutaneous and 4.0% on placebo arm.

Health-related and quality of life outcomes

In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 on both the subcutaneous and intravenous arms. The proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of > 0.3 units) was also comparable on the subcutaneous (65.2%) versus intravenous (67.4%) arms, with a weighted difference in proportions of - 2.3% (95% CI - 8.1, 3.4). For SF-36, the mean change from baseline at week 24 in the mental component score was 6.22 for the subcutaneous arm and 6.54 for the intravenous arm, and for the physical component score was also similar with 9.49 for the subcutaneous arm and 9.65 for the intravenous arm.

In study SC-II, mean decrease in HAQ-DI from baseline to week 24 was significantly greater for patients treated with tocilizumab subcutaneous every other week (0.4) versus placebo (0.3). Proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of > 0.3 units) was higher for tocilizumab subcutaneous every other week (58%) versus placebo (46.8%). SF-36 (mean change in mental and physical component scores) was significantly greater with tocilizumab subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9).

GCA

Subcutaneous Use

Clinical efficacy

Study WA28119 was a randomized, multi-center, double-blind placebo-controlled Phase III superiority study conducted to assess the efficacy and safety of Aktempa in patients with GCA.

Two hundred and fifty one (251) patients with new-onset or relapsing GCA were enrolled and assigned to one of four treatment arms. The study consisted of a 52-week blinded period (Part 1), followed by a 104-week open-label extension (Part 2). The purpose of Part 2 was to describe the long-term safety and maintenance of efficacy after 52 weeks of Aktempa therapy, to explore the rate of relapse and the requirement for Aktempa therapy beyond 52 weeks, and to gain insight into the potential long-term steroid-sparing effect of Aktempa.

Two subcutaneous doses of Aktempa (162 mg every week and 162 mg every other week) were compared to two different placebo control groups randomised 2:1:1:1.

All patients received background glucocorticoid (prednisone) therapy. Each of the Aktempa-treated groups and one of the placebo-treated groups followed a pre-specified prednisone-taper regimen over 26 weeks, while the second placebo-treated group followed a pre-specified prednisone-taper regimen over 52 weeks, designed to be more in keeping with standard practice.

The duration of glucocorticoid therapy during screening and before Aktempa (or placebo) was initiated, was similar in all 4 treatment groups (see Table 6).

Table 6. Duration of Corticosteroid Therapy During Screening in Study WA28119

The primary efficacy endpoint assessed by the proportion of patients achieving steroid free sustained remission at week 52 on Aktempa plus 26 weeks prednisone taper compared with placebo plus 26 weeks prednisone taper, was met (Table 7).

The key secondary efficacy endpoint also based on the proportion of patients achieving sustained remission at week 52, comparing tocilizumab plus 26 weeks prednisone taper with placebo plus 52 weeks prednisone taper, was also met (Table 7).

A statistically significant superior treatment effect was seen in favour of Aktempa over placebo in achieving steroid-free sustained remission at week 52 on Aktempa plus 26 weeks prednisone taper compared with placebo plus 26 weeks prednisone taper and with placebo plus 52 weeks prednisone taper.

The percentage of patients achieving sustained remission at week 52, are shown in the Table 7.

Secondary Endpoints

The assessment of the

Pharmacokinetic properties

The pharmacokinetics characterized in healthy subjects and RA patients suggested that PK is similar between the two populations. The clearance (CL) of tocilizumab decreased with increased doses. At the 10 mg per kg single dose in RA patients, mean CL was 0.29 ± 0.10 mL per hr per kg and mean apparent terminal t½ was 151 ± 59 hours (6.3 days).

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis of 1793 rheumatoid arthritis patients treated with Aktempa 4 and 8 mg per 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 per kg every 4 weeks. Maximum concentration (Cmax) increased dose-proportionally. At steady-state, estimated AUC and Cmin were 2.7 and 6.5-fold higher at 8 mg per kg as compared to 4 mg per kg, respectively. In a longterm study with dosing for 104 weeks, observed Cmin was sustained over time.

For doses of Aktempa 4 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 13000 ± 5800 mcg•h per mL, 1.49 ± 2.13 mcg per mL, and 88.3 ± 41.4 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 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 Cmin. For doses of Aktempa 8 mg per kg given every 4 weeks, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 35000 ± 15500 mcg•h per mL, 9.74 ± 10.5 mcg per mL, and 183 ± 85.6 mcg per mL, respectively. The accumulation ratios for AUC and Cmax were 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35). 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 at or above 100 kg, the estimated mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 mcg•h per mL, 19.0 ± 12.0 mcg per mL, and 269 ± 57 mcg per mL, respectively, which are higher than mean exposure values for the patient population. Therefore, Aktempa doses exceeding 800 mg per infusion are not recommended.

The pharmacokinetics of tocilizumab was characterized using a population pharmacokinetic analysis using a database composed of 1759 rheumatoid arthritis patients treated with 162 mg SC every week, 162 mg SC every other week, and 8 mg/kg every 4 weeks for 24 weeks.

The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the estimated mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.

For the 162 mg every other week dose, the estimated mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.

The pharmacokinetics of tocilizumab in GCA patients was determined using a population pharmacokinetic analysis on a dataset composed of 149 GCA patients treated with 162 mg SC every week or with 162 mg SC every other week.

For the 162 mg every week dose, the estimated mean (±SD) steady-state Cavg, Cmin and Cmax of tocilizumab were 71.3 ± 30.1 mcg/mL, 68.1± 29.5 mcg/mL, and 73 ± 30.4 mcg/mL, respectively. The accumulation ratios for Cavg or AUCtau, Cmin, and Cmax were 10.9, 9.6, and 8.9, respectively. Steady state was reached after 17 weeks.

For the 162 mg every other week dose, the estimated mean (±SD) steady-state Cavg, Cmin, and Cmax of tocilizumab were 16.2 ± 11.8 mcg/mL, 11.1 ± 10.3 mcg/mL, and 19.3 ± 12.8 mcg/mL, respectively. The accumulation ratios for Cavg or AUCtau, Cmin, and Cmax were 2.8, 5.6, and 2.3 respectively. Steady-state was reached after 14 weeks.

The pharmacokinetics of tocilizumab was determined using a population pharmacokinetic analysis on a database composed of 188 patients with polyarticular juvenile idiopathic arthritis.

For doses of 8 mg/kg tocilizumab (patients with a body weight at or above 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 29500 ± 8660 mcg•hr/mL, 182 ± 37 mcg/mL and 7.49 ± 8.2 mcg/mL, respectively.

For doses of 10 mg/kg tocilizumab (patients with a body weight less than 30 kg) given every 4 weeks, the estimated mean (± SD) AUC4weeks, Cmax and Cmin of tocilizumab were 23200 ± 6100 mcg•hr/mL, 175 ± 32 mcg/mL and 2.35 ± 3.59 mcg/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 less than 30 kg) and 8 mg/kg (BW at or above 30 kg) doses, respectively. No accumulation for Cmax was observed.

The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 75 patients with SJIA treated with 8 mg per kg (patients with a body weight at or above 30 kg) or 12 mg per kg (patients with a body weight less than 30 kg), given every 2 weeks. The estimated mean (± SD) AUC2weeks, Cmax and Cmin of tocilizumab were 32200 ± 9960 mcg•hr per mL, 245 ± 57.2 mcg per mL and 57.5 ± 23.3 mcg per mL, respectively. The accumulation ratio for Cmin (week 12 over week 2) was 3.2 ± 1.3. Steady state was reached on or after week 12. Mean estimated tocilizumab exposure parameters were similar between the two dose groups defined by body weight.

Absorption

Following SC dosing in RA and GCA patients, the absorption half-life was around 4 days. The bioavailability for the SC formulation was 0.8.

In RA patients the median values of Tmax were 2.8 days after the tocilizumab every week dose and 4.7 days after the tocilizumab every other week dose.

In GCA patients, the median values of Tmax were 3 days after the tocilizumab every week dose and 4.5 days after the tocilizumab every other week dose.

Distribution

Following intravenous dosing, tocilizumab undergoes biphasic elimination from the circulation. In rheumatoid arthritis patients the central volume of distribution was 3.5 L and the peripheral volume of distribution was 2.9 L, resulting in a volume of distribution at steady state of 6.4 L.

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L resulting in a volume of distribution at steady state of 7.46 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

Aktempa is eliminated by a combination of linear clearance and nonlinear elimination. The concentration-dependent nonlinear elimination plays a major role at low tocilizumab concentrations. Once the nonlinear pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. The saturation of the nonlinear elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of Aktempa do not change with time.

Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

The linear clearance in the population pharmacokinetic analysis was estimated to be 12.5 mL per h in RA patients, 6.7 mL per h in GCA patients, 5.8 mL per h in pediatric patients with PJIA, and 7.1 mL per h in pediatric patients with SJIA.

Due to the dependence of total clearance on Aktempa serum concentrations, the half-life of Aktempa is also concentration-dependent and varies depending on the serum concentration level.

For IV administration in RA patients, the concentration-dependent apparent t½ is up to 11 days for 4 mg per kg and up to 13 days for 8 mg per kg every 4 weeks in patients with RA at steady-state. For SC administration in RA patients, the concentration-dependent apparent t½ 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.

In GCA patients at steady state, the effective t½ of tocilizumab varied between 18.3 and 18.9 days for 162 mg SC every week dosing regimen and between 4.2 and 7.9 days for 162 mg SC every other week dosing regimen.

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 at or above 30 kg or 10 mg/kg for body weight below 30 kg) during a dosing interval at steady state.

The t½ of tocilizumab in pediatric patients with SJIA is up to 23 days for the two body weight categories at week 12.

The pharmacokinetics of Aktempa is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of Aktempa elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of Aktempa do not change with time. Due to the dependence of total clearance on Aktempa serum concentrations, the half-life of Aktempa 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.

RA

Intravenous use

The pharmacokinetics of Aktempa were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with a one-hour infusion of 4 or 8 mg/kg Aktempa every 4 weeks for 24 weeks or with 162 mg tocilizumab given subcutaneously either once a week or every other week for 24 weeks.

The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg Aktempa given every 4 weeks: steady-state area under curve (AUC) = 38000 ± 13000 h-µg/mL, trough concentration (Cmin) = 15.9 ± 13.1 μg/mL and maximum concentration (Cmax) = 182 ± 50.4 µg/mL, and. the accumulation ratios for AUC and Cmax were small, 1.32 and 1.09, respectively. The accumulation ratio was higher for Cmin (2.49), which was expected based on the non-linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for Cmax and after 8 and 20 weeks for AUC and Cmin, respectively. Aktempa 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 Aktempa were 50000 ± 16800 μg-h/mL, 24.4 ± 17.5 μg/mL, and 226 ± 50.3 μg/mL, respectively, which are higher than mean exposure values for the patient population (i.e. all body weights) reported above. The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in Aktempa concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 800 mg of Aktempa. Therefore, Aktempa doses exceeding 800 mg per infusion are not recommended.

The pharmacokinetics of Aktempa in pJIA patients was characterized by a population pharmacokinetic analysis which included 237 patients who were treated with 8 mg/kg IV every 4 weeks (patients weighing > 30 kg), 10 mg/kg IV every 4 weeks (patients weighing below 30 kg), 162 mg SC every 2 weeks (patients weighing > 30 kg), or 162 mg SC every 3 weeks (patients weighing below 30 kg).

Table 8. Predicted mean ± SD PK parameters at steady-state after IV or SC dosing in pJIA

* = 4 weeks for IV regimens, 2 week or 3 week for the two SC regimens, respectively

After IV dosing, approximately 90% of the steady-state was reached by Week 12 for the 10 mg/kg (BW < 30 kg), and by Week 16 for the 8 mg/kg (BW > 30 kg) dose. After SC dosing, approximately 90% of the steady-state was reached by Week 12 for both the 162 mg SC Q2W and Q3W regimens.

Distribution

In RA patients the central volume of distribution was 3.72 L, the peripheral volume of distribution was 3.35 L resulting in a volume of distribution at steady state of 7.07 L.

Elimination

Following intravenous administration, Aktempa undergoes biphasic elimination from the circulation. The total clearance of Aktempa was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 9.5 ml/h. The concentration-dependent non-linear clearance plays a major role at low Aktempa concentrations. Once the non-linear clearance pathway is saturated, at higher Aktempa concentrations, clearance is mainly determined by the linear clearance.

The t1/2 of Aktempa was concentration-dependent. At steady-state following a dose of 8 mg/kg every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval from 18 days to 6 days.

Linearity

Pharmacokinetic parameters of Aktempa did not change with time. A more than dose-proportional increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased dose-proportionally. At steady-state, predicted AUC and Cmin were 3.2 and 30 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.

Subcutaneous use

The pharmacokinetics of Aktempa were determined using a population pharmacokinetic analysis on a database composed of 3552 RA patients treated with 162 mg subcutaneous every week, 162 mg subcutaneous every other week, and or 4 or 8 mg/kg intravenous every 4 weeks for 24 weeks.

The pharmacokinetic parameters of Aktempa did not change with time. For the 162 mg every week dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of Aktempa were 7970 ± 3432 µg-h/mL, 43.0 ± 19.8 µg/mL, and 49.8 ± 21.0 µg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.32, 6.30, and 5.27, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.

For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmax of Aktempa were 3430 ± 2660 µg-h/mL, 5.7 ± 6.8 µg/mL, and 13.2 ± 8.8 µg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 6.02, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.

Absorption

Following subcutaneous dosing in RA patients, the time to peak serum Aktempa concentrations tmax was 2.8 days. The bioavailability for the subcutaneous formulation was 79%.

Following SC dosing in pJIA patients, the absorption half-life was around 2 days, and the bioavailability for the SC formulation in pJIA patients was 96%.

Distribution

In paediatric patients with pJIA, the central volume of distribution was 1.97 L, the peripheral volume of distribution was 2.03 L, resulting in a volume of distribution at steady state of 4.0 L.

Elimination

For subcutaneous administration, the effective 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. Population pharmacokinetic analysis for pJIA patients showed body size related impact on linear clearance so that body-weight based dosing should be taken into consideration (see Table 8).

After subcutaneous administration, the effective t1/2 of Aktempa in pJIA patients is up to 10 days for patients < 30 kg (162 mg SC Q3W) and up to 7 days for patients >= 30 kg (162 mg SC Q2W) during a dosing interval at steady state. Following intravenous administration, tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 6.25 ml/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.

GCA

Subcutaneous use

The PK of Aktempa in GCA patients were determined using a population PK model from an analysis dataset composed of 149 GCA patients treated with 162 mg subcutaneous every week or 162 mg subcutaneous every other week. The developed model had the same structure as the population PK model developed earlier based on data from RA patients (see Table 9).

Table 9. Predicted mean ± SD PK parameters at steady-state after subcutaneous dosing in GCA

The steady-state profile following the Aktempa weekly dose was almost flat, with very little fluctuations between trough and peak values, while there were substantial fluctuations for the Aktempa every other weekly dose. Approximately 90% of the steady-state (AUC) was reached by week 14 in the every other weekly and week 17 in the weekly dose groups.

Based on the current characterization of PK, Aktempa trough concentration at steady state are 50% higher in this population relative to average concentrations in a large dataset from the RA population. These differences occur due to unknown reasons. PK differences are not accompanied by marked differences in PD parameters and so the clinical relevance is unknown.

In GCA patients, higher exposure was observed in patients with lower body weight. For the 162 mg every week dosing regimen, the steady-state Cavg was 51% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. For the 162 mg every other week regimen, the steady-state Cavg was 129% higher in patients with body weight less than 60 kg compared to patients weighing between 60 to 100 kg. There is limited data for patients above 100 kg (n=7).

Absorption

Following subcutaneous dosing in GCA patients, the absorption t½ was around 4 days. The bioavailability for the SC formulation was 0.8. The median values of Tmax were 3 days after the Aktempa weekly dose and 4.5 days after the tocilizumab every other week dose.

Distribution

In GCA patients, the central volume of distribution was 4.09 L, the peripheral volume of distribution was 3.37 L, resulting in a volume of distribution at steady state of 7.46 L.

Elimination

The total clearance of Aktempa 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 6.7 mL/h in GCA patients,

In GCA patients, at steady state, the effective t ½ of Aktempa varied between 18.3 and 18.9 days for 162 mg weekly regimen, and between 4.2 and 7.9 days for 162 mg every other weekly regimen. At high serum concentrations, when total clearance of Aktempa is dominated by linear clearance, an effective t ½ of approximately 32 days was derived from the population parameter estimates.

Special populations

Renal impairment: No formal study of the effect of renal impairment on the pharmacokinetics of Aktempa has been conducted. Most of the patients in the RA and GCA studies population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance based on Cockcroft-Gault formula ) did not impact the pharmacokinetics of Aktempa.

Approximately one-third of the patients in the GCA study had moderate renal impairment at baseline (estimated creatinine clearance of 30-59 mL/min). No impact on Aktempa exposure was noted in these patients.

No dose adjustment is required in patients with mild or moderate renal impairment.

Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of Aktempa has been conducted.

Age, gender and ethnicity: Population pharmacokinetic analyses in RA and GCA patients, showed that age, gender and ethnic origin did not affect the pharmacokinetics of Aktempa.

Results of the population PK analysis for pJIA patients confirmed that body size is the only covariate which has an appreciable impact on the pharmacokinetics of Aktempa including elimination and absorption so that body-weight based dosing should be taken into consideration (see Table 8).

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Included as part of the PRECAUTIONS section.

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Aktempa. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with Aktempa. Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.

Do not administer Aktempa in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Aktempa in patients:

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of serious or an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with Aktempa, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants.

Hold Aktempa if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Aktempa should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

Evaluate patients for tuberculosis risk factors and test for latent infection prior to initiating Aktempa.

Consider anti-tuberculosis therapy prior to initiation of Aktempa in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Closely monitor patients for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

It is recommended that patients be screened for latent tuberculosis infection prior to starting Aktempa. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating Aktempa.

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with Aktempa. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in patients treated with Aktempa. Use Aktempa with caution in patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients presenting with new onset abdominal symptoms for early identification of gastrointestinal perforation.

Rheumatoid Arthritis and Giant Cell Arteritis

Treatment with Aktempa was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.

• It is not recommended to initiate Aktempa treatment in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm³. In patients who develop an absolute neutrophil count less than 500 per mm³ treatment is not recommended.
• Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on ANC results see DOSAGE AND ADMINISTRATION).

Treatment with Aktempa was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials.

• It is not recommended to initiate Aktempa treatment in patients with a platelet count below 100,000 per mm³. In patients who develop a platelet count less than 50,000 per mm³ treatment is not recommended.
• Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. For recommended modifications based on platelet counts see DOSAGE AND ADMINISTRATION.

Treatment with Aktempa was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with Aktempa.

In one case, a patient who had received Aktempa 8 mg per kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with Aktempa. Transaminases normalized when both treatments were held, but elevations recurred when MTX and Aktempa were restarted at lower doses. Elevations resolved when MTX and Aktempa were discontinued.

• It is not recommended to initiate Aktempa treatment in patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN treatment is not recommended.
• Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases.

Treatment with Aktempa was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.

• Assess lipid parameters approximately 4 to 8 weeks following initiation of Aktempa therapy, then at approximately 24 week intervals.
• Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with Aktempa treatment in the PJIA and SJIA populations. Monitor neutrophils, platelets, ALT and AST at the time of the second infusion and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Monitor lipids as above for approved adult indications.

The impact of treatment with Aktempa on the development of malignancies is not known but malignancies were observed in clinical studies. Aktempa is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity reactions, including anaphylaxis, have been reported in association with Aktempa and anaphylactic events with a fatal outcome have been reported with intravenous infusion of Aktempa. Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials of intravenous Aktempa, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous Aktempa, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. In the PJIA controlled trial with intravenous Aktempa, 0 out of 188 patients (0%) in the Aktempa all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria. Injection site reactions were categorized separately.

In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and death have occurred in patients treated with a range of doses of intravenous Aktempa, with or without concomitant therapies. Events have occurred in patients who received premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of Aktempa. Aktempa for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For Aktempa subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of Aktempa immediately and discontinue Aktempa permanently. Do not administer Aktempa to patients with known hypersensitivity to Aktempa.

The impact of treatment with Aktempa on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Aktempa in patients with preexisting or recent onset demyelinating disorders.

Treatment with Aktempa is not recommended in patients with active hepatic disease or hepatic impairment.

Avoid use of live vaccines concurrently with Aktempa 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 Aktempa.

No data are available on the effectiveness of vaccination in patients receiving Aktempa. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Aktempa therapy. The interval between live vaccinations and initiation of Aktempa therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Advise patients and parents or guardians of minors with PJIA, SJIA, or CRS of the potential benefits and risks of Aktempa.

Inform patients that Aktempa may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.

Inform patients that some patients who have been treated with Aktempa have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.

Assess patient suitability for home use for SC injection. Inform patients that some patients who have been treated with Aktempa have developed serious allergic reactions, including anaphylaxis. Advise patients to seek immediate medical attention if they experience any symptom of serious allergic reactions.

Perform the first injection under the supervision of a qualified healthcare professional. If a patient or caregiver is to administer subcutaneous Aktempa, instruct him/her in injection techniques and assess his/her ability to inject subcutaneously to ensure proper administration of subcutaneous Aktempa and the suitability for home use.

Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature outside of the carton for 30 minutes, out of the reach of children. Do not warm Aktempa in any other way.

Advise patients to consult their healthcare provider if the full dose is not received.

A puncture-resistant container for disposal of needles and syringes should be used and should be kept out of the reach of children. Instruct patients or caregivers in the technique as well as proper syringe and needle disposal, and caution against reuse of these items.

Inform patients that there is a pregnancy registry to monitor fetal outcomes of pregnant women exposed to Aktempa.

Inform female patients of reproductive potential that Aktempa may cause fetal harm and to inform their prescriber of a known or suspected pregnancy.

No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab. Literature indicates that the IL-6 pathway can mediate anti-tumor responses by promoting increased immune cell surveillance of the tumor microenvironment. However, available published evidence also supports that IL-6 signaling through the IL-6 receptor may be involved in pathways that lead to tumorigenesis. The malignancy risk in humans from an antibody that disrupts signaling through the IL-6 receptor, such as tocilizumab, is presently unknown.

Fertility and reproductive performance were unaffected in male and female mice that received a murine analogue of tocilizumab administered by the intravenous route at a dose of 50 mg/kg every three days.

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Aktempa during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

The limited available data with Aktempa in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal antibodies, such as tocilizumab, are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses 1.25 times and higher than the maximum recommended human dose by the intravenous route of 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. Based on the animal data, there may be a potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Fetal/Neonatal Adverse Reactions

Monoclonal antibodies are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to Aktempa in utero

Animal Data

An embryo-fetal developmental toxicity study was performed in which pregnant Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre-and postnatal development phase when dosed at 50 mg/kg intravenously with treatment every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.

Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity leading to potential delays of parturition. For mice deficient in IL-6 (Il6-/-null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Administration of recombinant IL-6 to ll6-/-null mice restored the normal timing of delivery.

No information is available on the presence of tocilizumab in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination of the risk of Aktempa to an infant during lactation; therefore the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Aktempa and the potential adverse effects on the breastfed child from tocilizumab or from the underlying maternal condition.

Aktempa by intravenous use is indicated for the treatment of pediatric patients with:

• Active systemic juvenile idiopathic arthritis in patients 2 years of age and older
• Active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older
• Severe or life-threatening CAR T cell-induced cytokine release syndrome (CRS) in patients 2 years of age and older.

Safety and effectiveness of Aktempa in pediatric patients with conditions other than PJIA, SJIA or CRS have not been established. Children under the age of two have not been studied. SC administration has not been studied in pediatric patients. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

In the retrospective analysis of pooled outcome data for patients treated with Aktempa for CAR T cell-induced CRS, 25 patients were children (2 years up to 12 years of age), and 17 patients were adolescents (12 years up to 18 years of age). There were no differences between the pediatric patients and the adults for safety or efficacy.

Of the 2644 patients who received Aktempa in Studies I to V , a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. Of the 1069 patients who received Aktempa-SC in studies SC-I and SC-II there were 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency of serious infection among Aktempa treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Clinical studies that included Aktempa for CRS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

The safety and efficacy of Aktempa have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology.

No dose adjustment is required in patients with mild or moderate renal impairment. Aktempa has not been studied in patients with severe renal impairment.

No studies on the potential for Aktempa to cause dependence have been performed. However, there is no evidence from the available data that Aktempa treatment results in dependence.

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including Aktempa. Aktempa treatment must not be initiated in patients with active infections. Administration of Aktempa 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 Aktempa in patients with a history of recurring or chronic infections or with underlying conditions (e.g.) diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving

immunosupressive agents such as Aktempa for moderate to severe RA, pJIA or GCA as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Tuberculosis

As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting Aktempa therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating Aktempa. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.

Patients should be advised to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade (fever) suggestive of a tuberculosis infection occur during or after therapy with Aktempa.

Viral reactivation

Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with Aktempa , patients who screened positive for hepatitis were excluded.

Complications of diverticulitis

Events of diverticular perforations as complications of diverticulitis have been reported uncommonly in patients treated with Aktempa. Aktempa 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, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.

Hypersensitivity reactions

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with Aktempa. Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment with tocilizumab even if they have received premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of Aktempa should be stopped immediately, appropriate therapy initiated and tocilizumab should be permanently discontinued.

Active hepatic disease and hepatic impairment

Treatment with Aktempa, particularly when administered concomitantly with MTX, 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.

Hepatic transaminase elevations

In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with Aktempa treatment, without progression to hepatic injury. An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with Aktempa. When clinically indicated, other liver function tests including bilirubin should be considered.

Caution should be exercised when considering initiation of Aktempa treatment in patients with elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.

In RA and GCA patients, ALT and AST levels should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For ALT or AST elevations > 3-5 x ULN, Aktempa treatment should be interrupted.

In pJIA patients, ALT and AST should be monitored at the time of the second administration and thereafter according to good clinical practice.

Haematological abnormalities

Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX. There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.

In patients not previously treated with Aktempa, initiation is not recommended in patients with an ANC below 2 x 109/L. Caution should be exercised when considering initiation of Aktempa treatment in patients with a low platelet count (i.e. platelet count below 100 x 103/ μL). In patients who develop an ANC < 0.5 x 109/ L or a platelet count < 50 x 103/μL, continued treatment is not recommended.

Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with Aktempa to date.

In RA and GCA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice.

In pJIA patients, neutrophils and platelets should be monitored at the time of the second administration and thereafter according to good clinical practice.

Lipid parameters

Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab. 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 all patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of Aktempa therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

Neurological disorders

Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with Aktempa is currently unknown.

Malignancy

The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with Aktempa as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with Aktempa 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 paediatric or elderly patients, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating Aktempa therapy. The interval between live vaccinations and initiation of Aktempa therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

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 Aktempa with TNF antagonists or other biological treatments for RA patients. Aktempa is not recommended for use with other biological agents.

GCA

Aktempa monotherapy should not be used for the treatment of acute relapses as efficacy in this setting has not been established. Glucocorticoids should be given according to medical judgement and practice guidelines.

Effects on ability to drive and use machines

Aktempa has a minor influence on the ability to drive and use machines.

Dosage (Posology) and method of administration

Aktempa may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.

The recommended dosage of Aktempa for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Doses exceeding 800 mg per infusion are not recommended in RA patients.

Recommended Subcutaneous (SC) Dosage Regimen

When transitioning from Aktempa intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.

The recommended dose of Aktempa for adult patients with GCA is 162 mg given once every week as a subcutaneous injection in combination with a tapering course of glucocorticoids.

A dose of 162 mg given once every other week as a subcutaneous injection in combination with a tapering course of glucocorticoids may be prescribed based on clinical considerations.

Aktempa can be used alone following discontinuation of glucocorticoids.

• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Intravenous administration is not approved for GCA.

Aktempa may be used alone or in combination with methotrexate. The recommended dosage of Aktempa for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Recommended Intravenous PJIA Dosage Every 4 Weeks

• Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for PJIA.

Aktempa may be used alone or in combination with methotrexate. The recommended dose of Aktempa for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

Recommended Intravenous SJIA Dosage Every 2 Weeks

• Do not change a dose based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Subcutaneous administration is not approved for SJIA.

Use only the intravenous route for treatment of CRS. The recommended dose of Aktempa for treatment of CRS given as a 60-minute intravenous infusion is:

Recommended Intravenous CRS Dosage

• If no clinical improvement in the signs and symptoms of CRS occurs after the first dose, up to 3 additional doses of Aktempa may be administered. The interval between consecutive doses should be at least 8 hours.
• Doses exceeding 800 mg per infusion are not recommended in CRS patients.
• Subcutaneous administration is not approved for CRS.

• Aktempa has not been studied in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection. Avoid using Aktempa with biological DMARDs.
• It is recommended that Aktempa not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm³, platelet count below 100,000 per mm³, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).
  • Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or the CRS. The decision to administer Aktempa should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with Aktempa.

Aktempa for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

• Patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% or 0.45% Sodium Chloride Injection, USP, and then follow steps 1 and 2 below.
• Patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.
  • Step 1. Withdraw a volume of 0.9% or 0.45% Sodium Chloride Injection, USP, equal to the volume of the Aktempa injection required for the patient's dose from the infusion bag or bottle.

For Intravenous Use: Volume of Aktempa Injection per kg of Body Weight

• Step 2. Withdraw the amount of Aktempa for intravenous infusion from the vial(s) and add slowly into the 0.9% or 0.45% Sodium Chloride Injection, USP infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.
• The fully diluted Aktempa solutions for infusion using 0.9% Sodium Chloride Injection, USP may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light.
• The fully diluted Aktempa solutions for infusion using 0.45% Sodium Chloride Injection, USP may be stored at 2° to 8°C (36° to 46°F) for up to 24 hours or room temperature for up to 4 hours and should be protected from light.
• Aktempa solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted Aktempa solution to reach room temperature prior to infusion.
• The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
• Aktempa should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of Aktempa with other drugs.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used.
• Fully diluted Aktempa solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

• Aktempa for subcutaneous injection is only approved for adult indications and is not indicated for the treatment of pediatric patients with PJIA or SJIA. Aktempa for subcutaneous injection is not intended for intravenous drip infusion.
• Assess suitability of patient for SC home use and instruct patients to inform a healthcare professional before administering the next dose if they experience any symptoms of allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions. Aktempa subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject Aktempa or the patient’s caregiver may administer Aktempa if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use Aktempa prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or discoloration. Aktempa for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS appears to be damaged.
• Patients using Aktempa for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL), which provides 162 mg of Aktempa, according to the directions provided in the IFU.
• Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Hold Aktempa treatment if a patient develops a serious infection until the infection is controlled.

Liver Enzyme Abnormalities

Dose reduction of Aktempa has not been studied in the PJIA and SJIA populations. Dose interruptions of Aktempa are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold Aktempa dosing until the clinical situation has been evaluated. In PJIA and SJIA the decision to discontinue Aktempa for a laboratory abnormality should be based upon the medical assessment of the individual patient.

Tocilizumab SC formulation is administered with a single-use PFS+NSD. Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, pJIA and / or GCA. The first injection should be performed under the supervision of a qualified health care professional. A patient can self-inject Aktempa 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.

Patients who transition from tocilizumab 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.

All patients treated with Aktempa should be given the Patient Alert Card.

Suitability of the patient or parent/guardian for subcutaneous home use should be assessed and patients or parent/guardian instructed to inform a healthcare professional before administering the next dose if they experience symptoms of an allergic reaction. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions.

Posology

Aktempa subcutaneous formulation is not intended for intravenous administration.

RA

The recommended posology is subcutaneous 162 mg once every week.

Limited information is available regarding switching patients from Aktempa intravenous formulation to Aktempa subcutaneous fixed dose formulation. The once every week dosing interval should be followed.

Patients transitioning from intravenous to subcutaneous formulation should administer their first subcutaneous dose instead of the next scheduled intravenous dose under the supervision of a qualified healthcare professional.

GCA

The recommended posology is subcutaneous 162 mg once every week in combination with a tapering course of glucocorticoids. Aktempa can be used alone following discontinuation of glucocorticoids.

Aktempa monotherapy should not be used for the treatment of acute relapses (see 4.4).

Based upon the chronic nature of GCA, treatment beyond 52 weeks should be guided by disease activity, physician discretion, and patient choice.

RA and GCA

Dose adjustments due to laboratory abnormalities.

- Liver enzyme abnormalities

- Low absolute neutrophil count (ANC)

In patients not previously treated with Aktempa, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/L

- Low platelet count

Missed dose

If a patient misses a subcutaneous weekly injection of Aktempa within 7 days of the scheduled dose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient misses a subcutaneous once every other week injection of Aktempa within 7 days of the scheduled dose, he/she should be instructed to take the missed dose immediately and the next dose on the next scheduled day.

Special populations

Elderly patients:

No dose adjustment is required in patients aged 65 years and older.

Renal impairment:

No dose adjustment is required in patients with mild or moderate renal impairment. Aktempa has not been studied in patients with severe renal impairment. Renal function should be monitored closely in these patients.

Hepatic impairment:

Aktempa has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.

Paediatric patients

The safety and efficacy of Aktempa subcutaneous formulation in children from birth to less than 2 years have not been established. There is no data.

pJIA Patients:

A change in dose should only be based on a consistent change in the patient's body weight over time.

The recommended posology in patients above 2 years of age is subcutaneous 162 mg once every 2 weeks in patients weighing greater than or equal to 30 kg or subcutaneous 162 mg once every 3 weeks in patients weighing less than 30 kg.

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 effect laboratory values in pJIA, the decision to discontinue tocilizumab for a laboratory abnormality should be based upon the medical assessment of the individual patient.

- Liver enzyme abnormalities

- Low absolute neutrophil count (ANC)

- Low platelet count

Reduction of tocilizumab dosing frequency due to laboratory abnormalities has not been studied in pJIA patients.

The safety and efficacy of Aktempa subcutaneous formulation in children with conditions other than pJIA have not been established.

Available data with the IV formulation suggest that clinical improvement is observed within 12 weeks of initiation of treatment with Aktempa. Continued therapy should be carefully reconsidered in a patient exhibiting no improvement within this timeframe.

Missed dose

If a pJIA patient misses a subcutaneous injection of Aktempa within 7 days of the scheduled dose, he/she should take the missed dose as soon as they remember and take the next dose at the regular scheduled time. If a patient misses a subcutaneous injection of Aktempa by more than 7 days of the scheduled dose or is unsure when to inject Aktempa, call the doctor or pharmacist.

Method of administration

Aktempa is for subcutaneous use.

After proper training in injection technique, patients may self-inject with Aktempa if their physician determines that it is appropriate. The total content (0.9 ml) of the pre-filled syringe should be administered as a subcutaneous injection. 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.

The pre-filled syringe should not be shaken.

Special precautions for disposal and other handling

Aktempa is supplied in a single use pre-filled syringe fitted into a needle safety device. After removing the pre-filled syringe from the refrigerator the pre-filled syringe should be allowed to reach room temperature (18°C to 28C°) by waiting for 25 to 30 minutes, before injecting Aktempa. The syringe should not be shaken. After removing the cap the injection must be started within 5 minutes, to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe is not used within 5 minutes of removing the cap, you must dispose of it in a puncture resistant container and use a new pre-filled syringe.

If following insertion of the needle you cannot depress the plunger, you must dispose of the pre-filled syringe in a puncture resistant container and use a new pre-filled syringe.

Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to slightly yellowish, or any part of the pre-filled syringe appears to be damaged.

Comprehensive instructions for the administration of Aktempa in a pre-filled syringe are given in the package leaflet.

Any unused product or waste material should be disposed of in accordance with local requirements.