ACTEMRA® IV Injection (Tocilizumab)

Table of Content

For the use only of a Registered Medical Practitioner or a Hospital or a Laboratory

Black Box Warnings

1. Infections

Actemra has been associated with serious and sometimes fatal infections including sepsis and pneumonia. Actemra exerts its therapeutic effects by suppressing the action of IL-6, a cytokine that induces acute phase reactions (fever, increase in C-reactive protein , etc.). Treatment with Actemra suppresses these reactions and accordingly suppresses signs and symptoms associated with infection, which may delay the detection of infections. As a result, it may potentially make the infection more serious. Therefore, patients should be monitored closely and interviewed during treatment with Actemra. Changes in white blood cell and neutrophil counts should be carefully evaluated even when symptoms are mild and no acute phase reaction is observed. If infection is suspected, a chest X-ray, CT scan, etc., should be performed and appropriate measures should be taken.

2. Actemra treatment should be started only after patients are thoroughly informed that adverse drug reactions such as serious infections may occur and that Actemra may not completely resolve their disease, and only when the potential benefit of treatment is judged to outweigh the potential risk.

3. Before treatment with Actemra is given to patients with rheumatoid arthritis (RA) and polyarticular-course juvenile idiopathic arthritis (pJIA), use of one or more disease-modifying anti-rheumatic drugs (DMARDs) should be thoroughly considered. Actemra should be used by a physician with sufficient knowledge of Actemra and experience with the treatment of RA and/or pJIA.

4. For patients with systemic juvenile idiopathic arthritis (sJIA), Actemra should be used by a physician with sufficient knowledge of Actemra and experience with the treatment of sJIA.

1 Description

1.1 Therapeutic/Pharmacologic Class of Drug

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass.

ATC Code: L04AC07.

1.2 Type of Dosage Form

Concentrate solution for infusion

1.3 Route of Administration

Intravenous (IV) infusion

1.4 Sterile/Radioactive Statement

Sterile

1.5 Qualitative and Quantitative Composition

Active ingredient: tocilizumab

Excipients: Sucrose, Polysorbate 80, Disodium phosphate dodecahydrate, Sodium dihydrogen phosphate dihydrate and Water for injections

Tocilizumab solution for intravenous (IV) infusion is a clear to opalescent, colourless to pale yellow liquid, supplied in preservative-free, non-pyrogenic single-use vials, supplied in 10 mL and 20 mL vials containing 4 mL, 10 mL or 20 mL of Tocilizumab (20 mg/mL).

2 Clinical Particulars

2.1 Therapeutic Indications

For the following diseases which do not show sufficient response to the existing therapies:

  • Rheumatoid arthritis (RA), (including inhibition of structural joint damage)
  • Polyarticular-course juvenile idiopathic arthritis (pJIA),
  • Systemic juvenile idiopathic arthritis (sJIA).
  • Tocilizumab has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with Methotrexate (MTX).
  • Improvement of various symptoms (e.g. generalised fatigue) and laboratory findings (increased C-reactive protein, fibrinogen, and erythrocyte sedimentation rate, decreased haemoglobin and albumin) associated with Castleman’s disease.

2.2 Dosage and Administration

General

Substitution by any other biological medicinal product may be recorded by the physician.

For adult patients with RA, tocilizumab may be administered as an IV infusion.

For patients with pJIA, sJIA and Castleman’s disease, tocilizumab is administered as an IV infusion.

Tocilizumab IV formulation should be diluted by a healthcare professional with sterile 0.9% w/v sodium chloride solution using aseptic technique (see section 4.2 Special Instructions for Use, Handling and Disposal). The recommended duration of IV infusion is 1 hour.

Rheumatoid Arthritis

Intravenous Dosing regimen:

The recommended dose of Tocilizumab for adult patients is 8 mg/kg body weight, given once every four weeks as an IV infusion. Tocilizumab can be used alone or in combination with MTX and/or other DMARDs.

For individuals whose body weight is more than 100 kilograms (kg), doses exceeding 800 mg per infusion are not recommended (see Section 3.2 Pharmacokinetic Properties)

Tocilizumab IV formulation is not intended for subcutaneous administration.

Dose Modification Recommendations for RA:

(see section 2.4.4 Laboratory Tests)

  • Liver enzyme abnormalities

Laboratory Value

Action

> 1 to 3 x Upper Limit of Normal (ULN)

Dose modify concomitant DMARDs (RA) if appropriate

For patients on intravenous tocilizumab (RA only) with persistent increases in this range, reduce tocilizumab dose to 4 mg/kg or interrupt tocilizumab until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalized

Restart with 4 mg/kg or 8 mg/kg, as clinically appropriate.

> 3 to 5x ULN

 

Interrupt tocilizumab dosing until < 3x ULN and follow recommendations above for >1 to 3x ULN

For persistent increases > 3x ULN (confirmed by repeat testing, see section 2.4.4), discontinue tocilizumab

> 5x ULN

Discontinue tocilizumab

 

  • Low absolute neutrophil count (ANC)

Laboratory Value
(cells x 109/L)

Action

ANC > 1

Maintain dose

ANC 0.5 to 1

Interrupt tocilizumab dosing

For patients on intravenous tocilizumab (RA only), when ANC > 1 x 109/l resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate

ANC < 0.5

Discontinue tocilizumab

 

  • Low platelet count

Laboratory Value
(cells x 103/
mL)

Action

50 to 100

Interrupt tocilizumab dosing

For patients on intravenous tocilizumab (RA only), when platelet count is > 100 x 103/mL resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate

< 50

Discontinue tocilizumab

pJIA: The recommended dose of tocilizumab (genetical recombination) is 8 mg/kg as a single intravenous drip infusion administered at 4-week intervals.

sJIA and Castleman’s disease: The recommended dose of tocilizumab (genetical recombination) is 8 mg/kg as a single intravenous drip infusion administered at 2-week intervals. The dosing interval can be shortened to a minimum of 1 week depending on the patient’s disease condition.

Precautions related to dosage and administration for Castleman’s disease: The CRP level should be determined at each administration. The dosing interval can be shortened as indicated by the CRP level, but this is limited to cases in which the improvement of symptoms is assessed to be insufficient.

Precautions related to dosage and administration for sJIA: The dosing interval can be shortened, but this is limited to cases in which improvement of symptoms is insufficient and the suppression of IL-6 effects is assessed to be insufficient as indicated by the CRP level.

2.2.1 Special Dosage Instructions

Children:

The safety and efficacy of tocilizumab in children with conditions other than pJIA or sJIA have not been established. Children under the age of two have not been studied.

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

Renal impairment: No dose adjustment is required in patients with mild renal impairment (see section 3.2.5 Pharmacokinetics in Special Populations). Tocilizumab has not been studied in patients with severe renal impairment. Renal function should be monitored closely in these patients.

Hepatic impairment: The safety and efficacy of tocilizumab has not been studied in patients with hepatic impairment (see section 2.4.1 Warnings and Precautions, General).

2.3 Contraindications

Known hypersensitivity to tocilizumab or to any of the excipients.

2.4 Warnings and Precautions

2.4.1 General

In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.

All indications

Infections

Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 2.6, Undesirable Effects). Tocilizumab treatment should not be initiated in patients with active infections. Administration of tocilizumab should be interrupted if a patient develops a serious infection until the infection is controlled. Healthcare professionals should exercise caution when considering the use of tocilizumab in patients with a history of recurring infection or with underlying conditions (e.g. diverticulitis, diabetes) which may predispose patients to infections.

Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents, such as tocilizumab, for moderate to severe RA, pJIA or sJIA as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactions. Patients (which include younger children who may be less able to communicate their symptoms) and parents/guardians of minors should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.

Complications of diverticulitis

Events of diverticular perforation as complications of diverticulitis have been reported in patients treated with tocilizumab (see section 2.6 Undesirable effects). Tocilizumab should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, should be evaluated promptly for early identification of gastrointestinal perforation.

Tuberculosis

As recommended for other biologic therapies in all patients should be screened for latent tuberculosis infection prior to starting tocilizumab therapy. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating tocilizumab.

Vaccinations

Live and live attenuated vaccines should not be given concurrently with tocilizumab as clinical safety has not been established.

No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab.

In a randomized open-label study, adult RA patients treated with tocilizumab and MTX were able to mount an effective response to both the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines which was comparable to the response seen in patients on MTX only.

It is recommended that all patients, particularly pediatric or elderly patients, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Hypersensitivity Reactions

Serious hypersensitivity reactions, including anaphylaxis have been reported in association with tocilizumab (see section 2.6 Undesirable Effects). In the post marketing setting, events of serious hypersensitivity and anaphylaxis have occurred in patients treated with a range of doses of tocilizumab, with or without concomitant therapies, premedication, and / or a previous hypersensitivity reaction. In the post marketing setting, cases with a fatal outcome have been reported with intravenous tocilizumab. These events have occurred as early as the first infusion of tocilizumab (see sections 2.3 Contraindications, 2.6.2 Post Marketing).

Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during infusion with tocilizumab. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of tocilizumab should be stopped immediately and tocilizumab should be permanently discontinued (see section 2.2 Dosage and Administration).

Active Hepatic Disease and Hepatic Impairment

Treatment with tocilizumab 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 (see section 2.2.1 Special Dosage Instructions, 2.6 Undesirable Effects).

Hepatotoxicity

Mild and moderate elevations of hepatic transaminases have been observed with tocilizumab treatment (see section 2.6.1 Undesirable Effects, Clinical Trials). Increased frequency of these elevations was observed when drugs, which are known to cause hepatotoxicity (e.g. methotrexate (MTX)), were used in combination with tocilizumab.

Serious drug-induced liver injury, including acute liver failure, hepatitis and jaundice, have been observed with tocilizumab (see section 2.6.2 Undesirable  Effects, Post Marketing Experience). Serious hepatic injury occurred between 2 weeks to more than 5 years after initiation of tocilizumab. Cases of liver failure resulting in liver transplantation have been reported.

Caution should be exercised when considering initiation of tocilizumab treatment  in patients with elevated transaminases ALT or AST above 1.5x ULN. In patients with elevated ALT or AST above 5x ULN treatment is not recommended.

In RA, GCA, pJIA and sJIA, ALT/AST should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended dose modifications, including tocilizumab discontinuation, based on transaminases levels, see section 2.2 Dosage and Administration.

Viral reactivation

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

Demyelinating disorders

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

sJIA and Castleman’s disease

Following temporary or permanent discontinuation of treatment with Tocilizumab, the biological actions of IL-6 may be excessively expressed, which may exacerbate the pathological state. The additional use or increased dose of a corticosteroid or other appropriate measures should be considered as necessary.

sJIA

Macrophage activation syndrome (MAS)

MAS is a serious life-threatening disorder that may develop in patients with sJIA. In clinical trials, tocilizumab has not been studied in patients during an episode of active MAS.

The treatment of MAS should take priority, and Tocilizumab treatment should not be started in patients with concomitant MAS. If MAS occurs while a patient is receiving Tocilizumab, treatment with Tocilizumab should be discontinued, and an appropriate treatment for MAS should be given immediately.

2.4.2 Drug Abuse and Dependence

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

2.4.3 Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machine have been performed. However, there is no evidence from the available data that tocilizumab treatment affects the ability to drive and use machines.

2.4.4 Laboratory Tests

Rheumatoid Arthritis, pJIA and sJIA

Neutropenia

Treatment with tocilizumab was associated with a higher incidence of neutropenia. Treatment-related neutropenia was not associated with serious infection in clinical trials (see section 2.6.1.1 Laboratory Abnormalities).

Caution should be exercised when considering initiation of tocilizumab treatment in patients with a low neutrophil count i.e. absolute neutrophil count (ANC) below 2 x 109/L. In patients with an absolute neutrophil count below 0.5 x 109/L treatment is not recommended.

In RA, neutrophils should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended dose modifications based on ANC results, see section 2.2 Dosage and Administration.

In pJIA and sJIA, neutrophils should be monitored at the time of the second infusion and thereafter according to good clinical practice (see section 2.2 Dosage and Administration).

Thrombocytopenia

Treatment with tocilizumab was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials (see section 2.6.1.1 Laboratory Abnormalities).

Caution should be exercised when considering initiation of tocilizumab treatment in patients with a platelet count below 100 x 103/µL. In patients with a platelet count below 50 x 103/µL treatment is not recommended.

In RA, platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to good clinical practice. For recommended dose modifications based on platelet counts, see section 2.2 Dosage and Administration.

In pJIA and sJIA, platelets should be monitored at the time of the second infusion and thereafter according to good clinical practice (see section 2.2 Dosage and Administration).

Lipids parameters

Elevations of lipid parameters such as total cholesterol, triglycerides and/or low density lipoprotein (LDL) cholesterol have been observed (see section 2.6.1.1 Laboratory Abnormalities).

In patients treated with tocilizumab, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of tocilizumab therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.

2.4.5 Interactions with other Medicinal Products and other Forms of Interaction

Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance in RA patients.

Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Tocilizumab has not been studied in combination with other biological DMARDs.

The expression of hepatic CYP450 enzymes is suppressed by the cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab is introduced.

In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalizes expression of these enzymes.

The effect of tocilizumab on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index, and/or where the dose is individually adjusted.

In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar or slightly higher than those observed in healthy subjects.

When starting or stopping therapy with tocilizumab, patients taking medicinal products, which are individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses of these products may need to be adjusted to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

2.5 Use in Special Populations

2.5.1 Pregnancy

There are no adequate data from the use of tocilizumab in pregnant women. A study in monkeys did not indicate any dysmorphogenic potential but has yielded a higher number   of spontaneous abortion/embryo‑foetal death at a high dose (see section 3.3 Pre-clinical Safety). The relevance of these data for humans is unknown.

Tocilizumab should not be used during pregnancy unless clearly indicated by medical need.

2.5.2 Nursing Mothers

It is unknown whether tocilizumab is excreted in human breast milk. Although endogenous immunoglobulins of the IgG isotope are secreted into human milk, a systemic absorption of tocilizumab via breast feeding is unlikely due to the rapid proteolytic degradation of such proteins in the digestive system. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with tocilizumab should be made taking into account the benefit of breast-feeding to the child and the benefit of tocilizumab therapy to the woman.

2.5.3 Paediatric Use

(See section 2.2.1 Special Dosage Instructions).

2.5.4 Geriatric Use

(See section 2.2.1 Special Dosage Instructions, section 3.2.5 Pharmacokinetics in Special Populations).

2.5.5 Renal Impairment

(See section 2.2.1 Special Dosage Instructions, section 3.2.5 Pharmacokinetics in Special Populations).

2.5.6 Hepatic Impairment

(See section 2.2.1 Special Dosage Instructions, section 3.2.5 Pharmacokinetics in Special Populations).

2.6 Undesirable Effects

2.6.1 Clinical Trials

The safety profile in this section comes from patients exposed to tocilizumab in clinical trials; the majority of these patients were participating in RA studies while the remaining experience comes from pJIA, sJIA, and Castleman’s disease studies. The safety profile of tocilizumab across these indications remains similar and undifferentiated.

ADRs are listed according to clinical importance to the patient. Frequencies are defined as very common (≥1/10), common (≥1/100 to < 1/10) or uncommon (≥1/1000 to < 1/100).

Table 1: Summary of ADRs occurring in patients treated with Tocilizumab

System Organ Class

Very Common

 

Common

 

Uncommon

 

Infections and infestations

Upper respiratory tract infections

Cellulitis, Oral herpes simplex, Herpes zoster

Diverticulitis

Gastrointestinal disorders

 

Abdominal pain, Mouth ulceration, Gastritis

Stomatitis, Gastric ulcer

Skin and subcutaneous tissue disorders

 

Rash, Pruritus, Urticaria

 

Nervous system disorders

 

Headache, Dizziness

 

Investigations

 

Hepatic transaminases increased, Weight increased,

Total bilirubin increased

Vascular disorders

 

Hypertension

 

Blood and lymphatic system disorders

 

Leukopenia,

Neutropenia

 

 

Metabolism and nutrition disorders

 

Hypercholesterolaemia

Hypertriglyceridaemia

General disorders and administration site conditions

 

Peripheral oedema Hypersensitivity reactions, Injection site reaction

 

Respiratory, thoracic and mediastinal disorders

 

Cough, Dyspnoea

 

Eye disorders

 

Conjunctivitis

 

Renal disorders

 

 

Nephrolithiasis

Endocrine disorders

 

 

Hypothyroidism

Rheumatoid Arthritis

Patients Treated with Intravenous Tocilizumab:

The safety of tocilizumab has been studied in 5 Phase III, double-blind controlled trials and their extension periods.

The all control population includes all patients from the double-blind phases of each core study from randomization until either the first change in the treatment regimen, or two years is reached. The control period in 4 of the studies was 6 months and in 1 study was up to 2 years. In the double-blind controlled studies, 774 patients received tocilizumab 4 mg/kg in combination with MTX, 1870 patients received Tocilizumab 8 mg/kg in combination with MTX/other DMARDs, and 288 patients received tocilizumab 8 mg/kg monotherapy.

The all exposure population includes all patients who received at least one dose of tocilizumab either in the double-blind control period or open label extension phase in studies. Of the 4009 patients in this population, 3577 received treatment for at least 6 months, 3296 for at least one year; 2806 received treatment for at least 2 years and 1222 for 3 years.

Infections

In the 6-month controlled trials, the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient (pt) years compared to 112 events per 100 pt years in the placebo + DMARD group. In the all exposure population, the overall rate of infections with tocilizumab was 108 events per 100 pt years exposure.

In 6-month controlled clinical trials, the rate of serious infections (bacterial, viral and fungal) with tocilizumab 8 mg/kg + DMARD was 5.3 events per 100 pt years exposure compared to 3.9 events per 100 pt years exposure in the placebo+ DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 pt years of exposure in the tocilizumab group and 1.5 events per 100 pt years of exposure in the MTX group.

In the all exposure population, the overall rate of serious infections was 4.7 events per 100 pt years. Reported serious infections, some with fatal outcome, included pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, bacterial arthritis. Cases of opportunistic infections have also been reported.

Gastrointestinal Perforation

During the 6 month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 pt years with tocilizumab therapy.  In the all exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 pt years.  Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalized purulent peritonitis, lower GI perforation, fistula and abscess.

Infusion reactions

In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg + DMARD and 5.1% of patients in the placebo + DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.

The rate of anaphylactic reactions (occurring in a total of 6/3778 patients) was several-fold higher in the 4 mg/kg arm in comparison to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in a total of 13 out of 3778 patients (0.3%) treated with tocilizumab during the controlled and open label clinical trials. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 2.4.1 Warnings and Precautions, General).

Immunogenicity

A total of 2876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Forty six patients (1.6%) developed positive anti-tocilizumab antibodies of whom 5 had an associated medically significant hypersensitivity reaction leading to withdrawal. Thirty patients (1.1%) developed neutralising antibodies.

Early Rheumatoid Arthritis

Study VI (WA19926) evaluated 1162 patients with early, moderate to severe RA who were naïve to treatment with both MTX and a biologic agent. The overall safety profile observed in the tocilizumab treatment groups was consistent with the known safety profile of tocilizumab (see Table 1) (see section 3.2 Clinical/Efficacy Studies).

Monotherapy: tocilizumab versus adalimumab

In a 24 week double-blinded, parallel study (monotherapy with tocilizumab 8 mg/kg IV q4w (N=162) compared to adalimumab 40 mg SC q2w (N=162)), the overall clinical adverse event profile was similar between tocilizumab and adalimumab. The proportion of patients with serious adverse events was balanced between the treatment groups (tocilizumab 11.7% vs. adalimumab 9.9%) with the most common event being infections (3.1% each). Both study treatments induced the same pattern of changes in laboratory safety parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, the magnitude of change and the frequency of marked abnormalities was higher with tocilizumab compared with adalimumab. Four (2.5%) patients in the tocilizumab arm and two (1.2%) patients in the adalimumab arm experienced CTC grade 3 or 4 neutrophil count decreases. Eleven (6.8%) patients in the tocilizumab arm and five (3.1%) patients in the adalimumab arm experienced ALT increases of CTC grade 2 or higher. The mean LDL increase from baseline was 0.64 mmol/L (25 mg/dL) for patients in the tocilizumab arm and 0.19 mmol/l (7 mg/dL) for patients in the adalimumab arm. The safety observed in the tocilizumab arm was consistent with the known safety profile of tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1) (see section 3.1.2 Clinical/Efficacy Studies).

Patients Treated with Subcutaneous Tocilizumab (approved but not yet launched in India )

The safety of subcutaneous tocilizumab in RA was studied in SC-I. The study compared the efficacy and safety of tocilizumab 162 mg administered every week SC versus 8 mg/kg IV in 1262 subjects with adult RA. All patients in the study received background non-biologic DMARD(s). The safety and immunogenicity observed for tocilizumab administered SC was consistent with the known safety profile of IV tocilizumab and no new or unexpected adverse drug reactions were observed (see Table 1). A higher frequency of injection site reactions was observed in the SC arms compared with placebo SC injections in the IV 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 SC tocilizumab and the SC placebo (IV 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 tocilizumab 162 mg weekly were tested for anti-tocilizumab antibodies in the 6 month controlled period. Five patients (0.8%) developed positive anti-tocilizumab antibodies; of these, all developed neutralizing anti-tocilizumab antibodies.

A total of 1454 SC tocilizumab all exposure patients have been tested for anti-tocilizumab antibodies, thirteen patients (0.9%) developed positive anti-tocilizumab antibodies, and of these 12 patients (0.8%) developed neutralizing anti-tocilizumab antibodies.

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

Polyarticular Juvenile Idiopathic Arthritis

The safety of intravenous tocilizumab was studied in 188 paediatric patients, 2 to 17 years of age, with pJIA. The total patient exposure in the tocilizumab all exposure population was 184.4 patient years. In general, the types of adverse drug reactions in patients with pJIA were similar to those seen in RA and sJIA patients (see Undesirable Effects section).

Infections

The rate of infections in the tocilizumab all exposure population was 163.7 per 100 patient years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing below< 30 kg treated with 10 mg/kg tocilizumab (12.2 per 100 patient years) compared to patients weighing ≥30 kg, treated with 8 mg/kg Tocilizumab (4.0 per 100 patient years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing below< 30 kg treated with 10 mg/kg tocilizumab (21.4%) compared to patients weighing ≥30 kg, treated with 8 mg/kg tocilizumab (7.6%).

Infusion Reactions

In pJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the tocilizumab all exposure population, 11 patients (5.9%) experienced infusion reactions during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension and within 24 hours of infusion were dizziness and hypotension. In general, the adverse drug reactions observed during or within 24 hours of an infusion were similar in nature to those seen in RA and sJIA patients (see Undesirable Effects section).

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

Immunogenicity

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

Systemic Juvenile Idiopathic Arthritis

The safety of intravenous tocilizumab in sJIA has been studied in 112 pediatric patients 2 to 17 years of age. In the 12 week double-blind, controlled portion of the clinical trial 75 patients received treatment with tocilizumab (8 or 12 mg/kg based upon body weight). After 12 weeks or at the time of escape, due to disease worsening, patients were treated in the on-going open-label extension phase. In general, the adverse drug reactions in patients with sJIA were similar in type to those seen in RA patients (see Undesirable Effects section above).

Infections

In the 12 week controlled trial the rate of all infections in the tocilizumab group was 344.7 per 100 patient-years and 287.0 per 100 patient-years in the placebo group. In the on-going open label extension study (Part II) the overall rate of infections remained similar at 306.6 per 100 patient- years.

In the 12 week controlled trial the rate of serious infections in the tocilizumab group was 11.5 per 100 patient years. In the on-going open label extension study the overall rate of serious infections remained stable at 11.3 per 100 patient years. Reported serious infections were similar to those seen in RA patients with the addition of varicella and otitis media.

Infusion Reactions

For sJIA patients, infusion related reactions are defined as all events occurring during or within 24 hours of an infusion. In the 12 week controlled trial, four percent (4.0%) of patients from the tocilizumab group experienced events occurring during infusion, one event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment.

In the 12 week controlled trial experience, 16% of patients in the tocilizumab group and 5.4% of patients in the placebo group experienced an event within 24 hours of infusion. In the tocilizumab group, the events included, but not limited to rash, urticaria, diarrhoea, epigastric discomfort, arthralgia and headache. One of these events, (urticaria) was considered serious.

Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation, were reported in 1 out of 112 patients (<below 1%) treated with tocilizumab during the controlled and open-label parts of the clinical trial.

Immunogenicity

All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies with one of these patients having a hypersensitivity reaction leading to withdrawal.

2.6.1.1 Laboratory Abnormalities

Haematological abnormalities:

Neutrophils

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

Rheumatoid Arthritis

Intravenous Administration:

In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ L occurred in 3.4% of patients on tocilizumab 8 mg/kg + DMARD compared to below 0.1% of patients on placebo + DMARD. Approximately half of the instances of ANC below 1 x 109/ L occurred within 8 weeks after starting therapy. Decreases below 0.5 x 109/ L were reported in 0.3% patients receiving tocilizumab 8 mg/kg + DMARD (see sections 2.2 Dosage and Administration, 2.4.4 Laboratory Tests).

In the all control and all exposure population, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.

Subcutaneous Administration (approved but not yet launched in India  ):

During routine laboratory monitoring in the tocilizumab 6-month controlled period of clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on tocilizumab 162 mg SC weekly.

Polyarticular Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the tocilizumab all exposure population, a decrease in neutrophil count below 1 × 109/L occurred in 3.7% of patients.

Systemic Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the 12 week controlled trial, a decrease in neutrophil counts below 1 × 109/L occurred in 7% of patients in the tocilizumab group, and in none in the placebo group.

In the ongoing open-label extension study decreases in neutrophil counts below 1 x 109/L, occurred in 15% of the tocilizumab group.

Platelets

Rheumatoid Arthritis

Intravenous Administration:

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

In the all control and all exposure population, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.

Subcutaneous Administration ( approved but not yet launched in India ):

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

Polyarticular Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the tocilizumab all exposure population, 1% of patients had a decrease in platelet count to 50 × 103 / μL without associated bleeding events.

Systemic Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the 12 week controlled trial, 3% of patients in the placebo group and 1% in the tocilizumab group had a decrease in platelet count to  100 × 103 / μL.

In the ongoing open-label extension study decreases in platelet counts below 100 x 103 / μL occurred in 3% of patients of the tocilizumab group, without associated bleeding events.

Liver Enzyme elevations

Rheumatoid Arthritis

Intravenous Administration:

During the 6-month controlled trials transient elevations in ALT/AST above 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX, and in 6.5% of patients who received tocilizumab 8 mg/kg + DMARD compared to 1.5% of patients on placebo + DMARDs. The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST above 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab + DMARD patients, the majority of whom were discontinued from tocilizumab treatment (see section 2.2 Dosage and Administration, 2.4.4 Laboratory Tests). During routine laboratory monitoring, the incidence of indirect bilirubin greater than the upper limit of normal was 6.2% in patients treated with 8 mg/kg Tocilizumab + DMARD in the all control population.

In the all control and all exposure population, the pattern and incidence of elevations in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.

In Study VI, MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months) experienced more transient elevations in ALT above 3xULN compared with the all control population. This was observed in both tocilizumab treated patients and MTX monotherapy patients.

In Study WA25204, of the 1538 patients with moderate to severe RA (see  Section 3.1.2 Clinical/Efficacy Studies) and treated with tocilizumab, elevations in  ALT or AST >3 x ULN occurred in 5.3% and 2.2% patients, respectively.  One serious event of drug induced hepatitis with hyperbilirubinemia was reported in association with tocilizumab treatment (see section 2.4.1 Warnings and Precautions)

Subcutaneous Administration (approved but not yet launched in India ):

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

Polyarticular Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the tocilizumab all exposure population, elevation in ALT or AST ≥3 x ULN occurred in 3.7% and below 1% of patients, respectively.

Systemic Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the 12 week controlled trial, elevation in ALT or AST ≥ 3xULN occurred in 5% and 3% of patients, respectively, in the Tocilizumab group, and in 0% of placebo patients.

In the ongoing open-label extension study, elevation in ALT or AST ≥ 3xULN occurred in 12% and 4% of patients, respectively, in the tocilizumab group.

Elevations in Lipid parameters

Rheumatoid Arthritis

Intravenous Administration:

During routine laboratory monitoring in the 6 month controlled trials, elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were observed in patients treated with tocilizumab. Approximately 24% of patients receiving tocilizumab in clinical trials experienced sustained elevations in total cholesterol above 6.2 mmol/ L (240 mg/dL), with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/ L (160 mg/dL).

In the majority of patients there was no increase in atherogenic indices, and elevations in total cholesterol responded to treatment with lipid-lowering agents.

In the all control and all exposure population, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6month controlled clinical trials.

Subcutaneous Administration (approved but not yet launched in India ):

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

Polyarticular Juvenile Idiopathic Arthritis

Intravenous Administration:

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

Systemic Juvenile Idiopathic Arthritis

Intravenous Administration:

During routine laboratory monitoring in the 12 week controlled trial, elevation in total cholesterol above> 1.5 x ULN to 2 x ULN occurred in 1.5% of the tocilizumab group and in 0% of placebo patients. Elevation in LDL above 1.5 x ULN to 2 x ULN occurred in 1.9% of patients in the tocilizumab group and 0% of the placebo group.

In the ongoing open-label extension study the pattern and incidence of elevations in lipid parameters remained consistent with the 12 week controlled trial data.

From Japanese Studies in RA, pJIA, sJIA, Castleman’s disease

Of a total of 828 patients in the Safety analysis set of Japanese clinical studies on Castleman's disease (35 patients), RA (625 patients), pJIA (19 patients), and sJIA (149 patients), there have been 802 patients (96.9%) with ADRs. The most frequently reported

ADRs were upper respiratory tract infection in 571 patients (69.0%), increased cholesterol in 309 patients (37.3%), rash in 237 patients (28.6%), increased low density lipoprotein in 163 patients (19.7%), Gastroenteritis in 144 patients (17.4%), etc.

Of a total of 9342 patients in the Safety analysis set from postmarketing surveillance on RA (8747 patients), pJIA (178 patients), and sJIA (417 patients), there have been 3986 patients (42.7%) with ADRs. The most frequently reported ADRs were hepatic function abnormal in 487 patients (5.2%), upper respiratory tract infection in 462 patients (4.9%), white blood cell count decreased in 393 patients (4.2%), pneumonia in 262 patients (2.8%), cholesterol increased in 206 patients (2.2%), etc.

The frequencies in “Clinically significant adverse reactions” and “Other adverse reactions” were calculated in accordance with the above results.

(1) Clinically significant adverse drug reactions

1) Anaphylactic shock (<0.1%) or anaphylaxis (0.1 %): Decreased blood pressure, dyspnoea, loss of consciousness, dizziness, nausea, vomiting, pruritus, flushing and other reactions may occur. Therefore, the patient’s condition should be closely monitored during Actemra treatment. If any abnormality is observed, Actemra treatment should be discontinued immediately, and appropriate measures, such as administration of adrenaline, corticosteroids or antihistamines, should be taken. Patients should then be closely followed up until the symptoms resolve. After Actemra administration, patients should be checked for any symptom or sign.

2) Infections: Serious infections including opportunistic infections, such as pneumonia , herpes zoster , infectious gastroenteritis , cellulitis , infectious arthritis , sepsis , nontuberculous mycobacteriosis , tuberculosis , and Pneumocystis pneumonia , may occur, and some cases may be fatal. During Actemra treatment, patient condition should be closely monitored, and if any abnormality is observed, appropriate measures, such as discontinuing treatment, should be taken.

3) Interstitial pneumonia (0.6%): In patients with rheumatoid arthritis, interstitial pneumonia may occur, so patients should be monitored for respiratory symptoms (pyrexia, cough, dyspnoea, etc.). If any abnormality is observed, tests such as chest X-ray, CT scan or blood gas testing should be promptly performed after discontinuing Actemra treatment, and appropriate measures should be taken while considering differential diagnosis from Pneumocystis pneumonia (measurement of β-D-glucan, etc.). Patients with a history of interstitial pneumonia should be carefully monitored, such as routine interviews.

4) Intestinal perforation (0.2%): Intestinal perforation has been reported. Actemra may suppress symptoms (abdominal pain, pyrexia, etc.) of acute abdomen such as diverticulitis, etc., and may result in delaying the detection of acute abdomen and lead to perforation. Therefore, if any abnormality is observed, abdominal X-rays or CT scans should be thoroughly examined and appropriate measures should be taken.

5) Agranulocytosis (<0.1%), decreased white blood cell count (4.6%), decreased neutrophil count (1.6%) and decreased platelet count (2.1%): Since agranulocytosis, decreased white blood cell count, decreased neutrophil count and decreased platelet count may occur, patients should be closely monitored, and if any abnormality is observed, appropriate measures, such as discontinuing Actemra treatment, should be taken.

6) Cardiac failure (0.2%): Since cardiac failure has been reported, patient condition should be closely monitored. If any abnormality is observed, appropriate measures, such as discontinuing Actemra treatment, should be taken.

(2) Other adverse drug reactions

If any of the following adverse drug reactions occur, appropriate measures such as temporary or permanent discontinuation should be taken.

 

³1%

³0.1% to <1%

<0.1%

Resistance mechanism

Herpes virus infection

Influenza, oral candidiasis, parotitis, wound infection

 

Respiratory system

Upper respiratory tract infection (10.2%), bronchitis, pharyngolaryngeal pain

Cough, sinusitis, rhinitis, rhinorrhoea, pleurisy, haemoptysis, asthma, pharynx discomfort, pharyngeal erythema, nasal congestion, epistaxis

Bronchiectasis

Metabolism

Cholesterol increased (5.1%), triglycerides increased, hyperlipidaemia, hypercholesterolaemia, low density lipoprotein increased

Blood lactate dehydrogenase increased, high density lipoprotein increased, hypertriglyceridaemia, blood uric acid increased, creatine phosphokinase increased, protein total decreased, diabetes mellitus aggravated, blood potassium decreased, blood sugar increased, blood phosphorus increased, serum ferritin decreased

Blood phosphorus decreased, blood calcium decreased

Hepatic

Hepatic function abnormal, alanine aminotransferase increased, aspartate aminotransferase increased

Gammaglutamyltransferase increased, bilirubin increased, alkaline phosphatase increased, hepatic steatosis, cholelithiasis

 

Cardiovascular

Hypertension

Blood pressure increased, blood pressure decreased, palpitations, T wave inversion/, T wave amplitude decreased, supraventicular extrasystoles, ventricular extrasystoles

ST segment elevation/, ST segment depression, T wave amplitude increased

Blood-coagulation system

Lymphocyte count decreased

Anaemia, white blood cell count increased, fibrinogen decreased, eosinophil count increased, fibrin degradation products increased, haematocrit decreased, haemoglobin decreased, lymphadenitis, lymph nodes swollen, neutrophil count increased, red blood cell count decreased

Thrombin-antithrombin III complex increased

Gastrointestinal

Stomatitis, diarrhea, gastroenteritis, abdominal pain

Nausea, constipation, vomiting, abdominal discomfort, cheilitis, abdominal distension, anorexia, gastric/colonic polyp, reflux oesophagitis, haemorrhoids, dyspepsia, glossitis, gastric ulcer, acute pancreatitis

Thirst

 

Periodontal disease, dental caries, gingivitis, toothache

 

Psychoneurologic

Headache

Dizziness, hypoaesthesia, insomnia, neuropathy peripheral

 

Ear

 

Otitis media, vertigo, sudden hearing loss, otitis externa, tinnitus

Ear discomfort

Eye

 

Conjunctivitis, hordeolum, dry eye, conjunctival haemorrhage, chalazion, cataract, blepharitis

Vitreous floaters, retinal haemorrhage

Skin

Rash , pruritus, tinea, skin infection

Nail infection, urticaria, erythema, skin ulcer, haemorrhage subcutaneous, in growing nail, acne, dry skin, blister, keratosis, alopecia, dermal cyst

 

Musculoskeletal

 

Arthralgia, back pain, myalgia , pain in extremity, osteoporosis, bone density decreased, neck pain, juvenile arthritis aggravated

 

Urinary system

 

Cystitis, urinary tract infection, blood urea nitrogen increased, red blood cells urine positive, pyelonephritis, sugar in urine, protein urine, kidney stone, N-acetyl-β-D-glucosaminidase increased, pollakiuria

White blood cells urine positive

Reproductive system

 

Vaginal infection, genital haemorrhage

Cervical polyp

Others

Abscess, pyrexia

Oedema, malaise, immunoglobulin G decreased, chest pain, chest discomfort, seasonal allergy, C-reactive protein increased, chills, flushing, rhinitis allergic, feeling bad, feeling hot, injection site reaction (erythema, swelling, haematoma, pain, phlebitis, rash, etc.), thrombophlebitis, DNA antibody positive*3), weight increased, antinuclear antibody positive*3)

Rheumatoid factor positive,

dyshidrosis

*3) The time courses of DNA antibody levels in two Phase III studies of rheumatoid arthritis showed a negative change in 10 of 217 patients (4.6%) and a positive change in 0 patients. The time courses of antinuclear antibody levels in these studies showed a negative change in 24 of 216 patients (11.1%) and a positive change in 18 of 216 patients (8.3%).

2.6.2 Post Marketing

The safety profile in post marketing experience is consistent with clinical trial data with the exception of reports of fatal anaphylaxis during intravenous tocilizumab treatment (see sections 2.3 Contraindications, 2.4 Warnings and Precautions). Stevens - Johnson syndrome (SJS) has been reported during treatment with Tocilizumab.

The following adverse drug reactions have been identified from post marketing experience with tocilizumab (Table 2) based on spontaneous case reports, literature cases and cases from non-interventional study programs. Adverse drug reactions are listed according to system organ classes in MedDRA and the corresponding frequency category estimation for each adverse drug reaction is based on the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 2: Adverse drug reactions from post marketing experience

Adverse reaction (MedDRA)

Incidence4

Frequency Category

Immune System Disorders

Anaphylaxis (fatal)1, 2

Not observed in clinical trials 

Rare

Skin and Subcutaneous Tissue Disorders

Stevens-Johnson syndrome3

Not observed in clinical trials 

Rare

Blood and lymphatic system disorders

Hypofibrinogenemia

1.3 per 100 patient years

Common

Hepatobiliary disorders

Drug-induced liver injury

0.2  per 100

patient years

Rare

Hepatitis

0.035 per 100

patient years

Rare

Hepatic failure

0.004 per 100

patient years

Very Rare

Jaundice3

Not observed in

clinical trials

Rare

1 See section 2.3 Contraindications

2 See section 2.4.1 Warnings and Precautions, General

3 This adverse reaction was identified through post marketing surveillance but not observed in clinical trials. The frequency category was estimated as the upper limit of the 95% confidence interval calculated on the basis of the total number of patients exposed to TCZ in clinical trials.

4 Incidence rate calculated based on all-exposure data obtained from relevant completed clinical trials for all indications.

2.7 Overdose

There are limited data available on overdosage with tocilizumab. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg IV. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg IV, although dose-limiting neutropenia was observed.

3 Pharmacological Properties and Effects

3.1 Pharmacodynamic Properties

In clinical studies with tocilizumab in RA, rapid decreases in C-Reactive Protein (CRP), erythrocyte sedimentation rate (ESR) and serum amyloid A were observed. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability.

In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg, absolute neutrophil counts decreased to their lowest 3 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following tocilizumab administration (see section 2.4.4 Laboratory Tests).

Mechanism of action

Tocilizumab is a recombinant humanized anti-human interleukin-6 (IL-6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Tocilizumab binds to both soluble and membrane-bound IL 6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit sIL-6R and mIL-6R-mediated signaling. IL-6 is a multifunctional cytokine, produced by a variety of cell types involved in local paracrine function as well as regulation of systemic physiological and pathological processes such as induction of immunoglobulin secretion, T-cell activation, induction of hepatic acute phase proteins and stimulation of haematopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis, and neoplasia.

The possibility exists for tocilizumab to affect host defences against infections and malignancies. The role of Il-6 receptor inhibition in the development of malignancies is not known.

3.1.2 Clinical / Efficacy Studies

Rheumatoid Arthritis

The efficacy of intravenously administered tocilizumab in alleviating the signs and symptoms of rheumatoid arthritis was assessed in five randomised, double-blind, multicentre studies. Studies I-V required patients ≥ age 18 with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria and who had at least 8 tender and 6 swollen joints at baseline.

Tocilizumab was administered intravenously every 4 weeks as monotherapy (Study I), in combination with MTX (Studies II, III, V) or with other disease-modifying antirheumatic drugs (DMARDs) (Study IV).

Study I evaluated 673 patients who had not been treated with MTX within 6 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 tocilizumab 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 8 week period). The primary endpoint was the proportion of patients who achieved an ACR20 response at week 24.

Study II, a 2 year study, evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks as blinded therapy for 52 weeks, in combination with stable MTX (10 - 25 mg weekly). The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response criteria. At week 52 the co-primary endpoints were prevention of joint damage and improvement in physical function.

Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 - 25 mg weekly). Study IV evaluated 1220 patients who had an inadequate response to their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg tocilizumab or placebo were given every four weeks, in combination with the stable DMARD. Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or more anti-TNF therapies. The anti-TNF agent was discontinued prior to randomisation. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 - 25 mg weekly). The primary endpoint for studies III-V was the proportion of patients who achieved an ACR20 response at week 24.

The percent of patients achieving ACR 20, 50 and 70 responses in Studies I to V are shown in Table 3.

Table 3: ACR responses in MTX/ Placebo Controlled Trials (Percent of Patients)

 

Study I
MTX-Naïve

 

Study II
Inadequate Response to MTX

Study III
Inadequate Response to MTX

Study IV
Inadequate Response to DMARD

Study V
Inadequate Response to TNF Blocking Agent

Response Rate

TCZ

8 mg/kg

 

 

N=286

MTX

 
 

N=284

TCZ 8 mg/kg +MTX

 N= 398

Placebo + MTX
 

 

N=393

TCZ

8 mg/kg +MTX
 
N= 205

Placebo + MTX
 
 
N=204

TCZ

8 mg/kg + DMARD
N=803

Placebo + DMARD
 

 N=413

TCZ 8 mg/kg +MTX
 
N=170

Placebo + MTX
 

N=158

ACR20

Week 24

70%***

52%

56%***

27%

59%***

26%

61%***

24%

50%***

10%

Week 52

 

 

56%***

25%

 

 

 

 

 

 

ACR50

Week 24

44%**

33%

32%***

10%

44%***

11%

38%***

9%

29%***

4%

Week 52

 

 

36 %***

10%

 

 

 

 

 

 

ACR70

Week 24

28%**

15%

13%***

2%

22%***

2%

21%***

3%

12%**

1%

Week 52

 

 

20%***

4%

 

 

 

 

 

 

MCR† by week 52

 

 

7%

1%

 

 

 

 

 

 

                                 

TCZ = tocilizumab

* p<0.05, tocilizumab vs. placebo+MTX/DMARD

** p<0.01, tocilizumab vs. placebo+MTX/DMARD

*** p<0.0001, tocilizumab vs. placebo+MTX/DMARD

† MCR = major clinical response, defined as an ACR70 response maintained for any 24 consecutive weeks or more.

In all studies, 8 mg/kg tocilizumab-treated patients had statistically significant higher ACR 20, 50, 70 response rates at 6 months compared to control (Table 3). The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the magnitude of response continued to improve with duration of treatment. Continued durable responses were seen for over 3 years in the ongoing open label extension studies of Studies I – V.

In the 8 mg/kg tocilizumab-treated patients significant improvements were noted on all individual components of the ACR response (tender and swollen joint counts, patient and physician global assessment, disability index scores (HAQ), pain assessment and CRP compared to patients receiving placebo +MTX/DMARDs in all studies.

Tocilizumab 8 mg/kg treated patients had a statistically significantly greater reduction in disease activity score (DAS28) than patients treated with placebo+DMARD. A good to moderate EULAR response was achieved by significantly more tocilizumab treated patients compared to patients treated with placebo+DMARD (Table 4)

Table 4 Cross-Study Comparison of DAS and EULAR Responses at Week 24

 

Study I
MTX Naive

 

Study II
Inadequate Response to MTX

Study III
Inadequate Response to MTX

Study IV
Inadequate Response to DMARD

Study V
Inadequate Response to TNF Blocking Agent

 

TCZ

 8 mg/kg

 
 
N=286

MTX

 

N=284

TCZ
8 mg/kg
 +MTX

 

N= 398

Placebo + MTX
 
 
N=393

TCZ
8 mg/kg
 +MTX

 

N= 205

Placebo + MTX
 

 

N=204

TCZ
8 mg/kg
+ DMARD

N=803

Placebo + DMARD

N=413

TCZ 8 mg/kg +MTX
 

N=170

Placebo
+MTX

 N=158

Change in DAS28

Week 24

-3.31 (0.12)

-2.05 (0.12)

-3.11 (0.09)***

-1.45 (0.11)

 -3.43
(0.12)***

-1.55 (0.15)

-3.17 (0.07)***

-1.16 (0.09)

-3.16
(0.14)

***

-0.95 (0.22)

DAS<2.6 response (%)

Week 24

33.6%

12.1%

33.3%***

3.8%

27.5%***

0.8%

30.2%***

3.4%

30.1%

***

1.6%

EULAR response (%)

None

18%

35%

26%

65%

20%

65%

20%

62%

32%

84%

Moderate

42%

48%

34%

29%

41%

32%

40%

33%

31%

15%

Good†

40%

17%

41%***

6%

38%***

3%

40%***

4%

37%***

2%

                           

TCZ = tocilizumab

†The p value compares across all the EULAR categories

* p<0.05, tocilizumab vs. placebo+MTX/DMARD

** p<0.01, tocilizumab vs. placebo+MTX/DMARD

*** p<0.0001, tocilizumab vs. placebo+MTX/DMARD

≠ In study II, 47% of patients achieved a DAS28 < 2.6 at 52 weeks compared to 33% of patients at week 24

Major Clinical Response

After 2 years of treatment with tocilizumab/MTX, 14% of patients achieved a major clinical response (maintenance of an ACR70 response for 24 weeks or more).

Radiographic response – Intravenous administration

In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was assessed radiographically and expressed as change in modified Sharp score and its components, the erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with significantly less radiographic progression in patients receiving tocilizumab compared to control.

In the open-label extension of Study II the inhibition of progression of structural joint damage in tocilizumab/MTX-treated patients was maintained in the second year of treatment.

Table 5: Radiographic mean changes over 52 and 104 weeks in Study II

 

PBO + MTX

(+option of  TCZ from week 16)

 

 

TCZ 8 mg/kg + MTX
 

Changes from baseline to Week 52

 

 

n

294

353

Total Sharp-Genant score

1.17

0.25

Erosion score

0.76

0.15

JSN score

0.41

0.10

Change from week 52 to week104

 

 

n

294

353

Total Sharp-Genant score

0.79

0.12

Erosion score

0.48

0.07

JSN score

0.31

0.05

PBO - Placebo

MTX - Methotrexate

TCZ Tocilizumab

JSN - Joint space narrowing

All data presented was read together in campaign 2 which consists of the evaluations of the baseline, week 24, week 52, week 80, week 104 and early withdrawal or escape therapy readings taken up to week 104 visit

Following 1 year of treatment with tocilizumab/ MTX, 83% of patients had no progression of structural damage, as defined by a change in the Total Sharp Score (TSS) of zero or less, compared with 67% of placebo/MTX-treated patients. This remained consistent following 2 years of treatment (83%). Ninety three percent (93%) of patients had no progression between week 52 and week 104.

Quality of life outcomes – Intravenous administration

Clinically significant improvements in disability index (HAQ-DI, Health Assessment Questionnaire Disability Index), fatigue (FACIT-Fatigue, Functional Assessment of Chronic Illness Therapy Fatigue) and improvement in both the physical (PCS, Physical Component Summary) and mental health (MCS, Mental Component Summary) domains of the SF-36 (Short Form 36) were observed in patients treated with 8 mg/kg tocilizumab (monotherapy or combination with DMARDs) compared to patients treated with MTX/DMARDs (Table 6).

At week 24, the proportion of 8 mg/kg tocilizumab treated patients showing a clinically relevant improvement in HAQ-DI (defined as an individual total score decrease of >0.25), was significantly higher than among patients receiving placebo + MTX/DMARDs in all studies. During the open-label period of Study II the improvement in physical function has been maintained for up to 2 years.

Table 6: Comparison of SF-36, HAQ and FACIT-Fatigue Responses at Week 24

Study I
MTX-Naïve

 

Study II
Inadequate Response to MTX

Study III
Inadequate Response to MTX

Study IV
Inadequate Response to DMARD

Study V
Inadequate Response to TNF Blocking Agent

TCZ

 8 mg/kg
 

 

N=286

MTX

 

 

N=284

TCZ

8 mg/kg
 +MTX

 

N= 398

Placebo + MTX
 
 
N=393

TCZ

8 mg/kg
 +MTX

 

N= 205

Placebo + MTX
 
 
N=204

TCZ

8 mg/kg
 + DMARD

N= 803

Placebo +DMARD
 
 
N=413

TCZ

8 mg/kg
 +MTX

 

N=170

Placebo + MTX
 
 

N=158

Change in PCS

10.2 (0.7)

8.4 (0.7)

8.1 (0.6)**

5.6

(0.7)

9.5 (0.8)***

5.0

(1.0)

8.9 (0.4)***

4.1

 (0.6)

8.0 (0.9)**

2.2

 (1.3)

Change in MCS

6.7

(0.9)

5.0 (0.9)

4.2

(0.8)

2.8

 (0.9)

7.3 (1.1)**

2.7

(1.3)

5.3 (0.6)**

2.3

(0.7)

4.1

 (1.3)

4.1

 (1.9)

Change in HAQ-DI

-0.70 (0.05)

-0.52 (0.05)

-0.5 (0.04)**

-0.3 (0.04)

-0.55 (0.06)**

-0.34 (0.07)

-0.47 (0.03)***

-0.2

(0.03)

-0.39 (0.05)***

-0.05 (0.07)

Change in FACIT-Fatigue

9.3

(0.8)

7.0 (0.8)

6.4

(0.7)

5.4

(0.8)

8.6 (0.9)***

4.0

(1.0)

8.0 (0.5)***

3.6

(0.7)

8.8

(1.0)*

4.2 (1.6)

                         

TCZ = tocilizumab

* p<0.05, tocilizumab vs. placebo+MTX/DMARD

** p<0.01, tocilizumab vs. placebo+MTX/DMARD

*** p<0.0001, tocilizumab vs. placebo+MTX/DMARD

In study II, changes in PCS, MCS and FACIT-Fatigue at 52 weeks were 10.1***, 5.4 and 8.4**, respectively, in the TCZ 8 mg/kg + MTX group compared to 5.6, 3.8 and 5.5, respectively, in the Placebo plus MTX group. At Week 52, the mean change in HAQ-DI was -0.58 in the TCZ 8 mg/kg + MTX group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was maintained at Week 104 in the TCZ 8 mg/kg + MTX group (-0.61).

Laboratory Evaluations

Treatment with 8 mg/kg tocilizumab in combination with DMARD/MTX or as monotherapy resulted in a highly statistically significant improvement in haemoglobin levels compared with placebo + MTX/DMARD (p<0.0001) at week 24. The greatest improvement was observed in patients with chronic anaemia associated with RA; mean haemoglobin levels increased by week 2 and remained within normal range through week 24.

A marked decrease in mean levels of acute phase reactants, CRP, ESR, and serum amyloid A occurred rapidly after tocilizumab administration. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range.

MTX naïve, Early RA

Study VI, a 2 year study with the planned primary analysis at week 52 evaluated 1162 MTX-naïve adult patients with moderate to severe, active early RA (mean disease duration ≤ 6 months). This study evaluated the efficacy of IV tocilizumab 4 or 8 mg/kg every 4 weeks/MTX combination therapy, IV tocilizumab 8 mg/kg monotherapy and MTX monotherapy in reducing the signs and symptoms and rate of progression of joint damage for 104 weeks. The primary endpoint was the proportion of patients achieving DAS28 remission (DAS28 below 2.6) at week 24. A significantly higher proportion of patients in the tocilizumab 8 mg/kg + MTX and tocilizumab monotherapy groups met the primary endpoint compared with MTX alone. The tocilizumab 8 mg/kg + MTX group also showed statistically significant results across the key secondary endpoints. Numerically greater responses compared with MTX alone were observed in the tocilizumab 8 mg/kg monotherapy group in all secondary endpoints, including radiographic endpoints. In this study, ACR/EULAR remission (Boolean and Index) were also analysed as pre-specified exploratory endpoints, with higher responses observed in the tocilizumab groups. The results from study VI are shown in Table 7.

Table 7:Efficacy Results for Study VI (WA19926) on MTX-naïve, early RA patients
 

TCZ 8 mg/kg + MTX

N=290

TCZ 8 mg/kg + placebo

N=292

Placebo + MTX

N=287

Primary Endpoint

DAS28 Remission                       

 

 

 

Week 24                        n (%)

130 (44.8)***

113 (38.7)***

43 (15.0)

Key Secondary Endpoints

DAS 28 remission

 

 

 

Week 52                          n (%)

142 (49.0)***

115 (39.4)

56 (19.5)

ACR

 

 

 

Week 24            ACR20, n (%)

216 (74.5)*

205 (70.2)

187 (65.2)

ACR50, n (%)

165 (56.9)**

139 (47.6)

124 (43.2)

ACR70, n (%)

112 (38.6)**

88 (30.1)

73 (25.4)

Week 52            ACR20, n (%)

195 (67.2)*

184 (63.0)

164 (57.1)

ACR50, n (%)

162 (55.9)**

144 (49.3)

117 (40.8)

ACR70, n (%)

125 (43.1)**

105 (36.0)

83 (28.9)

HAQ-DI (adjusted mean change from baseline)

 

 

 

Week 52

-0.81*

-0.67

-0.64

Radiographic Endpoints (mean change from baseline)

Week 52                          mTSS

0.08***

0.26

1.14

Erosion Score

0.05**

0.15

0.63

JSN

0.03

0.11

0.51

Radiographic Non-Progression n (%) 

(change from baseline in mTSS of ≤0)

226 (83)

226 (82)

194 (73)

Exploratory Endpoints

Week 24: ACR/EULAR Boolean Remission, n (%)

47 (18.4)

38 (14.2)

25 (10.0)

      ACR/EULAR Index Remission, n (%)

73 (28.5)

60 (22.6)

41 (16.4)

Week 52: ACR/EULAR Boolean Remission, n (%)

59 (25.7)

43 (18.7)

34 (15.5)

                    ACR/EULAR Index Remission, n (%)

83 (36.1)

69 (30.0)

49 (22.4)

         

All efficacy comparisons vs Placebo + MTX. ***p≤0.0001; **p<0.001; *p<0.05;

‡p-value < 0.05 vs. Placebo + MTX, but endpoint was exploratory (not included in the hierarchy of statistical testing and has therefore not been controlled for multiplicity)

Monotherapy: tocilizumab versus adalimumab

Study WA19924 evaluated 326 patients with RA who were intolerant of MTX or where continued treatment with MTX was considered inappropriate (including MTX inadequate responders). Patients in the tocilizumab arm received an intravenous (IV) infusion of tocilizumab (8 mg/kg) every 4 weeks (q4w) and a subcutaneous (SC) placebo injection every 2 weeks (q2w). Patients in the adalimumab arm received an adalimumab SC injection (40 mg) q2w plus an IV placebo infusion q4w.

A statistically significant superior treatment effect was seen in favour of tocilizumab over adalimumab in control of disease activity from baseline to week 24 for the primary endpoint of change in DAS28 and for all secondary endpoints (Table 8)

Table 8: Efficacy Results for Study WA 19924
 

ADA + Placebo (IV)

N = 162

TCZ + Placebo (SC)

N = 163

p-value(a)

 

Primary Endpoint - Mean Change from baseline at Week 24

DAS28 (adjusted mean)

-1.8

-3.3

 

 

Difference in adjusted mean (95% CI)

-1.5 (-1.8, -1.1)

<0.0001

 

Secondary Endpoints - Percentage of Responders at Week 24 (b)

 

DAS28 < 2.6, n (%)

18 (10.5)

65 (39.9)

<0.0001

 

DAS28 ≤ 3.2, n (%)

32 (19.8)

84 (51.5)

<0.0001

 

ACR20 response, n (%)

80 (49.4)

106 (65.0)

0.0038

 

ACR50 response, n (%)

45 (27.8)

77 (47.2)

0.0002

 

ACR70 response, n (%)

29 (17.9)

53 (32.5)

0.0023

 

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

Japanese studies in pJIA, sJIA & Castleman’s disease

Polyarticular-course Juvenile Idiopathic Arthritis (pJIA)

Nineteen patients with pJIA were administered 8 mg/kg tocilizumab three times at 4-week intervals. Improvement of 30%, 50%, and 70% in the JIA criteria# at the last observation was seen in respectively 94.7%, 94.7%, and 57.9% of patients, showing clear improvement of their underlying disease.

#The standard core set criteria for evaluation of drug response in patients with juvenile idiopathic arthritis proposed by Giannini et al.

Systemic Juvenile Idiopathic Arthritis (sJIA)

Phase III study - Blind period

Either tocilizumab (n=20) or placebo (n=23) was administered six times at 2-week intervals in a double-blind controlled study to the 43 eligible patients who showed an improvement of 30% or higher according to the JIA criteria and an improvement in CRP level of less than 0.5 mg/dL in the open period of the phase III study in which tocilizumab was administered three times at 2-week intervals at a dose of 8 mg/kg to 56 patients with sJIA. The maintenance rate and period of improvement rate of 30% or higher and CRP level of 1.5 mg/dL or less were compared. The rate of maintained response was 80.0% in the tocilizumab group, which was significantly higher than that in the placebo group (17.4%) (P<0.001). Similarly, the period in which response was maintained was also significantly longer in the tocilizumab group than in the placebo group (P<0.001).

Figure 1: Time course of rates of maintained response (Kaplan-Meier curve)

Castleman’s disease

(1) Phase II study

Stage I

To evaluate the efficacy of tocilizumab, the drug was administered intravenously at doses of 2, 4, and 8 mg/kg by intrapatient ascending dose to seven patients with Castleman’s disease. Each dose was given three times at 2-week intervals. At doses of 2 and 4 mg/kg, inflammatory markers such as CRP decreased 1 week after each administration; and in some patients, the markers increased again 2 weeks after administration. At a dose of 8 mg/kg, the tendency of the marker levels to decrease was sustained throughout the treatment period in almost all patients.

Note: The approved dose of Actemra is 8mg/kg as a single intravenous drip infusion (see Dosage and Administration).

Stage II

Tocilizumab was administered eight times at a dose of 8 mg/kg at 2-week intervals to 28 patients with Castleman’s disease. Inflammatory markers (CRP, fibrinogen, and ESR), generalised fatigue (evaluated by visual analog scale), anemia (Hb), and hypoalbuminemia, etc., significantly improved after the initial dose and throughout the treatment period (Table 9).

Table 9: Time course of efficacy endpoints (Stage II)

Variable

Baseline

From Week 6

From Week 16

CRP (mg/dL)

8.7 ± 5.0

1.2 ± 1.7**

0.9 ± 2.0**

Fibrinogen (mg/dL)

639 ± 188

356 ± 149**

317 ± 138**

ESR (mm/hr)

114 ± 34

63 ± 36

48 ± 40**

Generalised fatigue

(0-100mm)

29.9 ± 22.8

17.4 ± 17.2*

17.1 ± 16.5**

Hb (g/dL)

9.2 ± 2.3

11.6 ± 1.9**

12.0 ± 2.1**

Albumin (g/dL)

2.7 ± 0.5

3.6 ± 0.5**

3.7 ± 0.2**

*P<0.05,**P<0.01, paired t test (n=24-28; mean ± SD)

(2) Extension study

Of the patients with Castleman’s disease who participated in the Phase II studies, 33 continued to receive tocilizumab at a dose of 8 mg/kg, at 2-week intervals, in a long-term extension study (maximum: 1568 days; mean: 1191 days). As a result, therapeutic response, such as reduction in inflammatory marker levels, was maintained. Furthermore, in the seven patients in whom there was insufficient therapeutic response, inflammatory markers showed improvement when the dosing interval was shortened (to a minimum of one week).

3.2 Pharmacokinetics Properties

PK of tocilizumab is characterized by nonlinear elimination which is a combination of linear clearance and Michaelis-Menten elimination. The nonlinear part of Tocilizumab elimination leads to an increase in exposure that is more than dose-proportional. The pharmacokinetic parameters of tocilizumab do not change with time. Due to the dependence of total clearance on tocilizumab serum concentrations, the half-life of tocilizumab is also concentration-dependent and varies depending on the serum concentration level. Population pharmacokinetic analyses in any patient population tested so far indicate no relationship between apparent clearance and the presence of anti-drug antibodies.

Rheumatoid Arthritis

The pharmacokinetics in healthy subjects and RA patients suggest that PK is similar between the two populations. The table below shows model predicted secondary PK parameters at each of the four approved dose regimens. The population PK (popPK) model was developed from an analysis dataset composed of an IV dataset of 1793 patients from studies WA17822, WA17824, WA18062 and WA18063 and IV and SC dataset of 1759 patients from studies WA22762 and NA25220. Cmean is included in the table since for dosing regimens with different inter-dose interval, the mean concentration over the dosing period characterizes the comparative exposure better than AUCτ.

Table 10: Predicted mean ± SD PK parameters at steady-state after IV and SC dosing in RA

 

IV

SC

TCZ PK Parameter

4 mg/kg Q4W

8 mg/kg Q4W

162 mg Q2W

162 mg QW

Cmax (mcg/mL)

83.8 ± 23.1

182 ± 50.4

13.2 ± 8.8

49.8 ± 21.0

Ctrough (mcg/mL)

0.5 ± 1.5

15.9 ± 13.1

5.7 ± 6.8

43.0 ± 19.8

Cmean (mcg/mL)

 17.8 ± 6.1

56.6 ±  19.3

10.2 ± 8.0

47.4 ± 20.5

 

 

 

 

 

Accumulation Cmax

1.01

1.09

2.12

5.27

Accumulation Ctrough

2.62

2.47

6.02

6.30

Accumulation Cmean or AUCτ *

1.09

1.32

2.67

6.32

*τ = 4 weeks for IV regimens, 2 week or 1 week for the two SC regimens, respectively

At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal half-life of approximately 21.5 days was derived from the population parameter estimates.

While after IV administration maximum concentration (Cmax) increased dose-proportionally between doses of 4 and 8 mg/kg IV every 4 weeks, a greater than dose-proportional increase was observed in the average concentration (Cmean) and trough concentration (Ctrough). At steady-state, Cmean and Ctrough were 3.2 and 32 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.  Exposures after the 162 mg SC QW regimen were greater by 4.6 (Cmean) to 7.5 fold (Ctrough) compared to the 162 SC Q2W regimen.

The accumulation ratios for AUC and Cmax after multiple doses of 4 and 8 mg/kg Q4W are low, while the accumulation ratios are higher for Ctrough (2.62 and 2.47). Accumulation ratios after multiple doses of either SC regimen were higher than after IV regimen with the highest ratios for Ctrough (6.02 and 6.30). The higher accumulation for Ctrough was expected based on the nonlinear clearance contribution at lower concentrations.

For Cmax, more than 90% of the steady-state was reached after the 1st IV infusion, and after the 12th SC and the 5th SC injection in QW and Q2W regimens respectively. For AUCτ and Cmean, 90% of the steady-state was reached after the 1st and 3rd infusion for the 4 mg/kg and 8 mg/kg IV, respectively, and after the 6th and 12th injections for the 162 mg SC Q2W and QW regimens respectively. For Ctrough, approximately 90% of the steady-state was reached after the 4th IV infusion, the 6th and 12th injections for the respective SC regimens. 

Population PK analysis identified body weight as a significant covariate impacting pharmacokinetics of tocilizumab. When given IV on a mg/kg basis, individuals with body weight ≥ 100 kg are predicted to have mean steady-state exposures higher than mean values for the patient population. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended in patients ³ 100 kg (see section 2.2 Dosage and Administration).  Due to the flat dosing employed for SC administration of tocilizumab, no modifications are necessary by this dosing route.

Pharmacokinetics in patients with polyarticular-course juvenile idiopathic arthritis (pJIA)

Tocilizumab at a dose of 8 mg/kg was administered (intravenous infusion over 1 hour) three times at 4-week intervals to 19 patients (age: 3-19 yr; median: 12 yr) with pJIA. A comparison of pharmacokinetic parameters of serum Tocilizumab concentrations after the initial infusion are shown in Table 11. There are some patients in the group aged less than 7 years who showed a faster rate of elimination of serum tocilizumab.

Table 11: Pharmacokinetic parameters following repeated administration in patients with pJIA

Age

C1hr

(µg//mL)

AUCfinite

(µg *hr/mL)

t½

(hr)

CLtotal (mL/hr/kg)

MRT

(hr)

Vdss (mL/kg)

3 to < 7

107.8 ± 15.0

12970 ± 2511

NA

NA

NA

NA

7 to <15

158.6 ± 34.4

20878 ± 5328

99 ± 12

0.3 ± 0.0

150 ± 9

48.0 ± 7.0

> 15

158.1 ± 36.2

25954 ± 6157

143 ± 43

0.3 ± 0.1

200 ± 49

60.5 ± 12.2

All

145.0 ± 37.5

25275 ± 6722

123 ± 41

0.3 ± 0.1

178 ± 46

58.3 ± 13.9

(mean ± SD, NA: not calculated)

(3 to <7 years: C1hr and AUCfinite: n=5, 7 to <15 years: C1hr and AUCfinite: n=7, other parameters: n=4, ≥15: n=7)

Pharmacokinetics in patients with systemic juvenile idiopathic arthritis (sJIA)

Tocilizumab was administered (intravenous infusion over 1 hour) three times at 2-week intervals at a dose of 8 mg/kg to patients with sJIA (age: 2-19 yr; median: 8 yr), and thereafter, for those who showed response to treatment, tocilizumab was administered a further six times (total nine times, 18 weeks after initial administration).

Pharmacokinetic parameters after the initial and 3rd infusions are shown in Table 12. There are some patients in the group aged less than 7 years who showed a faster rate of elimination of serum tocilizumab.

The time course of serum tocilizumab concentration was considered to have reached a steady state during the period from week 8 through week 14 following the initial dose, and the trough concentration was measured to be 57.4 μg/mL (18 weeks after the initial dose, n=13).

Serum tocilizumab levels were eliminated at a faster rate in some patients with a low body weight, height, or age.

Table 12: Pharmacokinetic parameters following repeated administration in patients with sJIA

Age

No. of doses

C1hr (µg//mL)

AUCfinite

(µg *hr/mL)

t½

(hr)

CLtotal (mL/hr/kg)

MRT (hr)

Vdss (mL/kg)

2 to < 7

1

142.8 ± 31.6

17677 ± 5193

NA

NA

NA

NA

3

171. 7 ± 51.2

23706 ± 9704

100 ± 38

0.3 ± 0.1

155 ± 60

45.4 ± 7.6

7 to < 15

1

176.7 ± 48.5

24701 ±7611

NA

NA

NA

NA

3

239.8 ± 70.2

35333 ± 11668

127 ± 26

0.2 ± 0.2

188 ± 49

43.0 ± 17.5

> 15

1

166.0 ± 31.8

23653 ± 3571

NA

NA

NA

NA

3

214.0 ± 40.0

33336 ± 8115

139 ± 30

249 ± 21

249 ± 21

43.6 ± 11.2

(Mean ± SD, NA: not calculated)

(2 to <7 years: n=19-23, 7 to <15 years: n=25-28, ≥15: n=4-5)

Pharmacokinetics in patients with Castleman’s disease

Repeated dose study

Tocilizumab was administered (intravenous infusion over 1 hour) eight times at 2-week intervals at a dose of 8 mg/kg to 28 patients with Castleman’s disease. The mean serum tocilizumab concentration was 36.6 ± 17.5 μg/mL immediately before the eighth dose, with concentrations showing an increase from the initial dose. The t1/2 and MRT were prolonged up to the sixth dose after the initial dose and values maintained almost constant levels from the sixth dose (Table 13).

Table 13: Pharmacokinetic parameters following repeated administration in patients Castleman’s disease

Dose (mg/kg)

No. of doses

Cmax

(µg/mL)

AUCfinite

(µg *hr/mL)

t½

(hr)

CL total (mL/hr/kg)

MRT

(hr)

Vd25 (mL/kg

 

8

1

112.9 ± 24.7

13092 ± 3254

99.7 ± 17.1

0.6 ± 0.2

145 ± 26.8

80.1 ± 15.0

8

192.3 ± 38.7

28423 ± 7410

139 ± 37.4

0.2 ± 0.1

 

205 ± 54.2

46.8 ± 8.8

 

(n=26-28; mean ± SD)

3.2.1 Absorption

No text.

3.2.2 Distribution

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

In paediatric 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 paediatric 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.

3.2.3 Metabolism

No text.

3.2.4 Elimination

The total clearance of tocilizumab was concentration-dependent and is the sum of the linear clearance and the nonlinear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 12.5 mL/h in RA patients, 5.8 mL/h in paediatric patients with polyarticular juvenile idiopathic arthritis and 7.1 mL/h in paediatric patients with systemic juvenile idiopathic arthritis. The concentration-dependent nonlinear clearance plays a major role at low tocilizumab concentrations. Once the nonlinear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance. Due to dependence of total clearance on tocilizumab serum concentrations, t1/2 of tocilizumab is also concentration dependent and can only be calculated at a given serum concentration level.

In RA patients, for intravenous administration, the concentration-dependent apparent t1/2 is up to 11 days for 4 mg/kg and 13 days for 8 mg/kg every 4 weeks in patients with RA at steady-state. At high serum concentrations, when total clearance of tocilizumab is dominated by linear clearance, a terminal t1/2 of approximately 21.5 days was derived from the population parameter estimates.

3.2.5. Pharmacokinetics in Special Populations

Hepatic Impairment

No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab was conducted.

Renal impairment

No formal study of the effect of renal impairment on the pharmacokinetics of tocilizumab has been conducted.

Most of the patients in the RA population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (estimated creatinine clearance based on Cockcroft-Gault formula) did not impact the pharmacokinetics of tocilizumab.

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

Other special populations

Population pharmacokinetic analyses in adult RA patients showed that age, sex and race did not affect pharmacokinetics of tocilizumab. No dose adjustment is necessary for these demographic factors.

3.3 Preclinical Safety

3.3.1 Carcinogenicity

A carcinogenicity study of tocilizumab has not been conducted. Available preclinical data, showed the contribution of the pleiotropic cytokine IL-6 to malignant progression and apoptosis resistance of various cancer types. These data do not suggest a relevant risk for cancer initiation and progression under therapy with tocilizumab. Accordingly, proliferate lesions have not been observed in a chronic cynomolgus monkey 6-month toxicity study nor were they described in IL-6 knock-out mice under chronic IL-6 depletion.

3.3.2 Mutagenicity

Standard genotoxicity studies with tocilizumab in both prokaryotic and eukaryotic cells were all negative.

3.3.3 Impairment of Fertility

Preclinical data do not suggest an effect on fertility under treatment with an analogue of tocilizumab. Effects on endocrine active organs or on organs of the reproductive system were not seen in a chronic cynomolgus monkey toxicity study, nor was the reproductive performance affected in IL-6 deficient male and female mice.

3.3.4 Teratogenicity

When tocilizumab was administered intravenously to cynomolgus monkeys during early gestation, no direct or indirect harmful effects on pregnancy or embryo-foetal development were observed.

3.3.5 Other

In an embryo-foetal toxicity study conducted in cynomolgus monkeys a slight increase of abortion/embryo-foetal death was observed with high systemic cumulative exposure (above 100 times human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. The abortion incidence was within the historical background for the cynomolgus monkey in captivity and the individual cases of abortions/embryo-foetal death did not show any consistent relationship to dosing or duration of dosing with tocilizumab. Although IL-6 does not seem to be a critical cytokine for either foetal growth or the immunological control of the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.

Transfer of a murine analogue of tocilizumab into the milk of lactating mice has been observed.

Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

The non-clinical safety profile of tocilizumab in the cynomolgus monkey does not suggest a difference between IV and SC routes of administration.

4 Pharmaceutical Particulars

4.1 Storage

Intravenous tocilizumab:

This medicine should not be used after the expiry date (Expiry date) shown on the pack.

For vials: Store between2ºC – 8ºC, do not freeze. Keep the container in the outer carton in order to protect from light.

For prepared infusion solution: The prepared infusion solution of tocilizumab is physically and chemically stable in 0.9% w/v sodium chloride solution at 30ºC for 24 hours.

From a microbiological point of view, the prepared infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not be longer than 24 hours at 2ºC – 8ºC, unless dilution has taken place in controlled and validated aseptic conditions.

4.2 Special Instructions for Use, Handling and Disposal

Intravenous tocilizumab:

Parenteral medications should be inspected visually for particulate matter or discoloration prior to administration. Only solutions which are clear to opalescent, colourless to pale yellow and free of visible particles must be infused.

From a 100 mL infusion bag, withdraw a volume of 0.9% Sodium Chloride solution equal to the volume of the tocilizumab solution required for the patient’s dose. Withdraw the required amount of tocilizumab (0.4 mL/kg) under aseptic conditions and dilute to a calculated tocilizumab concentration in a 100 mL infusion bag containing sterile, non-pyrogenic 0.9% Sodium Chloride solution. To mix the solution, gently invert the bag to avoid foaming.

4.3 Shelf Life

Unopened vial: 30 months when stored at recommended storage conditions.

Disposal of unused/expired medicines

The release of pharmaceuticals in the environment should be minimized. Medicines should not be disposed of via wastewater, and disposal through household waste should be avoided. Use established ‘collection systems' if available in your location.

4.4 Pack Sizes (vials for IV infusion use only)

Presentations                                    Pack sizes

Vials 80 mg/4 ml                   1

Vials 200 mg/10 ml              1

Vials 400 mg/20 ml              1

Keep out of reach of children

5 Description

Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical H2L2 polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Actemra has a molecular weight of approximately 148 kDa. The antibody is produced in mammalian (Chinese hamster ovary) cells.

Actemra (tocilizumab) injection is a clear to opalescent, colourless to pale yellow liquid, supplied in preservative-free, non-pyrogenic single-use vials, supplied in 10 mL and 20 mL vials containing 4 mL, 10 mL or 20 mL of Tocilizumab (20 mg/mL).

Each single-dose vial, formulated with a disodium phosphate dodecahydrate/sodium dihydrogen phosphate dihydrate buffered solution, is available at a concentration of 20 mg/mL containing 80 mg/4 mL, 200 mg/10 mL, or 400 mg/20 mL of Tocilizumab. Each mL of solution contains polysorbate 80 (0.5 mg), sucrose (50 mg), and Water for Injection.

6 Patient Counseling Information

Patient Counseling

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

Infections

  • Inform patients that Actemra 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.

Gastrointestinal Perforation

  • Inform patients that some patients who have been treated with Actemra 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.

Hypersensitivity and Serious Allergic Reactions

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

7 Details of Manufacturer

Manufactured by: F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070, Basel, Switzerland at Chugai Pharma Manufacturing Co., Ltd., 16-3, Kiyohara Kogyodanchi, Utsunomiya-City, Tochigi 321-3231, Japan

Imported by: Roche Products (India) Pvt. Ltd., Plot No.13-A, Paper Box House, Survey
No.78, Hissa No.1, CTS No.46/15, Mahakali Road, Andheri (East), Mumbai- 400093
India

Distributed and Marketed by: Cipla Ltd., Cipla House, Peninsula Business Park,
Ganpatrao Kadam Marg, Lower Parel, Mumbai 400 013, India

8 Details of Permission or Licence Number with Date

Import permission No. Import-930/08 dated 29 Aug 2008.

9 Date of Revision

Current at February 2020, Version 10.0