英文药名：RoACTEMRA(tocilizumab injection in prefilled syringe)

中文药名：托珠单抗注射预充式注射器

生产厂家：Roche（罗氏）
药品介绍
RoACTEMRA（托珠单抗注射预充式注射器）成为首个也是唯一一个可静脉滴注给药（IV）和皮下注射给药（SC）用于治疗中度至重度活动性类风湿性关节炎（RA）成人患者。
RoActemra 162mg solution for injection in pre-filled syringe
1. Name of the medicinal product
RoActemra 162mg solution for injection in pre-filled syringe.
2. Qualitative and quantitative composition
Each pre-filled syringe contains 162mg of tocilizumab in 0.9 ml.
Tocilizumab is a recombinant humanized, anti-human monoclonal antibody of the immunoglobulin G1 (IgG1) sub-class directed against soluble and membrane-bound interleukin 6 receptors.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Solution for injection (injection).
A colourless to slightly yellowish solution.
4. Clinical particulars
4.1 Therapeutic indications
RoActemra, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate.
RoActemra 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.
4.2 Posology and method of administration
Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA. All patients treated with RoActemra should be given the Patient Alert Card. Suitability of the patient for subcutaneous home use should be assessed and instruct patients to inform a healthcare professional if they experience symptoms of an allergic reaction before administering the next dose. Patients should seek immediate medical attention if developing symptoms of serious allergic reactions (see section 4.4).
Posology
The recommended posology is subcutaneous 162mg once every week.
Limited information is available regarding switching patients from RoActemra intravenous formulation to RoActemra subcutaneous fixed dose formulation. The once every week dosing interval should be followed.
Patients transitioning from intravenous to subcutaneous formulation should administer their first subcutaneous dose instead of the next scheduled intravenous dose under the supervision of a qualified healthcare professional.
Dose adjustments due to laboratory abnormalities (see section 4.4).
• Liver enzyme abnormalities

Laboratory Value	Action
> 1 to 3 x Upper Limit of Normal (ULN)	Dose modify concomitant DMARDs if appropriate. For persistent increases in this range, reduce RoActemra dose frequency to every other week injection or interrupt RoActemra until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised. Restart with weekly or every other week injection, as clinically appropriate.
> 3 to 5 x ULN	Interrupt RoActemra dosing until < 3 x ULN and follow recommendations above for > 1 to 3 x ULN. For persistent increases > 3 x ULN (confirmed by repeat testing, see 4.4.), discontinue RoActemra.
> 5 x ULN	Discontinue RoActemra.

• Low absolute neutrophil count (ANC)
In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/l.

Laboratory Value (cells x 109/ l )	Action
ANC > 1	Maintain dose.
ANC 0.5 to 1	Interrupt RoActemra dosing. When ANC increases > 1 x 109/ l resume RoActemra dosing every other week and increase to every week injection, as clinically appropriate.
ANC < 0.5	Discontinue RoActemra.

• Low platelet count

Laboratory Value (cells x 103/ μl)	Action
50 to 100	Interrupt RoActemra dosing. When platelet count > 100 x 103/ μl resume RoActemra dosing every other week and increase to every week injection as clinically appropriate.
< 50	Discontinue RoActemra.

Missed dose
If a patient misses a subcutaneous weekly injection of RoActemra within 7 days of the scheduled dose, he/she should be instructed to take the missed dose on the next scheduled day. If a patient misses a subcutaneous once every other week injection of RoActemra within 7 days of the scheduled dose, he/she should be instructed to take the missed dose immediately and the next dose on the next scheduled day.
Special populations
Elderly patients:
No dose adjustment is required in patients aged 65 years and older.
Renal impairment:
No dose adjustment is required in patients with mild renal impairment. RoActemra has not been studied in patients with moderate to severe renal impairment (see section 5.2). Renal function should be monitored closely in these patients.
Hepatic impairment:
RoActemra has not been studied in patients with hepatic impairment. Therefore, no dose recommendations can be made.
Paediatric patients
The safety and efficacy of RoActemra subcutaneous formulation in children from birth to less than 18 years have not been established. No data are available.
Method of administration
RoActemra is for subcutaneous use.
After proper training in injection technique, patients may self-inject with RoActemra if their physician determines that it is appropriate. The total content (0.9 ml) of the pre-filled syringe should be administered as a subcutaneous injection. The recommended injection sites (abdomen, thigh and upper arm) should be rotated and injections should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
The pre-filled syringe should not be shaken.
Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given in the package leaflet , see section 6.6.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Active, severe infections (see section 4.4).
4.4 Special warnings and precautions for use
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including RoActemra (see section 4.8, Undesirable effects). RoActemra treatment must not be initiated in patients with active infections (see section 4.3). Administration of RoActemra should be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of RoActemra in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease which may predispose patients to infections.
Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments for moderate to severe RA as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection should be considered when evaluating a patient for a potential infection. Patients should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment.
Tuberculosis
As recommended for other biological treatments, RA, patients should be screened for latent tuberculosis (TB) infection prior to starting RoActemra therapy. Patients with latent TB should be treated with standard anti-mycobacterial therapy before initiating RoActemra. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised.
Patients should be advised to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade (fever) suggestive of a tuberculosis infection occur during or after therapy with RoActemra.
Viral reactivation
Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therapies for RA. In clinical studies with tocilizumab, patients who screened positive for hepatitis were excluded.
Complications of diverticulitis
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly with RoActemra in RA patients (see section 4.8). RoActemra should be used with caution in patients with previous history of intestinal ulceration or diverticulitis. Patients presenting with symptoms potentially indicative of complicated diverticulitis, such as abdominal pain, haemorrhage and/or unexplained change in bowel habits with fever should be evaluated promptly for early identification of diverticulitis which can be associated with gastrointestinal perforation.
Hypersensitivity reactions
Serious hypersensitivity reactions, including anaphylaxis have been reported in association with RoActemra (see section 4.8). Such reactions may be more severe, and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment with tocilizumab even if they have received premedication with steroids and antihistamines. If an anaphylactic reaction or other serious hypersensitivity reaction occurs, administration of RoActemra should be stopped immediately, appropriate therapy initiated and tocilizumab should be permanently discontinued.
Active hepatic disease and hepatic impairment
Treatment with RoActemra, 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 sections 4.2 and 4.8).
Hepatic transaminase elevations
In clinical trials, transient or intermittent mild and moderate elevations of hepatic transaminases have been reported commonly with RoActemra treatment, without progression to hepatic injury (see section 4.8). An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with RoActemra. When clinically indicated, other liver function tests including bilirubin should be considered.
Caution should be exercised when considering initiation of RoActemra treatment in patients with elevated ALT or AST > 1.5 x ULN. In patients with baseline ALT or AST > 5 x ULN, treatment is not recommended.
In RA patients, ALT and AST levels should be monitored every 4 to 8 weeks for the first 6 months of treatment followed by every 12 weeks thereafter. For recommended modifications based on transaminases see section 4.2. For ALT or AST elevations > 3–5 x ULN, RoActemra treatment should be interrupted.
Haematological abnormalities
Decreases in neutrophil and platelet counts have occurred following treatment with tocilizumab 8 mg/kg in combination with MTX (see section 4.8). There may be an increased risk of neutropenia in patients who have previously been treated with a TNF antagonist.
In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/l. Caution should be exercised when considering initiation of RoActemra treatment in patients with a low platelet count (i.e. platelet count below 100 x 103/ μl). In patients who develop an ANC < 0.5 x 109/ l or a platelet count < 50 x 103/μl, continued treatment is not recommended.
Severe neutropenia may be associated with an increased risk of serious infections, although there has been no clear association between decreases in neutrophils and the occurrence of serious infections in clinical trials with RoActemra to date.
In RA patients, neutrophils and platelets should be monitored 4 to 8 weeks after start of therapy and thereafter according to standard clinical practice. For recommended dose modifications based on ANC and platelet counts, see section 4.2.
Lipid parameters
Elevations in lipid parameters including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides were observed in patients treated with tocilizumab (see section 4.8). 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 RA patients, assessment of lipid parameters should be performed 4 to 8 weeks following initiation of RoActemra therapy. Patients should be managed according to local clinical guidelines for management of hyperlipidaemia.
Neurological disorders
Physicians should be vigilant for symptoms potentially indicative of new-onset central demyelinating disorders. The potential for central demyelination with RoActemra is currently unknown.
Malignancy
The risk of malignancy is increased in patients with RA. Immunomodulatory medicinal products may increase the risk of malignancy.
Vaccinations
Live and live attenuated vaccines should not be given concurrently with RoActemra as clinical safety has not been established. In a randomized open-label study, adult RA patients treated with RoActemra 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, be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating RoActemra therapy. The interval between live vaccinations and initiation of RoActemra therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
Cardiovascular risk
RA patients have an increased risk for cardiovascular disorders and should have risk factors (e.g. hypertension, hyperlipidaemia) managed as part of usual standard of care.
Combination with TNF antagonists
There is no experience with the use of RoActemra with TNF antagonists or other biological treatments for RA patients. RoActemra is not recommended for use with other biological agents.
Traceability
In order to improve the traceability of biological medicinal products, the tradename of the administered product should be clearly recorded (or stated) in the patient file.
4.5 Interaction with other medicinal products and other forms of interaction
Interaction studies have only been performed in adults.
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.
Population pharmacokinetic analyses did not detect any effect of MTX, non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids on tocilizumab clearance.
The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced.
In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes.
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 to, or slightly higher than, those observed in healthy subjects.
When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses may need to be increased 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.
4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential must use effective contraception during and up to 3 months after treatment.
Pregnancy
There are no adequate data from the use of tocilizumab in pregnant women. A study in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown.
RoActemra should not be used during pregnancy unless clearly necessary.
Breast-feeding
It is unknown whether tocilizumab is excreted in human breast milk. The excretion of tocilizumab in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with RoActemra should be made taking into account the benefit of breast-feeding to the child and the benefit of RoActemra therapy to the woman.
Fertility
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.
4.7 Effects on ability to drive and use machines
RoActemra has a minor influence on the ability to drive and use machines (see section 4.8, dizziness).
4.8 Undesirable effects
Summary of the safety profile
The most commonly reported Adverse Drug Reactions (ADRs) (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT.
The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity reactions.
Intravenous use
The safety of tocilizumab has been studied in 4 placebo-controlled studies (studies II, III, IV and V), 1 MTX-controlled study (study I) and their extension periods (see section 5.1).
The double-blind controlled period was 6 months in four studies (studies I, III, IV and V) and was up to 2 years in one study (study II). 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 or other DMARDs and 288 patients received tocilizumab 8 mg/kg monotherapy.
The long-term 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 the 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.
Tabulated summary of adverse reactions
The ADRs listed in Table 1 are presented by system organ class and frequency categories, defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100) rare (>1/10,000 to <1/1,000) or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Table 1. Summary of ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period

System Organ Class[A1]	Very Common	Common	Uncommon
Blood and lymphatic system disorders		Leukopenia, Neutropenia
Endocrine disorders			Hypothyroidism
Eye disorders		Conjunctivitis
Gastrointestinal disorders		Abdominal pain, Mouth ulceration, Gastritis	Stomatitis, Gastric ulcer
General disorders and administration site conditions		Peripheral oedema Hypersensitivity reaction, Injection site reaction
Infections and infestations	Upper respiratory tract infections	Cellulitis, Pneumonia, Oral herpes simplex, Herpes zoster	Diverticulitis
Investigations		Hepatic transaminases increased, Weight increased, Total bilirubin increased*
Metabolism and nutrition disorders	Hypercholesterolaemia*		Hypertriglyceridaemia
Nervous system disorders		Headache, Dizziness
Renal disorders			Nephrolithiasis
Respiratory, thoracic and mediastinal disorders		Cough, Dyspnoea
Skin and subcutaneous tissue disorders		Rash, Pruritus, Urticaria
Vascular disorders		Hypertension

* Includes elevations collected as part of routine laboratory monitoring (see text below)
Description of selected adverse reactions
Infections
In the 6-month controlled studies the rate of all infections reported with tocilizumab 8 mg/kg plus DMARD treatment was 127 events per 100 patient years compared to 112 events per 100 patient years in the placebo plus DMARD group. In the long-term exposure population, the overall rate of infections with RoActemra was 108 events per 100 patient years exposure.
In 6-month controlled clinical studies, the rate of serious infections with tocilizumab 8 mg/kg plus DMARDs was 5.3 events per 100 patient years exposure compared to 3.9 events per 100 patient years exposure in the placebo plus DMARD group. In the monotherapy study the rate of serious infections was 3.6 events per 100 patient years of exposure in the tocilizumab group and 1.5 events per 100 patient years of exposure in the MTX group.
In the long-term exposure population, the overall rate of serious infections (bacterial, viral and fungal) was 4.7 events per 100 patient years. Reported serious infections, some with fatal outcome, included active tuberculosis, which may present with intrapulmonary or extrapulmonary disease, invasive pulmonary infections, including candidiasis, aspergillosis, coccidioidomycosis and pneumocystis jirovecii, pneumonia, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Cases of opportunistic infections have been reported.
Interstitial lung disease
Impaired lung function may increase the risk for developing infections. There have been post-marketing reports of interstitial lung disease (including pneumonitis and pulmonary fibrosis), some of which had fatal outcomes
Gastrointestinal perforation
During the 6-month controlled clinical trials, the overall rate of gastrointestinal perforation was 0.26 events per 100 patient years with tocilizumab therapy. In the long-term exposure population the overall rate of gastrointestinal perforation was 0.28 events per 100 patient years. Reports of gastrointestinal perforation on tocilizumab were primarily reported as complications of diverticulitis including generalised purulent peritonitis, lower gastrointestinal perforation, fistulae and abscess.
Infusion reactions
In the 6-month controlled trials adverse events associated with infusion (selected events occurring during or within 24 hours of infusion) were reported by 6.9% of patients in the tocilizumab 8 mg/kg plus DMARD group and 5.1% of patients in the placebo plus DMARD group. Events reported during the infusion were primarily episodes of hypertension; events reported within 24 hours of finishing an infusion were headache and skin reactions (rash, urticaria). These events were not treatment limiting.
The rate of anaphylactic reactions (occurring in a total of 8/4,009 patients, 0.2%) was several fold higher with the 4 mg/kg dose, compared to the 8 mg/kg dose. Clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported in a total of 56 out of 4,009 patients (1.4%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth infusions of tocilizumab (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during treatment with intravenous tocilizumab (see section 4.4)
Immunogenicity
A total of 2,876 patients have been tested for anti-tocilizumab antibodies in the 6-month controlled clinical trials. Of the 46 patients (1.6%) who developed anti-tocilizumab antibodies, 6 had an associated medically significant hypersensitivity reaction, of which 5 led to permanent discontinuation of treatment. Thirty patients (1.1%) developed neutralising antibodies.
Haematological abnormalities:
Neutrophils
In the 6-month controlled trials decreases in neutrophil counts below 1 x 109/ l occurred in 3.4% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 0.1% of patients on placebo plus DMARDs. Approximately half of the patients who developed an ANC < 1 x 109/ l did so within 8 weeks after starting therapy. Decreases below 0.5 x 109/ l were reported in 0.3% patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in neutrophil counts remained consistent with what was seen in the 6-month controlled clinical trials.
Platelets
In the 6-month controlled trials decreases in platelet counts below 100 x 103/ μl occurred in 1.7% of patients on tocilizumab 8 mg/kg plus DMARDs compared to < 1% on placebo plus DMARDs. These decreases occurred without associated bleeding events.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of decreases in platelet counts remained consistent with what was seen in the 6-month controlled clinical trials.
Very rare reports of pancytopenia have occurred in the post marketing setting.
Hepatic transaminase elevations
During the 6-month controlled trials transient elevations in ALT/AST > 3 x ULN were observed in 2.1% of patients on tocilizumab 8 mg/kg compared to 4.9% of patients on MTX and in 6.5% of patients who received 8 mg/kg tocilizumab plus DMARDs compared to 1.5% of patients on placebo plus DMARDs.
The addition of potentially hepatotoxic drugs (e.g. MTX) to tocilizumab monotherapy resulted in increased frequency of these elevations. Elevations of ALT/AST > 5 x ULN were observed in 0.7% of tocilizumab monotherapy patients and 1.4% of tocilizumab plus DMARD patients, the majority of whom were discontinued permanently from tocilizumab treatment. These elevations were not associated with clinically relevant increase in direct bilirubin, nor were they associated with clinical evidence of hepatitis or hepatic impairment. During the double-blind controlled period, the incidence of indirect bilirubin greater than the upper limit of normal, collected as a routine laboratory parameter, is 6.2% in patients treated with 8 mg/kg tocilizumab + DMARD. A total of 5.8% of patients experienced an elevation of indirect bilirubin of > 1 to 2 x ULN and 0.4% had an elevation of > 2 x ULN.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevation in ALT/AST remained consistent with what was seen in the 6-month controlled clinical trials.
Lipid parameters
During the 6-month controlled trials, increases of lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol have been reported commonly. With routine laboratory monitoring it was seen that approximately 24% of patients receiving RoActemra in clinical trials experienced sustained elevations in total cholesterol ≥ 6.2 mmol/ l, with 15% experiencing a sustained increase in LDL to ≥ 4.1 mmol/ l. Elevations in lipid parameters responded to treatment with lipid-lowering agents.
During the double-blind controlled period and with long-term exposure, the pattern and incidence of elevations in lipid parameters remained consistent with what was seen in the 6-month controlled trials.
Malignancies
The clinical data are insufficient to assess the potential incidence of malignancy following exposure to tocilizumab. Long-term safety evaluations are ongoing.
Skin Reactions
Very rare reports of Stevens-Johnson Syndrome have occurred in the post marketing setting.
Subcutaneous use
The safety of subcutaneous tocilizumab in RA includes a double-blind, controlled, multicenter study, SC-I. SC-I was a non-inferiority study that compared the efficacy and safety of tocilizumab 162 mg administered every week versus 8 mg/kg intravenous in 1262 patients with RA. All patients received background non-biologic DMARD(s). The safety and immunogenicity observed for tocilizumab administered subcutaneous was consistent with the known safety profile of intravenous 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 subcutaneous arms compared with placebo subcutaneous injections in the intravenous arms.
Injection site reactions
During the 6-month controlled period, in SC-I, the frequency of injection site reactions was 10.1% (64/631) and 2.4% (15/631) for the subcutaneous tocilizumab and the subcutaneous placebo ( intravenous group) weekly injections, respectively. These injection site reactions (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. The majority was resolved without any treatment and none necessitated drug discontinuation.
Immunogenicity
In SC-I, a total of 625 patients treated with tocilizumab 162mg 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. One patient was tested positive for IgE isotype (0.2%).
In SC-II, a total of 434 patients treated with tocilizumab 162mg every other week were tested for anti-tocilizumab antibodies in the 6 month controlled period. Seven patients (1.6%) developed positive anti-tocilizumab antibodies; of these, six (1.4%) developed neutralizing anti-tocilizumab antibodies. Four patients were tested positive for IgE isotype (0.9%).
No correlation of antibody development to clinical response or adverse events was observed.
Haematological abnormalities:
Neutrophils
During routine laboratory monitoring in the tocilizumab 6 month controlled clinical trial SC-I, a decrease in neutrophil count below 1 × 109/L occurred in 2.9% of patients on the subcutaneous weekly dose.
There was no clear relationship between decreases in neutrophils below 1 x 109/L and the occurrence of serious infections.
Platelets
During routine laboratory monitoring in the tocilizumab 6 month clinical trial SC-I, none of the patients on the SC weekly dose had a decrease in platelet count to ≤50 × 103 / μl.
Hepatic transaminase elevations
During routine laboratory monitoring in the tocilizumab 6-month controlled clinical trial SC-I, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively on the subcutaneous weekly dose.
Lipid parameters
During routine laboratory monitoring in the tocilizumab 6 month controlled clinical trial SC-I, 19% of patients experienced sustained elevations in total cholesterol > 6.2 mmol/l (240 mg/dl), with 9% experiencing a sustained increase in LDL to ≥ 4.1 mmol/l (160 mg/dl) on the subcutaneous weekly dose.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions (see details below).
Ireland
HPRA Pharmacovigilance
Earlsfort Terrace
IRL - Dublin 2
Tel: +353 1 6764971
Fax: +353 1 6762517
Website: www.hpra.ie
email: medsafety@hpra.ie
Malta
ADR Reporting
The Medicines Authority
Post-Licensing Directorate
203 Level 3, Rue D'Argens
GŻR-1368 Gżira
Website: www.medicinesauthority.gov.mt
e-mail: postlicensing.medicinesauthority@gov.mt
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
There are limited data available on overdose with RoActemra. One case of accidental overdose was reported in which a patient with multiple myeloma received a single dose of 40 mg/kg administered intravenously. No adverse reactions were observed.
No serious adverse reactions were observed in healthy volunteers who received a single dose up to 28 mg/kg, although dose limiting neutropenia was observed.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosupressants, Interleukin inhibitors; ATC code: L04AC07.
Mechanism of action
Tocilizumab binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R). Tocilizumab has been shown to inhibit sIL-6R and mIL-6R-mediated signalling. IL-6 is a pleiotropic pro-inflammatory cytokine produced by a variety of cell types including T- and B-cells, monocytes and fibroblasts. IL-6 is involved in diverse physiological processes such as T-cell activation, induction of immunoglobulin secretion, induction of hepatic acute phase protein synthesis and stimulation of haemopoiesis. IL-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia.
Pharmacodynamic effects
In clinical studies with tocilizumab, rapid decreases in CRP, erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) were observed. Consistent with the effect on acute phase reactants, treatment with tocilizumab was associated with reduction in platelet count within the normal range. Increases in haemoglobin levels were observed, through tocilizumab decreasing the IL-6 driven effects on hepcidin production to increase iron availability. In tocilizumab-treated patients, decreases in the levels of CRP to within normal ranges were seen as early as week 2, with decreases maintained while on treatment.
In healthy subjects administered tocilizumab in doses from 2 to 28 mg/kg intravenously and 81 to 162 mg subcutaneously, absolute neutrophil counts decreased to their lowest 2 to 5 days following administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrate a comparable (to healthy subjects) decrease of absolute neutrophil counts following tocilizumab administration (see section 4.8).
Intravenous use
Clinical efficacy
The efficacy of tocilizumab in alleviating the signs and symptoms of RA was assessed in five randomised, double-blind, multi-centre studies. Studies I-V enrolled patients ≥ 18 years of age with active RA diagnosed according to the American College of Rheumatology (ACR) criteria and who had at least eight tender and six swollen joints at baseline.
In Study I, tocilizumab was administered intravenously every four weeks as monotherapy. In Studies II, III and V, tocilizumab was administered intravenously every four weeks in combination with MTX vs. placebo and MTX. In Study IV, tocilizumab was administered intravenously every 4 weeks in combination with other DMARDs vs. placebo and other DMARDs. The primary endpoint for each of the five studies was the proportion of patients who achieved an ACR 20 response at week 24.
Study I evaluated 673 patients who had not been treated with MTX within six months prior to randomisation and who had not discontinued previous MTX treatment as a result of clinically important toxic effects or lack of response. The majority (67%) of patients were MTX-naïve. Doses of 8 mg/kg of 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 eight week period).
Study II, a two year study with planned analyses at week 24, week 52 and week 104, evaluated 1196 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg of tocilizumab or placebo were given every four weeks as blinded therapy for 52 weeks in combination with stable MTX (10 mg to 25 mg weekly). After week 52, all patients could receive open-label treatment with tocilizumab 8 mg/kg. Of the patients who completed the study who were originally randomised to placebo + MTX, 86% received open-label tocilizumab 8 mg/kg in year 2. The primary endpoint at week 24 was the proportion of patients who achieved an ACR 20 response. At week 52 and week 104 the co-primary endpoints were prevention of joint damage and improvement in physical function.
Study III evaluated 623 patients who had an inadequate clinical response to MTX. Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks, in combination with stable MTX (10 mg to 25 mg weekly).
Study IV evaluated 1,220 patients who had an inadequate response to their existing rheumatologic therapy, including one or more DMARDs. Doses of 8 mg/kg tocilizumab or placebo were given every four weeks in combination with stable DMARDs.
Study V evaluated 499 patients who had an inadequate clinical response or were intolerant to one or more TNF antagonist therapies. The TNF antagonist therapy was discontinued prior to randomisation. Doses of 4 or 8 mg/kg tocilizumab or placebo were given every four weeks in combination with stable MTX (10 mg to 25 mg weekly).
Clinical response
In all studies, patients treated with tocilizumab 8 mg/kg had statistically significant higher ACR 20, 50, 70 response rates at 6 months compared to control (Table 2). In study I, superiority of tocilizumab 8 mg/kg was demonstrated against the active comparator MTX.
The treatment effect was similar in patients independent of rheumatoid factor status, age, gender, race, number of prior treatments or disease status. Time to onset was rapid (as early as week 2) and the magnitude of response continued to improve with duration of treatment. Continued durable responses were seen for over 3 years in the ongoing open label extension studies I-V.
In patients treated with tocilizumab 8 mg/kg, significant improvements were noted on all individual components of the ACR response including: tender and swollen joint counts; patients and physician global assessment; disability index scores; pain assessment and CRP compared to patients receiving placebo plus MTX or other DMARDs in all studies.
Patients in studies I – V had a mean Disease Activity Score (DAS28) of 6.5–6.8 at baseline. Significant reduction in DAS28 from baseline (mean improvement) of 3.1–3.4 were observed in tocilizumab-treated patients compared to control patients (1.3-2.1). The proportion of patients achieving a DAS28 clinical remission (DAS28 < 2.6) was significantly higher in patients receiving tocilizumab (28–34%) compared to 1–12% of control patients at 24 weeks. In study II, 65% of patients achieved a DAS28 < 2.6 at week 104 compared to 48% at 52 weeks and 33% of patients at week 24.
In a pooled analysis of studies II, III and IV, the proportion of patients achieving an ACR 20, 50 and 70 response was significantly higher (59% vs. 50%, 37% vs. 27%, 18% vs. 11%, respectively) in the tocilizumab 8 mg/kg plus DMARD vs. the tocilizumab 4 mg/kg plus DMARD group (p< 0.03). Similarly the proportion of patients achieving a DAS 28 remission (DAS28 < 2.6) was significantly higher (31% vs. 16% respectively) in patients receiving tocilizumab 8 mg/kg plus DMARD than in patients receiving tocilizumab 4 mg/kg plus DMARD (p< 0.0001).
Table 2. ACR responses in placebo-/MTX-/DMARDs-controlled studies (% patients)

Study I AMBITION		Study II LITHE		Study III OPTION		Study IV TOWARD		Study V RADIATE
Week	TCZ 8 mg/kg	MTX	TCZ 8 mg/kg + MTX	PBO + MTX	TCZ 8 mg/kg + MTX	PBO + MTX	TCZ 8 mg/kg + DMARD	PBO + DMARD	TCZ 8 mg/kg + MTX	PBO + MTX
	N = 286	N = 284	N = 398	N = 393	N = 205	N = 204	N = 803	N = 413	N = 170	N = 158
ACR 20
24	70%***	52%	56%***	27%	59%***	26%	61%***	24%	50%***	10%
52			56%***	25%
ACR 50
24	44%**	33%	32%***	10%	44%***	11%	38%***	9%	29%***	4%
52			36%***	10%
ACR 70
24	28%**	15%	13%***	2%	22%***	2%	21%***	3%	12%**	1%
52			20%***	4%

TCZ - Tocilizumab
MTX - Methotrexate
PBO - Placebo
DMARD - Disease modifying anti-rheumatic drug
** - p< 0.01, TCZ vs. PBO + MTX/DMARD
*** - p< 0.0001, TCZ vs. PBO + MTX/DMARD
Major clinical response
After 2 years of treatment with tocilizumab plus MTX, 14% of patients achieved a major clinical response (maintenance of an ACR70 response for 24 weeks or more).
Radiographic response
In Study II, in patients with an inadequate response to MTX, inhibition of structural joint damage was assessed radiographically and expressed as change in modified Sharp score and its components, the erosion score and joint space narrowing score. Inhibition of joint structural damage was shown with significantly less radiographic progression in patients receiving tocilizumab compared to control (Table 3).
In the open-label extension of Study II the inhibition of progression of structural joint damage in tocilizumab plus MTX-treated patients was maintained in the second year of treatment. The mean change from baseline at week 104 in total Sharp-Genant score was significantly lower for patients randomised to tocilizumab 8 mg/kg plus MTX (p<0.0001) compared with patients who were randomised to placebo plus MTX.
Table 3. Radiographic mean changes over 52 weeks in Study II

PBO + MTX (+ TCZ from week 24) N = 393	TCZ 8 mg/kg + MTX N = 398
Total Sharp-Genant score	1.13	0.29*
Erosion score	0.71	0.17*
JSN score	0.42	0.12**

PBO - Placebo
MTX - Methotrexate
TCZ - Tocilizumab
JSN - Joint space narrowing
* - p≤ 0.0001, TCZ vs. PBO + MTX
** - p< 0.005, TCZ vs. PBO + MTX
Following 1 year of treatment with tocilizumab plus MTX, 85% of patients(n=348) had no progression of structural joint damage, as defined by a change in the Total Sharp Score of zero or less, compared with 67% of placebo plus MTX-treated patients(n=290) (p ≤ 0.001). This remained consistent following 2 years of treatment (83%; n=353). Ninety three percent (93%; n=271) of patients had no progression between week 52 and week 104.
Health-related and quality of life outcomes
Tocilizumab-treated patients reported an improvement in all patient-reported outcomes (Health Assessment Questionnaire Disability Index - HAQ-DI), Short Form-36 and Functional Assessment of Chronic Illness Therapy questionnaires. Statistically significant improvements in HAQ-DI scores were observed in patients treated with RoActemra compared with patients treated with DMARDs. During the open-label period of Study II, the improvement in physical function has been maintained for up to 2 years. At Week 52, the mean change in HAQ-DI was -0.58 in the tocilizumab 8 mg/kg plus MTX group compared with -0.39 in the placebo + MTX group. The mean change in HAQ-DI was maintained at Week 104 in the tocilizumab 8 mg/kg plus MTX group (-0.61).
Haemoglobin levels
Statistically significant improvements in haemoglobin levels were observed with tocilizumab compared with DMARDs (p< 0.0001) at week 24. Mean haemoglobin levels increased by week 2 and remained within normal range through to week 24.
Tocilizumab versus adalimumab in monotherapy
Study VI (WA19924), a 24 week double-blinded study that compared tocilizumab monotherapy with adalimumab monotherapy, evaluated 326 patients with RA who were intolerant of MTX or where continued treatment with MTX was considered inappropriate (including MTX inadequate responders). Patients in the 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 4).
Table 4: Efficacy Results for Study VI (WA19924)

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 (%)	17 (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
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%). The types of adverse drug reactions in the tocilizumab arm were consistent with the known safety profile of tocilizumab and adverse drug reactions were reported at a similar frequency compared with Table 1. A higher incidence of infections and infestations was reported in the tocilizumab arm (48% vs. 42%), with no difference in the incidence of serious infections (3.1%). Both study treatments induced the same pattern of changes in laboratory safety parameters (decreases in neutrophil and platelet counts, increases in ALT, AST and lipids), however, the magnitude of change and the frequency of marked abnormalities was higher with 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).
Subcutaneous use
Clinical efficacy
The efficacy of subcutaneous administered tocilizumab in alleviating the signs and symptoms of RA and radiographic response, was assessed in two randomised, double-blind, controlled, multi-center studies. For study I (SC-I), patients were required to be >18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 4 tender and 4 swollen joints at baseline. All patients received background non-biologic DMARD(s). For study II (SC-II), patients were required to be > 18 years of age with moderate to severe active RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline.
Switching from 8 mg/kg intravenous once every 4 weeks to 162 mg subcutaneous once every week, will alter exposure in the patient. The extent varies with the patient's body weight (increased in light body weight patients and decreased in heavy body weight patients) but clinical outcome is consistent with that observed in intravenous treated patients
Clinical response
Study SC-I evaluated patients with moderate to severe active RA who had an inadequate clinical response to their existing rheumatologic therapy, including one or more DMARD(s) where approximately 20% had a history of inadequate response to at least one TNF inhibitor. In SC-I, 1262 patients were randomized 1:1 to receive tocilizumab subcutaneous 162 mg every week or tocilizumab intravenous 8 mg/kg every four weeks in combination with non-biologic DMARD(s). The primary endpoint in the study was the difference in the proportion of patients who achieved an ACR20 response at week 24. The results from study SC-I is shown in Table 5.
Table 5. ACR responses in study SC-I (% patients) at Week 24

SC-Ia
	TCZ SC 162 mg every week + DMARD N=558	TCZ IV 8 mg/kg + DMARD N=537
ACR20 Week 24	69.4%	73.4%
Weighted difference (95% CI)	-4.0 (-9.2, 1.2)
ACR50 Week 24	47.0%	48.6%
Weighted difference (95% CI)	-1.8 (-7.5, 4.0)
ACR70 Week 24	24.0%	27.9%
Weighted difference (95% CI)	-3.8 (-9.0, 1.3)

TCZ = tocilizumab
a = Per Protocol Population
Patients in study SC-I had a mean Disease Activity Score (DAS28) at baseline of 6.6 and 6.7 on the subcutaneous and intravenous arms, respectively. At week 24, a significant reduction in DAS28 from baseline (mean improvement) of 3.5 was observed on both treatment arms, and a comparable proportion of patients had achieved DAS28 clinical remission (DAS28 < 2.6) on the subcutaneous (38.4%) and IV (36.9%) arms.
Radiographic response
The radiographic response of subcutaneous administered tocilizumab was assessed in a double-blind, controlled, multicenter study in patients with active RA (SC-II). Study SC-II evaluated patients with moderate to severe active RA who had an inadequate clinical response to their existing rheumatologic therapy, including one or more DMARD(s) where approximately 20% had a history of inadequate response to at least one TNF inhibitor. Patients were required to be >18 years of age with active RA diagnosed according to ACR criteria who had at least 8 tender and 6 swollen joints at baseline. In SC-II, 656 patients were randomized 2:1 to tocilizumab subcutaneous 162 mg every other week or placebo, in combination with non-biologic DMARD(s).
In study SC-II, inhibition of structural joint damage was assessed radiographically and expressed as a change from baseline in the van der Heijde modified mean total Sharp score (mTSS). At week 24, inhibition of structural damage was shown, with significantly less radiographic progression in patients receiving tocilizumab subcutaneous compared to placebo (mean mTSS of 0.62 vs. 1.23, p=0.0149 (van Elteren). These results are consistent with those observed in patients treated with intravenous tocilizumab.
In study SC-II, at week 24 there was ACR20 of 60.9%, ACR50 of 39.8% and ACR70 of 19.7% for patients treated with tocilizumab subcutaneous every other week versus placebo ACR20 of 31.5%, ACR50 of 12.3% and ACR70 of 5.0%. Patients had mean DAS28 at baseline of 6.7 on subcutaneous and 6.6 on placebo arms. At week 24, a significant reduction in DAS28 from baseline of 3.1 was observed on subcutaneous and 1.7 on placebo arm, and for DAS28 < 2.6, 32.0% was observed on subcutaneous and 4.0% on placebo arm.
Health-related and quality of life outcomes
In study SC-I, the mean decrease in HAQ-DI from baseline to week 24 was 0.6 on both the subcutaneous and intravenous arms. The proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was also comparable on the subcutaneous (65.2%) versus intravenous (67.4%) arms, with a weighted difference in proportions of - 2.3% (95% CI - 8.1, 3.4). For SF-36, the mean change from baseline at week 24 in the mental component score was 6.22 for the subcutaneous arm and 6.54 for the intravenous arm, and for the physical component score was also similar with 9.49 for the subcutaneous arm and 9.65 for the intravenous arm.
In study SC-II, mean decrease in HAQ-DI from baseline to week 24 was significantly greater for patients treated with tocilizumab subcutaneous every other week (0.4) versus placebo (0.3). Proportion of patients achieving a clinically relevant improvement in HAQ-DI at week 24 (change from baseline of ≥ 0.3 units) was higher for tocilizumab subcutaneous every other week (58%) versus placebo (46.8%). SF-36 (mean change in mental and physical component scores) was significantly greater with tocilizumab subcutaneous group (6.5 and 5.3) versus placebo (3.8 and 2.9).
The European Medicines Agency has deferred the obligation to submit the results of studies with RoActemra in one or more subsets of the paediatric population in the treatment of chronic idiopathic arthritis (including rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis and juvenile idiopathic arthritis). See section 4.2 for information on paediatric use.
5.2 Pharmacokinetic properties
Intravenous use
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 1,793 RA patients treated with a one-hour infusion of 4 and 8 mg/kg tocilizumab every 4 weeks for 24 weeks.
The following parameters (predicted mean ± SD) were estimated for a dose of 8 mg/kg tocilizumab given every 4 weeks: steady-state area under curve (AUC) = 35000 ± 15500 h µg/ml, trough concentration (Cmin) = 9.74 ± 14.8 μg/ml and maximum concentration (Cmax) = 183 ± 85.6 µg/ml, and. the accumulation ratios for AUC and Cmax were small, 1.22 and 1.06, respectively. The accumulation ratio was higher for Cmin (2.35), which was expected based on the non-linear clearance contribution at lower concentrations. Steady-state was reached following the first administration for Cmax and after 8 and 20 weeks for AUC and Cmin, respectively. Tocilizumab AUC, Cmin and Cmax increased with increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, Cmin and Cmax of tocilizumab were 55500 ± 14100 μg•h/mL, 19.0 ± 12.0 μg/mL, and 269 ± 57 μg/mL, respectively, which are higher than mean exposure values for the patient population (AUC = 35000 ± 15500 h µg/ml, Cmin = 9.74 ± 10.5 μg/ml and Cmax = 183 ± 85.6 µg/ml). The dose-response curve for tocilizumab flattens at higher exposure, resulting in smaller efficacy gains for each incremental increase in tocilizumab concentration such that clinically meaningful increases in efficacy were not demonstrated in patients treated with > 800 mg of tocilizumab. Therefore, tocilizumab doses exceeding 800 mg per infusion are not recommended (see section 4.2).
Distribution
In RA 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.
Elimination
Following intravenous administration, tocilizumab undergoes biphasic elimination from the circulation. The total clearance of tocilizumab was concentration-dependent and is the sum of the linear and non-linear clearance. The linear clearance was estimated as a parameter in the population pharmacokinetic analysis and was 12.5 ml/h. The concentration-dependent non-linear clearance plays a major role at low tocilizumab concentrations. Once the non-linear clearance pathway is saturated, at higher tocilizumab concentrations, clearance is mainly determined by the linear clearance.
The t1/2 of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/kg every 4 weeks, the effective t1/2 decreased with decreasing concentrations within a dosing interval from 14 days to 8 days.
Linearity
Pharmacokinetic parameters of tocilizumab did not change with time. A more than dose-proportional increase in the AUC and Cmin was observed for doses of 4 and 8 mg/kg every 4 weeks. Cmax increased dose-proportionally. At steady-state, predicted AUC and Cmin were 2.7 and 6.5 fold higher at 8 mg/kg as compared to 4 mg/kg, respectively.
Subcutaneous use
The pharmacokinetics of tocilizumab were determined using a population pharmacokinetic analysis on a database composed of 1759 RA patients treated with 162 mg subcutaneous every week, 162 mg subcutaneous every other week, and 8 mg/kg intravenous every 4 weeks for 24 weeks.
The pharmacokinetic parameters of tocilizumab did not change with time. For the 162 mg every week dose, the predicted mean (±SD) steady-state AUC1week, Cmin and Cmax of tocilizumab were 8200 ± 3600 mcg•h/mL, 44.6 ± 20.6 mcg/mL, and 50.9 ± 21.8 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 6.83, 6.37, and 5.47, respectively. Steady state was reached after 12 weeks for AUC, Cmin, and Cmax.
For the 162 every other week dose, the predicted mean (±SD) steady-state AUC2week, Cmin, and Cmax of tocilizumab were 3200 ± 2700 mcg•h/mL, 5.6 ± 7.0 mcg/mL, and 12.3 ± 8.7 mcg/mL, respectively. The accumulation ratios for AUC, Cmin, and Cmax were 2.67, 5.6, and 2.12, respectively. Steady state was reached after 12 weeks for AUC and Cmin, and after 10 weeks for Cmax.
Absorption
Following subcutaneous dosing in RA patients, the time to peak serum tocilizumab concentrations tmax was 2.8 days. The bioavailability for the subcutaneous formulation was 80%.
Elimination
For subcutaneous administration, the concentration-dependent apparent t 1/2 is up to 13 days for 162 mg every week and 5 days for 162 mg every other week in patients with RA at steady-state.
Special populations
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 population pharmacokinetic analysis had normal renal function or mild renal impairment. Mild renal impairment (creatinine clearance based on Cockcroft-Gault < 80 ml/min and ≥ 50 ml/min) did not impact the pharmacokinetics of tocilizumab.
Hepatic impairment: No formal study of the effect of hepatic impairment on the pharmacokinetics of tocilizumab has been conducted.
Age, gender and ethnicity: Population pharmacokinetic analyses in RA patients, showed that age, gender and ethnic origin did not affect the pharmacokinetics of tocilizumab.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and toxicity to reproduction and development.
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to have intrinsic carcinogenic potential.
Available non-clinical data demonstrated the effect of IL-6 on malignant progression and apoptosis resistance to various cancer types. This data does not suggest a relevant risk for cancer initiation and progression under tocilizumab treatment. Additionally, proliferative lesions were not observed in a 6-month chronic toxicity study in cynomolgus monkeys or in IL-6 deficient mice.
Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment. Effects on endocrine active and reproductive system organs were not observed in a chronic cynomolgus monkey toxicity study and reproductive performance was not affected in IL-6 deficient mice. Tocilizumab administered to cynomolgus monkeys during early gestation, was observed to have no direct or indirect harmful effect on pregnancy or embryonal-foetal development. However, a slight increase in abortion/embryonal-foetal death was observed with high systemic exposure (> 100 x human exposure) in the 50 mg/kg/day high-dose group compared to placebo and other low-dose groups. Although IL-6 does not seem to be a critical cytokine for foetal growth or the immunological control of the maternal/foetal interface, a relation of this finding to tocilizumab cannot be excluded.
Treatment with a murine analogue did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.
The non-clinical safety profile of tocilizumab in the cynomolgus monkey does not suggest a difference between intravenous and subcutaneous routes of administration.
6. Pharmaceutical particulars
6.1 List of excipients
L-Histidine
L-Histidine monohydrochloride monohydrate
L-Arginine
L-Arginine hydrochloride
L-Methionine
Polysorbate 80
Water for injections
6.2 Incompatibilities
In the absence of compatability studies, this medicinal product must not be mixed with other medicinal products.
6.3 Shelf life
30 months.
Once removed from the refrigerator, RoActemra must be administered within 8 hours and should not be kept above 30°C.
6.4 Special precautions for storage
Store in a refrigerator (2°C–8°C). Do not freeze.
Keep the pre-filled syringes in the outer carton in order to protect from light and moisture.
6.5 Nature and contents of container
0.9 ml solution in a pre-filled syringe (type I glass) with a staked-in needle . The syringe is closed by a rigid needle shield (elastomer seal with a polypropylene shell) and a plunger stopper (butyl rubber with a fluororesin coating).
Pack sizes of 4 pre-filled syringes and multipacks containing 12 (3 packs of 4) pre-filled syringes.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
RoActemra is supplied in a single use pre-filled syringe fitted into a needle safety device. After removing the pre-filled syringe from the refrigerator the pre-filled syringe should be allowed to reach room temperature (18°C to 28C°) by waiting for 25 to 30 minutes, before injecting RoActemra . The syringe should not be shaken. After removing the cap the injection must be started within 5 minutes, to prevent the medicine from drying out and blocking the needle. If the pre-filled syringe is not used within 5 minutes of removing the cap, you must dispose of it in a puncture resistant container and use a new pre-filled syringe.
If following insertion of the needle you cannot depress the plunger, you must dispose of the pre-filled syringe in a puncture resistant container and use a new pre-filled syringe.
Do not use if the medicine is cloudy or contains particles, is any colour besides colourless to slightly yellowish, or any part of the pre-filled syringe appears to be damaged.
Comprehensive instructions for the administration of RoActemra in a pre-filled syringe are given in the package leaflet.
Any unused product or waste material should be disposed of in accordance with local requirements.
7. Marketing authorisation holder
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8. Marketing authorisation number(s)
EU/1/08/492/007
EU/1/08/492/008
9. Date of first authorisation/renewal of the authorisation
16 January 2009
10. Date of revision of the text
1 September 2014
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
托珠单抗皮下注射剂型RoACTEMRA获欧盟批准
罗氏（Roche）4月28日宣布，皮下注射（subcutaneous，SC）剂型RoACTEMRA（欧洲以外名为ACTEMRA，通用名：tocilizumab，托珠单抗）获欧盟委员会（EC）批准，用于既往经一种或多种疾病修饰抗风湿药物（DMARDs）或肿瘤坏死因子（TNF）抑制剂治疗反应不足、或对这些药物不耐受的中度至重度活动性类风湿性关节炎（RA）成人患者的治疗。这是RoACTEMRA欧洲标签的第4个更新，将显著扩大该药的患者群体。
此次获批，使RoACTEMRA成为首个也是唯一一个可静脉滴注给药（IV）和皮下注射给药（SC）的人源化白细胞介素6受体拮抗剂单克隆抗体。与静脉注射（intravenous，IV）剂型一样，皮下注射剂型RoACTEMRA可作为单药疗法，同时也可与甲氨蝶呤（MTX）或其他非生物类DMARDs联合用药。
此前，皮下注射剂型RoACTEMRA已于2013年10月获FDA批准，商品名为ACTEMRA SC。
皮下注射剂型RoACTEMRA的获批，是基于III期临床试验SUMMACTA和BREVACTA研究的数据：
SUMMACTA是一项随机、双盲、活性药物对照、平行组、多中心III期临床研究，在1262例中度至重度活动性RA患者中开展。研究结果表明，皮下注射剂型（subcutaneous，SC）RoACTEMRA（162mg/周）达到了与静脉注射剂型（intravenous，IV）RoACTEMRA（8mg/kg/4周）相媲美的疗效，各组在24周时达到ACR20反应的患者比例相似（RoACTEMRA SC vs RoACTEMRA IV ：69% vs 73% ）。24周时的安全性分析表明，除SC组注射部位反应外，SC组和IV组不良事件相当。
BREVACTA是一项随机、双盲、平行组III期研究，调查了皮下注射剂型RoACTEMRA联合DMARDs用于治疗中度至重度活动性类风湿性关节炎患者时相对于安慰剂和DMARDs的疗效和安全性。研究结果表明，与安慰剂+DMARDs治疗组相比，RoACTEMRA SC+DMARDs治疗组有更多的患者达到ACR20反应（61% vs 32%）。该项研究中，除注射位点反应外，未发现临床意义的新安全信号。