SUMMARY OF PRODUCT CHARACTERISTICS
Name of the medicinal product RoActemra 20 mg/ml concentrate for solution for infusion. Pharmaceutical form/qualitative and quantitative composition Concentrate for solution
for infusion (sterile concentrate). Clear to opalescent, colourless to pale yellow solution. Each ml concentrate contains 20 mg tocilizumab. Each 4ml vial contains 80 mg of tocilizumab
and 0.10 mmol (2.21 mg) sodium. Each 10 ml vial contains 200 mg of tocilizumab and 0.20 mmol (4.43 mg) sodium. Each 20 ml vial contains 400 mg of tocilizumab and 0.39 mmol
(8.85 mg) sodium. Tocilizumab is a humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in Chinese hamster ovary (CHO) cells by recombinant
DNA technology.
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.
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. Posology The recommended posology is 8 mg/kg body weight, given once every four weeks. For individuals whose body weight is
more than 100 kg, doses exceeding 800 mg per infusion are not recommended. Doses above 1.2 g have not been evaluated in clinical studies. Dose adjustments due to laboratory
abnormalities Liver enzyme abnormalities Laboratory Value > 1 to 3 x Upper Limit of Normal (ULN): Dose modify concomitant MTX if appropriate. For persistent increases in this range,
reduce RoActemra dose to 4 mg/kg or interrupt RoActemra until alanine aminotransferase (ALT) or aspartate aminotransferase (AST) have normalised. Restart with 4 mg/kg or 8 mg/kg,
as clinically appropriate. Laboratory Value > 3 to 5 x ULN (confirmed by repeat testing): Interrupt RoActemra dosing until < 3 x ULN and follow recommendations above for > 1 to 3 x
ULN. For persistent increases > 3 x ULN, discontinue RoActemra. Laboratory Value > 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 10
9
/l. Laboratory Value (cells x 10
9
/ l) ANC > 1: Maintain dose. ANC
0.5 to 1: Interrupt RoActemra dosing. When ANC increases > 1 x 10
9
/ l resume RoActemra at 4 mg/kg and increase to 8 mg/kg as clinically appropriate. ANC < 0.5: Discontinue
RoActemra. Low platelet count Laboratory Value (cells x 10
3
/l) 50 to 100: Interrupt RoActemra dosing. When platelet count > 100 x 10
3
/ l resume RoActemra at 4 mg/kg and increase
to 8 mg/kg as clinically appropriate. Laboratory Value < 50: Discontinue RoActemra. Special populations Paediatric patients: See complete information for use in systemic juvenile
idiopathic arthritis (sJIA). 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. 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. Method of administration After dilution, RoActemra
should be administered as an intravenous infusion over 1 hour. RoActemra should be diluted to a final volume of 100 ml with sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%)
solution for injection using aseptic technique.
Contraindications Hypersensitivity to the active substance or to any of the excipients. Active, severe infections. Undesirable effects The
safety of tocilizumab has been studied in 4 placebo-controlled studies, 1 MTX-controlled study and their extension periods. The double-blind controlled period was 6 months in four
studies and was up to 2 years in one study. 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 1 year, 2806 received treatment for at least 2 years and 1222 for 3 years. The most commonly reported 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 ADRs listed
below are presented by system organ class and frequency categories, defined using the following convention: very common ( 1/10); common ( 1/100 to < 1/10) or uncommon
( 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 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:
Very Common: Infections and infestations (upper respiratory tract
infections); Metabolism and nutrition disorders (hypercholesterolaemia*)
Common: Infections and infestations (cellulitis, pneumonia, oral herpes simplex, herpes zoster); Gastrointestinal
disorders (abdominal pain, mouth ulceration, gastritis); 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);
General disorders and administration site conditions (peripheral oedema, hypersensitivity reactions); Eye disorders (conjunctivitis); Respiratory, thoracic and mediastinal disorders
(cough, dyspnoea)
Uncommon: Infections and infestations (diverticulitis); Gastrointestinal disorders (stomatitis, gastric ulcer); Metabolism and nutrition disorders (hypertriglyceridaemia);
Renal disorders (nephrolithiasis); Endocrine disorders (hypothyroidism). *Includes elevations collected as part of routine laboratory monitoring (see text below) 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 six 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 6/3,778 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 13 out of 3,778 patients (0.3%) treated with tocilizumab during the controlled and open label clinical studies. These reactions were generally observed during the second to fifth
infusions of tocilizumab. Fatal anaphylaxis has been reported after marketing authorisation during treatment with tocilizumab. 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 10
9
/ 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 10
9
/ l did so within 8 weeks after starting therapy. Decreases below 0.5 x 10
9
/ l were reported in
0.3% patients receiving tocilizumab 8 mg/kg plus DMARDs. Infections with neutropenia have been reported. It is not clear if the infections were related to neutropenia. 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 10
3
/ l 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 six
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.
Marketing authorisation holder Roche
Registration Limited. United Kingdom.
Marketing authorisation number(s) EU/1/08/492/002; EU/1/08/492/004; EU/1/08/492/006. Date of first authorisation 16 January 2009 Date
of revision of the text 25 May 2012. On medical prescription. Complete scientific information on request.