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. 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:
RoActemra is not recommended for use in children below 18 years of age due to insufficient data on safety and efficacy. 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), investigations (total bilirubin increased), 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. 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 1 August 2011. On
medical prescription. Complete scientific information on request.
R. E.: Dr Chr
. Lenaerts - Br 9674 - 08/201
1
Price per vial:
RoACTEMRA
®
: 80mg : e151,02
RoACTEMRA
®
: 200mg : e375,02
RoACTEMRA
®
: 400mg : e748,30
Consistently high
remission* rates across
patient types in RA
* measured by DAS28<2.6 at 24 weeks