ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
RoActemra 20 mg/ml concentrate for solution for infusion.
2.
Each ml concentrate contains 20 mg tocilizumab*.
Each vial contains 80 mg of tocilizumab* in 4 ml (20 mg/ml).
Each vial contains 200 mg of tocilizumab* in 10 ml (20 mg/ml).
Each vial contains 400 mg of tocilizumab* in 20 ml (20 mg/ml).
*humanised IgG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor produced in
Chinese hamster ovary (CHO) cells by recombinant DNA technology.
Excipients
:
Each 80 mg vial contains 0.10 mmol (2.21 mg) sodium.
Each 200 mg vial contains 0.20 mmol (4.43 mg) sodium.
Each 400 mg vial contains 0.39 mmol (8.85 mg) sodium.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion (sterile concentrate).
Clear to opalescent, colourless to pale yellow solution.
4.
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.
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 (see Section 5.2).
Doses above 1.2 g have not been evaluated in clinical studies (see section 5.1).
2
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 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
> 3 to 5 x ULN
Interrupt RoActemra dosing until < 3 x ULN and follow recommendations
above for > 1 to 3 x ULN
(confirmed by
repeat testing, see
section 4.4).
For persistent increases > 3 x ULN, 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 10
9
/l.
Laboratory Value
(cells x 10
9
/ l )
Action
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
/ μl)
Action
50 to 100
Interrupt RoActemra dosing
When platelet count > 100 x 10
3
/ μl resume RoActemra at 4 mg/kg and increase
to 8 mg/kg as clinically appropriate
< 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.
3
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.
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.
For further information on dilution prior to administration, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Active, severe infections (see section 4.4).
Infections
Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive
agents including RoActemra (see section 4.8, Undesirable Effects). RoActemra treatment should 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) 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 reaction. 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 in 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.
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.
Complications of diverticulitis
Events of diverticular perforations as complications of diverticulitis have been reported uncommonly
with RoActemra (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
4
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 have been reported in association with infusion of RoActemra (see
section 4.8). Such reactions may be more severe, and potentially fatal in patients who have
experienced hypersensitivity reactions during previous infusions even if they have received
premedication with steroids and antihistamines. Appropriate treatment should be available for
immediate use in the event of an anaphylactic reaction during treatment with RoActemra. If an
anaphylactic reaction or other serious hypersensitivity / serious infusion related reaction occurs,
administration of RoActemra should be stopped immediately and RoActemra 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.
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, confirmed by repeat testing, 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 10
9
/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
10
3
/ μl). In patients who develop an ANC < 0.5 x 10
9
/ l or a platelet count < 50 x 10
3
/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.
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
5
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.
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.
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. RoActemra is not recommended for use with other biological agents.
Sodium
This medicinal product contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg. To
be taken into consideration by patients on a controlled sodium diet. Doses below 1025 mg of this
medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium free’.
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, phenytoin, ciclosporin, or benzodiazepines) should be
monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination
6
half-life (t
1/2
), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks
after stopping therapy.
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. Women of childbearing potential must use effective
contraception during and up to 3 months after treatment.
RoActemra should not be used during pregnancy unless clearly necessary.
Lactation
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.
No studies on the effects on the ability to drive and use machines have been performed. However,
given that dizziness has been commonly reported, patients who experience this adverse reaction
should be advised not to drive or use machines until it has resolved.
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..
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 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) or uncommon
(≥ 1/1,000 to < 1/100). Within each frequency grouping, undesirable effects are presented in order of
decreasing seriousness.
7
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
Very Common
Common
Uncommon
Infections and
infestations
Upper respiratory
tract infections
Cellulitis, Pneumonia,
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
Hypercholesterolae
mia*
Hypertriglyceridaemia
General disorders
and
administration
site conditions
Peripheral oedema
Hypersensitivity
reactions
Eye disorders
Conjunctivitis
Respiratory,
thoracic and
mediastinal
disorders
Cough, Dyspnoea
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
8
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 (see section 4.4). Fatal anaphylaxis has been reported after marketing authorisation during
treatment with 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 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
/ 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.
9
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.
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. 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.
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
10
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.
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, 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 4.8).
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).
11
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
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< 0.05, TCZ vs. PBO + MTX/DMARD
**
- p< 0.01, TCZ vs. PBO + MTX/DMARD
***
- p< 0.0001, TCZ vs. PBO + MTX/DMARD
12
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
≤
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.
5.2 Pharmacokinetic properties
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.
13
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.
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
85.6 µg/ml, and.
the accumulation ratios for AUC and C
max
were small, 1.22 and 1.06, respectively. The accumulation
ratio was higher for C
min
(2.35), which was expected based on the non-linear clearance contribution at
lower concentrations. Steady-state was reached following the first administration for C
max
and after 8
and 20 weeks for AUC and C
min
, respectively. Tocilizumab AUC, C
min
and C
max
increased with
increase of body weight. At body weight ≥ 100 kg, the predicted mean (± SD) steady-state AUC, C
min
and C
max
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
±
10.5
μ
g/ml and maximum concentration (C
max
) = 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).
15500 h µg/ml, C
min
= 9.74
±
10.5
μ
g/ml and C
max
= 183
±
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 t
1/2
of tocilizumab was concentration-dependent. At steady-state following a dose of 8 mg/kg
every 4 weeks, the effective t
1/2
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 C
min
was observed for doses of 4 and 8 mg/kg every 4 weeks. C
max
increased
dose-proportionally. At steady-state, predicted AUC and C
min
were 2.7 and 6.5 fold higher at 8 mg/kg
as compared to 4 mg/kg, respectively.
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 adult 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 and genotoxicity.
Carcinogenicity studies were not performed because IgG1 monoclonal antibodies are not deemed to
have intrinsic carcinogenic potential.
14
The following parameters (predicted mean
concentration (C
min
) = 9.74
±
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.
6.
6.1 List of excipients
Sucrose
Polysorbate 80
Disodium phosphate dodecahydrate
Sodium dihydrogen phosphate dihydrate
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
Unopened vial
: 30 months
Diluted product
: After dilution, the prepared solution for infusion is physically and chemically stable
in sodium chloride 9 mg/ml (0.9%) solution for injection at 30ºC for 24 hours.
From a microbiological point of view, the prepared solution for 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 would normally not be longer than 24 hours at 2°C–8°C, unless dilution has taken place in
controlled and validated aseptic conditions.
RoActemra is supplied as a sterile concentrate that does not contain preservatives.
6.4 Special precautions for storage
Store vials in a refrigerator (2°C–8°C). Do not freeze.
Keep the vial(s) in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product see section 6.3.
15
6.5 Nature and contents of container
RoActemra is supplied in a vial (type I glass) with a stopper (butyl rubber) containing 4 ml, 10 ml or
20 ml concentrate. Pack sizes of 1 and 4 vials.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Instructions for dilution prior to administration
Parenteral medicinal products 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 should be diluted
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection
from a 100 ml infusion bag, equal to the volume of RoActemra concentrate required for the patients
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 ml/kg) should be
withdrawn from the vial and placed in the 100 ml infusion bag. This should be a final volume of
100 ml. To mix the solution, gently invert the infusion bag to avoid foaming.
RoActemra is for single-use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
8.
EU/1/08/492/001
EU/1/08/492/002
EU/1/08/492/003
EU/1/08/492/004
EU/1/08/492/005
EU/1/08/492/006
9.
16 January 2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu/.
16
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
17
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Chugai Pharma Manufacturing Co., Ltd.
16-3 Kiyohara Kogyodanchi
Utsunomiya City
Tochigi, 321-3231
Japan
Name and address of the manufacturer responsible for batch release
Roche Pharma AG
Emil-Barell-Strasse 1
D-79639 Grenzach-Wyhlen
Germany
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
The
Marketing Authorisation Holder (
MAH) shall ensure that, at launch, all healthcare professionals
who are expected to prescribe/use RoActemra are provided with educational materials containing the
following:
•
Physician Information Pack
•
Nurse Information Pack
•
Patient Information Pack
The Physician Information pack should contain the following key elements:
•
The Summary of Product Characteristics
•
Dose calculation, preparation of infusion and infusion rate
•
Risk of serious infections
o
The product should not be given to patients with active or suspected infection
o
The product may lessen signs and symptoms of acute infection delaying the diagnosis
•
Serious infusion reaction and their management
•
Serious hypersensitivity reactions and their management
•
Risk of gastrointestinal perforations especially in patients with history of diverticulitis or
intestinal ulcerations
•
Reporting of serious adverse drug reactions
•
The Patient Information Packs (to be given to patients by healthcare professionals)
The Nurse Information Pack should contain the following key elements:
•
Prevention of medical errors and infusion reactions
o
Preparation of infusion
o
Infusion rate
18
•
Monitoring of the patient for infusion reactions
•
Reporting of serious adverse drug reactions
The Patient Information Pack should contain the following key elements:
•
Patient Information Leaflet
•
Patient Alert Card
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 4.1 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 11.0 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
19
ANNEX III
LABELLING AND PACKAGE LEAFLET
20
A. LABELLING
21
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
RoActemra 20 mg/ml concentrate for solution for infusion
Tocilizumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 80 mg tocilizumab.
3.
LIST OF EXCIPIENTS
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate
and water for injections. See package leaflet for further information.
4.
Concentrate for solution for infusion
80 mg/4 ml
1 vial of 4 ml
4 vials of 4 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous infusion after dilution
The diluted product should be used immediately
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
22
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
Keep the vial in the outer carton in order to protect from light
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/08/492/001
EU/1/08/492/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
RoActemra 20 mg/ml concentrate for solution for infusion
Tocilizumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 200 mg tocilizumab.
3.
LIST OF EXCIPIENTS
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate
and water for injections. See package leaflet for further information.
4.
Concentrate for solution for infusion
200 mg/10 ml
1 vial of 10 ml
4 vials of 10 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous infusion after dilution
The diluted product should be used immediately
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
24
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
Keep the vial in the outer carton, in order to protect from light
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/08/492/003
EU/1/08/492/004
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
25
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
CARTON
1.
RoActemra 20 mg/ml concentrate for solution for infusion
Tocilizumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
1 vial contains 400 mg tocilizumab.
3.
LIST OF EXCIPIENTS
Polysorbate 80, sucrose, disodium phosphate dodecahydrate, sodium dihydrogen phosphate dihydrate
and water for injections. See package leaflet for further information.
4.
Concentrate for solution for infusion
400 mg/20 ml
1 vial of 20 ml
4 vials of 20 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous infusion after dilution
The diluted product should be used immediately
Read the package leaflet before use
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
26
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
Do not freeze
Keep the vial in the outer carton, in order to protect from light
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
EU/1/08/492/005
EU/1/08/492/006
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
27
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
RoActemra 20 mg/ml sterile concentrate
Tocilizumab
IV
2.
METHOD OF ADMINISTRATION
IV infusion
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
80 mg/4 ml
6.
OTHER
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
RoActemra 20 mg/ml sterile concentrate
Tocilizumab
IV
2.
METHOD OF ADMINISTRATION
IV infusion
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
200 mg/10 ml
6.
OTHER
29
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
RoActemra 20 mg/ml sterile concentrate
Tocilizumab
IV
2.
METHOD OF ADMINISTRATION
IV infusion
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
400 mg/20 ml
6.
OTHER
30
RoActemra Patient Alert Card
This patient alert card contains important safety
information that you need to be aware of before
and during treatment with RoActemra.
Complications of Diverticulitis
Patients using RoActemra may develop
complications of diverticulitis which can
become serious if not treated.
•
Show this card to any doctor involved in
your care.
-
Seek medical attention immediately if
you develop stomach pain, colic, or
notice blood in your stools.
•
Read the RoActemra package leaflet for
more information.
Dates of
RoActemra
Treatment:
Infections
Start:
______________________
RoActemra increases the risk of getting
infections which can become serious if not
treated. In addition, some previous infections
may reappear.
-
-You should not be treated with
RoActemra if you have a severe
infection.
-
You should have been screened for
tuberculosis prior to treatment with
RoActemra
-
Talk to your doctor about any
vaccinations you may need before you
start treatment with RoActemra
-
If you have an infection of any kind
(even a head cold) at the time of your
next treatment, the infusion should be
delayed until you are feeling better
-
Seek medical attention immediately if
you develop symptoms such as fever,
persistent cough, weight loss, throat pain
or soreness, wheezing, red or swollen
skin blisters, tears, wounds, severe
weakness or tiredness.
-
Tell your doctor if you have hepatitis B
or if you know or suspect you are a
carrier of the hepatitis B virus.
Most recent:
______________________
•
Please make sure you also have a list of all
your other medicines with you at any visit
to a healthcare professional.
Patient’s Name: __________________
Doctor’s Name: __________________
Doctor’s Phone: __________________
Keep this card with you for 3 months after the
last RoActemra dose, since side effects could
occur for some time after your last dose of
RoActemra.
31
B. PACKAGE LEAFLET
32
PACKAGE LEAFLET: INFORMATION FOR THE USER
RoActemra 20 mg/ml concentrate for solution for infusion
Tocilizumab
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In addition to this leaflet, you will be given a
Patient Alert Card
, which contains important safety
information that you need to be aware of before and during treatment with RoActemra.
In this leaflet
:
1.
What RoActemra is and what it is used for
2.
Before you use RoActemra
4.
Possible side effects
5.
How to store RoActemra
6.
Further information
1.
WHAT ROACTEMRA IS AND WHAT IT IS USED FOR
RoActemra contains the active substance tocilizumab, a monoclonal antibody that blocks the action of
a specific protein (cytokine) called interleukin-6. This protein is involved in inflammatory processes of
the body, and blocking it can reduce the inflammation in your body.
RoActemra is used to treat adults with moderate to severe active rheumatoid arthritis (RA), an
autoimmune disease, if previous therapies did not work well enough. RoActemra helps to reduce
symptoms such as pain and swelling in your joints and can also improve your performance of daily
tasks. RoActemra has been shown to slow the damage to the cartilage and bone of the joints caused by
the disease and to improve your ability to do normal daily activities.
RoActemra is usually given in combination with methotrexate. However, RoActemra can be given
alone if your doctor determines that methotrexate is inappropriate.
2.
BEFORE YOU USE ROACTEMRA
Do not use RoActemra
-
if you are allergic (hypersensitive) to tocilizumab or any of the other ingredients of RoActemra
(listed in section 6, ‘What RoActemra contains’).
-
if you have an active, severe infection.
Take special care with RoActemra
-
If you experience allergic reactions such as chest tightness, wheezing, severe dizziness or light-
headedness, swelling of the lips or skin rash during or after the infusion, then tell your doctor
immediately.
-
If you have any kind of
infection,
short- or long-term,
or if you often get infections. Tell your
doctor immediately if you feel unwell. RoActemra can reduce your body’s ability to respond to
33
-
Keep this leaflet. You may need to read it again.
3.
How to use RoActemra
infections and may make an existing infection worse or increase the chance of getting a new
infection.
-
If you have had
tuberculosis, tell your doctor. Your doctor will check for signs and symptoms
-
If you have had
intestinal ulcers or diverticulitis, tell your doctor. Symptoms would include
abdominal pain and unexplained changes in bowel habits with a fever.
-
If you have liver disease,
tell your doctor. Before you use RoActemra, your doctor may examine
your liver function.
-
If you have recently got or are planning to get vaccinated
,
tell your doctor. Certain types of
vaccines should not be given while receiving RoActemra.
-
If you have cancer, tell your doctor. Your doctor will have to decide if you can still be given
RoActemra.
-
If you have cardiovascular risk factors such as raised blood pressure and raised cholesterol
levels, tell your doctor. These factors need to be monitored while receiving RoActemra.
-
If you have moderate to severe kidney function problems, your doctor will monitor you.
Your doctor will perform a blood test before you receive RoActemra, to determine if you have a low
white blood cell count, low platelet count or high liver enzymes.
RoActemra is not recommended for use in children or adolescents under 18 years of age.
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. RoActemra can affect the way some medicines work, and
the dose of these may require adjustment. You should tell your doctor if you are using medicines
containing any of the following active substances:
•
atorvastatin, used to reduce cholesterol levels
•
calcium channel blockers (e.g. amlodipine), used to treat raised blood pressure
•
theophylline, used to treat asthma
•
warfarin, used as a blood thinning agent
•
phenytoin, used to treat convulsions
•
ciclosporin, used to suppress your immune system during organ transplants
•
benzodiazepines (e.g. temazepam), used to relieve anxiety
Due to lack of clinical experience, RoActemra is not recommended for use with other biological
medicines for the treatment of RA.
Pregnancy and breast-feeding
Talk to your doctor if you are pregnant, may be pregnant, intend to become pregnant or if you are
breast-feeding. Women of childbearing potential must use effective contraception during and up to
3 months after treatment. RoActemra should not be used during pregnancy unless clearly necessary.
It is not known whether RoActemra is excreted in breast milk. If you are a nursing mother, you should
stop breast-feeding if you are to be given RoActemra. Before starting breast-feeding, your last
treatment with RoActemra should be at least 3 months ago.
Driving and using machines
There are no studies on the effects of RoActemra on the ability to drive and use machines. However, if
you experience dizziness, a common side effect, then you should not drive or use machines.
34
of tuberculosis before starting RoActemra.
Important information about some of the ingredients of RoActemra
This medicinal product contains 26.55 mg sodium per maximum dose of 1200 mg (8.85 mg sodium
per 400 mg vial). To be taken into consideration by patients on a controlled sodium diet. Doses below
1025 mg of this medicinal product contain less than 1 mmol sodium (23 mg), i.e. essentially ‘sodium
free’.
3.
HOW TO USE ROACTEMRA
The usual dose of RoActemra is 8 mg per kg of body weight. Depending on your response, your
doctor may decrease your dose to 4 mg/kg then increase back to 8 mg/kg when appropriate.
You will receive RoActemra once every 4 weeks through a drip in your vein (intravenous infusion)
over one hour.
After dilution, RoActemra will be given to you by a doctor or nurse, who will also monitor you during
and after administration.
If you use more RoActemra than you should
Since RoActemra is given by a doctor or nurse, it is unlikely that you will be given too much.
However, if you are worried, talk to your doctor.
If you forget to use RoActemra
Since RoActemra is given by a doctor or nurse, it is unlikely that you will miss a dose. However, if
you are worried, talk to your doctor.
If you stop using RoActemra
You should not stop using RoActemra without discussing with your doctor first.
If you have any further questions on the use of RoActemra, then please ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, RoActemra can cause side effects, although not everybody gets them.
Side effects could occur at least up to 3 months after your last dose of RoActemra.
The most common side effects of RoActemra are upper respiratory tract infections, with typical
symptoms such as cough, blocked nose, runny nose, sore throat and headache.
Possible serious side effects
include serious infections and allergic (hypersensitivity) reactions, that
may, in a small number of cases, be life-threatening.
If you notice any of the following signs of:
allergic reactions
during or after infusion, tell your doctor
immediately
:
-
difficulty with breathing or light-headedness
-
rash, itching, hives, swelling of the lips.
infections
, tell your doctor
as soon as possible
:
-
mouth or skin blisters
-
stomach ache
-
persistent headaches.
The symptoms described above can be signs of the side effects listed below, all of which have been
observed with RoActemra in clinical studies.
35
-
fever and chills
Side effects may occur with certain frequencies, which are defined as follows:
-
very common: affects more than 1 user in 10
-
common: affects 1 to 10 users in 100
-
uncommon: affects 1 to 10 users in 1,000
-
very rare: affects less than 1 user in 10,000
-
not known: frequency cannot be estimated from the available data.
Very common side effects
:
upper respiratory tract infections like coughs and colds, and high
cholesterol levels.
Common side effects
:
lung infection (pneumonia),
cold sores (oral herpes simplex), blisters, shingles
(herpes zoster), skin infection sometimes with fever and chills, low white blood cell counts
shown by blood tests (neutropenia, leucopenia), headache, dizziness, high blood pressure,
mouth ulceration, stomach pain, abnormal liver function tests (increased transaminases),
increased bilirubin shown by blood tests, rash and itching, hives, fluid retention (oedema) in the
lower legs, cough, shortness of breath, weight increase, eye infection (conjunctivitis) and
allergic (hypersensitivity) reactions
Uncommon side effects
:
diverticulitis (fever, nausea, diarrhoea, constipation, stomach pain), red
swollen (inflamed) areas in the mouth, high blood fat (triglycerides), stomach ulcer, kidney stones and
underactive thyroid.
Very rare side effects:
low blood measurements for white blood cells, red blood cells and platelet
count.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE ROACTEMRA
Keep out of the reach and sight of children.
Store in a refrigerator (2°C–8°C). Do not freeze.
Keep the vial in the outer carton in order to protect from light.
6.
FURTHER INFORMATION
What RoActemra contains
-
The active substance is tocilizumab.
Each 4 ml vial contains 80 mg tocilizumab (20 mg/ml).
Each 10 ml vial contains 200 mg tocilizumab (20 mg/ml).
Each 20 ml vial contains 400 mg tocilizumab (20 mg/ml).
-
The other ingredients are sucrose, polysorbate 80, disodium phosphate dodecahydrate, sodium
dihydrogen phosphate dihydrate and water for injections.
What RoActemra looks like and contents of the pack
RoActemra is a concentrate for solution for infusion. The concentrate is a clear to opalescent,
colourless to pale yellow liquid.
RoActemra is supplied as vials containing 4 ml, 10 ml and 20 ml concentrate for solution for infusion.
Pack size of 1 and 4 vials. Not all pack sizes may be marketed.
Marketing Authorisation Holder
Roche Registration Limited
36
-
rare: affects 1 to 10 users in 10,000
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom
Manufacturer
Roche Pharma AG
Emil-Barell-Str. 1
D-79639 Grenzach-Wyhlen
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
N.V. Roche S.A.
Tél/Tel: +32 (0) 2 525 82 11
Luxembourg/Luxemburg
(Voir/siehe Belgique/Belgien)
България
Рош България ЕООД
Тел: +359 2 818 44 44
Magyarország
Roche (Magyarország) Kft.
Tel: +36 - 23 446 800
Česká republika
Roche s. r. o.
Tel: +420 - 2 20382111
Malta
(See United Kingdom,
Roche Products Ltd.
Tel: +44 (0) 1707 366000)
Danmark
Roche a/s
Tlf: +45 - 36 39 99 99
Nederland
Roche Nederland B.V.
Tel: +31 (0) 348 438050
Deutschland
Roche Pharma AG
Tel: +49 (0) 7624 140
oder
Chugai Pharma Marketing Ltd.
Zweigniederlassung Deutschland
Tel: +49 (0) 69 663000 0
Norge
Roche Norge AS
Tlf: +47 - 22 78 90 00
Eesti
Roche Eesti OÜ
Tel: + 372 - 6 177 380
Österreich
Roche Austria GmbH
Tel: +43 (0) 1 27739
Ελλάδα
Roche (Hellas) A.E.
Τηλ: +30 210 61 66 100
Polska
Roche Polska Sp.z o.o.
Tel: +48 - 22 345 18 88
España
Roche Farma S.A.
Tel: +34 - 91 324 81 00
Portugal
Roche Farmacêutica Química, Lda
Tel: +351 - 21 425 70 00
37
France
Roche
Tél: +33 (0) 1 46 40 50 00
ou
Chugai Pharma France
Tél: +33 (0) 1 56 37 05 20
România
Roche România S.R.L.
Tel: +40 21 206 47 01
Ireland
Roche Products (Ireland) Ltd.
Tel: +353 (0) 1 469 0700
Slovenija
Roche farmacevtska družba d.o.o.
Tel: +386 - 1 360 26 00
Ísland
Roche a/s
c/o Icepharma hf
Sími: +354 540 8000
Slovenská republika
Roche Slovensko, s.r.o.
Tel: +421 - 2 52638201
Italia
Roche S.p.A.
Tel: +39 - 039 2471
Suomi/Finland
Roche Oy
Puh/Tel: +358 (0) 10 554 500
Kύπρος
Γ.Α.Σταμάτης & Σια Λτδ.
Τηλ: +357 - 22 76 62 76
Sverige
Roche AB
Tel: +46 (0) 8 726 1200
Latvija
Roche Latvija SIA
Tel: +371 - 6 7039831
United Kingdom
Roche Products Ltd.
Tel: +44 (0) 1707 366000
or
Chugai Pharma UK Ltd.
Tel: +44 (0) 208 987 5600
Lietuva
UAB “Roche Lietuva”
Tel: +370 5 2546799
This leaflet was last approved
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu/
The following information is intended for medical or healthcare professionals only
Instructions for dilution prior to administration
Parenteral medicinal products 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 should be diluted
Withdraw a volume of sterile, non-pyrogenic sodium chloride 9 mg/ml (0.9%) solution for injection
from a 100 ml infusion bag, equal to the volume of RoActemra concentrate required for the patients
dose, under aseptic conditions. The required amount of RoActemra concentrate (0.4 ml/kg) should be
withdrawn from the vial and placed in the 100 ml infusion bag. This should be a final volume of
100 ml. To mix the solution, gently invert the infusion bag to avoid foaming.
RoActemra is for single-use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
38
Source: European Medicines Agency
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