ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
TYSABRI 300 mg concentrate for solution for infusion.
2.
2.1 General description
Concentrate: Each ml of concentrate contains 20 mg of natalizumab.
Natalizumab is a recombinant humanised anti-α4-integrin antibody produced in a murine cell line by
recombinant DNA technology.
2.2 Qualitative and quantitative composition
When diluted (see section 6.6), the solution for infusion contains approximately 2.6 mg/ml of
natalizumab.
For a full list of excipients, see section 6.1.
3.
Concentrate for solution for infusion.
Colourless, clear to slightly opalescent solution.
4.
TYSABRI is indicated as single disease modifying therapy in highly active relapsing remitting
multiple sclerosis for the following patient groups:
Patients with high disease activity despite treatment with a beta-interferon.
These patients may be defined as those who have failed to respond to a full and adequate course
(normally at least one year of treatment) of beta-interferon. Patients should have had at least 1
relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in
cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be
defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as
compared to the previous year.
or
Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or
more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain
MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.
2
TYSABRI therapy is to be initiated and continuously supervised by specialised physicians
experienced in the diagnosis and treatment of neurological conditions, in centres with timely access to
MRI.
Patients treated with TYSABRI must be given the patient alert card and be informed about the risks of
Tysabri (see also patient information leaflet). After 2 years of treatment, patients should be re-
informed about the risks of Tysabri, especially the increased risk of PML, and should be instructed
together with their caregivers on early signs and symptoms of PML.
Resources for the management of hypersensitivity reactions and access to MRI should be available.
Patients can switch directly from beta interferon or glatiramer acetate to natalizumab providing there
are no signs of relevant treatment-related abnormalities e.g. neutropenia. If there are signs of
treatment-related abnormalities these must return to normal before treatment with natalizumab is
started.
Some patients may have been exposed to immunosuppressive medications (e.g. mitoxantrone,
cyclophosphamide, azathioprine). These drugs have the potential to cause prolonged
immunosuppression, even after dosing is discontinued. Therefore the physician must confirm that
such patients are not immunocompromised before starting treatment with TYSABRI (see also section
4.4).
Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic
benefit beyond 6 months.
Data on the safety and efficacy of natalizumab at 2 years were generated from controlled, double–
blind studies. Continued therapy beyond this time should be considered only following a
reassessment of the potential for benefit and risk.
Posology
Adults
TYSABRI 300 mg is administered by intravenous infusion once every 4 weeks.
Elderly
TYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this
population.
Paediatric Population
TYSABRI is contraindicated in children below the age of 18 years (see section 4.3).
Renal and hepatic impairment
Studies have not been conducted to examine the effects of renal or hepatic impairment.
The mechanism for elimination and results from population pharmacokinetics suggest that dose
adjustment would not be necessary in patients with renal or hepatic impairment.
Method of Administration
For instructions on dilution of the medicinal product before administration, see section 6.6.
3
After dilution (see section 6.6), the infusion is to be administered over approximately 1 hour and
patients are to be observed during the infusion and for 1 hour after the completion of the infusion for
signs and symptoms of hypersensitivity reactions.
TYSABRI must not be administered
as a bolus injection.
Readministration
The efficacy of re-administration has not been established, for safety see section 4.4.
Hypersensitivity to natalizumab or to any of the excipients.
Progressive multifocal leukoencephalopathy (PML).
Patients with increased risk for opportunistic infections, including immunocompromised patients
(including those currently receiving immunosuppressive therapies or those immunocompromised by
prior therapies, e.g. mitoxantrone or cyclophosphamide, see also sections 4.4 and 4.8).
Combination with beta-interferons or glatiramer acetate.
Known active malignancies, except for patients with cutaneous basal cell carcinoma.
Children below the age of 18 years.
Progressive Multifocal Leukoencephalopathy (PML)
Use of TYSABRI has been associated with an increased risk of PML which may be fatal or result in
severe disability. The risk of PML increases with treatment duration, especially beyond 2 years. There
is limited experience in patients who received more than 3 years of Tysabri treatment therefore the
risk of PML in these patients cannot currently be estimated. The risk of PML is also increased in
patients who have been treated with an immunosuppressant prior to receiving TYSABRI. This
increased risk appears to be independent of TYSABRI treatment duration. Due to this increased risk
of developing PML, the benefits and risks of Tysabri treatment should be individually reconsidered by
the specialist physician and the patient.
The patient should be re-informed about the risks of Tysabri after 2 years especially the increased risk
of PML, and should be instructed together with their caregivers on early signs and symptoms of PML.
Before initiation of treatment with TYSABRI, a recent (usually within 3 months) Magnetic
Resonance Image (MRI) should be available as a reference, and be repeated on a yearly routine basis
to update this reference. Patients must be monitored at regular intervals throughout treatment for any
new or worsening neurological symptoms or signs that may be suggestive of PML.
If PML is suspected, further dosing must be suspended until PML has been excluded.
The clinician should evaluate the patient to determine if the symptoms are indicative of neurological
dysfunction, and if so, whether these symptoms are typical of MS or possibly suggestive of PML. If
any doubt exists, further evaluation, including MRI scan preferably with contrast (compared with pre-
treatment MRI), CSF testing for JC Viral DNA and repeat neurological assessments, should be
considered as described in the Physician Information and Management Guidelines (see educational
4
guidance). Once the clinician has excluded PML (if necessary, by repeating clinical, imaging and/or
laboratory investigations if clinical suspicion remains), dosing of natalizumab may resume.
The physician should be particularly alert to symptoms suggestive of PML that the patient may not
notice (e.g. cognitive or psychiatric symptoms). Patients should also be advised to inform their
partner or caregivers about their treatment, since they may notice symptoms that the patient is not
aware of.
If a patient develops PML the dosing of TYSABRI must be permanently discontinued.
Following reconstitution of the immune system in immunocompromised patients with PML improved
outcome has been seen.
PML and IRIS (Immune Reconstitution Inflammatory Syndrome)
IRIS occurs in almost all TYSABRI PML patients after withdrawal or removal of TYSABRI, e.g. by
plasma exchange (see section 5.2). IRIS is thought to result from the restoration of immune function
in patients with PML, which can lead to serious neurological complications and may be fatal.
Monitoring for development of IRIS, which has occurred within days to several weeks after plasma
exchange in TYSABRI treated patients with PML, and appropriate treatment of the associated
inflammation during recovery from PML should be undertaken (see the Physician Information and
Management Guidelines for further information).
Other Opportunistic Infections
Other opportunistic infections have been reported with use of TYSABRI, primarily in patients with
Crohn’s disease who were immunocompromised or where significant co-morbidity existed, however
increased risk of other opportunistic infections with use of TYSABRI in patients without these co-
morbidities cannot currently be excluded. Opportunistic infections were also detected in MS patients
treated with TYSABRI as a monotherapy (see section 4.8).
Prescribers should be aware of the possibility that other opportunistic infections may occur during
TYSABRI therapy and should include them in the differential diagnosis of infections that occur in
TYSABRI-treated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be
suspended until such infections can be excluded through further evaluations.
If a patient receiving TYSABRI develops an opportunistic infection, dosing of TYSABRI must be
permanently discontinued.
Educational guidance
All physicians who intend to prescribe TYSABRI must ensure they are familiar with the Physician
Information and Management Guidelines.
Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them
with a Patient Alert Card. Patients should be instructed that if they develop any infection then they
should inform their physician that they are being treated with TYSABRI.
Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early
months of treatment (see hypersensitivity).
Hypersensitivity
Hypersensitivity reactions have been associated with TYSABRI, including serious systemic reactions
(see section 4.8). These reactions usually occurred during the infusion or up to 1 hour after
completion of the infusion. The risk for hypersensitivity was greatest with early infusions and in
patients re-exposed to TYSABRI following an initial short exposure (one or two infusions) and
5
extended period (three months or more) without treatment. However, the risk of hypersensitivity
reactions should be considered for every infusion administered.
Patients are to be observed during the infusion and for 1 hour after the completion of the infusion (see
section 4.8). Resources for the management of hypersensitivity reactions should be available.
Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or
signs of hypersensitivity.
Patients who have experienced a hypersensitivity reaction must be permanently discontinued from
treatment with TYSABRI.
Concurrent or prior treatment with immunosuppressants
The safety and efficacy of TYSABRI in combination with other immunosuppressive and
antineoplastic therapies have not been fully established. Concurrent use of these agents with
TYSABRI may increase the risk of infections, including opportunistic infections, and is
contraindicated (see section 4.3).
Patients with a treatment history of immunosuppressant medications are at increased risk for PML.
Care should be taken with patients who have previously received immunosuppressants to allow
sufficient time for immune function recovery to occur. Physicians must evaluate each individual case
to determine whether there is evidence of an immunocompromised state prior to commencing
treatment with TYSABRI (see section 4.3).
In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids
was not associated with an increased rate of infection. Short courses of corticosteroids can be used in
combination with TYSABRI.
Immunogenicity
Disease exacerbations or infusion related events may indicate the development of antibodies against
natalizumab. In these cases the presence of antibodies should be evaluated and if these remain
positive in a confirmatory test after 6 weeks, treatment should be discontinued, as persistent
antibodies are associated with a substantial decrease in efficacy of TYSABRI and an increased
incidence of hypersensitivity reactions (see section 4.8).
Since patients who have received an initial short exposure to TYSABRI and then had an extended
period without treatment are more at risk for hypersensitivity upon redosing, the presence of
antibodies should be evaluated and if these remain positive in a confirmatory test after 6 weeks
treatment should not be resumed.
Hepatic Events
Spontaneous serious adverse reactions of liver injury have been reported during the post marketing
phase. These liver injuries may occur at any time during treatment, even after the first dose. In some
instances, the reaction reoccurred when TYSABRI was reintroduced. Some patients with a past
medical history of an abnormal liver test have experienced an exacerbation of abnormal liver test
while on TYSABRI. Patients should be monitored as appropriate for impaired liver function, and be
instructed to contact their physician in case signs and symptoms suggestive of liver injury occur, such
as jaundice and vomiting. In cases of significant liver injury TYSABRI should be discontinued.
Stopping TYSABRI therapy
If a decision is made to stop treatment with natalizumab, the physician needs to be aware that
natalizumab remains in the blood, and has pharmacodynamic effects (e.g increased lymphocyte
6
counts) for approximately 12 weeks following the last dose. Starting other therapies during this
interval will result in a concomitant exposure to natalizumab. For drugs such as interferon and
glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in
clinical trials. No data are available in MS patients regarding concomitant exposure with
immunosuppressant medication. Use of these medicines soon after the discontinuation of natalizumab
may lead to an additive immunosuppressive effect. This should be carefully considered on a
case-by-case basis, and a wash-out period of natalizumab might be appropriate. Short courses of
steroids used to treat relapses were not associated with increased infections in clinical trials.
See section 4.3.
Women of childbearing potential
If a woman becomes pregnant while taking TYSABRI, discontinuation of TYSABRI should be
considered.
Pregnancy
There are no adequate data from the use of natalizumab in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Natalizumab should not be used during pregnancy unless the clinical condition of the women requires
treatment with TYSABRI.
Breastfeeding
TYSABRI is excreted in human milk. The effect of natalizumab on newborn/infants is unknown.
Breast-feeding should be discontinued during treatment with Tysabri.
Fertility
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human
dose; natalizumab did not affect male fertility. It is considered unlikely that natalizumab will affect
fertility performance in humans following the maximum recommended dose.
Based on the pharmacological mechanism of action of natalizumab, the use of TYSABRI has no or
negligible influence on the ability to drive and use machines.
4.8 Undesirable effect
In placebo-controlled trials in 1,617 MS patients treated with natalizumab for up to 2 years (placebo:
1,135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with
natalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated with
natalizumab reported adverse drug reactions (placebo: 39.6%)
1
. Adverse drug reactions reported
with natalizumab with an incidence of 0.5% greater than reported with placebo are shown below. The
reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class.
Frequencies were defined as follows:
Common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100).
1
An adverse event judged related to therapy by the investigating physician.
7
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Nervous system disorders
Common Headache
Dizziness
Gastrointestinal disorders
Common Vomiting
Nausea
Musculoskeletal and connective tissue disorders
Common Arthralgia
Infections and infestations
Common Urinary tract infection
Nasopharyngitis
General disorders and administration site conditions
Common Rigors
Pyrexia
Fatigue
Immune system disorders
Common
Urticaria
Uncommon
Hypersensitivity
Infusion reactions
In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse
event occurring during the infusion or within 1 hour of the completion of the infusion. These
occurred in 23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more
commonly with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.
Hypersensitivity reactions
In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of
patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving
TYSABRI. Hypersensitivity reactions usually occurred during the infusion or within the 1-hour
period after the completion of the infusion (See section 4.4). In post-marketing experience, there have
been reports of hypersensitivity reactions which have occurred with one or more of the following
associated symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema,
in addition to more usual symptoms such as rash and urticaria.
Immunogenicity
In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in
MS patients. Persistent anti-natalizumab antibodies (one positive test reproducible on retesting at least
6 weeks later) developed in approximately 6% of patients. Antibodies were detected on only one
occasion in an additional 4% of patients. Persistent antibodies were associated with a substantial
decrease in the effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions.
Additional infusion-related reactions associated with persistent antibodies included rigors, nausea,
vomiting and flushing (see section 4.4).
If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced
efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a
8
subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the
incidence of hypersensitivity or infusion-related reactions may be increased in a patient with
persistent antibodies, treatment should be discontinued in patients who develop persistent antibodies.
Infections, including PML and opportunistic infections
In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per
patient-year in both natalizumab- and placebo-treated patients. The nature of the infections was
generally similar in natalizumab- and placebo-treated patients. A case of
cryptosporidium
diarrhoea
was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections
have been reported, some of which were fatal. In clinical trials, herpes infections (Varicella-Zoster
virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in
placebo-treated patients. In post marketing experience, there have been reports of serious cases,
including one fatal case of herpes encephalitis. See section 4.4.
The majority of patients did not interrupt natalizumab therapy during infections and recovery
occurred with appropriate treatment.
In clinical trials, cases of PML have been reported. PML usually leads to severe disability or
death
(see section 4.4). In pivotal clinical trials, two cases, including one fatality, occurred in MS patients
who were being treated with concomitant interferon beta-1a therapy for more than 2 years. In another
trial, one patient with Crohn’s disease, who had a long history of treatment with immunosuppressants
and associated lymphopenia also developed PML and died.
PML has been reported in post-marketing experience in patients treated with TYSABRI monotherapy.
Hepatic Events
Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been
reported during the post marketing phase (see section 4.4).
Malignancies
No differences in incidence rates or the nature of malignancies between natalizumab- and
placebo-treated patients were observed over 2 years of treatment. However, observation over longer
treatment periods is required before any effect of natalizumab on malignancies can be excluded. See
section 4.3.
Effects on laboratory tests
TYSABRI treatment was associated with increases in circulating lymphocytes, monocytes,
eosinophils, basophils and nucleated red blood cells. Elevations in neutrophils were not seen.
Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to
140% for individual cell types but mean cell counts remained within normal ranges. During treatment
with TYSABRI, small reductions in haemoglobin (mean decrease 0.6 g/dl), haematocrit (mean
decrease 2%) and red blood cell counts (mean decrease 0.1 x 10
6
/l) were seen. All changes in
haematological variables returned to pre-treatment values, usually within 16 weeks of last dose of
TYSABRI and the changes were not associated with clinical symptoms.
No case of overdose has been reported.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Selective Immunosuppressive Agent, ATC code: L04AA23.
Pharmacodynamic effects
Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human
integrins, which is highly expressed on the surface of all leukocytes, with the exception of
neutrophils. Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its
cognate receptor, vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an
alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the
interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1).
Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across
the endothelium into inflamed parenchymal tissue. A further mechanism of action of natalizumab
may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of
α4-expressing leukocytes with their ligands in the extracellular matrix and on parenchymal cells. As
such, natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit
further recruitment of immune cells into inflamed tissues.
In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier
(BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on
inflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and its
targets is an important component of pathological inflammation in the brain and disruption of these
interactions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in
the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is
upregulated on endothelial cells and possibly on glial cells near the sites of inflammation. In the
setting of central nervous system (CNS) inflammation in MS, it is the interaction of α4β1 with
VCAM-1, CS-1 and osteopontin that mediates the firm adhesion and transmigration of leukocytes into
the brain parenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the
molecular interactions of α4β1 with its targets reduces inflammatory activity present in the brain in
MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation
or enlargement of MS lesions.
Clinical efficacy
Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo-controlled
study lasting 2 years (AFFIRM study)
in relapsing-remitting MS patients who had experienced at least
1 clinical relapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale
(EDSS) score between 0 and 5. Median age was 37 years, with a median disease duration of 5 years.
The patients were randomised with a 2:1 ratio to receive TYSABRI 300 mg (n = 627) or placebo
(n = 315) every 4 weeks for up to 30 infusions. Neurological evaluations were performed every
12 weeks and at times of suspected relapse. MRI evaluations for T1-weighted gadolinium
(Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.
Study features and results are presented in the table below.
10
AFFIRM study: Main features and results
Design
Monotherapy; randomised double-blind placebo-controlled
parallel-group trial for 120 weeks
Subjects
RRMS (McDonald criteria)
Treatment
Placebo / Natalizumab 300 mg i.v. every 4 weeks
One year endpoint
Relapse rate
Two year endpoint
Progression on EDSS
Secondary endpoints
Relapse rate derived variables / MRI-derived variables
Subjects
Placebo
Natalizumab
Randomised
315
627
Completing 1 years
296
609
Completing 2 years
285
589
Age yrs, median (range)
37 (19-50)
36 (18-50)
MS-history yrs, median (range)
6.0 (0-33)
5.0 (0-34)
Time since diagnosis, yrs median
(range)
2.0 (0-23)
2.0 (0-24)
Relapses in previous 12 months,
median (range)
1.0 (0-5)
1.0 (0-12)
EDSS-baseline, median (range)
2 (0-6.0)
2 (0-6.0)
RESULTS
Annual relapse rate
After one year (primary endpoint)
0.805
0.261
After two years
0.733
0.235
One year
Rate ratio 0.33 CI
95%
0.26 ; 0.41
Two years
Rate ratio 0.32 CI
95%
0.26 ; 0.40
Relapse free
After one year
53%
76%
After two years
41%
67%
Disability
Proportion progressed
1
(12-week
confirmation; primary outcome)
29%
17%
Hazard ratio 0.58, CI
95%
0.43; 0.73, p<0.001
Proportion progressed
1
(24-week
confirmation)
23%
11%
Hazard ratio 0.46, CI
95%
0.33; 0.64, p<0.001
MRI (0-2 years)
Median % change in T2-
hyperintense lesion volume
+8.8%
-9.4%
(p<0.001)
Mean number of new or newly-
enlarging T2-hyperintense lesions
1.9
(p<0.001)
11.0
Mean number of T1-hypointense
lesions
4.6
1.1
(p<0.001)
Mean number of Gd-enhancing
lesions
0.1
(p<0.001)
1.2
1
Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline
EDSS >=1.0 sustained for 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline
EDSS =0 sustained for 12 or 24 weeks.
In the sub-group of patients indicated for treatment of rapidly evolving relapsing remitting MS
(patients with 2 or more relapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in
11
the TYSABRI treated group (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001). Hazard
ratio for disability progression was 0.36 (95% CI : 0.17, 0.76) p = 0.008. These results were obtained
from a
post hoc
analysis and should be interpreted cautiously. No information on the severity of the
relapses before inclusion of patients in the study is available.
5.2 Pharmacokinetic properties
Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean
maximum observed serum concentration was 110 ± 52 μg/ml. Mean average steady-state trough natalizumab
concentrations over the dosing period ranged from 23 μg/ml to 29 μg/ml. The predicted time to steady-state
was approximately 36 weeks.
A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients receiving
doses ranging from 3 to 6 mg/kg natalizumab. Of these, 581 patients received a fixed 300 mg dose as
monotherapy. The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/h, with a mean ± SD half-life of
16 ± 4 days. The analysis explored the effects of selected covariates including body weight, age, gender,
hepatic and renal function, and presence of anti-natalizumab antibodies upon pharmacokinetics. Only body
weight and the presence of anti-natalizumab antibodies were found to influence natalizumab disposition. Body
weight was found to influence clearance in a less-than-proportional manner, such that a 43% change in body
weight resulted in a 31% to 34% change in clearance. The change in clearance was not clinically significant.
The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold,
consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients
,
(see section 4.8).
The pharmacokinetics of natalizumab in paediatric MS patients or in patients with renal or hepatic
insufficiency has not been studied.
The effect of plasma exchange on natalizumab clearance and pharmacodynamics was evaluated in a study of
12 MS patients. Estimates of the total drug removal after 3 plasma exchanges (over a 5-8 day interval) was
approximately 70-80%. This compares to approximately 40% seen in earlier studies in which measurements
occurred after drug discontinuation over a similar period of observation. The impact of plasma exchange on
the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown.
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.
Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes was
seen as white blood cell increases as well as increased spleen weights in most
in vivo
studies. These
changes were reversible and did not appear to have any adverse toxicological consequences.
In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemia
tumour cells was not increased by the administration of natalizumab.
No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human
chromosomal aberration assays. Natalizumab showed no effects on
in vitro
assays of
α4-integrin-positive tumour line proliferation or cytotoxicity.
Reductions in female guinea pig fertility were observed in one study at doses in excess of the human
dose; natalizumab did not affect male fertility.
The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 in
cynomolgus
monkeys. These studies showed no evidence of teratogenic effects or effects on growth
of offspring. In one study in guinea pigs, a small reduction in pup survival was noted. In a study in
monkeys, the number of abortions was doubled in the natalizumab 30 mg/kg treatment groups versus
12
matching control groups. This was the result of a high incidence of abortions in treated groups in the
first cohort that was not observed in the second cohort. No effects on abortion rates were noted in any
other study. A study in pregnant
cynomolgus
monkeys demonstrated natalizumab-related changes in
the foetus that included mild anaemia, reduced platelet counts, increased spleen weights and reduced
liver and thymus weights. These changes were associated with increased splenic extramedullary
haematopoiesis, thymic atrophy and decreased hepatic haematopoiesis. Platelet counts were also
reduced in offspring born to mothers treated with natalizumab until parturition, however there was no
evidence of anaemia in these offspring. All changes were observed at doses in excess of the human
dose and were reversed upon clearance of natalizumab.
In
cynomolgus
monkeys treated with natalizumab until parturition, low levels of natalizumab were
detected in the breast milk of some animals.
6.
6.1 List of excipients
Sodium phosphate, monobasic, monohydrate
Sodium phosphate, dibasic, heptahydrate
Sodium chloride
Polysorbate 80 (E433)
Water for Injections.
6.2 Incompatibilities
TYSABRI must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Concentrate
4 years
Diluted solution
After dilution, immediate use is recommended. If not used immediately, the diluted solution must be
stored at 2˚C - 8˚C and infused within 8 hours of dilution. In-use storage times and conditions prior to
use are the responsibility of the user.
6.4 Special precautions for storage
Concentrate
Store in a refrigerator (2˚C - 8˚C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
For storage conditions of the diluted medicinal product see section 6.3.
6.5 Nature and contents of container
15 ml TYSABRI in a vial (type I glass) with a stopper (bromobutyl rubber) and a seal (aluminium)
with a flip-off cap. Pack size of one vial per carton.
13
6.6 Special precautions for disposal and other handling
Instructions for use:
1.
Inspect the TYSABRI vial for particles prior to dilution and administration. If particles are
observed and/or the liquid in the vial is not colourless, clear to slightly opalescent, the vial must
not be used.
2.
Use aseptic technique when preparing TYSABRI
solution for intravenous (IV) infusion.
Remove flip-off cap from the vial. Insert the syringe needle into the vial through the centre of
the rubber stopper and remove 15 ml concentrate for solution for infusion.
3.
Add the 15 ml concentrate for solution for infusion to 100 ml sodium chloride 9 mg/ml (0.9)
solution for injection. Gently invert the TYSABRI solution to mix completely. Do not shake.
4.
TYSABRI must not be mixed with other medicinal products or diluents.
5
Visually inspect the diluted product for particles or discolouration prior to administration. Do
not use if it is discoloured or if foreign particles are seen.
6.
The diluted product is to be used as soon as possible and within 8 hours of dilution. If the
diluted product is stored at 2˚C - 8˚C (do not freeze), allow the solution to warm to room
temperature prior to infusion.
7.
The diluted solution is to be infused intravenously over 1 hour at a rate of approximately
2 ml/minute.
8.
After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/ml (0.9)
solution for injection.
9.
Each vial is for single–use only.
10. Any unused product or waste material must be disposed of in accordance with local
requirements.
7.
Elan Pharma International Ltd., Monksland, Athlone, County Westmeath, Ireland
8.
EU/1/06/346/001
9.
27
th
June 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu/.
14
ANNEX II
A.
MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDERS RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
15
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Biogen Idec Inc
5000 Davis Drive
Research Triangle Park
NC 27709-4627
USA
Name and address of the manufacturers responsible for batch release
Biogen Idec Denmark Manufacturing ApS
Biogen Idec Allé 1
DK-3400 Hillerød
Denmark
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
Based on how patients treated with TYSABRI are currently treated at national level, the Marketing
Authorisation Holder (MAH) shall discuss and agree with the National Competent Authorities
measures to enhance further this monitoring (e.g. registries, post-marketing surveillance studies) as
appropriate. The MAH shall implement agreed measures for monitoring with a time frame agreed
with the National Competent Authorities.
The Marketing Authorisation Holder must, following discussions and agreement with the National
Competent Authorities in each Member State where Tysabri is marketed, ensure that all physicians
who intend to prescribe TYSABRI are provided with a physician pack containing the following
elements:
Summary of Product Characteristics and Package Leaflet
Physician information about TYSABRI
Patient alert card
Treatment initiation and treatment continuation forms
The physician information about TYSABRI shall contain the following key elements:
That TYSABRI therapy is to be initiated and continuously supervised by specialised physicians
experienced in the diagnosis and treatment of neurological conditions, in centres with timely
access to MRI.
Information that atypical/opportunistic infections, in particular PML, may occur with Tysabri
and include:
o
That the risk of PML increases with increasing duration of treatment and that treatment
beyond 24 months carries additional risk
o
Diagnosis of PML including differentiation between PML and MS relapse
16
o
PML management algorithm
o
Possibility of other opportunistic infections
o
The recommendation that patients should have MRI scans at the following times
Within 3 months prior to starting Tysabri
Annually during treatment with Tysabri
At the first sign of any symptoms indicative of the possibility of PML.
o
The need to inform patients about the benefits and risk of TYSABRI and provide them
with:
A copy of the treatment initiation form
A patient alert card including a core text agreed by the CHMP
o
If treatment is to be continued for longer than 24 months, the need to inform patients
about the increased risk of PML and provide them with a copy of the treatment
continuation form
o
The need to inform the National Competent Authority about any cases of PML
Information about the following adverse reactions:
o
Infusion reactions
o
Hypersensitivity reactions
o
Antibody formation
Information about any registry or other monitoring system set up in the Member State and how
to enter patients
The treatment initiation form should contain the following elements:
That the aim of the treatment initiation form is to provide patients with information on PML and
IRIS
Information on PML and IRIS
Confirmation that the doctor has discussed the risks of PML and the risk of IRIS if treatment is
discontinued following suspicion of PML
Confirmation of patient understanding of the risks of PML and that they have received a copy of
the form and a patient alert card
Patient details, signature and date
Prescriber name, signature and date
Date treatment started
The treatment continuation form should contain the elements of the treatment initiation form and, in
addition, a statement that the risks of PML increase with duration of treatment and that treatment
beyond 24 months carries additional risk.
The MAH shall provide the European Medicines Agency with an update on the implementation of the
risk minimisation activities and monitoring system in each Member State at 6 months and 1 year
following this Opinion.
OTHER CONDITIONS
Pharmacovigilance System
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, 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 9 of the Risk Management Plan (RMP) presented in
Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the
CHMP.
17
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
The MAH will submit PSURs on 6 monthly basis until otherwise agreed by the CHMP.
18
ANNEX III
LABELLING AND PACKAGE LEAFLET
19
A. LABELLING
20
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
1.
TYSABRI 300 mg concentrate for solution for infusion
natalizumab
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each 15 ml vial of concentrate contains 300 mg natalizumab (20 mg/ml);
3.
LIST OF EXCIPIENTS
sodium phosphate, monobasic, monohydrate; sodium phosphate, dibasic, heptahydrate; sodium
chloride; polysorbate 80 (E433) and water for injections.
4.
1 x 15 ml vial
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intravenous use. Do not shake. Dilute before infusion.
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:
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2˚C - 8˚C). Do not freeze. Keep the vial in the outer carton in order to protect
from light.
21
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Elan Pharma International Ltd.
Monksland
Athlone
County Westmeath
Ireland
EU/1/06/346/001
13. BATCH NUMBER
Lot:
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.
22
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
1.
TYSABRI 300 mg concentrate for solution for infusion
natalizumab
2.
METHOD OF ADMINISTRATION
Intravenous use. Do not shake. Dilute before infusion.
Read the package leaflet before use.
3.
EXPIRY DATE
EXP:
4.
BATCH NUMBER
Lot:
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
15 ml
6.
OTHER
23
B. PACKAGE LEAFLET
24
PACKAGE LEAFLET: INFORMATION FOR THE USER
TYSABRI 300 mg concentrate for solution for infusion
natalizumab
Read all of this leaflet carefully before you start using this medicine.
In addition to this leaflet you will be given a Patient Alert Card, which contains important safety
information that you need to know before you are given TYSABRI (pronounced tie-SA-bree) and
during treatment with TYSABRI.
-
Keep this leaflet and the Patient Alert Card. You may need to read them again.
-
It is important that you keep the Alert Card with you during treatment and for six months after
the last dose of TYSABRI, since side effects may occur even after you have stopped treatment.
-
If you have any further questions, ask your doctor
-
This leaflet will explain about side effects that some patients experience on TYSABRI. If you
have any worrying side effects, or if you notice any side effects not listed in this leaflet, please
tell your doctor or nurse
In this leaflet
:
1. What TYSABRI is and what it is used for
2. Before you use TYSABRI
3. How to use TYSABRI
4. Possible side effects
5.
How to store TYSABRI
6.
Further information
1.
WHAT TYSABRI IS AND WHAT IT IS USED FOR
TYSABRI is used to treat multiple sclerosis (MS).
The symptoms of MS vary from patient to patient, and you may experience some or none of them.
Symptoms can include; walking problems, numbness in the face, arms or legs, problems seeing things,
tiredness, feeling off-balance or light headed, bladder and bowel problems, difficulty in thinking and
concentrating, depression, acute or chronic pain, sexual problems, and stiffness and muscle spasms.
When the symptoms flare up, it is called a relapse (also known as an exacerbation or an attack).
When a relapse occurs, you may notice the symptoms suddenly, within a few hours, or slowly
progressing over several days. Your symptoms will then usually improve gradually (this is called a
remission).
MS causes inflammation in the brain that damages the nerve cells. In TYSABRI the active ingredient
is natalizumab, a protein similar to your own antibodies. It stops the cells that cause inflammation
from going into your brain. This reduces nerve damage caused by MS.
In clinical trials, TYSABRI approximately halved the progression
of the disabling effects of MS and
also decreased the number of MS attacks by about two-thirds. However, TYSABRI cannot repair the
damage that has already been caused by MS. When you receive TYSABRI you might not notice any
improvement, but TYSABRI may still be working to prevent your MS becoming worse.
It is important to continue with your medicine for as long as you and your doctor decide that it is
helping you.
25
2.
BEFORE YOU USE TYSABRI
Before you start treatment with TYSABRI, it is important that you and your doctor have discussed the
benefits you would expect to receive from this treatment and the risks that are associated with it.
Do not use TYSABRI
If you are allergic (hypersensitive) to natalizumab or any of the other ingredients of TYSABRI
(see section 6 for the ingredients).
If your doctor has told you that you have PML (progressive multifocal leukoencephalopathy).
PML is a rare infection of the brain.
If your doctor tells you that you have a
serious problem with your immune system (due to
disease for example, leukaemia or HIV or due to a medicine you are taking or have previously
taken).
If you are taking medicines that cannot be used with TYSABRI (see Using other medicines,
below).
If you have cancer (unless it is a type of skin cancer called basal cell carcinoma).
If you are under 18 years of age.
Take special care with TYSABRI
There have been cases of a rare brain infection called PML (progressive multifocal
leukoencephalopathy) that have occurred in patients who have been given TYSABRI. PML may lead
to severe disability or death. The risk of PML increases the longer that you are on treatment especially
if you have been on treatment for more than two years. It is not known if the chance of getting PML
continues to rise, remains the same, or falls after you have been on TYSABRI for more than three
years. The risk of PML is also greater if you have previously taken a medicine that weakens your
immune system.
In patients with PML a reaction known as IRIS (Immune Reconstitution
Inflammatory Syndrome) is likely to occur after treatment for PML, as TYSABRI is removed from
your body. IRIS may lead to your condition getting worse, including worsening of brain function.
The symptoms of PML may be similar to an MS relapse (e.g. weakness or visual changes). Therefore,
if you believe your MS is getting worse or if you notice any new symptoms, it is very important that
you speak to your doctor as soon as possible.
Speak with your partner or caregivers and inform them about your treatment. Symptoms might arise
that you might not become aware of by yourself, such as changes in mood or behaviour, memory
lapses, speech and communication difficulties, which your doctor may need to investigate further to
rule out PML.
You will also find this information in the Patient Alert Card you have been given by your doctor. It is
important that you keep this Alert Card and show it to your partner or caregivers.
Serious infections may occur with TYSABRI. If you develop any infection, or if you develop
symptoms like an unexplained fever, severe diarrhoea, prolonged dizziness / headache / stiff neck,
weight loss, or listlessness, or other symptoms potentially associated with an infection whilst
receiving TYSABRI, speak to your doctor as soon as possible and show the Patient Alert Card and
this package leaflet to him.
You will also find this information in the Patient Alert Card you have been given by your doctor. It is
important that you keep this Alert Card.
26
Using other medicines
Please tell your doctor if you are taking or have recently taken any other medicines, including
medicines you may have obtained without a prescription. You may not be able to use TYSABRI with
some medicines that affect your immune system.
Pregnancy and breast-feeding
You should not use TYSABRI if you are pregnant
unless you have discussed this with your doctor.
Be sure to tell your doctor immediately if you are pregnant, think you may be pregnant, or if you are
planning to become pregnant.
Do not breast-feed whilst using TYSABRI. You should discuss with your doctor whether you choose
to breast-feed or to use TYSABRI.
Ask your doctor or pharmacist for advice before taking any other medicine with TYSABRI.
Driving and using machines
TYSABRI is not expected to have an effect on your ability to drive or to operate machines. If you are
concerned, discuss this with your doctor.
3.
HOW TO USE TYSABRI
TYSABRI will be prepared and given to you by a doctor.
Information for medical or healthcare professionals on how to prepare and administer TYSABRI is
provided at the end of this leaflet.
The adult dose is 300 mg given once every 4 weeks.
TYSABRI must be diluted before it is given to you. It is given as a drip into a vein (by intravenous
infusion), usually in your arm. This takes about 1 hour.
A few patients have had an allergic reaction to TYSABRI. Your doctor will check for allergic
reactions during the infusion and for 1 hour afterwards.
It is important to continue with your medicine for as long as you and your doctor decide that it is
helping you. Continuous dosing with TYSABRI is important, especially during the first few months
of treatment. This is because patients who received one or two doses of TYSABRI and then had a gap
in treatment of three months or more, were more likely to have an allergic reaction when resuming
treatment.
If you miss your dose of TYSABRI
If you miss your usual dose of TYSABRI, arrange with your doctor to receive it as soon as you can.
You can then continue to receive your dose of TYSABRI every 4 weeks.
If you have any further questions on TYSABRI, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, TYSABRI can cause side effects, although not everybody gets them.
If you have any worrying side effects, including any not listed in this leaflet, please tell your doctor,
nurse or pharmacist as soon as possible.
27
Speak to your doctor or nurse immediately if you notice any of the following:
Signs of allergy to TYSABRI, during or shortly after your infusion:
Itchy rash (hives)
Swelling of your face, lips or tongue
Difficulty breathing
Chest pain or discomfort
Increase or decrease in your blood pressure (your doctor or nurse will notice this if they are
monitoring your blood pressure).
Signs of a possible liver problem:
Yellowing of your skin or the whites of your eyes
Unusual darkening of the urine.
TYSABRI can also have other side effects.
Side effects are listed below by how commonly they have been reported in clinical trials:
Common side effects
that may occur in less than 10 in 100 patients:
Urinary tract infection
Sore throat and runny or blocked up nose
Shivering
Itchy rash (hives)
Headache
Dizziness
Feeling sick (nausea)
Being sick (vomiting)
Joint pain
Fever
Tiredness.
Uncommon side effects
that may occur in less than 1 in 100 patients:
Severe allergy (hypersensitivity).
Rare side effects
that may occur in less than 1 in 1000 patients
:
Unusual
infections (so-called “Opportunistic infections”)
Progressive multifocal leukoencephalopathy (PML), a rare brain infection.
What to do if your MS gets worse or you notice new symptoms
There have been reports of a rare brain infection called PML (progressive multifocal
leukoencephalopathy) that have occurred in patients who have been given TYSABRI. PML usually
leads to severe disability or death.
The symptoms of PML may be similar to an MS relapse.
Therefore, if you believe your MS is getting worse or if you notice any new symptoms, it is
important that you speak to your doctor as soon as possible.
Discuss your treatment with your partner or caregivers. They might see new symptoms that you
might not notice such as changes in mood or behaviour, memory lapses, speech and
communication difficulties, which your doctor may need to investigate further to rule out PML.
Show the Alert Card and this package leaflet to any doctor involved with your treatment, not
only to your neurologist.
Serious infections may occur with TYSABRI. The symptoms of infections include:
an unexplained fever
28
severe diarrhoea
shortness of breath
prolonged dizziness
headache
stiff neck
weight loss
listlessness.
Speak to your doctor as soon as possible if you think you have an infection
.
Show the Alert Card and this package leaflet to any doctor involved with your treatment, not
only to your neurologist.
You will also find this information in the Patient Alert Card you have been given by your doctor.
Will TYSABRI always work?
In a few patients who use TYSABRI, over time the body’s natural defence may stop TYSABRI from
working properly (the body develops antibodies to TYSABRI). Your doctor can decide whether
TYSABRI is not working properly for you by testing your blood and will stop TYSABRI, if
necessary.
5.
HOW TO STORE TYSABRI
Keep out of the reach and sight of children.
Unopened vial:
Store in a refrigerator (2C to 8C).
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
Do not use TYSABRI after the expiry date stated on the label and carton.
Diluted solution:
After dilution, immediate use is recommended. If not used immediately, the diluted solution must be
stored at 2˚C - 8˚C and infused within 8 hours of dilution.
Do not use TYSABRI if you notice particles in the liquid and/or the liquid in the vial is discoloured.
6.
FURTHER INFORMATION
What TYSABRI contains
Each 15 ml vial of concentrate contains 300 mg natalizumab (20 mg/ml).
The other ingredients are:
Sodium phosphate, monobasic, monohydrate
Sodium phosphate, dibasic, heptahydrate
Sodium chloride
Polysorbate 80 (E433)
Water for injections.
What TYSABRI looks like and contents of the pack
TYSABRI is a clear, colourless to slightly cloudy liquid. Each carton contains one glass vial.
TYSABRI must be diluted before it is given to you.
29
Marketing Authorisation Holder
Elan Pharma International Ltd.
Monksland
Athlone
County Westmeath
Ireland
Manufacturer
Biogen Idec Denmark Manufacturing ApS
Biogen Idec Allé 1
DK-3400 Hillerød
Denmark
For any further information about this medicine, please contact the local representative of the
Marketing Authorisation Holder. This information is provided at the end of the leaflet.
België/Belgique/Belgien
Biogen Idec Belgium N.V./S.A.
Tél/Tel: +32 2 219 12 18
Luxembourg/Luxemburg
Biogen Idec Belgium N.V./S.A.
Tél/Tel: +32 2 219 12 18
България
ТП ЕВОФАРМА
Teл.: +359 2 962 12 00
Magyarország
Gedeon Richter Plc.
Tel.: +36 1 505 7032
Česká republika
Biogen Idec (Czech Republic) s.r.o.
Tel: +420 222 191 640
Malta
Interpharma Co. Ltd
Tel: +356 21354582
Danmark
Biogen Idec Denmark A/S
Tlf: +45 77 41 57 88
Nederland
Biogen Idec International B.V.
Tel: +31 20 542 2000
Deutschland
Biogen Idec GmbH
Tel: +49 (0) 89 99 6170
Norge
Biogen Idec Norway AS
Tlf: +47 23 00 52 50
Eesti
Richter Gedeon Eesti filiaal
Tel: +372 742 0200
Österreich
Biogen Idec Austria GmbH
Tel: +43 1 484 46 13
Ελλά
Genesis Pharma SA
Τηλ: +30 210 8771500
Polska
Gedeon Richter Plc. S.A.
Przedstawicielstwo w Polsce
Tel.: +48 22 642 67 39
España
Biogen Idec Iberia SL
Tel: +34 91 310 7110
Portugal
Biogen Idec Portugal Sociedade Farmacêutica
Unipessoal, Lda
Tel: +351 21 318 8450
France
Biogen Idec France
Tél: +33 (0)1 41 37 95 95
România
MEDISON PHARMA SRL
Tel: +40 31 7104035
30
Ireland
Biogen Idec (Ireland) Ltd.
Tel: +353 (0)1 463 7799
Slovenija
Biogen Idec d.o.o.
Tel: +386 1 58 99 104
Ísland
Icepharma hf
Sími: +354 540 8000
Slovenská republika
Biogen Idec (Slovak Republic) s.r.o.
Tel: +421 2 324 101 88
Italia
Biogen-Dompé s.r.l.
Tel: +39 02 583 831
Suomi/Finland
Biogen Idec Finland Oy
Puh/Tel: +358 207 401 200
Κύπρς
Genesis Pharma Cyprus Ltd
Τηλ: +357 22 769946
Sverige
Biogen Idec Sweden AB
Tel: +46 8 594 113 60
Latvija
Gedeon Richter Plc.
Tel: +37 16 784 5338
United Kingdom
Biogen Idec Limited
Tel: +44 (0) 1628 50 1000
Lietuva
Gedeon Richter Plc.
Tel: +37 05 268 5392
This leaflet was last approved in
{MM/YYYY}.
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
---------------------------------------------------------------------------------------------------------------------------
The following information is intended for medical or healthcare professionals only:
1.
Inspect the TYSABRI vial for particles prior to dilution and administration. If particles are
observed and/or the liquid in the vial is not colourless, clear to slightly opalescent, the vial must
not be used.
2.
Use aseptic technique when preparing TYSABRI
solution for intravenous (IV) infusion.
Remove flip-top from the vial. Insert the syringe needle into the vial through the centre of the
rubber stopper and remove 15 ml concentrate for solution for infusion.
3.
Add the 15 ml concentrate for solution for infusion to 100 ml sodium chloride 9 mg/ml (0.9)
solution for injection. Gently invert the TYSABRI solution to mix completely. Do not shake.
4.
TYSABRI must not be mixed with other medicinal products or diluents.
5.
Visually inspect the diluted product for particles or discolouration prior to administration. Do
not use if it is discoloured or if foreign particles are seen.
6.
The diluted product is to be used as soon as possible and within 8 hours of dilution. If the
diluted product is stored at 2C - 8C (do not freeze), allow the solution to warm to room
temperature prior to infusion.
7.
The diluted solution is to be infused intravenously over 1 hour at a rate of approximately
2 ml/minute.
31
8.
After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/ml (0.9)
solution for injection.
9.
Each vial is for single–use only.
10. Any unused product or waste material must be disposed of in accordance with local
requirements.
32
Source: European Medicines Agency
- Please bookmark this page (add it to your favorites).
- If you wish to link to this page, you can do so by referring to the URL address below this line.
https://theodora.com/drugs/eu/tysabri.html
Copyright © 1995-2021 ITA all rights reserved.