Spectrila : EPAR

EMA/829066/2015
Summary of the risk management plan (RMP) for
Spectrila (asparaginase)
This is a summary of the risk management plan (RMP) for Spectrila, which details the measures to be
taken in order to ensure that Spectrila is used as safely as possible. For more information on RMP
summaries, see here.
This RMP summary should be read in conjunction with the EPAR summary and the product information
for Spectrila, which can be found on Spectrila’s EPAR page.
Overview of disease epidemiology
Spectrila is a medicine for treating patients with acute lymphoblastic leukaemia (ALL), a cancer of
white blood cells called lymphoblasts.
ALL is more common in children than in adults. About 1 in 100,000 adult persons per year gets this
disease. In children this rate is between 2 and 4 per 100,000 persons per year. The average age of
children with ALL is 4.9 years. Slightly more boys than girls are affected. In adults, half the cases are
in patients under the age of 50, and ALL is rare over the age of 70.
Summary of treatment benefits
In a main study in 199 children with ALL, Spectrila was as effective as another asparaginase medicine
(both used in combination with other medicines) in reducing blood asparagine: 95% of patients treated
with Spectrila and 94% of those treated with the other medicine containing asparaginase had complete
depletion (reduction) of blood asparagine.
Unknowns relating to treatment benefits
Asparaginase, the active substance in Spectrila, has been in clinical use for more than 2 decades.
Spectrila has been shown to be as effective and safe as a reference asparaginase preparation.
Summary of safety concerns
Important identified risks
Risk
What is known
Preventability
Infections (including
Since asparaginase has
Monitoring of early symptoms like fever
opportunistic and
fungal infections)
immunosuppressive activity (i.e. it
is required to start effective treatment in
reduces the activity of the immune
time.
system), infections may occur
Preventive treatment with antibiotics in
during treatment with
asparaginase medicines.
case of e.g. very low levels of white
blood cells.
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Risk
What is known
Severe
Asparaginase is a foreign protein
hypersensitivity
and may therefore cause allergic
(allergic) reactions
reactions. Allergic reactions
observed in clinical studies were
usually mild to moderate and
rarely severe. Patients usually
recover without further
complications.
Preventability
Which patient will experience an allergic
reaction is unknown. Therefore,
monitoring of early symptoms like rash,
flushing, swelling of the face and throat,
difficulty in breathing, hives (an itchy
skin rash) or dizziness, is required to
start effective treatment in time.
Decreased
Antibodies may develop against
It is not possible to predict which patient
asparaginase activity
Spectrila and reduce its activity.
will develop antibodies against
This can occur without an allergic
asparaginase. Regular monitoring of
reaction.
asparaginase blood levels allows early
detection of decreased Spectrila activity.
Decrease in blood
Decreases in blood clotting factors
Blood clotting values should be
clotting factors
are observed in most patients
monitored before and regularly
(coagulation factor
during treatment with
throughout treatment. Patients with very
deficiencies
asparaginase.
low levels of these blood clotting factors
sometimes receive blood preparations
containing these clotting factors
intravenously
Treatment with asparaginase should be
interrupted if patients develop
coagulation disorders.
Bleeding
Bleeding, most often nose
Blood clotting values should be
(haemorrhage)
bleeding, bruising and petechiae
monitored before and regularly
(pinpoint flat round red spots
throughout treatment.
under the skin surface) have been
reported commonly in patients
receiving asparaginase. All
patients who received Spectrila
Treatment with asparaginase should be
interrupted if patients develop
coagulation disorder.
and experienced bleeding
recovered without further
complications.
Bleeding is also a commonly
observed symptom of the
underlying disease because of
impaired bone marrow function.
Blood clots
Blood clots are a known
Blood clotting values should be
(thromboembolic
complication of leukaemia and of
monitored before and regularly
events)
several agents used to treat the
throughout treatment.
condition like asparaginase.
They have been reported
commonly with Spectrila and
affect predominantly the veins of
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Risk
What is known
Preventability
the limbs (leading to a painful
swelling of the limbs [deep vein
thrombosis]) or specific veins
draining blood from the brain
(leading to neurological symptoms
such as headache or seizures).
Liver toxicity
Most frequently observed liver
Liver laboratory values such as
disorders during asparaginase
transaminases and bilirubin levels should
treatment are mild to moderate
be monitored before and regularly
changes in liver parameters, e.g.
throughout therapy. Treatment with
bilirubin and transaminases, which
Spectrila should be interrupted if
usually resolve without further
patients develop severe liver
complications after the end of
impairment.
treatment. Severe liver disorders
requiring prolonged hospital
treatment are rare.
Inflammation of the
Pancreatitis (with sudden onset)
Patient who have or have ever had
pancreas
causing severe pain in the
pancreatitis must not receive Spectrila.
(pancreatitis)
abdomen and back has been
observed in less than 1 in 10
patients during treatment with
other asparaginase preparations,
An increase of serum levels of
amylase and lipase (two enzymes
produced by the pancreas) may
indicate development of
pancreatitis in some but not all
patients.
Most patients usually recover
without further complications,
however in a few cases, so-called
pseudocysts develop in the
pancreas which may require
surgical treatment. Deaths have
been observed very rarely.
Nerve disorders
Most frequently reported nerve
Several factors may contribute to the
(neurotoxicity)
disorders include nervousness
development of neurological disorders,
(agitation), dizziness, somnolence
e.g. the underlying disease itself,
(sleepiness), headache, and
treatment with other medicines,
changes in the
blockage of blood vessels in the brain,
electroencephalogram (a graph
and some metabolic disorders.
showing the electrical activity of
Discontinuation or dose reduction of
your brain). Seizures, severe
concomitantly administered
impairment of consciousness,
immunosuppressive medicines may be
including coma, and stroke were
necessary. Expert advice should be
observed in up to 1 in 1,000
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Risk
What is known
Preventability
people.
sought.
High blood sugar
High blood sugar levels have been
Patients with pre-existing risk factors like
(glucose) levels
observed in more than 1 patient in
diabetes mellitus, obesity, and
(hyperglycaemia)
10 during treatment with
concomitant treatment with
Spectrila. This is usually mild and
glucocorticoids (cortisone and its
transient, and generally resolves
analogues) may be at risk of developing
after giving insulin.
high blood sugar levels.
Hospitalisation is usually not
Serum and urine glucose levels should
required and no long-term
be regularly monitored and managed as
complications have been reported
clinically indicated.
so far.
Severe complications of
hyperglycaemia (diabetic
ketoacidosis) have been reported
rarely.
Changes in blood fats
An increase in blood fat levels
No preventive measures exist.
(triglycerides and cholesterol) has
been observed in more than 1
patient in 10 during clinical studies
conducted with Spectrila. These
levels usually return to normal
within a few days after stopping
Spectrila treatment and only rarely
require treatment.
Increased ammonia
An increase of blood ammonia
Patients with severe liver impairment
levels in blood
levels has been observed in
should not receive asparaginase.
(hyperammonaemia)
patients treated with Spectrila,
especially in patients with severe
liver impairment. This only rarely
causes clinical symptoms such as
prolonged vomiting. Very rarely it
may result in abnormal brain
function such as seizures and
coma.
Embryotoxic and
Studies with Spectrila in mice,
Spectrila should not be used during
teratogenic effects
rats, chicken and rabbits have
pregnancy. Women should use effective
(malformations of an
shown malformations of embryos
contraception during treatment and up
embryo or fetus)
or fetuses. The potential risk for
to three months thereafter.
humans after treatment with
Spectrila as a single treatment is
unknown.
Interaction with
Men should use effective contraceptive
measures while receiving asparaginase.
Combined use of Spectrila and
Treating physicians need to be aware of
methotrexate may alter the
this schedule-dependent interaction
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Risk
What is known
Preventability
methotrexate
efficacy of methotrexate in
when both substances are given
different ways depending on which
concomitantly.
substance is given first.
When Spectrila is given first the
Spectrila should always be given after
methotrexate.
efficacy of methotrexate is
reduced. Conversely, when
Spectrila is given after
methotrexate it may increase the
efficacy of methotrexate.
Interaction with
Combined use of Spectrila and
cytarabine
cytarabine may alter the efficacy
this schedule-dependent interaction
of cytarabine in different ways
when both substances are given
depending on which substance is
concomitantly.
given first.
When Spectrila is given first the
Treating physicians need to be aware of
Spectrila should always be given after
cytarabine.
efficacy of cytarabine is reduced.
Conversely, when Spectrila is
given after cytarabine it may
increase the efficacy of cytarabine.
Interaction with
The use of glucocorticoids (anti-
Caution is needed when Spectrila is
glucocorticoids
inflammation medicines) at the
given with glucocorticoids. Blood clotting
same time as Spectrila may alter
values should be monitored regularly
some blood clotting values
throughout treatment..
(fibrinogen, antithrombin III).
Furthermore, investigations in
mice have shown that these
medicines may increase the risk of
bone damage (osteonecrosis).
Important potential risks
Risk
What is known
Reversible posterior
Patients treated with asparaginase-containing treatment may be at an
leukoencephalopathy
increased risk of developing a syndrome known as RPLS. Symptoms of RPLS
syndrome (RPLS)
include raised blood pressure, seizures, headaches, changes in mental state
and acute visual impairment. Although the condition is reversible,
complications, such as bleeding in the brain and stroke, may occur.
Discontinuation or dose reduction of concomitantly administered
immunosuppressive medicines may be necessary. Expert advice should be
sought.
Tumour lysis
During treatment with asparaginase, large amounts of tumour cells can be
syndrome (TLS)
destroyed in a short time. This could potentially lead to kidney failure;
however, this has not yet been seen in clinical practice.
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Risk
What is known
Off-label
Although some other asparaginase products are authorised for use by
(unauthorised) use
injection into a muscle, Spectrila has only been investigated (and approved)
via injection into a
for infusion into a vein.
muscle
Potential interaction
Vincristine (another chemotherapy medicine that is frequently used in patients
with vincristine
with leukaemia) is often co-administered with Spectrila. There may potentially
be an increase in toxicity when both agents are used together; however, this
has not yet been proven in clinical practice.
Potential interaction
The use of Spectrila can lead to a change in blood coagulation factors. This
with anticoagulants
can promote tendency to either bleeding or blood clotting. Caution is therefore
(used to prevent
needed when anticoagulants are given at the same time.
blood clots)
Potential interaction
Spectrila may increase the side effects of other medicines through its effect on
with other medicines
liver function. Therefore, caution should be exercised in patients receiving
where impaired liver
other medicines broken down by the liver.
metabolism could
increase toxicity
Potential interaction
Concomitant vaccination with vaccines containing live organisms may increase
with live vaccines
the risk of serious infection. Immunisation with live vaccines should therefore
take place three months after completion of the cancer treatment at the
earliest.
Missing information
Risk
What is known
Safety in patients
Experience with asparaginase treatment in patients older than 65 years of age
above 65 years of age
is limited.
Summary of risk minimisation measures by safety concern
All medicines have a summary of product characteristics (SmPC) which provides physicians,
pharmacists and other healthcare professionals with details on how to use the medicine, and also
describes the risks and recommendations for minimising them. Information for patients is available in
lay language in the package leaflet. The measures listed in these documents are known as ‘routine risk
minimisation measures’.
The SmPC and the package leaflet are part of the medicine’s product information. The product
information for Spectrila can be found on Spectrila’s EPAR page.
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Planned post-authorisation development plan
List of studies in post-authorisation development plan
Study/activity
(including
study number)
Objectives
Safety concerns
/efficacy issue
addressed
Status
Planned date for
submission of
(interim and)
final results
Clinical phase IV
Assessment of
Efficacy and safety of
Planned
Interim reports
study
pharmacokinetics,
Spectrila in adult
will be provided in
pharmacodynamics,
patients
the RMP updates
MCSpectrila.1/ALL
safety and immuno-
and PSURs,
genicity of Spectrila after
together with
repeated-dose treatment
analyses of
of patients with newly
spontaneous
diagnosed ALL.
reports from
adults treated
with Spectrila in
other studies.
Final report will be
submitted
approximately 35
months after the
granting
Marketing
Authorisation for
Spectrila
Studies which are a condition of the marketing authorisation
The above study is not a condition of the marketing authorisation.
Summary of changes to the risk management plan over time
Not applicable.
This summary was last updated in 12-2015.
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