EMA/283271/2014
Summary of the risk management plan (RMP) for Mekinist (trametinib)
This is a summary of the risk management plan (RMP) for Mekinist, which details the measures to be taken in order to ensure that Mekinist 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 Mekinist, which can be found on Mekinist’s EPAR page.
Overview of disease epidemiology Mekinist is used to treat melanoma (a type of skin cancer) that has metastasised (spread to other parts of the body) or cannot be surgically removed. The number of people with this cancer is increasing worldwide. In 2008, around 69,000 new melanomas occurred in the 27 European countries (EU-27). In about 6 out of 100 newly-diagnosed cases, the melanoma is inoperable or has metastasised. This suggests that newly-diagnosed inoperable or metastatic melanomas in the EU-27 number over 4,000 per year. Mekinist is specifically for patients whose melanoma cells have a mutation (change) in the ‘BRAF’ gene called 'BRAF V600', which may have caused the melanoma to develop. Around one third of the total melanoma patients in the UK, Germany, France, Spain and Italy in 2012 had a BRAF gene mutation and these patients may be suited to treatments that target BRAF activity.
Summary of treatment benefits In a main study involving 322 patients, patients were treated with either Mekinist or chemotherapy (treatment with the cancer medicines dacarbazine or paclitaxel). The study’s main measure of effectiveness was how long patients lived until their disease got worse (progression-free survival) and Mekinist was shown to be more effective than chemotherapy: patients taking Mekinist lived on average for 4.8 months without their disease getting worse compared with 1.5 months for those on chemotherapy.
Unknowns relating to treatment benefits Most patients in studies with Mekinist were white Caucasian adults less than 65 years of age. However, there is no evidence to suggest that results would differ in non-white patients or those aged over 65 years. Mekinist has not been studied in patients under 18 years.
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Summary of safety concerns Important identified risks Risk
What is known
Preventability
Skin problems, e.g.
About 9 in 10 patients treated with
The package leaflet informs the
rash or redness
Mekinist experienced skin problems
patient that severe skin reactions
such as rash or redness. These skin
(rash) may occur when taking
problems appeared within 1 month of
Mekinist and that patients who
Mekinist treatment. These unwanted
develop severe rash, and blisters or
side effects were mild to moderate
sores, should seek immediate help
and in the majority of cases did not
from their doctor.
(Skin problems e.g., acneiform dermatitis)
lead to an interruption or reduction in the treatment dose.
Skin problems can be treated with medicines, in most cases without reducing the dose or stopping treatment with Mekinist.
Diarrhoea
About 5 in 10 patients treated with
There is no known way of preventing
Mekinist experienced diarrhoea (loose
diarrhoea resulting from treatment
and watery stools). Most of the
with Mekinist. However, diarrhoea can
reported cases of diarrhoea were mild
usually be treated with medicines.
to moderate and started within 14 days of Mekinist treatment. Heart problems (e.g.
In studies with Mekinist, about 1 in
Doctors should temporarily stop
a drop in the amount
10 patients experienced heart
treatment with Mekinist if the patient
of blood pumped to
problems linked to the pumping of
is showing symptoms of heart
the rest of the body
blood to the rest of the body. Most of
problems. If the patient recovers,
and problems with
the cases were mild to moderate in
treatment with Mekinist may be
how the heart pumps
nature and occurred within 2 to 3
restarted, but at a reduced dose and
blood)
months of the start of Mekinist
the patient should be carefully
treatment.
monitored.
Eye problems (e.g.
Studies indicate that about 13% of
Treatment with Mekinist is not
blood clot in a vein in
patients treated with Mekinist may
recommended in patients with a
the eye, damage to
experience eye problems. Most of the
history of blockage of the vein
the retina, swelling
eye problems in studies were mild to
draining the eye.
(Left ventricular systolic dysfunction e.g., LVEF decreased and left ventricular dysfunction)
and redness of the
moderate and included blurred vision,
iris and other parts of
dry eye and some disturbance in
the eye)
vision. Four out of 329 patients were reported to have a blood clot in a vein in the eye with 2 of the 4 cases
(Ocular events e.g.,
resulting in a decrease in vision. Both
retinal vein occlusion,
patients experienced an improvement
retinal pigment
in vision after treatment was stopped.
epithelial
Patients experiencing mild to moderate eye problems while receiving Mekinist may have their Mekinist dose lowered or stopped for a short time. If eye problems persist at the lower dose or after treatment is restarted, then Mekinist treatment may be stopped completely.
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Risk
What is known
Preventability
detachment)
The studies indicate that eye
There is a possibility that in some
problems may occur at any time from
patients severe eye problems may not
2 days after starting treatment.
recover completely after the treatment is stopped.
Inflammation inside
Studies show that about 2% of
Lung inflammation following
the lungs
patients treated with Mekinist may
treatment with Mekinist may require
experience inflammation in the lungs
the dose to be adjusted, or treatment
which can be severe. Of the 6 out of
temporarily stopped or completely
329 cases of lung inflammation in
discontinued (depending on the
studies, 5 were reported to be
severity of the lung inflammation). In
serious. However, in most of the
most cases, following changes to their
cases, the patient recovered, or was
treatment, patients recover from the
reported to be improving, after the
lung problems, or experience an
dose was reduced or stopped.
improvement in the symptoms linked
(Pneumonitis)
to the lung inflammation. Liver problems (Hepatic events – AST, ALT, increased)
Increased levels of 2 naturally
Most cases of increased levels of
occurring liver enzymes in the body,
enzymes ALT and AST in liver tests do
ALT and AST, may sometimes
not require treatment.
indicate inflammation of the liver, due to injury or damage.
Lowering the dose of Mekinist, or stopping treatment for a short time,
In studies of Mekinist, 12% of
will help enzyme levels to improve or
patients (39 out of 329) had
return to normal in most cases.
increased levels of the 2 enzymes, ALT or AST. Most of the cases were mild or moderate, involved small increases in ALT or AST levels and occurred about 30 days after starting treatment with Mekinist. Raised blood pressure (Hypertension)
In studies, about 15% of patients
Doctors are advised that they should
treated with Mekinist had increased
monitor their patient’s blood pressure
blood pressure. All of the reported
routinely. Appropriate treatment to
cases were mild to moderate
lower blood pressure should be given
increases in blood pressure and
based on the doctor’s judgement,
occurred within 2 weeks of starting
taking into account the possibility that
Mekinist treatment was started.
the patient may have an existing
In the majority of cases, the raised blood pressure was managed without requiring changes to the patient’s
medical condition, or may be taking medication for other medical conditions.
treatment. Swelling and
Swelling and puffiness due to a build-
Studies indicate that the majority of
puffiness under the
up of fluid can occur in most parts of
the cases of swelling or puffiness can
skin (oedema) e.g.
the body; it is most common around
be managed with standard medical
around the feet and
the feet and ankles.
care, and a change to the dose of
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Risk
What is known
Preventability
ankles
Swelling and puffiness under the skin
Mekinist is usually not required.
was a common side effect in studies with Mekinist. In almost all cases (94%), the swelling or puffiness was mild to moderate, and treatment with Mekinist was continued without interruption or the need to lower the dose. In one study, a patient (1 out of 84
Although allergic reactions are rare,
who received Mekinist) experienced
information in the package leaflet
an allergic reaction 7 days after
informs the patient that they should
beginning treatment. The patient
seek medical advice (from a doctor,
reported fever, asthma, disturbance
nurse or pharmacist) if they
in vision and other symptoms of an
experience symptoms of an allergic
allergic reaction.
reaction.
Breakdown of muscle
There may be a risk that Mekinist can
Patients taking Mekinist should report
fibres which leads to
cause rhabdomyolysis, a condition in
any muscle tenderness (pain),
the release of a
which muscle breakdown causes pain,
weakness or stiffness to their doctor.
protein called
vomiting, and possibly kidney failure.
myoglobin into the
Patients taking Mekinist should report
bloodstream
these symptoms to their doctor.
Allergic reaction (Hypersensitivity)
(Rhabdomyolysis) Bleeding events (Haemorrhagic events)
Mekinist may increase the risk of
Patients taking Mekinist should report
bleeding. Bleeding can occur at
any unusual or excessive bleeding to
different sites in the body. Most cases
their doctor.
of bleeding are minor but they can be severe requiring treatment in hospital or blood transfusion. Rare cases of bleeding in the brain have been fatal.
Important potential risks Risk
What is known
Use to treat cancers for which
Mekinist has been developed to treat melanomas with the BRAF
Mekinist is not approved
gene mutation. Mekinist is specifically for use in the treatment
(Off-label use: in resectable/resected melanoma
of melanomas which cannot be removed surgically or which have spread to other sites in the body (metastatic melanoma).
(adjuvant therapy), in non-
There may be a risk that some doctors may consider using
melanoma tumours harbouring a
Mekinist to treat patients with cancers for which it has not been
BRAF V600-mutation, melanoma
widely tested, or approved. This unapproved, or off-label use,
tumours negative for BRAF V600
may include: treating melanomas which can be surgically
mutation, in patients with tumour
removed or which have not spread to other sites in the body, or Page 4/10
Risk
What is known
progression during prior treatment
skin cancers which do not have the BRAF gene mutation.
with BRAF inhibitor therapy, use in combination with other anti-cancer agents, or when non-validated tests
Information on the appropriate patients for treatment will be provided in the prescriber’s information (SmPC).
are used) Liver failure (Hepatic failure)
There may be a risk that Mekinist can cause damage to the liver. This damage can be permanent liver damage or lead to liver failure. Patients are advised to tell their doctor if they have liver problems. Their doctor will also do some blood tests to monitor how well a patient’s liver is working before and during treatment with Mekinist.
Problems with the ability to have
Early studies in animals have shown that Mekinist may affect the
children in women
ability to have children both when taking the medication and after it has been stopped. It is not known whether these effects will also be seen in humans, as there have been no human
(Impaired female fertility)
studies to look at whether Mekinist can affect a woman’s ability to have children. As the effects of the Mekinist on human’s reproductive organs is unknown, patients are advised to speak to their doctor about options to improve the chances of having children, before starting treatment with Mekinist.
Problems with the development of
Early studies in animals have shown that Mekinist cause
the unborn child
problems in the development of the fetus in pregnant animals (problems seen include lower than average weight and poor development of bones or the skeleton). It is not known whether
(Developmental toxicity)
these effects will also be seen in humans, as there have been no human studies looking at the effect of Mekinist when used during pregnancy. Women who are able to become pregnant should use appropriate contraception whilst being treated with trametinib, and for up to 4 months after stopping treatment with trametinib.
Missing information Risk
What is known
Use in patients with heart failure
Patients with current or a history of heart failure have not been
(Use in patients with reduced cardiac function or symptomatic
included in studies with Mekinist. There are no ongoing or planned patient studies that would include this patient group.
Class II, III, or IV heart failure –
The package leaflet warns patients that Mekinist can affect how
NYHA functional classification
well the heart pumps blood and that this side effect may be
system)
more likely in patients with an existing heart problem. Patients taking Mekinist will be checked for any heart problems
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Risk
What is known while taking the medicine.
Use in patients with severe kidney
Patients with severe kidney problems were not included in
impairment
studies; therefore results on the effect of Mekinist in this patient group are not available. Mekinist should be used with caution in patients with severe kidney problems. Patients are advised to tell their doctor if they have kidney problems, as this may affect the way Mekinist will work in the body.
Use in patients with moderate to
There is no information from studies about the effect of Mekinist
severe liver impairment
in patients with moderate or severe liver problems. Mekinist should be used with caution in patients with moderate or severe liver problems. Liver problems may affect the way Mekinist works in the body. Patients should inform their doctor if they have liver problems. Their doctor will also do some blood tests to monitor how well a patient’s liver is working before and during treatment with Mekinist.
Use in non-white population
Almost all the patients in studies with Mekinist were white. As melanoma occurs mostly in white Caucasians, the patient studies largely reflect the patients expected to use this medicine. There is, however, no evidence to suggest that results would be any different in non-white patients.
Limited information on pregnancy
There is no information on developmental effects in babies
and in breastfeeding women
following use of Mekinist in pregnant or breastfeeding women. The product labelling and package leaflet contains information on use in pregnancy or during breastfeeding.
Use in children and adolescents
Mekinist is not tested or approved for use in children and
(patients less than 18 years)
adolescents. Mekinist is not recommended for children and adolescents younger than 18 years as the effects in this patient group are not known.
Use in patients with moderate to
The ECOG (Eastern Cooperative Oncology Group) scale is a
severe physical disability (ECOG 2-
method for assessing the performance and physical ability of
4)
cancer patients. An ECOG grade of 2 to 4 denotes patients that have moderate to severe health and physical issues. A grade of 2 indicates a patient is mobile and capable of self-care, but is not able to carry out work or strenuous activity. A status of 4 applies to a patient who is completely disabled, bed- or chairbound and not able to care for themselves. There is no information on whether Mekinist is appropriate for use in patients with an ECOG grade of between 2 to 4.
Safety in elderly (65 years and
There are limited study data on the safety of Mekinist in patients Page 6/10
Risk
What is known
over) patients
aged 65 years and over. A study with 27% of the melanoma patients (58 out of 211) aged over 65 years, showed that the proportion of patients over 65 years of age experiencing side effects during treatment was similar to the proportion seen in patients below 65 years. However, patients aged over 65 years were more likely to need a reduction in the dose of the medicine or to need their treatment to be temporarily or permanently stopped because of side effects.
Safety in patients with abnormal
The effect of Mekinist is not known in patients with a history of
heart rate, recent problems with
heart problems, including: poor supply of blood to the heart,
blood supply to the heart and high
problems following treatment for narrowing of the blood vessels
blood pressure that cannot be
to the heart, irregular heartbeat and blood pressure which
controlled by medicine..
cannot be controlled by medicines.
(Safety in patients with baseline
Information on the effect of treatment with Mekinist in patients
QTc ≥480 msec QT prolongation,
with a history of these heart problems will be collected over time
recent (within 6 months) acute
from patient studies and use in the general population.
coronary syndrome including unstable angina, coronary angioplasty, stenting or cardiac arrhythmias (except sinus arrhythmia), treatment refractory hypertension (blood pressure of
Patients are more likely to develop heart problems if they have an existing heart problem. Patients should tell their doctor as soon as possible if they have signs of heart problems (pounding or racing heart, dizziness, shortness of breath, tiredness, feeling light-headed or swelling in the legs).
systolic> 140 mmHg and/or
Patients will be checked for any heart problems whilst taking
diastolic > 90 mm Hg which cannot
Mekinist.
be controlled by anti-hypertensive therapy)) Safety in patients with a history of
Eye problems such as blood clots in veins of the eye and fluid
eye problems
beneath the retina were reported in studies involving patients
(Safety in patients with history of
receiving Mekinist.
retinal vein occlusion or central
It is not known whether the risk of experiencing serious eye
serous retinopathy (reclassified as
problems is greater in patients who have a history of serious eye
Retinal Pigment Epithelial
problems. However, Mekinist is not recommended for patients
Detachment, RPED))
who have ever had a clot in a vein in the eye. Patients should tell their doctor if they experience any eye problems (blurred vision, loss of vision, seeing coloured dots or seeing halos – a blurred outline around objects). Patients will be checked for any eye problems whilst taking Mekinist
Safety in patients with inflammation
There have been some reported cases of inflammation of the
inside the lungs or conditions
lungs (pneumonitis) in patients receiving Mekinist. These cases
causing inflammation of the tissue
have been infrequent, occurring in 2 out of every 100 patients
around the lungs
treated with Mekinist. It is not known whether patients with a history of these lung conditions are at an increased risk of Page 7/10
Risk
What is known
(Safety in patients with history of
experiencing lung problems when treated with Mekinist.
pneumonitis or interstitial lung disease) Limited information on long-term
Some patients in the Mekinist studies took Mekinist for a sustained period of over one year. There is no evidence that
use
they experienced different side effects compared with patients who received Mekinist for periods of less than one year. [Long-term treatment (>12 months)]
Ongoing monitoring of reported side effects in patients taking Mekinist for long periods will continue (this is a standard procedure). It is unknown if some medicines may affect levels of Mekinist in
Drug interaction effects (Drug-drug interactions i.e.,
the body, or if Mekinist may affect levels of other medicines.
enzymes responsible for the hydrolytic cleavage of Mekinist, potential for saturation of P-gp and BCRP, whether Mekinist is a substrate of OATP1B1 and OATP1B3 and whether Mekinist is an inhibitor of OCT2, OAT1, or OAT3)
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 Mekinist can be found on Mekinist’s EPAR page. This medicine has no additional risk minimisation measures.
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
A study sponsored by
The main objective is to
Dose
Study start
Final report
the National Cancer
determine the proper
adjustments
planned Q2
completion Q4
Institute that will help
dose of trametinib to be
potentially
2014
2017
determine the correct
taken in patients who
needed in
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Study/activity (including study number)
Objectives
Safety concerns /efficacy issue addressed
dose of trametinib in
have moderate to
patients who
patients who have
severe liver problems
have moderate to
moderate to severe
severe liver
liver problems
problems
Status
Planned date for submission of (interim and) final results
[MEC116354] Annual
To identify and
Heart problems
Ongoing –
Final report
reports/analyses will be
characterise the risk of
(e.g. a drop in
Interim
completion Q4
submitted about heart
heart problems in
the amount of
reports will
2020
problems (e.g. a drop
patients taking
blood pumped
be submitted
in the amount of blood
trametinib alone or in
around the body
annually
pumped to the body by
combination with other
by the heart,
the heart, general
anti-cancer medicines
general problems
problems with how the
with how the
heart pumps blood to
heart pumps
the body) that are
blood around the
reported in patients
body)
who are enrolled in certain clinical trials using trametinib A study conducted in a
To identify and
Sensitivity to
Study start
Final report
lab (not in humans or
characterise the risk of
sunlight
planned Q2
completion Q1
animals (in vitro)) to
sensitivity to sunlight in
2014
2015
determine the risk of
patients taking
sensitivity to sunlight
trametinib alone or in
in patients taking
combination with other
trametinib
anti-cancer medicines
A study to investigate
To help predict drug-
Drug-drug
Start start
Final report
the possibility of drug-
drug interactions
interactions
planned Q2
completion Q1
2014
2015
drug interaction with certain enzymes involved in the breakdown of trametinib [GSK1120212B] Studies to determine
To better characterise
Drug-drug
Start
Final report
the potential for drug-
the risk of drug-drug
interactions
planned Q2
completion Q1
drug interactions with
interactions
2014
2015
certain proteins involved in the breakdown of trametinib
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Study/activity (including study number)
Objectives
Safety concerns /efficacy issue addressed
Status
Planned date for submission of (interim and) final results
Studies to determine
To better characterise
Drug-drug
Start
Final report
whether certain
the risk of drug-drug
interactions
planned Q2
completion Q1
proteins affect
interactions
2014
2015
Ongoing
Q4 2015
trametinib and whether trametinib affects certain proteins A study to evaluate the
To evaluate the effect
Characterisation
possibility of an
of repeat oral dosing of
of the potential
electrical abnormality
trametinib on electrical
risk of a type of
in the heart in patients
activity of the heart in
electrical
taking trametinib
subjects with solid
abnormality in
tumours.
the heart (QT
[MEK114655]
prolongation)
Studies which are a condition of the marketing authorisation None of the above studies is a condition of the marketing authorisation.
Summary of changes to the risk management plan over time Not applicable.
This summary was last updated in 05-2014.
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