EMA/642231/2015

Summary of the risk management plan (RMP) for Blincyto (blinatumomab)

This is a summary of the risk management plan (RMP) for Blincyto, which details the measures to be taken in order to ensure that Blincyto 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 Blincyto, which can be found on Blincyto’s EPAR page.

Overview of disease epidemiology Blincyto is a cancer medicine used to treat adult patients with B-precursor acute lymphoblastic leukaemia (ALL), a type of blood cancer. In B-precursor ALL, certain cells that give rise to B-cells (a type of white blood cell) multiply too quickly and eventually these abnormal cells replace normal blood cells. Blincyto is used when the ALL has come back or has not responded to previous treatment. It is used when the patients are ‘Philadelphia-chromosome-negative’ (Ph-). This means that they do not have the Philadelphia chromosome, a special chromosome formed when some of the genes are re-arranged, and which is found in some patients with ALL. Acute lymphoblastic leukemia occurs in approximately 27 of every 100,000 people in the European Union. Approximately 40% of the cases are in adults. Risk factors for acute lymphoblastic leukemia include gender (male), race (white), and age (above 70 years). Approximately 35% of patients aged 18 to 60 years with acute lymphoblastic leukemia survive for at least 5 years or longer.

Summary of treatment benefits Blincyto contains blinatumomab, a type of antibody, as the active substance. It has been studied in one main study in 189 patients with Ph- B-cell precursor ALL whose leukaemia had come back or had not responded to treatment. Patients were given Blincyto for up to five treatment cycles. In this study, Blincyto was not compared with any other treatment. The main measure of effectiveness was based on the percentage of patients who, after two treatment cycles, responded to treatment, measured as resolution of signs of leukaemia and complete or partial normalisation of blood cell counts. The study showed that 42.9% (81 out of 189) of patients given Blincyto responded to treatment. In those patients who had a response, in most cases there was no evidence of cancer cells left. The average survival time before the cancer came back was around 6 months, which could enable suitable patients to undergo a blood stem cell transplant.

Unknowns relating to treatment benefits The treatment benefits of Blincyto have not been studied in certain populations such as patients with liver or kidney disease, HIV positive patients or patients with hepatitis B or C infection, children and Page 1/10

adolescents, elderly patients and patients receiving other cancer medicines (such as immunotherapy or radiotherapy).

Summary of safety concerns Important identified risks Risk

What is known

Preventability

Neurological

Neurological problems (such as fits,

Patients should talk to their doctor,

problems (problems

problems with speech, alterations in

pharmacist or nurse before using

affecting the

consciousness, confusion and

Blincyto if they have ever had

function of the brain

disorientation, problems with

neurological problems (for example fits,

and/or nerves)

balance and coordination) occur in

memory loss, confusion, disorientation,

approximately 50% of patients

loss of balance, difficulty in speaking).

treated with Blincyto.

Patients should immediately inform their doctor, pharmacist or nurse if they experience fits, difficulty in speaking, confusion and disorientation or loss of balance. It is recommended that a neurological examination is performed in patients before starting Blincyto therapy and that patients are clinically monitored for signs and symptoms of neurologic events (e.g. writing test). In case of neurological problems treatment may have to be interrupted. In patients who develop fits, anticonvulsant medicines may be needed.

Infections

Patients treated with Blincyto are at

Patients should talk to their doctor,

a higher risk of infections including

pharmacist, or nurse before using

fungal, bacterial and viral infections.

Blincyto if they have an infection. Patients should take their temperature as they may have a fever. Patients should tell their doctor or nurse immediately if they develop chills or shivering, or feel warm – these may be symptoms of an infection. In case patients develop an infection during treatment with Blincyto, treatment may have to be interrupted.

Immune system

Patients treated with Blincyto are at

Before the patient receives Blincyto,

reactions (cytokine

higher risk of experiencing cytokine

other medicines will be given to help

release syndrome)

release syndrome (a complication

reduce the risk of cytokine release

due to massive release in the blood

syndrome. Patients should be closely

of proteins which stimulate

monitored for signs and symptoms of

inflammation). Symptoms include Page 2/10

Risk

What is known

Preventability

fever, swelling, chills, decreased or

these events.

increased blood pressure, and fluid in the lungs, which may become severe. Infusion-related

Blincyto is given as an infusion into

Before the patient is given treatment

reactions

a vein. Reactions related to the

with Blincyto, other medicines will be

infusion of Blincyto may include,

given to help reduce infusion reactions

wheezing, flushing, face swelling,

and other possible side effects.

difficulty breathing, low blood pressure and high blood pressure. Complications due

Patients treated with Blincyto may

Patients will be monitored for tumour

to the break down

get complications due to the break

lysis syndrome during treatment with

of cancer cells

down of their cancer cells. This can

Blincyto and may be given fluids to help

(tumor lysis

lead to increased blood levels of

prevent it. Patients should be closely

syndrome)

potassium, uric acid, and

monitored for tumour lysis syndrome

phosphorus and decreased blood

(including renal function and fluid

levels of calcium.

balance) for the first 48 hours after their first infusion. Patients who develop tumor lysis syndrome may have to stop taking Blincyto

Leakage of fluid

Patients treated with Blincyto may

Patients treated with Blincyto and who

from small blood

get leakage of fluid from small blood

develop capillary leak syndrome should

vessels (capillary

vessels. This can cause pain and

be managed promptly.

leak syndrome)

swelling of the affected area(s) and low blood pressure.

Elevated liver

Patients treated with Blincyto may

Liver enzyme levels should be regularly

enzymes

get high levels of liver enzymes in

monitored during treatment.

blood tests. This could be a sign of liver problems. If this happens, it usually occurs at the beginning of treatment. Mistakes when

Blincyto is infused continuously

Detailed instructions are provided to

preparing or giving

using a pump device. Mistakes when

healthcare professionals who prepare

Blincyto treatment

preparing or giving the Blincyto

and give Blincyto treatment.

(medication errors)

infusion can result in patients getting a dose that is too high or too low. Mistakes in setting up the pump, or problems with the pump

Patients should tell their doctor or nurse immediately if they notice any problems with their infusion pump.

can also cause medication errors. Decreased levels of

Treatment may result in a very low

The blood counts should be regularly

white blood cells

white blood cell count (neutropenia)

monitored during treatment, especially

with or without

or very low white blood cell count

during the first 9 days of the first cycle.

fever (febrile

with a fever (febrile neutropenia).

neutropenia/

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Risk

What is known

Preventability

Low levels of

Patients treated with Blincyto may

Patients should measure their body

antibodies called

have a reduction in their levels of

temperature if they develop chills or

“immunoglobulins”

immunoglobulins. This may make

shivering, or feel unusually warm. They

which help the

them more likely to get infections.

may have a fever, a sign of an infection.

neutropenia)

immune system fight infection

Important potential risks Risk

What is known

Off-label use (Use of

Blincyto should not be used for diseases other than Ph- relapsed or

Blincyto for diseases other

refractory acute lymphoblastic leukemia.

than adults with Philadelphia chromosome negative (Ph-) relapsed or refractory acute lymphoblastic leukemia) Changes to the white

Some patients have developed changes of the brain

matter of the brain

(leukoencephalopathy) during treatment with Blincyto. It is not yet known

(leukoencephalopathy

whether these changes were due to Blincyto treatment, or were due to

[including progressive

other medical conditions and treatments that these patients had.

multifocal leukoencephalopathy, a rare viral disease])

Because of the potential for progressive multifocal leukoencephalopathy (PML), patients should be monitored for signs and symptoms. If these are consistent with PML events, the doctor should consider referral to a neurologist, brain MRI and examination of cerebral spinal fluid. No cases of PML were reported during the main study with Blincyto.

Blood clots

Blood clots (venous thromboembolism) in the veins can occur commonly

(thromboembolic events),

in patients with cancers. Some patients being treated with Blincyto have

including disseminated

experienced thromboembolic events including disseminated intravascular

intravascular coagulation

coagulation (a condition in which blood clots form in blood vessels thoughout the body, potentially cutting off the supply to organs). However the relationship to Blincyto is unclear.

Risk of antibody

With any medicine that is a protein (such as an antibody) there is a

production against

potential for the body to recognise the protein as ‘foreign’ and create

Blincyto (immunogenicity)

antibodies to neutralise it. While a small number of patients have

which may result in a lack

developed antibodies to Blincyto, this did not impact its activity, so

of effect or allergic

Blincyto was still effective.

reactions Use in patients with

Blincyto has not been studied in patients with liver disease; however, it is

existing liver problems

not expected to be harmful to the liver.

(hepatic impairment)

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Risk

What is known

Use in patients with active

For patients with relevant neurological pathology (e.g. epilepsy, stroke,

or history of high risk

Parkinson’s disease), the potential benefits of treatment should be

neurological (central

carefully weighed against the risk of neurological events and caution

nervous system)

should be exercised when administering Blincyto.

pathology including

It is recommended that a neurological examination is performed in

patients with untreated

patients before starting Blincyto therapy and that these patients are

acute lymphoblastic

clinically monitored for signs and symptoms of neurological events (e.g.

leukemia in the central

writing test).

nervous system

There is little experience with Blincyto in patients who have leukaemia cells in the brain or cerebrospinal fluid. However patients have been treated with Blincyto in clinical studies after clearance of ALL by directly infusing Blincyto in the brain/spinal cord areas (such as intrathecal chemotherapy). Therefore once the ALL is cleared in brain/spinal cord areas, treatment with Blincyto may be initiated. Blood disorders,

The effects of Blincyto in newborns are unknown. Blincyto could reduce

particularly decrease in

the activity of the immune system in the newborn. Blincyto should not be

the level of a certain type

used in pregnancy unless the potential benefits outweigh the potential

of white blood cell (B cell)

risk to the fetus.

in newborns exposed to Blincyto in pregnant women

If women are pregnant, think they may be pregnant or planning to have a baby, they should consult their doctor or nurse for advice before taking Blincyto.

Missing information Risk

What is known

Use in pregnancy and

The effects of Blincyto in pregnant and breastfeeding women are unknown. If

breastfeeding

women are pregnant, think they may be pregnant or planning to have a baby, they should consult their doctor or nurse for advice before taking this medicine. Women should not breastfeed during, and 48 hours after, finishing treatment with Blincyto.

Use in children

Blincyto should not be used in children below 18 years of age.

Use in the elderly

There is limited information in patients aged 75 years or above. However, patients aged 65 years or above experienced more serious neurologic events than subjects younger than 65.

Use in patients with

Blincyto has not been studied in patients with kidney disease; however, it is

existing kidney

not expected to be harmful to the kidneys. Clearance values in renal impaired

problems (renal

patients were within the range observed in patients with normal renal

impairment)

function, and therefore no clinically meaningful impact of renal function on clinical outcomes is expected.

Patients of different

Most of the people who participated in studies with Blincyto were Caucasian

ethnic origins

(white). More information is needed to determine the effect of ethnic origin

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Risk

What is known on either the efficacy or safety of Blincyto.

Patients with active

Blincyto is not intended for patients with active uncontrolled infections. In

uncontrolled

patients who are using Blincyto and who develop infections, treatment may

infections

have to be discontinued.

Use in patients with

Blincyto has not been studied in patients infected with HIV (human

human

immunodeficiency virus) or with chronic infection with hepatitis B virus or

immunodeficiency

hepatitis C virus.

virus positivity or chronic infection with hepatitis B virus or hepatitis C virus Use in patients after

Blincyto has not been studied in patients after recent blood (haematopoietic)

recent blood

stem cell transplantation.

(haematopoietic) stem cell transplantation Recent or

Blincyto has not been studied in patients receiving recent or concomitant

concomitant

treatment with other cancer therapies, including radiotherapy.

treatment with other cancer therapies (including radiotherapy) Recent or

Blincyto has not been studied in patients receiving recent or concomitant

concomitant

treatment with other immunotherapy.

treatment with other immunotherapy Effects on fertility

Blincyto’s effect on fertility has not been established.

Long-term safety

The long term effects of Blincyto have not been established.

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 Blincyto can be found on Blincyto’s EPAR page. This medicine has special conditions and restrictions for its safe and effective use (additional risk minimisation measures). Full details on these conditions and the key elements of any educational material can be found in Annex II of the product information which is published on Blincyto’s EPAR

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page; how they are implemented in each country however will depend upon agreement between the marketing authorisation holder and the national authorities. These additional risk minimisation measures are for the following risks:

Neurological events and medication errors Risk minimisation measure: Educational materials for doctors, pharmacists, nurses, and patients (including caregivers). In addition, patients will also receive a patient alert card. Objective and rationale: To provide advice on how to prevent neurological events; to reduce the risk of medication errors. Description: Educational material will be provided to patients, caregivers, doctors, nurses and pharmacists. These will stress the importance of reporting side effects, how to administer Blincyto and how to reduce the risk of medication errors while using the infusion pump. It will also include a description of the main signs and/or symptoms of neurological events and the importance of notifying the treating doctor or nurse immediately if symptoms occur.

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

Study 00103311

Primary objective:

This study will provide a more

Ongoing

Q1 2017

Planned

Protocol to be

(TOWER): A phase 3, randomized, open label study to investigate the efficacy of the BiTE Antibody Blinatumomab

- To evaluate the effect of Blincyto on overall survival when compared to standard of care chemotherapy.

complete dataset from which to evaluate overall survival seen with Blincyto and will help to better differentiate between the adverse events associated with Blincyto and those associated with cytotoxic

Versus Standard

chemotherapy in a heavily

of Care

pretreated patient population

Chemotherapy in

with a rapidly progressing

Adult Subjects

disease

With Relapsed/Refracto ry B precursor Acute Lymphoblastic Leukemia (ALL)

Study 20150136:

Primary objective:

Selected identified risks,

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Study/activity (including study number)

Objectives

Safety concerns /efficacy issue addressed

An observational

- To characterise

potential risks, and missing

developed

study of Blincyto

the safety profile

information, as well as other

within 2

safety and

of Blincyto in

serious adverse events

months of EC

effectiveness,

routine clinical

utilisation, and

practice in

treatment

countries in the

practices

EU. - To estimate the frequency and types of Blincyto medication errors identified.

Status

Planned date for submission of (interim and) final results

Decision Enrolment update will be provided in each PSUR Annual interim reports will be provided with corresponding

Secondary

PSUR starting

objectives:

with PSUR #3

- To estimate the

Final CSR

incidence of other

anticipated Q4

serious adverse

2021

events, ie, serious adverse events not included in the primary objective. - To evaluate safety and effectiveness endpoints among patient subgroups defined by demographic and clinical factors. - To characterise the effectiveness of Blincyto in routine clinical practice. - To describe Blincyto utilisation and select healthcare resource use in routine clinical practice.

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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

Study 20150163:

Primary objective:

Neurological events,

Planned

Final CSR

Survey of physicians, pharmacists, and nurses involved in the prescribing, preparation and administration of Blincyto in Europe to evaluate the effectiveness of additional risk

- To evaluate the

anticipated Q2

medication errors

2019

distribution, knowledge and effectiveness of additional risk minimisation measures for physicians, pharmacists and nurses.

minimization measures

Study 20150228: A cross sectional survey of patients and caregivers receiving Blincyto in routine clinical practice in Europe

Primary objective: - To assess

anticipated Q4 2017

educational materials. Secondary objective:

measures

medication errors

Final CSR

and receipt of the

effectiveness of minimization

Planned

knowledge about

to evaluate the additional risk

Neurological events,

- To determine the level of understanding of the information in the educational materials. - To evaluate adherence to the instructions in the patient educational materials.

Studies which are a condition of the marketing authorisation Study 00103311 and Study 20150136 are conditions of the marketing authorisation.

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Summary of changes to the risk management plan over time Major changes to the Risk Management Plan over time Not applicable.

This summary was last updated in 10-2015.

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