Rituzena (previously Tuxella)

European Union - English - EMA (European Medicines Agency)

Active ingredient:
rituximab
Available from:
Celltrion Healthcare Hungary Kft.
ATC code:
L01XC02
INN (International Name):
rituximab
Therapeutic group:
Antineoplastic agents,
Therapeutic area:
Lymphoma, Non-Hodgkin, Microscopic Polyangiitis, Leukemia, Lymphocytic, Chronic, B-Cell, Wegener Granulomatosis
Therapeutic indications:
Rituzena is indicated in adults for the following indications:Non-Hodgkin’s lymphoma (NHL)Rituzena is indicated for the treatment of previously untreated patients with stage III IV follicular lymphoma in combination with chemotherapy.Rituzena monotherapy is indicated for treatment of patients with stage III IV follicular lymphoma who are chemo resistant or are in their second or subsequent relapse after chemotherapy.Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell non Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.Chronic lymphocytic leukaemia (CLL)Rituzena in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including Rituzenaor patients refractory to previous Rituzena plus chemotherapy.Granulomatosis with pol
Product summary:
Revision: 7
Authorization status:
Withdrawn
Authorization number:
EMEA/H/C/004724
Authorization date:
2017-07-13
EMEA code:
EMEA/H/C/004724

Documents in other languages

Patient Information leaflet Patient Information leaflet - Bulgarian

18-02-2019

Summary of Product characteristics Summary of Product characteristics - Bulgarian

18-02-2019

Public Assessment Report Public Assessment Report - Bulgarian

26-09-2017

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Public Assessment Report Public Assessment Report - Spanish

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Public Assessment Report Public Assessment Report - Czech

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Patient Information leaflet Patient Information leaflet - German

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Public Assessment Report Public Assessment Report - Estonian

26-09-2017

Patient Information leaflet Patient Information leaflet - Greek

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Public Assessment Report Public Assessment Report - Greek

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Patient Information leaflet Patient Information leaflet - French

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Public Assessment Report Public Assessment Report - French

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Patient Information leaflet Patient Information leaflet - Italian

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Summary of Product characteristics Summary of Product characteristics - Italian

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Public Assessment Report Public Assessment Report - Italian

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Patient Information leaflet Patient Information leaflet - Latvian

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Summary of Product characteristics Summary of Product characteristics - Latvian

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Patient Information leaflet Patient Information leaflet - Lithuanian

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Public Assessment Report Public Assessment Report - Lithuanian

26-09-2017

Patient Information leaflet Patient Information leaflet - Hungarian

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Summary of Product characteristics Summary of Product characteristics - Hungarian

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Public Assessment Report Public Assessment Report - Hungarian

15-08-2017

Patient Information leaflet Patient Information leaflet - Maltese

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Summary of Product characteristics Summary of Product characteristics - Maltese

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Public Assessment Report Public Assessment Report - Maltese

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Patient Information leaflet Patient Information leaflet - Dutch

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Public Assessment Report Public Assessment Report - Dutch

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Public Assessment Report Public Assessment Report - Polish

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Patient Information leaflet Patient Information leaflet - Portuguese

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Summary of Product characteristics Summary of Product characteristics - Portuguese

18-02-2019

Public Assessment Report Public Assessment Report - Portuguese

26-09-2017

Patient Information leaflet Patient Information leaflet - Romanian

18-02-2019

Summary of Product characteristics Summary of Product characteristics - Romanian

18-02-2019

Public Assessment Report Public Assessment Report - Romanian

15-08-2017

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26-09-2017

Patient Information leaflet Patient Information leaflet - Slovenian

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Summary of Product characteristics Summary of Product characteristics - Slovenian

18-02-2019

Public Assessment Report Public Assessment Report - Slovenian

26-09-2017

Patient Information leaflet Patient Information leaflet - Finnish

18-02-2019

Summary of Product characteristics Summary of Product characteristics - Finnish

18-02-2019

Public Assessment Report Public Assessment Report - Finnish

26-09-2017

Patient Information leaflet Patient Information leaflet - Swedish

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Public Assessment Report Public Assessment Report - Swedish

26-09-2017

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Patient Information leaflet Patient Information leaflet - Icelandic

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Summary of Product characteristics Summary of Product characteristics - Icelandic

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Patient Information leaflet Patient Information leaflet - Croatian

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Summary of Product characteristics Summary of Product characteristics - Croatian

18-02-2019

Public Assessment Report Public Assessment Report - Croatian

26-09-2017

Read the complete document

B. PACKAGE LEAFLET

Package leaflet: Information for the patient

Rituzena 100 mg concentrate for solution for infusion

rituximab

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Rituzena is and what it is used for

What you need to know before you use Rituzena

How to use Rituzena

Possible side effects

How to store Rituzena

Contents of the pack and other information

1.

What Rituzena is and what it is used for

What Rituzena is

Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal

antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When

sticking to the surface of this cell, rituximab causes the cell to die.

What Rituzena is used for

Rituzena may be used for the treatment of several different conditions in adults. Your doctor may

prescribe Rituzena for the treatment of:

a)

Non-Hodgkin’s Lymphoma

This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes.

Rituzena can be given alone or with other medicines called “chemotherapy”.

b)

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects

B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with

CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood.

The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in

combination with chemotherapy destroys these cells.

c)

Granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called

Wegener’s granulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids.

Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the

blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well.

B-lymphocytes are involved in the cause of these conditions.

2.

What you need to know before you use Rituzena

Do not take Rituzena if:

you are allergic to rituximab, other proteins which are like rituximab, or any of the other

ingredients of this medicine (listed in section 6)

you have a severe active infection at the moment

you have a weak immune system

you have severe heart failure or severe uncontrolled heart disease and have granulomatosis with

polyangiitis or microscopic polyangiitis.

Do not have Rituzena if any of the above apply to you. If you are not sure, talk to your doctor,

pharmacist or nurse before you are given Rituzena.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Rituzena if:

you have ever had or might now have a hepatitis infection. This is because in a few cases,

Rituzena could cause hepatitis B to become active again, which can be fatal in very rare cases.

Patients who have ever had hepatitis B infection will be carefully checked by their doctor for

signs of this infection.

you have ever had heart problems (such as angina, palpitations or heart failure) or breathing

problems.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before

you are given Rituzena. Your doctor may need to take special care during your treatment with

Rituzena.

If you have granulomatosis with polyangiitis or microscopic polyangiitis also tell your doctor

if you think you may have an infection, even a mild one like a cold. The cells that are affected

by Rituzena help to fight infection and you should wait until the infection has passed before you

are given Rituzena. Also please tell your doctor if you have had a lot of infections in the past or

suffer from severe infections.

if you think you may need any vaccinations in the near future, including vaccinations for travel

to other countries. Some vaccines should not be given at the same time as Rituzena or in the

months after you receive Rituzena. Your doctor will check if you should have any vaccines

before you receive Rituzena.

Children and adolescents

Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child,

are under 18 years of age. This is because there is not much information about the use of Rituzena

in children and young people.

Other medicines and Rituzena

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other

medicines. This includes medicines obtained without a prescription and herbal medicines. This is

because Rituzena can affect the way some other medicines work. Also some other medicines can

affect the way Rituzena works.

In particular, tell your doctor:

if you are taking medicines for high blood pressure. You may be asked not to take these other

medicines 12 hours before you are given Rituzena. This is because some people have a fall in

their blood pressure while they are being given Rituzena.

if you have ever taken medicines which affect your immune system – such as chemotherapy or

immune-suppressive medicines.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before

you are given Rituzena.

Pregnancy and breast-feeding

You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are

planning to become pregnant. This is because Rituzena can transfer across the placenta and may

affect your baby.

If you can get pregnant, you and your partner must use an effective method of contraception

while using Rituzena. You must also do this for 12 months after your last treatment with

Rituzena.

Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months

after your last treatment with Rituzena. This is because Rituzena may pass into breast milk.

Driving and using machines

It is not known whether Rituzena has an effect on you being able to drive or use any tools or

machines.

3.

How Rituzena is given

How it is given

Rituzena will be given to you by a doctor or nurse who is experienced in the use of this treatment.

They will watch you closely while you are being given this medicine. This is in case you get any

side effects.

You will always be given Rituzena as a drip (intravenous infusion).

Medicines given before each Rituzena administration

Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or

reduce possible side effects.

How much and how often you will receive your treatment

a)

If you are being treated for non-Hodgkin’s Lymphoma

If you are having Rituzena alone

Rituzena will be given to you once a week for 4 weeks. Repeated treatment courses

with Rituzena are possible.

If you are having Rituzena with chemotherapy

Rituzena will be given to you on the same day as your chemotherapy. This is usually given

every 3 weeks up to 8 times.

b)

If you are being treated for chronic lymphocytic leukaemia

When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena

every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena

infusion. Your doctor will decide if you should receive other treatment at the same time.

c)

If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid

medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid

medicine given by mouth may be started at any time by your doctor to treat your condition.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of

these reactions have been fatal.

Infusion reactions

During or within the first 2 hours of the first infusion you may develop fever, chills and shivering.

Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness,

headache, breathing difficulties, tongue or throat swelling, itchy or runny nose, vomiting, flushing

or palpitations, heart attack or low number of platelets. If you have heart disease or angina, these

infusion reactions might get worse.

Tell the person giving you the infusion immediately

if you

develop any of these symptoms, as the infusion may need to be slowed down or stopped. You may

require additional treatment such as an antihistamine or paracetamol. When these symptoms go

away, or improve, the infusion can be continued. These reactions are less likely to happen after the

second infusion. Your doctor may decide to stop your Rituzena treatment if these reactions are

serious.

Infections

Tell your doctor immediately if you get signs of an infection including:

fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell

memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare,

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or

PML).

You might get infections more easily during your treatment with Rituzena.

These are often colds, but there have been cases of pneumonia or urinary infections. These are

listed below under “Other side effects”.

Skin reactions

Very rarely, severe blistering skin conditions that can be life-threatening may occur. Redness, often

associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth,

the genital areas or the eyelids, and fever may be present.

Tell your doctor immediately if you have

any of these symptoms.

Other side effects include:

a)

If you are being treated for non-Hodgkin’s Lymphoma or chronic lymphocytic leukaemia

Very common side effects (may affect more than 1 in 10 people):

bacterial or viral infections, bronchitis

low number of white blood cells sometimes with fever, or low number of blood cells called

“platelets”

feeling sick (nausea)

bald spots on the scalp, chills, headache

lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG)

in the blood which help protect against infection

Common side effects (may affect up to 1 in 10 people):

infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections,

fungal infections, infections of unknown origin, sinus inflammation, hepatitis B

low number of red blood cells (anaemia), low number of all blood cells

allergic reactions (hypersensitivity)

high blood sugar level, weight loss, swelling in the face and body, high levels of the

enzyme “lactate dehydrogenase (LDH)” in the blood, low calcium levels in the blood

unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping

skin feeling, reduced sense of touch

feeling restless, problems falling asleep,

becoming very red in the face and other areas of the skin as a consequence of dilation of

the blood vessels

feeling dizzy or anxious

producing more tears, tear duct problems, inflamed eye (conjunctivitis)

ringing sound in the ears, ear pain

heart problems – such as heart attack and uneven or fast heart rate

high or low blood pressure (low blood pressure especially when standing upright)

tightening of the muscles in the airways which causes wheezing (bronchospasm),

inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny

nose

being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat

and mouth, problems swallowing, constipation, indigestion

eating disorders: not eating enough, leading to weight loss

hives, increased sweating, night sweats

muscle problems – such as tight muscles, joint or muscle pain, back and neck pain

general discomfort or feeling uneasy or tired, shaking, signs of flu

multiple-organ failure.

Uncommon side effects (may affect up to 1 in 100 people):

blood clotting problems, decrease of red blood cell production and increase of red blood

cell destruction (aplastic haemolytic anaemia), swollen or enlarged lymph nodes

low mood and loss of interest or enjoyment in doing things, feeling nervous

taste problems – such as changes in the way things taste

heart problems – such as reduced heart rate or chest pain (angina)

asthma, too little oxygen reaching the body organs

swelling of the stomach.

Very rare side effects (may affect up to 1 in 10,000 people):

short term increase in the amount of some types of anti-bodies in the blood (called

immunoglobulins – IgM), chemical disturbances in the blood caused by break-down of

dying cancer cells

nerve damage in arms and legs, paralysed face

heart failure

inflammation of blood vessels including those leading to skin symptoms

respiratory failure

damage to the intestinal wall (perforation)

severe skin problems causing blisters that can be life-threatening. Redness, often

associated with blisters, may appear on the skin or on mucous membranes, such as inside

the mouth, the genital areas or the eyelids, and fever may be present.

kidney failure

severe vision loss

Not known (it is not known how often these side effects happen):

a reduction in white blood cells which does not happen straight away

reduced platelets number just after the infusion – this can be reversed, but can be fatal in

rare cases

hearing loss, loss of other senses

b)

If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Very common side effects (may affect more than 1 in 10 people):

infections, such as chest infections, urinary tract infections (pain on passing water), colds

and herpes infections

allergic reactions that are most likely to occur during an infusion, but can occur up to 24-

hours after infusion

diarrhoea

coughing or shortness of breath

nose bleeds

raised blood pressure

painful joints or back

muscle twitches or shakiness

feeling dizzy

tremors (shakiness, often in the hands)

difficulty sleeping (insomnia)

swelling of the hands or ankles

Common side effects (may affect up to 1 in 10 people):

indigestion

constipation

skin rashes, including acne or spots

flushing or redness of the skin

blocked nose

tight or painful muscles

pain in the muscles or in the hands or feet

low number of red blood cells (anaemia)

low numbers of platelets in the blood

an increase in the amount of potassium in the blood

changes in the rhythm of the heart, or the heart beating faster than normal

Very rare side effects (may affect up to 1 in 10,000 people):

severe blistering skin conditions that can be life-threatening. Redness, often associated

with blisters, may appear on the skin or on mucous membranes, such as inside the

mouth, the genital areas or the eyelids, and fever may be present.

recurrence of a previous Hepatitis B infection

Rituzena may also cause changes in laboratory tests carried out by your doctor.

Reporting of side effects

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any side effects not

listed in this leaflet. You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects you can help provide more information on the safety of this

medicine.

5.

How to store Rituzena

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP.

The expiry date refers to the last day of that month.

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from

light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines that you no longer use. These measures will help protect the

environment.

6.

Contents of the pack and other information

What Rituzena contains

The active ingredient in Rituzena is called rituximab. The vial contains 100 mg of

rituximab. Each mL of concentrate contains 10 mg of rituximab.

The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 and

water for injections.

What Rituzena looks like and contents of the pack

Rituzena is a clear, colourless solution, supplied as a concentrate for solution for infusion in a glass

vial. Pack of 2 vials.

Marketing Authorisation Holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Manufacturer

Biotec Services International Ltd.

Biotec House, Central Park, Western Avenue

Bridgend Industrial Estate

Bridgend, CF31 3RT, UK

Units 2100, 2110, 2010, 2120, 2130 and 2500

Phase 18, Central Park

Bridgend Industrial Estate

Bridgend, CF31 3TY, UK

Millmount Healthcare Ltd.

Block 7, City North Business Campus,

Stamullen, Co. Meath K32 YD60, Ireland

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/Belgique/Belgien

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Lietuva

EGIS PHARMACEUTICALS PLC atstovybė

Tel: +370 5 231 4658

България

EGIS Bulgaria EOOD

Teл.: + 359 2 987 6040

Luxembourg/Luxemburg

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Česká republika

EGIS Praha, spol. s r.o

Tel: +420 227 129 111

Magyarország

Egis Gyógyszergyár Zrt.

Tel.: + 36 1 803 5555

Danmark

Orion Pharma A/S

Tlf: + 45 86 14 00 00

Malta

Medical Logistics Ltd.

Tel: +356 2755 9990

Deutschland

Mundipharma GmbH

Tel: +49 (0) 69 506029-000

Nederland

Mundipharma Pharmaceuticals B.V

Tel: + 31 33 450 8270

Eesti

Orion Pharma Eesti OÜ

Tel: + 372 6 644 550

Norge

Orion Pharma AS

Tlf: + 47 40 00 42 10

Ελλάδα

ΒΙΑΝΕΞ Α.Ε.

Τηλ: +30 210 8009111 – 120

Österreich

Astro-Pharma GmbH

Tel: +43 1 97 99 860

España

Kern Pharma, S.L.

Tel: +34 93 700 2525

Polska

EGIS Polska Sp. z o.o.

Tel.: + 48 22 417 9200

France

Laboratoires Biogaran

Tél: +33 (0) 800 970 109

Portugal

PharmaKERN Portugal – Produtos Farmacêuticos,

Sociedade Unipessoal, Lda.

Tel: +351 214 200 290

Hrvatska

Oktal Pharma d.o.o.

Tel: +385 1 6595 777

România

Egis Pharmaceuticals PLC Romania

Tel: + 40 21 412 0017

Ireland

Mundipharma Pharmaceuticals Limited

Tel: +353 1 2063800

Slovenija

OPH Oktal Pharma d.o.o.

Tel: +386 1 519 29 22

Ísland

Vistor hf.

Sími: +354 535 7000

Slovenská republika

EGIS SLOVAKIA spol. s r.o

Tel: +421 2 3240 9422

Italia

Mundipharma Pharmaceuticals Srl

Tel: +39 02 31 82 88 1

Suomi/Finland

Orion Pharma

Puh/Tel: + 358 10 4261

Κύπρος

C.A. Papaellinas Ltd

Τηλ: +357 22741741

Sverige

Orion Pharma AB

Tel: + 46 8 623 64 40

Latvija

EGIS Pharmaceuticals PLC pārstāvniecība Latvijā

Tel: +371 67613859

United Kingdom

NAPP Pharmaceuticals Ltd.

Tel: +44 1223 424444

This leaflet was last revised in MM/YYYY

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.

Package leaflet: Information for the patient

Rituzena 500 mg concentrate for solution for infusion

rituximab

This medicine is subject to additional monitoring. This will allow quick identification of new

safety information. You can help by reporting any side effects you may get. See the end of section 4

for how to report side effects.

Read this leaflet carefully before you start taking this medicine because it contains important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor, pharmacist or nurse.

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet:

What Rituzena is and what it is used for

What you need to know before you use Rituzena

How to use Rituzena

Possible side effects

How to store Rituzena

Contents of the pack and other information

7.

What Rituzena is and what it is used for

What Rituzena is

Rituzena contains the active substance “rituximab”. This is a type of protein called a “monoclonal

antibody”. It is designed to stick to a type of white blood cell called “B-Lymphocyte”. When

sticking to the surface of this cell, rituximab causes the cell to die.

What Rituzena is used for

Rituzena may be used for the treatment of several different conditions in adults. Your doctor may

prescribe Rituzena for the treatment of:

d)

Non-Hodgkin’s Lymphoma

This is a disease of the lymph tissue (part of the immune system) that affects B-Lymphocytes.

Rituzena can be given alone or with other medicines called “chemotherapy”.

e)

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common form of adult leukaemia. CLL affects

B-lymphocytes, which originate in the bone marrow and develop in the lymph nodes. Patients with

CLL have too many abnormal lymphocytes, which accumulate mainly in the bone marrow and blood.

The spread of these abnormal B-lymphocytes is the cause of symptoms you may have. Rituzena in

combination with chemotherapy destroys these cells.

f)

Granulomatosis with polyangiitis or microscopic polyangiitis

Rituzena is used for inducing remission in granulomatosis with polyangiitis (formerly called

Wegener’s granulomatosis) or microscopic polyangiitis, taken in combination with corticosteroids.

Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the

blood vessels which mainly affects the lungs and kidneys, but may affect other organs as well.

B-lymphocytes are involved in the cause of these conditions.

8.

What you need to know before you use Rituzena

Do not take Rituzena if:

you are allergic to rituximab, other proteins which are like rituximab, or any of the other

ingredients of this medicine (listed in section 6)

you have a severe active infection at the moment

you have a weak immune system

you have severe heart failure or severe uncontrolled heart disease and have granulomatosis with

polyangiitis or microscopic polyangiitis.

Do not have Rituzena if any of the above apply to you. If you are not sure, talk to your doctor,

pharmacist or nurse before you are given Rituzena.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you are given Rituzena if:

you have ever had or might now have a hepatitis infection. This is because in a few cases,

Rituzena could cause hepatitis B to become active again, which can be fatal in very rare cases.

Patients who have ever had hepatitis B infection will be carefully checked by their doctor for

signs of this infection.

you have ever had heart problems (such as angina, palpitations or heart failure) or breathing

problems.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before

you are given Rituzena. Your doctor may need to take special care during your treatment with

Rituzena.

If you have granulomatosis with polyangiitis or microscopic polyangiitis also tell your doctor

if you think you may have an infection, even a mild one like a cold. The cells that are affected

by Rituzena help to fight infection and you should wait until the infection has passed before you

are given Rituzena. Also please tell your doctor if you have had a lot of infections in the past or

suffer from severe infections.

if you think you may need any vaccinations in the near future, including vaccinations for travel

to other countries. Some vaccines should not be given at the same time as Rituzena or in the

months after you receive Rituzena. Your doctor will check if you should have any vaccines

before you receive Rituzena.

Children and adolescents

Talk to your doctor, pharmacist or nurse before you are given this medicine if you, or your child,

are under 18 years of age. This is because there is not much information about the use of Rituzena

in children and young people.

Other medicines and Rituzena

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other

medicines. This includes medicines obtained without a prescription and herbal medicines. This is

because Rituzena can affect the way some other medicines work. Also some other medicines can

affect the way Rituzena works.

In particular, tell your doctor:

if you are taking medicines for high blood pressure. You may be asked not to take these other

medicines 12 hours before you are given Rituzena. This is because some people have a fall in

their blood pressure while they are being given Rituzena.

if you have ever taken medicines which affect your immune system – such as chemotherapy or

immune-suppressive medicines.

If any of the above apply to you (or you are not sure), talk to your doctor, pharmacist or nurse before

you are given Rituzena.

Pregnancy and breast-feeding

You must tell your doctor or nurse if you are pregnant, think that you might be pregnant or are

planning to become pregnant. This is because Rituzena can transfer across the placenta and may

affect your baby.

If you can get pregnant, you and your partner must use an effective method of contraception

while using Rituzena. You must also do this for 12 months after your last treatment with

Rituzena.

Do not breast-feed while you are being treated with Rituzena. Also do not breast-feed for 12 months

after your last treatment with Rituzena. This is because Rituzena may pass into breast milk.

Driving and using machines

It is not known whether Rituzena has an effect on you being able to drive or use any tools or

machines.

9.

How Rituzena is given

How it is given

Rituzena will be given to you by a doctor or nurse who is experienced in the use of this treatment.

They will watch you closely while you are being given this medicine. This is in case you get any

side effects.

You will always be given Rituzena as a drip (intravenous infusion).

Medicines given before each Rituzena administration

Before you are given Rituzena, you will be given other medicines (pre-medication) to prevent or

reduce possible side effects.

How much and how often you will receive your treatment

d)

If you are being treated for non-Hodgkin’s Lymphoma

If you are having Rituzena alone

Rituzena will be given to you once a week for 4 weeks. Repeated treatment courses

with Rituzena are possible.

If you are having Rituzena with chemotherapy

Rituzena will be given to you on the same day as your chemotherapy. This is usually given

every 3 weeks up to 8 times.

e)

If you are being treated for chronic lymphocytic leukaemia

When you are treated with Rituzena in combination with chemotherapy, you will receive Rituzena

every 28 days until you have received 6 doses. The chemotherapy should be given after the Rituzena

infusion. Your doctor will decide if you should receive other treatment at the same time.

f)

If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Treatment with Rituzena uses four separate infusions given at weekly intervals. A corticosteroid

medicine will usually be given by injection before the start of Rituzena treatment. Corticosteroid

medicine given by mouth may be started at any time by your doctor to treat your condition.

If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.

10.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Most side effects are mild to moderate but some may be serious and require treatment. Rarely, some of

these reactions have been fatal.

Infusion reactions

During or within the first 2 hours of the first infusion you may develop fever, chills and shivering.

Less frequently, some patients may get pain at the infusion site, blisters, itching, sickness, tiredness,

headache, breathing difficulties, tongue or throat swelling, itchy or runny nose, vomiting, flushing

or palpitations, heart attack or low number of platelets. If you have heart disease or angina, these

infusion reactions might get worse.

Tell the person giving you the infusion immediately

if you

develop any of these symptoms, as the infusion may need to be slowed down or stopped. You may

require additional treatment such as an antihistamine or paracetamol. When these symptoms go

away, or improve, the infusion can be continued. These reactions are less likely to happen after the

second infusion. Your doctor may decide to stop your Rituzena treatment if these reactions are

serious.

Infections

Tell your doctor immediately if you get signs of an infection including:

fever, cough, sore throat, burning pain when passing urine or feeling weak or generally unwell

memory loss, trouble thinking, difficulty walking or sight loss – these may be due to a very rare,

serious brain infection, which has been fatal (progressive multifocal leukoencephalopathy or

PML).

You might get infections more easily during your treatment with Rituzena.

These are often colds, but there have been cases of pneumonia or urinary infections. These are

listed below under “Other side effects”.

Skin reactions

Very rarely, severe blistering skin conditions that can be life-threatening may occur. Redness, often

associated with blisters, may appear on the skin or on mucous membranes, such as inside the mouth,

the genital areas or the eyelids, and fever may be present.

Tell your doctor immediately if you have

any of these symptoms.

Other side effects include:

c)

If you are being treated for non-Hodgkin’s Lymphoma or chronic lymphocytic leukaemia

Very common side effects (may affect more than 1 in 10 people):

bacterial or viral infections, bronchitis

low number of white blood cells sometimes with fever, or low number of blood cells called

“platelets”

feeling sick (nausea)

bald spots on the scalp, chills, headache

lower immunity – because of lower levels of anti-bodies called “immunoglobulins” (IgG)

in the blood which help protect against infection

Common side effects (may affect up to 1 in 10 people):

infections of the blood (sepsis), pneumonia, shingles, cold, bronchial tube infections,

fungal infections, infections of unknown origin, sinus inflammation, hepatitis B

low number of red blood cells (anaemia), low number of all blood cells

allergic reactions (hypersensitivity)

high blood sugar level, weight loss, swelling in the face and body, high levels of the

enzyme “lactate dehydrogenase (LDH)” in the blood, low calcium levels in the blood

unusual feelings of the skin – such as numbness, tingling, pricking, burning, a creeping

skin feeling, reduced sense of touch

feeling restless, problems falling asleep,

becoming very red in the face and other areas of the skin as a consequence of dilation of

the blood vessels

feeling dizzy or anxious

producing more tears, tear duct problems, inflamed eye (conjunctivitis)

ringing sound in the ears, ear pain

heart problems – such as heart attack and uneven or fast heart rate

high or low blood pressure (low blood pressure especially when standing upright)

tightening of the muscles in the airways which causes wheezing (bronchospasm),

inflammation, irritation in the lungs, throat or sinuses, being short of breath, runny

nose

being sick (vomiting), diarrhoea, pain in the stomach, irritation or ulcers in the throat

and mouth, problems swallowing, constipation, indigestion

eating disorders: not eating enough, leading to weight loss

hives, increased sweating, night sweats

muscle problems – such as tight muscles, joint or muscle pain, back and neck pain

general discomfort or feeling uneasy or tired, shaking, signs of flu

multiple-organ failure.

Uncommon side effects (may affect up to 1 in 100 people):

blood clotting problems, decrease of red blood cell production and increase of red blood

cell destruction (aplastic haemolytic anaemia), swollen or enlarged lymph nodes

low mood and loss of interest or enjoyment in doing things, feeling nervous

taste problems – such as changes in the way things taste

heart problems – such as reduced heart rate or chest pain (angina)

asthma, too little oxygen reaching the body organs

swelling of the stomach.

Very rare side effects (may affect up to 1 in 10,000 people):

short term increase in the amount of some types of anti-bodies in the blood (called

immunoglobulins – IgM), chemical disturbances in the blood caused by break-down of

dying cancer cells

nerve damage in arms and legs, paralysed face

heart failure

inflammation of blood vessels including those leading to skin symptoms

respiratory failure

damage to the intestinal wall (perforation)

severe skin problems causing blisters that can be life-threatening. Redness, often

associated with blisters, may appear on the skin or on mucous membranes, such as inside

the mouth, the genital areas or the eyelids, and fever may be present.

kidney failure

severe vision loss

Not known (it is not known how often these side effects happen):

a reduction in white blood cells which does not happen straight away

reduced platelets number just after the infusion – this can be reversed, but can be fatal in

rare cases

hearing loss, loss of other senses

d)

If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Very common side effects (may affect more than 1 in 10 people):

infections, such as chest infections, urinary tract infections (pain on passing water), colds

and herpes infections

allergic reactions that are most likely to occur during an infusion, but can occur up to 24-

hours after infusion

diarrhoea

coughing or shortness of breath

nose bleeds

raised blood pressure

painful joints or back

muscle twitches or shakiness

feeling dizzy

tremors (shakiness, often in the hands)

difficulty sleeping (insomnia)

swelling of the hands or ankles

Common side effects (may affect up to 1 in 10 people):

indigestion

constipation

skin rashes, including acne or spots

flushing or redness of the skin

blocked nose

tight or painful muscles

pain in the muscles or in the hands or feet

low number of red blood cells (anaemia)

low numbers of platelets in the blood

an increase in the amount of potassium in the blood

changes in the rhythm of the heart, or the heart beating faster than normal

Very rare side effects (may affect up to 1 in 10,000 people):

severe blistering skin conditions that can be life-threatening. Redness, often associated

with blisters, may appear on the skin or on mucous membranes, such as inside the

mouth, the genital areas or the eyelids, and fever may be present.

recurrence of a previous Hepatitis B infection

Rituzena may also cause changes in laboratory tests carried out by your doctor.

Reporting of side effects

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any side effects not

listed in this leaflet. You can also report side effects directly via the national reporting system listed in

Appendix V. By reporting side effects you can help provide more information on the safety of this

medicine.

11.

How to store Rituzena

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and the vial after EXP.

The expiry date refers to the last day of that month.

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from

light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines that you no longer use. These measures will help protect the

environment.

12.

Contents of the pack and other information

What Rituzena contains

The active ingredient in Rituzena is called rituximab. The vial contains 500 mg of

rituximab. Each mL of concentrate contains 10 mg of rituximab.

The other ingredients are sodium chloride, tri-sodium citrate dihydrate, polysorbate 80 and

water for injections.

What Rituzena looks like and contents of the pack

Rituzena is a clear, colourless solution, supplied as a concentrate for solution for infusion in a glass

vial. Pack of 1 vial.

Marketing Authorisation Holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

Manufacturer

Biotec Services International Ltd.

Biotec House, Central Park, Western Avenue

Bridgend Industrial Estate

Bridgend, CF31 3RT, UK

Units 2100, 2110, 2010, 2120, 2130 and 2500

Phase 18, Central Park

Bridgend Industrial Estate

Bridgend, CF31 3TY, UK

Millmount Healthcare Ltd.

Block 7, City North Business Campus,

Stamullen, Co. Meath K32 YD60, Ireland

For any information about this medicine, please contact the local representative of the Marketing

Authorisation Holder:

België/Belgique/Belgien

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Lietuva

EGIS PHARMACEUTICALS PLC atstovybė

Tel: +370 5 231 4658

България

EGIS Bulgaria EOOD

Teл.: + 359 2 987 6040

Luxembourg/Luxemburg

Mundipharma CVA

Tél/Tel: + 32 15 45 1180

Česká republika

EGIS Praha, spol. s r.o

Tel: +420 227 129 111

Magyarország

Egis Gyógyszergyár Zrt.

Tel.: + 36 1 803 5555

Danmark

Orion Pharma A/S

Tlf: + 45 86 14 00 00

Malta

Medical Logistics Ltd.

Tel: +356 2755 9990

Deutschland

Mundipharma GmbH

Tel: +49 (0) 69 506029-000

Nederland

Mundipharma Pharmaceuticals B.V

Tel: + 31 33 450 8270

Eesti

Orion Pharma Eesti OÜ

Tel: + 372 6 644 550

Norge

Orion Pharma AS

Tlf: + 47 40 00 42 10

Ελλάδα

ΒΙΑΝΕΞ Α.Ε.

Τηλ: +30 210 8009111 – 120

España

Kern Pharma, S.L.

Tel: +34 93 700 2525

Österreich

Astro-Pharma GmbH

Tel: +43 1 97 99 860

Polska

EGIS Polska Sp. z o.o.

Tel.: + 48 22 417 9200

France

Laboratoires Biogaran

Tél: +33 (0) 800 970 109

Portugal

PharmaKERN Portugal – Produtos Farmacêuticos,

Sociedade Unipessoal, Lda.

Tel: +351 214 200 290

Hrvatska

Oktal Pharma d.o.o.

Tel: +385 1 6595 777

România

Egis Pharmaceuticals PLC Romania

Tel: + 40 21 412 0017

Ireland

Mundipharma Pharmaceuticals Limited

Tel: +353 1 2063800

Slovenija

OPH Oktal Pharma d.o.o.

Tel: +386 1 519 29 22

Ísland

Vistor hf.

Sími: +354 535 7000

Slovenská republika

EGIS SLOVAKIA spol. s r.o

Tel: +421 2 3240 9422

Italia

Mundipharma Pharmaceuticals Srl

Tel: +39 02 31 82 88 1

Suomi/Finland

Orion Pharma

Puh/Tel: + 358 10 4261

Κύπρος

C.A. Papaellinas Ltd

Τηλ: +357 22741741

Sverige

Orion Pharma AB

Tel: + 46 8 623 64 40

Latvija

EGIS Pharmaceuticals PLC pārstāvniecība Latvijā

Tel: +371 67613859

United Kingdom

NAPP Pharmaceuticals Ltd.

Tel: +44 1223 424444

This leaflet was last revised in MM/YYYY

Other sources of information

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu

Read the complete document

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

See section 4.8 for how to report adverse reactions.

1.

NAME OF THE MEDICINAL PRODUCT

Rituzena 100 mg concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 100 mg of rituximab.

Each mL of concentrate contains 10mg of rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a

glycosylated immunoglobulin with human IgG1 constant regions and murine light

chain and

heavy

chain variable region sequences. The antibody is produced by mammalian (Chinese hamster

ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including

specific viral inactivation and removal procedures.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rituzena is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular

lymphoma in combination with chemotherapy.

Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma

who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell

non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,

prednisolone) chemotherapy.

Chronic lymphocytic leukaemia (CLL)

Rituzena in combination with chemotherapy is indicated for the treatment of patients with previously

untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for

patients previously treated with monoclonal antibodies including Rituzena or patients refractory to

previous Rituzena plus chemotherapy.

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult

patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic

polyangiitis (MPA).

4.2

Posology and method of administration

Rituzena should be administered under the close supervision of an experienced healthcare

professional, and in an environment where full resuscitation facilities are immediately available (see

section 4.4).

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and

diphenhydramine, should always be given before each administration of Rituzena.

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be

considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy.

In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis,

methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is

recommended prior to the first infusion of Rituzena (the last dose of methylprednisolone may be

given on the same day as the first infusion of Rituzena). This should be followed by oral prednisone

1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need)

during and after Rituzena treatment.

Posology

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Rituzena in combination with chemotherapy for induction treatment of

previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m

body

surface area per cycle, for up to 8 cycles.

Rituzena should be administered on day 1 of each chemotherapy cycle, after intravenous

administration of the glucocorticoid component of the chemotherapy if applicable.

Monotherapy

Relapsed/refractory follicular lymphoma

The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with

stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse

after chemotherapy is: 375 mg/m

body surface area, administered as an intravenous infusion once

weekly for four weeks.

For retreatment with Rituzena monotherapy for patients who have responded to previous treatment

with Rituzena monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is:

375 mg/m

body surface area, administered as an intravenous infusion once weekly for four weeks

(see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

Rituzena should be used in combination with CHOP chemotherapy. The recommended dosage is

375 mg/m

body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after

intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of Rituzena

have not been established in combination with other chemotherapies in diffuse large B cell

non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Rituzena are recommended. When Rituzena is given in combination with

chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be

applied.

Chronic lymphocytic leukaemia

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to

start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For

CLL patients whose lymphocyte counts are > 25 x 10

/L it is recommended to administer

prednisone/prednisolone 100 mg intravenous shortly before infusion with Rituzena to decrease the

rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of Rituzena in combination with chemotherapy for previously untreated

and relapsed/refractory patients is 375 mg/m

body surface area administered on day 0 of the first

treatment cycle followed by 500 mg/m

body surface area administered on day 1 of each

subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rituzena infusion.

Granulomatosis with polyangiitis and microscopic polyangiitis

Patients treated with Rituzena must be given the patient alert card with each infusion.

The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with

polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an

intravenous infusion once weekly for 4 weeks (four infusions in total).

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with

granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena

treatment, as appropriate.

Special populations

Elderly

No dose adjustment is required in elderly patients (aged >65 years).

Paediatric population

The safety and efficacy of Rituzena in children below 18 years has not been established. No data are

available.

Method of administration

The prepared Rituzena solution should be administered as an intravenous infusion through a

dedicated line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4).

Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or

hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma

should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory

tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be

restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest

X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the

previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the

treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to a

reduction in the rate of infusion. The infusion rate may be increased upon improvement of

symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated

in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

Subsequent doses of Rituzena can be infused at an initial rate of 100 mg/h, and increased by

100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.

4.3

Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in

section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic

polyangiitis

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in

section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease

(see section 4.4 regarding other cardiovascular diseases).

4.4

Special warnings and precautions for use

In order to improve traceability of biological medicinal products, the tradename and batch number of

the administered product should be clearly recorded (or stated) in the patient file.

Progressive multifocal leukoencephalopathy (PML)

All patients treated with rituximab for rheumatoid arthritis, granulomatosis with polyangiitis and

microscopic polyangiitis must be given the patient alert card with each infusion. The alert card

contains important safety information for patients regarding potential increased risk of infections,

including PML.

Very rare cases of fatal PML have been reported following the use of rituximab. Patients must be

monitored at regular intervals 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 possibly suggestive of PML.

Consultation with a neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal

fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not

notice (e.g. cognitive, neurological 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 rituximab must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML,

stabilisation or improved outcome has been seen. It remains unknown if early detection of PML

and suspension of rituximab therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion related reactions

Rituximab is associated with infusion-related reactions, which may be related to release of cytokines

and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable

from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and

anaphylactic and hypersensitivity reactions are described below.

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use

of the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after

starting the first rituximab intravenous infusion. They were characterised by pulmonary events and

in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to

fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by

bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This

syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia,

hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate

dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute

respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or

oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours

of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with

pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with

increased caution. Patients who develop severe cytokine release syndrome should have their infusion

interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment.

Since initial improvement of clinical symptoms may be followed by deterioration, these patients

should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been

resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms

has rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥25 x 10

/L) of circulating malignant

cells such as patients with CLL, who may be at higher risk of especially severe cytokine release

syndrome, should only be treated with extreme caution. These patients should be very closely

monitored throughout the first infusion. Consideration should be given to the use of a reduced

infusion rate for the first infusion in these patients or a split dosing over two days during the first

cycle and any subsequent cycles if the lymphocyte count is still >25 x 10

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with

rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in

10 % of patients) see section 4.8. These symptoms are usually reversible with interruption of

rituximab infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally,

oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine

release syndrome above for severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous

administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity

reactions typically occur within minutes after starting infusion. Medicinal products for the treatment

of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids,

should be available for immediate use in the event of an allergic reaction during administration of

rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of

the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been

reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary

oedema and acute reversible thrombocytopenia.

Since hypotension may occur during rituximab administration, consideration should be given to

withholding anti-hypertensive medicines 12 hours prior to the rituximab infusion.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or

myocardial infarction have occurred in patients treated with rituximab. Therefore, patients with a

history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when

considering treatment of patients with neutrophils < 1.5 x 10

/L and/or platelet counts < 75 x 10

as clinical experience in this population is limited

.

Rituximab has been used in 21 patients who

underwent autologous bone marrow transplantation and other risk groups with a presumable

reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during

rituximab therapy.

Infections

Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8).

Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis,

sepsis and opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of rituximab in patients with a history

of recurring or chronic infections or with underlying conditions which may further predispose

patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including

fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic

chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that

rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus

(HBV) screening should be performed in all patients before initiation of treatment with rituximab. At

minimum this should include HBsAg-status and HBcAb-status. These can be complemented with

other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not

be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb)

should consult liver disease experts before start of treatment and should be monitored and managed

following local medical standards to prevent hepatitis B reactivation.

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during

post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had

received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell

transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been

studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended.

Patients treated with rituximab may receive non-live vaccinations. However, with non-live vaccines

response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL

who received rituximab monotherapy when compared to healthy untreated controls had a lower rate

of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet

Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer).

For CLL patients similar results are assumable considering similarities between both diseases but

that has not been investigated in clinical trials.

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza

A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson

Syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event,

with a suspected relationship to rituximab, treatment should be permanently discontinued.

Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthritis

The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk

relationship has not been established.

Infusion related reactions

Rituximab is associated with infusion related reactions (IRRs), which may be related to release of

cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic

medicinal product and an anti-histaminic medicinal product, should always be administered before

each infusion of rituximab. In rheumatoid arthritis premedication with glucocorticoids should also be

administered before each infusion of rituximab in order to reduce the frequency and severity of IRRs

(see sections 4.2 and 4.8).

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the

post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials

were mild to moderate in severity. The most common symptoms were allergic reactions like headache,

pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion

of patients experiencing any infusion reaction was higher following the first infusion than following

the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses

(see section 4.8). The reactions reported were usually reversible with a reduction in rate, or

interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and,

occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely

monitor patients with pre-existing cardiac conditions and those who experienced prior

cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required

interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be

resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely

resolved.

Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline),

antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic

reaction during administration of rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III)

or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of

pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been

observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history,

and those who experienced prior cardiopulmonary adverse reactions the risk of cardiovascular

complications resulting from infusion reactions should be considered before treatment with rituximab

and patients closely monitored during administration. Since hypotension may occur during rituximab

infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours

prior to the rituximab infusion.

IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to

those seen for rheumatoid arthritis patients in clinical trials (see section 4.8).

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or

myocardial infarction have occurred in patients treated with rituximab. Therefore patients with

a history of cardiac disease should be monitored closely (see Infusion related reactions, above).

Infections

Based on the mechanism of action of rituximab and the knowledge that B cells play an important

role in maintaining normal immune response, patients have an increased risk of infection following

rituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy

with rituximab (see section 4.8).Rituximab should not be administered to patients with an active,

severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely

immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should

exercise caution when considering the use of rituximab in patients with a history of recurring or

chronic infections or with underlying conditions which may further predispose patients to serious

infection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin

levels are determined prior to initiating treatment with rituximab.

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly

evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment,

patients should be re-evaluated for any potential risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported

following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases

including Systemic Lupus Erythematosus (SLE) and vasculitis.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in

rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving

rituximab.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment

with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be

complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B

disease should not be treated with rituximab. Patients with positive hepatitis B serology (either

HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be

monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months

after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and

Stevens-Johnson Syndrome, some with fatal outcome, have been reported (see section 4.8). In

case of such an event with a suspected relationship to rituximab, treatment should be permanently

discontinued.

Immunisation

Physicians should review the patient’s vaccination status and follow current immunisation

guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to

first administration of rituximab.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied.

Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst

peripherally B cell depleted.

Patients treated with rituximab may receive non-live vaccinations. However, response rates to

non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated

with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs.

42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2

pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after

rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be

required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to

commencing the next course of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the

proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps,

rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs in rheumatoid arthritis

The concomitant use of rituximab and anti-rheumatic therapies other than those specified under the

rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other

DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5).

The available data indicate that the rate of clinically relevant infection is unchanged when such

therapies are used in patients previously treated with rituximab, however patients should be closely

observed for signs of infection if biologic agents and/or DMARDs are used following rituximab

therapy.

Malignancy

Immunomodulatory medicinal products may increase the risk of malignancy. On the basis of

limited experience with rituximab in rheumatoid arthritis patients (see section 4.8) the present data

do not seem to suggest any increased risk of malignancy. However, the possible risk for the

development of solid tumours cannot be excluded at this time.

4.5

Interaction with other medicinal products and other forms of interaction

Currently, there are limited data on possible medicinal product interactions with rituximab.

In CLL patients, co-administration with rituximab did not appear to have an effect on the

pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of

fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in

rheumatoid arthritis patients.

Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA)

titres may have allergic or hypersensitivity reactions when treated with other diagnostic or

therapeutic monoclonal antibodies.

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic

DMARD following rituximab. In these patients the rate of clinically relevant infection while on

rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following

treatment with the biologic DMARD.

4.6

Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing

potential should use effective contraceptive methods during and for 12 months following

treatment with rituximab.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to rituximab have not been studied in

clinical trials. There are no adequate and well-controlled data from studies in pregnant women,

however transient B-cell depletion and lymphocytopenia have been reported in some infants born to

mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies

(see section 5.3). For these reasons rituximab should not be administered to pregnant women unless

the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is

excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women

should not breastfeed while treated with rituximab and for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

4.7

Effects on ability to drive and use machines

No studies on the effects of rituximab on the ability to drive and use machines have been performed,

although the pharmacological activity and adverse reactions reported to date suggest that rituximab

would have no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia)

The overall safety profile of rituximab in non-Hodgkin’s lymphoma and CLL is based on data from

patients from clinical trials and from post-marketing surveillance. These patients were treated either

with rituximab monotherapy (as induction treatment or maintenance treatment following induction

treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were

IRRs which occurred in the majority of patients during the first infusion. The incidence of

infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after

eight doses of rituximab.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of

patients during clinical trials in patients with NHL and in 30-50% of patients during clinical trials

in patients with CLL

The most frequent reported or observed serious adverse drug reactions were:

IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

Infections, see section 4.4.

Cardiovascular events, see section 4.4.

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.)

Tabulated list of adverse reactions

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy

are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in

order of decreasing seriousness. Frequencies are defined as very common (

1/10), common (

1/100 to < 1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to < 1/1000), very rare (<

1/10,000) and not known (cannot be estimated from the available data).

The ADRs identified only during post-marketing surveillance, and for which a frequency could

not be estimated, are listed under “not known”.

Table 1

ADRs reported in clinical trials or during post-marketing surveillance in

patients with NHL and CLL disease treated with rituximab

monotherapy/maintenance or in combination with chemotherapy

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

Infections

and

infestations

bacterial

infection,

viral

infections,

bronchitis

sepsis,

pneumonia,

febrile

infection,

herpes zoster,

respiratory

tract

infection, fungal

infections,

infections of

unknown

aetiology,

acute

bronchitis,

sinusitis,

hepatitis B

serious viral

infection

Pneumocystis

jirovecii

Blood and

lymphatic

system

disorders

neutropenia,

leucopenia,

febrile

neutropenia,

thrombocyt

openia

anaemia,

pancytopenia,

granulocytopen

coagulation

disorders,

aplastic

anaemia,

haemolytic

anaemia,

lymphadenop

athy

transient

increase in

serum IgM

levels

late

neutropenia

Immune

system

disorders

infusion

related

reactions

angioedema

hypersensitivity

anaphylaxis

tumour lysis

syndrome,

cytokine

release

syndrome

serum

sickness

infusion-relate

d acute

reversible

thrombocytop

enia

Metabolism

and nutrition

disorders

hyperglycaemia,

weight

decrease,

peripheral

oedema, face

oedema,

increased LDH,

hypocalcaemia

Psychiatric

disorders

depression,

nervousness,

Nervous

system

disorders

paraesthesia,

hypoaesthesia,

agitation,

dysgeusia

peripheral

neuropathy,

facial nerve

cranial

neuropathy,

loss of other

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

insomnia,

vasodilatation,

dizziness,

anxiety

palsy

senses

Eye disorders

lacrimation

disorder,

conjunctivitis

severe vision

loss

Ear and

labyrinth

disorders

tinnitus, ear

pain

hearing loss

Cardiac

disorders

myocardial

infarction

and 6

arrhythmia,

atrial

fibrillation,

tachycardia,

cardiac

disorder

left

ventricular

failure,

supraventri-

cular

tachycardia,

+ventricular

tachycardia,

+angina,

+myocardial

ischaemia,

bradycardia

severe

cardiac

disoders

4 and 6

heart failure

and 6

Vascular

disorders

hypertension,

orthostatic

hypotension,

hypotension

vasculitis

(predominatel

y cutaneous),

leukocytoclast

ic vasculiti

Respiratory,

thoracic and

mediastinal

disorders

bronchospasm

respiratory

disease, chest

pain, dyspnoea,

increased

cough,

rhinitis

asthma,

bronchiolitis

obliterans,

lung disorder,

hypoxia

interstitial

lung disease

respiratory

failure

lung

infiltration

Gastrointesti

nal disorders

nausea

vomiting ,

diarrhoea,

abdominal pain,

dysphagia,

stomatitis,

constipation,

dyspepsia,

anorexia, throat

irritation

abdominal

enlargement

gastro-intestin

al perforation

Skin and

Subcutaneous

tissue

disorders

pruritus,

rash,

alopecia

urticaria,

sweating, night

sweats,

skin

disorder

severe bullous

skin reactions,

Stevens-Johns

on Syndrome

toxic

epidermal

necrolysis

(Lyell’s

Syndrome)

Musculoskele

tal,

connective

tissue and

bone

disorders

hypertonia,

myalgia,

arthralgia, back

pain, neck pain,

pain

Renal and

urinary

disorders

renal failure

General

disorders and

administratio

nsite

conditions

fever , chills,

asthenia,

headache

tumour pain,

flushing,

malaise,

cold syndrome,

fatigue,

shivering,

infusion site

pain

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

multi-organ

failure

Investigations

decreased

IgG levels

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked

with "+" where the frequency count was based only on severe (

grade 3 NCI common toxicity criteria) reactions. Only

the highest frequency observed in the trials is reported

includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL

see also section infection below

see also section haematologic adverse reactions below

see also section infusion-related reactions below. Rarely fatal cases reported

signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituximab

therapy

observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated

with infusion-related reactions

includes fatal cases

The following terms have been reported as adverse events during clinical trials, however,

were reported at a similar or lower incidence in the rituximab-arms compared to control

arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance,

pyrexia.

Description of selected adverse reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50%

of patients in clinical trials, and were predominantly seen during the first infusion, usually in the

first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other

symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash,

fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension,

dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related

reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional

reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary

oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions

such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure,

myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis

syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower

or unknown frequencies. The incidence of infusion-related symptoms decreased substantially

with subsequent infusions and is <1% of patients by the eighth cycle of rituximab-containing

treatment.

Infections

Rituximab induces B-cell depletion in about 70-80% of patients, but was associated with

decreased serum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in

the rituximab-containing arm of randomised studies. Severe infections were reported in about

4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall,

including grade 3 or 4 infections, were observed during rituximab maintenance treatment up

to 2 years when compared to observation. There was no cumulative toxicity in terms of

infections reported over a 2 year treatment period. In addition, other serious viral infections

either new, reactivated or exacerbated, some of which were fatal, have been reported with

rituximab treatment. The majority of patients had received rituximab in combination with

chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious

viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster

Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy

(PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and

retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation,have

been reported, the majority of which were in patients receiving rituximab in combination with

cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4

hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC.

Progression of Kaposi’s sarcoma has been observed in rituximab-exposed patients with pre-

existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority

of patients were HIV positive.

Haematologic adverse reactions

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalities

occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4)

neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients.

During rituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and

neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to

observation. The incidence of thrombocytopenia was low (<1% , grade 3/4) and was not different

between treatment arms. During the treatment course in studies with rituximab in combination with

chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%),

neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in

previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were

usually reported with higher frequencies when compared to chemotherapy alone. However, the

higher incidence of neutropenia in patients treated with rituximab and chemotherapy was not

associated with a higher incidence of infections and infestations compared to patients treated with

chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established

that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil

count remaining below 1x10

/L between day 24 and 42 after the last dose) or occurred with a late

onset (defined as neutrophil count below 1x10

/L later than 42 days after last dose in patients with

no previous prolonged neutropenia or who recovered prior to day 42) following treatment with

rituximab plus FC. There were no differences reported for the incidence of anaemia. Some cases of

late neutropenia occurring more than four weeks after the last infusion of rituximab were reported.

In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm

compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade ¾

thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in

the FC group.

In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases in

serum IgM levels have been observed following treatment initiation, which may be associated with

hyperviscosity and related symptoms. The transient IgM increase usually returned to at least

baseline level within 4 months.

Cardiovascular adverse reactions

Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8% of

patients with the most frequently reported events being hypotension and hypertension. Cases of grade

3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during

infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders

was comparable between patients treated with rituximab and observation. Cardiac events were

reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular

failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to <1% on

observation. In studies evaluating rituximab in combination with chemotherapy, the incidence of

grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia

and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the

CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a rituximab

infusion or were associated with predisposing conditions such as fever, infection, acute myocardial

infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP

and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart

failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall

incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and

in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

Cases of interstitial lung disease, some with fatal outcome, have been reported.

Neurologic disorders

During the treatment period (induction treatment phase comprising of R-CHOP for at most eight

cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced

thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference

between the treatment groups in the incidence of other thromboembolic events. In contrast, three

patients (1.5 %) had cerebrovascular events in the CHOP group, all of which occurred during the

follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low

both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3%

FC).

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

disturbance, headache, seizures and altered mental status, with or without associated hypertension. A

diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised

risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,

immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving

rituximab for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, rituximab was

administered with chemotherapy.

IgG levels

In the clinical trial evaluating rituximab maintenance treatment in relapsed/refractory follicular

lymphoma, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) after induction

treatment in both the observation and the rituximab groups. In the observation group, the median IgG

level subsequently increased to above the LLN, but remained constant in the rituximab group. The

proportion of patients with IgG levels below the LLN was about 60% in the rituximab group

throughout the 2 year treatment period, while it decreased in the observation group (36% after 2

years).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been

observed in paediatric patients treated with rituximab, in some cases severe and requiring long-term

immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric

patients are unknown.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Patient subpopulations - rituximab monotherapy

Elderly patients (

65 years):

The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared

to younger patients (<65 years).

Bulky disease

There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients

without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in

these two groups.

Re-treatment

The percentage of patients reporting ADRs upon re-treatment with further courses of rituximab was

similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4

ADRs).

Patient subpopulations - rituximab combination therapy

Elderly patients (

65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients

compared to younger patients (<65 years), with previously untreated or relapsed/refractory

CLL.

Summary of the safety profile (rheumatoid arthritis)

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from

clinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is

summarised in the sections below. In clinical trials more than 3,100 patients received at least one

treatment course and were followed for periods ranging from 6 months to over 5 years;

approximately 2,400 patients received two or more courses of treatment with over 1,000 having

received 5 or more courses. The safety information collected during post-marketing experience

reflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 x 1,000 mg of rituximab separated by an interval of two weeks; in addition to

methotrexate (10-25 mg/week). Rituximab infusions were administered after an intravenous infusion

of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.

Tabulated list of adverse reactions

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000

to <1/100) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are

presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of rituximab were IRRs. The overall

incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent

infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during

the initial course. In addition to adverse reactions seen in RA clinical trials for rituximab,

progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like

reaction have been reported during post marketing experience.

Table 2

Summary of adverse drug reactions reported in clinical trials or during post

marketing surveillance occurring in patients with rheumatoid arthritis receiving

rituximab

System organ class

Very common

Common

Uncommon

Rare

Very rare

Infections and

infestations

upper respiratory

tract infection,

urinary tract

infections

bronchitis,

sinusitis,

gastroenteritis,

tinea pedis

PML,

reactivation of

hepatitis B

Blood and

lymphatic

system

disorders

neutropenia

late neutropenia

serum sickness-

like reaction

Immune system

disorders

infusion related

reactions

(hypertension,

nausea, rash,

infusion related

reactions

(generalised

oedema,

System organ class

Very common

Common

Uncommon

Rare

Very rare

General

disorders and

administration

site conditions

pyrexia, pruritus,

urticaria, throat

irritation, hot

flush,

hypotension,

rhinitis, rigors,

tachycardia,

fatigue,

oropharyngeal

pain, peripheral

oedema,

erythma)

bronchospasm,

wheezing,

laryngeal

oedema,

angioneurotic

oedema,

generalised

pruritis,

anaphylaxis,

anaphylactoid

reaction)

Metabolism and

nutritional

Disorders

hypercholesterole

Psychiatric

disorders

depression,

anxiety

Nervous system

disorders

headache

paraesthesia,

migraine,

dizziness, sciatica

Cardiac disorders

angina pectoris,

atrial fibrillation,

heart failure,

myocardial

infarction

atrial flutter

Gastrointestinal

disorders

dyspepsia,

diarrhoea, gastro-

oesophageal

reflux, mouth

ulceration, upper

abdominal pain

Skin and

subcutaneous

tissue disorders

alopecia

toxic epidermal

necrolysis

(Lyell’s

Syndrome),

Stevens-Johnson

Syndrome

Musculo-

skeletal

disorders

arthralgia /

musculoskeletal

pain,

osteoarthritis,

bursitis

Investigations

decreased IgM

levels

decreased IgG

levels

Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials

Frequency category derived from post-marketing data.

Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a

result of hypersensitivity and/or to the mechanism of action.

Includes observations collected as part of routine laboratory monitoring.

Includes fatal cases

Description of selected adverse reactions

Multiple courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following

first exposure. The rate of all ADRs following first rituximab exposure was highest during the first

6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the

first treatment course), RA exacerbation and infections all of which were more frequent in the first

6 months of treatment.

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. Among the

3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with

733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure to

rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1%

(17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths

due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to

withdrawal decreased by course and were rare from course 3 onwards. Premedication with

intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2

and 4.4). Severe IRRs with fatal outcome have been reported in the postmarketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with

rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious

IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour

intravenous infusion of rituximab. Patients with a history of a serious infusion reaction to a biologic

therapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistent

with that observed historically. No serious IRRs were observed.

Infections

The overall rate of infection was approximately 94 per 100 patient years in rituximab treated

patients. The infections were predominately mild to moderate and consisted mostly of upper

respiratory tract infections and urinary tract infections. The incidence of infections that were serious

or required IV antibiotics, was approximately 4 per 100 patient years. The rate of serious infections

did not show any significant increase following multiple courses of rituximab. Lower respiratory

tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence

in the rituximab-arms compared to control arms.

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported

following use of rituximab for the treatment of autoimmune diseases. This includes rheumatoid

arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and

vasculitis.

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic

chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).

Reactivation of hepatitis B infection has also been very rarely reported in rheumatoid arthritis patients

receiving rituximab (see section 4.4).

Cardiovascular adverse reactions

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treated

patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients

experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

disturbance, headache, seizures and altered mental status, with or without associated hypertension. A

diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised

risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,

immunosuppressive therapy and/or chemotherapy.

Neutropenia

Events of neutropenia were observed with rituximab treatment, the majority of which were

transient and mild or moderate in severity. Neutropenia can occur several months after the

administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and

0.27% (2/731) of placebo-treated patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported

in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Laboratory abnormalities

Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA

patients treated with rituximab. There was no increased rate in overall infections or serious infections

after the development of low IgG or IgM (see section 4.4).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed

in paediatric patients treated with rituximab, in some cases severe and requiring long-term

immunoglobulin substitution therapy. The consequences of long-term B cell depletion in paediatric

patients are unknown.

Summary of the Safety Profile (granulomatosis with polyangiitis and microscopic polyangiitis)

In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were

treated with rituximab (375 mg/m

, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

Tabulated list of adverse reactions

The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the

rituximab group.

Table 3

Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving

rituximab, and at a higher frequency than the comparator group, in the

pivotal clinical study.

Body system

Adverse reaction

Rituximab (n=99)

Infections and infestations

Urinary tract infection

Bronchitis

Herpes zoster

Nasopharyngitis

Blood and lymphatic

system disorders

Thrombocytopenia

Immune system disorders

Cytokine release syndrome

Metabolism and nutrition disorders

Hyperkalaemia

Psychiatric disorders

Insomnia

Nervous system disorders

Dizziness

Tremor

Vascular disorders

Hypertension

Flushing

Body system

Adverse reaction

Rituximab (n=99)

Respiratory, thoracic and

mediastinal disorders

Cough

Dyspnoea

Epistaxis

Nasal congestion

Gastrointestinal

disorders

Diarrhoea

Dyspepsia

Constipation

Skin and subcutaneous

tissue disorders

Acne

Musculoskeletal and connective

tissue disorders

Muscle spasms

Arthralgia

Back pain

Muscle weakness

Musculoskeletal pain

Pain in extremities

General disorders and

administration site conditions

Peripheral oedema

Investigations

Decreased haemoglobin

Description of selected adverse drug reactions

Infusion related reactions

IRRs in the GPA and MPA clinical trial were defined as any adverse event occurring within 24

hours of an infusion and considered to be infusion-related by investigators in the safety population.

Ninety nine patients were treated with rituximab and 12% experienced at least one IRR. All IRRs

were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing,

throat irritation, and tremor. Rituximab was given in combination with intravenous glucocorticoids

which may reduce the incidence and severity of these events.

Infections

In the 99 rituximab patients, the overall rate of infection was approximately 237 per 100 patient years

(95% CI 197-285) at the 6-month primary endpoint. Infections were predominately mild to moderate

and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.

The rate of serious infections was approximately 25 per 100 patient years. The most frequently

reported serious infection in the rituximab group was pneumonia at a frequency of 4%.

Malignancies

The incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and

microscopic polyangiitis clinical study was 2.00 per 100 patient years at the study common closing

date (when the final patient had completed the follow-up period). On the basis of standardised

incidence ratios, the incidence of malignancies appears to be similar to that previously reported in

patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the

6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI

3-15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see

section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs and

symptoms included visual disturbance, headache, seizures and altered mental status, with or without

associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The

reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease,

hypertension, immunosuppressive therapy and/or chemotherapy.

Hepatitis B reactivation

A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported in

granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the post-

marketing setting.

Hypogammaglobulinaemia

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in

granulomatosis with polyangiitis and microscopic polyangiitis patients treated with rituximab. At 6

months, in the active-controlled, randomised, double-blind, multicentre, non-inferiority trial, in the

rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had

low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the

cyclophosphamide group. There was no increased rate in overall infections or serious infections in

patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in

granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the rituximab

group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or

greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in

rituximab-treated patients. The effect of multiple rituximab courses on the development of

neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been

studied in clinical trials.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation

is available from clinical trials in humans. The highest intravenous dose of rituximab tested in

humans to date is 5000 mg (2250 mg/m

), tested in a dose escalation study in patients with CLL. No

additional safety signals were identified.

Patients who experience overdose should have immediate interruption of their infusion and be closely

monitored.

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had

no reported adverse event. The two adverse events that were reported were flu-like symptoms, with

a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies

,

ATC code: L01XC02

Rituzena is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated

phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of

all B cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells,

pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalize

upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the

plasma as a free antigen and, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can

recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated

cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and

antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on

the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B

lymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B cell counts declined below normal following completion of the first dose of rituximab.

In patients treated for haematological malignancies, B cell recovery began within 6 months of

treatment and generally returned to normal levels within 12 months after completion of therapy,

although in some patients this may take longer (up to a median recovery time of 23 months

post-induction therapy). In patients with granulomatosis with polyangiitis or microscopic

polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly

infusions of rituximab 375 mg/m

, and remained at that level in most patients up to the 6 month time

point. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by

month 12, increasing to 87% of patients by month 18.

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL

received 375 mg/m

of rituximab as an intravenous infusion once weekly for four weeks. The overall

response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI

% 41% - 56%) with a 6%

complete response (CR) and a 42% partial response (PR) rate. The projected median time to

progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was

higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58%

vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs.

38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as

duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with

autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT.

Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or

high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test)

on response to rituximab. A statistically significant correlation was noted between response rates and

bone marrow involvement. 40% of patients with bone marrow involvement responded compared to

59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a

stepwise logistic regression analysis in which the following factors were identified as prognostic

factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky

disease.

Initial treatment, weekly for 8 doses

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular

B cell NHL received 375 mg/m

of rituximab as intravenous infusion weekly for eight doses. The

ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected

median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single

lesion ≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m

of rituximab as

intravenous infusion weekly for four doses. The ORR was 36 % (CI

% 21% – 51%; CR 3%, PR

33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular

B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were

re-treated with 375 mg/m

of rituximab as intravenous infusion weekly for four doses. Three of the

patients had received two courses of rituximab before enrolment and thus were given a third course

in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the

ORR was 38% (CI

% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for

responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP

achieved after the prior course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular

lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m

vincristine 1.4 mg/m

up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m

/day on

days 1 -5) every 3 weeks for 8 cycles or rituximab 375 mg/m

in combination with CVP (R-

CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321

patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median

follow up of patients was 53 months. R-CVP led to a significant benefit over CVP for the

primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test).

The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p<

0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment

with R-CVP significantly prolonged the time to disease progression or death compared to CVP,

33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of

response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p <

0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant

clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were

80.9% for patients in the R-CVP group compared to 71.1 % for patients in the CVP group

Results from three other randomised trials using rituximab in combination with chemotherapy

regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant

improvements in response rates, time-dependent parameters as well as in overall survival. Key

results from all four studies are summarised in table 4.

Table 4

Summary of key results from four phase III randomised studies evaluating

the benefit of rituximab with different chemotherapy regimens in follicular

lymphoma

Study

Treatment,

N

Median

FU,

months

ORR, %

CR,%

Median

TTF/PFS/ EFS

mo

OS

rates,

%

M39021

CVP, 159

R-CVP, 162

Median TTP:

14.7

33.6

P<0.0001

53-months

71.1

80.9

p=0.029

GLSG’00

CHOP, 205

R-CHOP,

Median TTF:

years

Not reached

p < 0.001

18-months

p = 0.016

OSHO

39

MCP, 96

R-MCP,

Median PFS:

28.8 Not

reached

p < 0.0001

48-months

p = 0.0096

FL2000

CHVP-IFN,

R-CHVP-

IFN, 175

Median EFS: 36

Not reached

p < 0.0001

42-months

p = 0.029

EFS – Event Free Survival

TTP – Time to progression or death

PFS – Progression-Free Survival

TTF – Time to Treatment Failure

OS rates – survival rates at the time of the analyses

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80

years) with diffuse large B cell lymphoma received standard CHOP chemotherapy

(cyclophosphamide 750 mg/m

, doxorubicin 50 mg/m

, vincristine 1.4 mg/m

up to a maximum of 2

mg on day 1, and prednisolone 40 mg/m

/day on days 1-5) every 3 weeks for eight cycles, or

rituximab 375 mg/m

plus CHOP (R-CHOP). Rituzena was administered on the first day of the

treatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a

median follow-up duration of approximately 31 months. The two treatment groups were well

balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-

CHOP treatment was associated with a clinically relevant and statistically significant improvement in

the duration of event-free survival (the primary efficacy parameter; where events were death, relapse

or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan

Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm

compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months,

estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm.

A subsequent analysis of the duration of overall survival, carried out with a median follow-up

duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071),

representing a risk reduction of 32 %.

The analysis of all secondary parameters (response rates, progression-free survival, disease-free

survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The

complete response rate after cycle 8 was 76.2 % in the R-CHOP group and 62.4 % in the CHOP

group (p=0.0028). The risk of disease progression was reduced by 46 % and the risk of relapse by

51 %. In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2

microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow

involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with

CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in

outcome for both high- and low-risk patients according to age adjusted IPI.

Clinical laboratory findings

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of

356 patients evaluated for HACA, 1.1 % (4 patients) were positive.

Chronic lymphocytic leukaemia

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients

with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25

mg/m

, cyclophosphamide 250 mg/m

, days 1-3) every 4 weeks for 6 cycles or rituximab in

combination with FC (R-FC). Rituximab was administered at a dosage of 375 mg/m

during the first

cycle one day prior to chemotherapy and at a dosage of 500 mg/m

on day 1 of each subsequent

treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had

previously been treated with monoclonal antibodies or if they were refractory (defined as failure to

achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total

of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 5a and Table 5b) and 552 patients

(276 R-FC, 276 FC) for the relapsed/refractory study (Table 6) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55

months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of

overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p =

0.0319, log-rank test) (Table 5a). The benefit in terms of PFS was consistently observed in most

patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 5b).

Table 5a

First-line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for rituximab plus FC vs. FC alone - 48.1 months

median observation time

Efficacy parameter

Kaplan-Meier estimate of median time

to event (months)

Risk

reduction

FC

(N = 409)

R-FC

(N=408)

Log-rank

p value

Progression

free survival (PFS)

32.8

55.3

<0.0001

Overall survival

0.0319

Event free survival

31.3

51.8

<0.0001

Response rate (CR, nPR, or PR)

CR rates

72.6%

16.9%

85.8%

36.0%

<0.0001

<0.0001

n.a.

n.a.

Duration of response*

36.2

57.3

<0.0001

Disease free survival (DFS)**

48.9

60.3

0.0520

Time to new treatment

47.2

69.7

<0.0001

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable

*: only applicable to patients achieving a CR, nPR, PR

**: only applicable to patients achieving a CR

Table 5b

First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage

(ITT) - 48.1 months median observation time

Number of

patients

Hazard ratio

(95% CI)

p-value (Wald

test, not

Progression

free survival (PFS)

FC

R

FC

adjusted)

Binet stage A

0.39 (0.15; 0.98)

0.0442

Binet stage B

0.52 (0.41; 0.66)

<0.0001

Binet stage C

0.68 (0.49; 0.95)

0.0224

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6

months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in

terms of PFS was observed in almost all patient subgroups analysed according to disease risk at

baseline. A slight but not significant improvement in overall survival was reported in the R-FC

compared to the FC arm.

Table 6

Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview

of efficacy results for rituximab plus FC vs. FC alone (25.3 months median

observation time)

Efficacy parameter

Kaplan-Meier estimate of

median time to event (months)

Risk

reduction

FC

(N = 276)

R-FC

(N=276

Log-

Rank p

Progression-free survival (PFS)

20.6

30.6

0.0002

Overall survival

51.9

0.2874

Event free survival

19.3

28.7

0.0002

Response rate (CR, nPR, or PR)

CR rates

Duration of response *

Disease free survival (DFS)**

Time to new CLL treatment

58.0%

13.0%

27.6

42.2

34.2

69.9%

24.3%

39.6

39.6

0.0034

0.0007

0.0252

0.8842

0.0024

n.a.

n.a.

Response rate and CR rates analysed using Chi-squared Test.

NR: not reached n.a. not applicable

*: only applicable to patients achieving a CR, nPR, PR;

**: only applicable to patients achieving a CR;

Results from other supportive studies using rituximab in combination with other chemotherapy

regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of

previously untreated and/or relapsed/refractory CLL patients have also demonstrated high

overall response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity

(especially myelotoxicity). These studies support the use of rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical

benefit (including CR) and are supportive for rituximab re-treatment.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

rituximab in all subsets of the paediatric population with follicular lymphoma and chronic

lymphocytic leukaemia. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis

(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator,

randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day)

for 3-6 months or rituximab (375 mg/m

) once weekly for 4 weeks. All patients in the

cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both

arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose

glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80

mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a

Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off

glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%.

The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission

(CR) at 6 months (Table 7).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing

disease (Table 8).

Table 7

Percentage of patients who achieved complete remission at 6 months

(Intent-to-treat population*)

Rituximab

(n

99)

Cyclophosphamide

(n

98)

Treatment difference

(Rituximab

--cyclophosphamide)

Rate

63.6%

53.1%

10.6%

95.1%

(−3.2%, 24.3%)

CI = confidence interval.

* Worst case imputation

Non-inferiority was demonstrated since the lower bound (−3.2%) was higher than the pre-determined

non-inferiority margin ( − 20%).

The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 8

Complete remission at 6-months by disease status

Rituximab

Cyclophosphamide

Difference (CI 95%)

All patients

Newly

diagnosed

n=99

n=48

n=51

n=98

n=48

n=50

Complete remission

All Patients

63.6%

53.1%

10.6% (

3.2, 24.3)

Newly diagnosed

60.4%

64.6%

− 4.2% (− 23.6, 15.3)

Relapsing

66.7%

42.0%

24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved

CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for

maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of

patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the

rituximab group compared with four in the cyclophosphamide group.

Retreatment with rituximab

Based upon investigator judgment, 15 patients received a second course of rituximab therapy for

treatment of relapse of disease activity which occurred between 6 and 18 months after the first

course of rituximab. The limited data from the present trial preclude any conclusions regarding the

efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and

microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses

(i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with

reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with

rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent

relapse. The efficacy and safety of rituximab in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 months.

None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance of

HACA formation in rituximab-treated patients is unclear.

5.2

Pharmacokinetic properties

Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or

multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied

rituximab doses ranged from 100 to 500 mg/m

), the typical population estimates of nonspecific

clearance (CL

), specific clearance (CL

) likely contributed by B cells or tumour burden, and

central compartment volume of distribution (V

) were 0.14 L/day, 0.59 L/day, and 2.7 L,

respectively. The estimated median terminal elimination half-life of rituximab was 22 days (range,

6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions

contributed to some of the variability in CL

of rituximab in data from 161 patients given 375

mg/m

as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell

counts or tumour lesions had a higher CL

. However, a large component of inter-individual

variability remained for CL

after correction for CD19-positive cell counts and tumour lesion size.

varied by body surface area (BSA) and CHOP therapy. This variability in V

(27.1% and 19.0%)

contributed by the range in BSA (1.53 to 2.32 m

) and concurrent CHOP therapy, respectively, were

relatively small. Age, gender and WHO performance status had no effect on the pharmacokinetics of

rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates

is not expected to result in a meaningful reduction in its pharmacokinetic variability.

Rituximab, administered as an intravenous infusion at a dose of 375 mg/m

at weekly intervals for 4

doses to 203 patients with NHL naive to rituximab, yielded a mean C

following the fourth

infusion of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of

patients 3 – 6 months after completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m

as an intravenous infusion at weekly

intervals for 8 doses to 37 patients with NHL, the mean C

increased with each successive

infusion, spanning from a mean of 243 µg/mL (range, 16 – 582 µg/mL) after the first infusion to 550

µg/mL (range, 171 – 1177 µg/mL) after the eighth infusion.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m

combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Chronic lymphocytic leukaemia

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m

increased

to 500 mg/m

each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL

patients. The mean C

(N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/

infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean

terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day

(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51

L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic

clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis

revealed that BSA and gender were the most significant covariates to explain inter-individual

variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume

of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic

differences are not considered to be clinically relevant and dose adjustment is not required. No

pharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg

and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were

dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first

infusion ranged from 157 to 171 µg/mL for 2 x 500 mg dose and ranged from 298 to 341 µg/mL for 2

x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 µg/mL for the2 x

500 mg dose and ranged from 355 to 404 µg/mL for the 2 x 1000 mg dose. Mean terminal elimination

half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000

mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first

infusion for both doses.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg

upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was

170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following

second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2

x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second

course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose.

PK parameters for rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the

same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum

concentration of 369 µg/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis and microscopic polyangiitis

Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with

polyangiitis and microscopic polyangiitis who received 375 mg/m

rituximab once weekly for four

doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days).

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726

L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these

patients appear similar to what has been observed in rheumatoid arthritis patients.

5.3

Preclinical safety data

Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in

cynomolgus monkeys have shown no other effect than the expected pharmacological depletion

of B cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to

100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the

foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the

lymphoid organs of the foetuses was observed, which persisted post natally and was accompanied

by a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in these

animals within 6 months of birth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant

for this molecule. No long-term animal studies have been performed to establish the carcinogenic

potential of rituximab.

Specific studies to determine the effects of rituximab on fertility have not been performed. In general

toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or

females were observed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Tri-sodium citrate dihydrate

Polysorbate 80

Water for injections

6.2

Incompatibilities

No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets

have been observed.

6.3

Shelf life

Unopened vial

3 years

Diluted product

The prepared infusion solution of rituximab is physically and chemically stable for 24 hours

at 2 °C - 8 °C and subsequently 12 hours at room temperature (not more than 30 °C).

From a microbiological point of view, the prepared infusion solution should be used immediately. If

not used immediately, in-use storage times and conditions prior to use are the responsibility of the

user and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place

in controlled and validated aseptic conditions.

6.4

Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from

light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Clear Type I glass vials with butyl rubber stopper containing 100 mg of rituximab in 10 mL. Pack of 2

vials.

6.6

Special precautions for disposal and other handling

Rituzena is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Aseptically withdraw the necessary amount of Rituzena, and dilute to a calculated concentration of

1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9

mg/mL (0.9%) solution for injection or 5 % D-Glucose in water. For mixing the solution, gently

invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared

solutions. Since the medicinal product does not contain any anti-microbial preservative or

bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be

inspected visually for particulate matter and discolouration prior to administration.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1206/002

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 July 2017

Date of latest renewal:

10.

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/

This medicinal product is subject to additional monitoring. This will allow quick identification of

new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

See section 4.8 for how to report adverse reactions.

1.

NAME OF THE MEDICINAL PRODUCT

Rituzena 500 mg concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 500 mg of rituximab.

Each mL of concentrate contains 10mg of rituximab.

Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody representing a

glycosylated immunoglobulin with human IgG1 constant regions and murine light

chain and

heavy

chain variable region sequences. The antibody is produced by mammalian (Chinese hamster

ovary) cell suspension culture and purified by affinity chromatography and ion exchange, including

specific viral inactivation and removal procedures.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless liquid.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Rituzena is indicated in adults for the following indications:

Non-Hodgkin’s lymphoma (NHL)

Rituzena is indicated for the treatment of previously untreated patients with stage III-IV follicular

lymphoma in combination with chemotherapy.

Rituzena monotherapy is indicated for treatment of patients with stage III-IV follicular lymphoma

who are chemo-resistant or are in their second or subsequent relapse after chemotherapy.

Rituzena is indicated for the treatment of patients with CD20 positive diffuse large B cell

non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine,

prednisolone) chemotherapy.

Chronic lymphocytic leukaemia (CLL)

Rituzena in combination with chemotherapy is indicated for the treatment of patients with previously

untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for

patients previously treated with monoclonal antibodies including Rituzena or patients refractory to

previous Rituzena plus chemotherapy.

See section 5.1 for further information.

Granulomatosis with polyangiitis and microscopic polyangiitis

Rituzena, in combination with glucocorticoids, is indicated for the induction of remission in adult

patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic

polyangiitis (MPA).

4.2

Posology and method of administration

Rituzena should be administered under the close supervision of an experienced healthcare

professional, and in an environment where full resuscitation facilities are immediately available (see

section 4.4).

Premedication consisting of an anti-pyretic and an antihistaminic, e.g. paracetamol and

diphenhydramine, should always be given before each administration of Rituzena.

In patients with non-Hodgkin’s lymphoma and CLL, premedication with glucocorticoids should be

considered if Rituzena is not given in combination with glucocorticoid-containing chemotherapy.

In patients with granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis,

methylprednisolone given intravenously for 1 to 3 days at a dose of 1000 mg per day is

recommended prior to the first infusion of Rituzena (the last dose of methylprednisolone may be

given on the same day as the first infusion of Rituzena). This should be followed by oral prednisone

1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based on clinical need)

during and after Rituzena treatment.

Posology

Non-Hodgkin’s lymphoma

Follicular non-Hodgkin's lymphoma

Combination therapy

The recommended dose of Rituzena in combination with chemotherapy for induction treatment of

previously untreated or relapsed/ refractory patients with follicular lymphoma is: 375 mg/m

body

surface area per cycle, for up to 8 cycles.

Rituzena should be administered on day 1 of each chemotherapy cycle, after intravenous

administration of the glucocorticoid component of the chemotherapy if applicable.

Monotherapy

Relapsed/refractory follicular lymphoma

The recommended dose of Rituzena monotherapy used as induction treatment for adult patients with

stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse

after chemotherapy is: 375 mg/m

body surface area, administered as an intravenous infusion once

weekly for four weeks.

For retreatment with Rituzena monotherapy for patients who have responded to previous treatment

with Rituzena monotherapy for relapsed/refractory follicular lymphoma, the recommended dose is:

375 mg/m

body surface area, administered as an intravenous infusion once weekly for four weeks

(see section 5.1).

Diffuse large B cell non-Hodgkin's lymphoma

Rituzena should be used in combination with CHOP chemotherapy. The recommended dosage is

375 mg/m

body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles after

intravenous infusion of the glucocorticoid component of CHOP. Safety and efficacy of Rituzena

have not been established in combination with other chemotherapies in diffuse large B cell

non-Hodgkin’s lymphoma.

Dose adjustments during treatment

No dose reductions of Rituzena are recommended. When Rituzena is given in combination with

chemotherapy, standard dose reductions for the chemotherapeutic medicinal products should be

applied.

Chronic lymphocytic leukaemia

Prophylaxis with adequate hydration and administration of uricostatics starting 48 hours prior to

start of therapy is recommended for CLL patients to reduce the risk of tumour lysis syndrome. For

CLL patients whose lymphocyte counts are > 25 x 10

/L it is recommended to administer

prednisone/prednisolone 100 mg intravenous shortly before infusion with Rituzena to decrease the

rate and severity of acute infusion reactions and/or cytokine release syndrome.

The recommended dosage of Rituzena in combination with chemotherapy for previously untreated

and relapsed/refractory patients is 375 mg/m

body surface area administered on day 0 of the first

treatment cycle followed by 500 mg/m

body surface area administered on day 1 of each

subsequent cycle for 6 cycles in total. The chemotherapy should be given after Rituzena infusion.

Granulomatosis with polyangiitis and microscopic polyangiitis

Patients treated with Rituzena must be given the patient alert card with each infusion.

The recommended dosage of Rituzena for induction of remission therapy of granulomatosis with

polyangiitis and microscopic polyangiitis is 375 mg/m2 body surface area, administered as an

intravenous infusion once weekly for 4 weeks (four infusions in total).

Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended for patients with

granulomatosis with polyangiitis or microscopic polyangiitis during and following Rituzena

treatment, as appropriate.

Special populations

Elderly

No dose adjustment is required in elderly patients (aged >65 years).

Paediatric population

The safety and efficacy of Rituzena in children below 18 years has not been established. No data are

available.

Method of administration

The prepared Rituzena solution should be administered as an intravenous infusion through a

dedicated line. It should not be administered as an intravenous push or bolus.

Patients should be closely monitored for the onset of cytokine release syndrome (see section 4.4).

Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or

hypoxia should have the infusion interrupted immediately. Patients with non-Hodgkin’s lymphoma

should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory

tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be

restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest

X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the

previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the

treatment should be seriously considered on a case by case basis.

Mild or moderate infusion-related reactions (IRRs) (section 4.8) usually respond to a

reduction in the rate of infusion. The infusion rate may be increased upon improvement of

symptoms.

First infusion

The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be escalated

in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.

Subsequent infusions

All indications

Subsequent doses of Rituzena can be infused at an initial rate of 100 mg/h, and increased by

100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h.

4.3

Contraindications

Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in

section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and microscopic

polyangiitis

Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients listed in

section 6.1.

Active, severe infections (see section 4.4).

Patients in a severely immunocompromised state.

Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease

(see section 4.4 regarding other cardiovascular diseases).

4.4

Special warnings and precautions for use

In order to improve traceability of biological medicinal products, the tradename and batch number of

the administered product should be clearly recorded (or stated) in the patient file.

Progressive multifocal leukoencephalopathy (PML)

All patients treated with rituximab for rheumatoid arthritis, granulomatosis with polyangiitis and

microscopic polyangiitis must be given the patient alert card with each infusion. The alert card

contains important safety information for patients regarding potential increased risk of infections,

including PML.

Very rare cases of fatal PML have been reported following the use of rituximab. Patients must be

monitored at regular intervals 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 possibly suggestive of PML.

Consultation with a neurologist should be considered as clinically indicated.

If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal

fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered.

The physician should be particularly alert to symptoms suggestive of PML that the patient may not

notice (e.g. cognitive, neurological 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 rituximab must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML,

stabilisation or improved outcome has been seen. It remains unknown if early detection of PML

and suspension of rituximab therapy may lead to similar stabilisation or improved outcome.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia

Infusion related reactions

Rituximab is associated with infusion-related reactions, which may be related to release of cytokines

and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable

from acute hypersensitivity reactions.

This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and

anaphylactic and hypersensitivity reactions are described below.

Severe infusion-related reactions with fatal outcome have been reported during post-marketing use

of the rituximab intravenous formulation, with an onset ranging within 30 minutes to 2 hours after

starting the first rituximab intravenous infusion. They were characterised by pulmonary events and

in some cases included rapid tumour lysis and features of tumour lysis syndrome in addition to

fever, chills, rigors, hypotension, urticaria, angioedema and other symptoms (see section 4.8).

Severe cytokine release syndrome is characterised by severe dyspnoea, often accompanied by

bronchospasm and hypoxia, in addition to fever, chills, rigors, urticaria, and angioedema. This

syndrome may be associated with some features of tumour lysis syndrome such as hyperuricaemia,

hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure, elevated lactate

dehydrogenase (LDH) and may be associated with acute respiratory failure and death. The acute

respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or

oedema, visible on a chest X-ray. The syndrome frequently manifests itself within one or two hours

of initiating the first infusion. Patients with a history of pulmonary insufficiency or those with

pulmonary tumour infiltration may be at greater risk of poor outcome and should be treated with

increased caution. Patients who develop severe cytokine release syndrome should have their infusion

interrupted immediately (see section 4.2) and should receive aggressive symptomatic treatment.

Since initial improvement of clinical symptoms may be followed by deterioration, these patients

should be closely monitored until tumour lysis syndrome and pulmonary infiltration have been

resolved or ruled out. Further treatment of patients after complete resolution of signs and symptoms

has rarely resulted in repeated severe cytokine release syndrome.

Patients with a high tumour burden or with a high number (≥25 x 10

/L) of circulating malignant

cells such as patients with CLL, who may be at higher risk of especially severe cytokine release

syndrome, should only be treated with extreme caution. These patients should be very closely

monitored throughout the first infusion. Consideration should be given to the use of a reduced

infusion rate for the first infusion in these patients or a split dosing over two days during the first

cycle and any subsequent cycles if the lymphocyte count is still >25 x 10

Infusion related adverse reactions of all kinds have been observed in 77% of patients treated with

rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in

10 % of patients) see section 4.8. These symptoms are usually reversible with interruption of

rituximab infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally,

oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see cytokine

release syndrome above for severe reactions.

Anaphylactic and other hypersensitivity reactions have been reported following the intravenous

administration of proteins to patients. In contrast to cytokine release syndrome, true hypersensitivity

reactions typically occur within minutes after starting infusion. Medicinal products for the treatment

of hypersensitivity reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids,

should be available for immediate use in the event of an allergic reaction during administration of

rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of

the cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been

reported less frequently than those attributed to cytokine release.

Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary

oedema and acute reversible thrombocytopenia.

Since hypotension may occur during rituximab administration, consideration should be given to

withholding anti-hypertensive medicines 12 hours prior to the rituximab infusion.

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or

myocardial infarction have occurred in patients treated with rituximab. Therefore, patients with a

history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely.

Haematological toxicities

Although rituximab is not myelosuppressive in monotherapy, caution should be exercised when

considering treatment of patients with neutrophils < 1.5 x 10

/L and/or platelet counts < 75 x 10

as clinical experience in this population is limited

.

Rituximab has been used in 21 patients who

underwent autologous bone marrow transplantation and other risk groups with a presumable

reduced bone marrow function without inducing myelotoxicity.

Regular full blood counts, including neutrophil and platelet counts, should be performed during

rituximab therapy.

Infections

Serious infections, including fatalities, can occur during therapy with rituximab (see section 4.8).

Rituximab should not be administered to patients with an active, severe infection (e.g. tuberculosis,

sepsis and opportunistic infections, see section 4.3).

Physicians should exercise caution when considering the use of rituximab in patients with a history

of recurring or chronic infections or with underlying conditions which may further predispose

patients to serious infection (see section 4.8).

Cases of hepatitis B reactivation have been reported in subjects receiving rituximab including

fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to cytotoxic

chemotherapy. Limited information from one study in relapsed/refractory CLL patients suggests that

rituximab treatment may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus

(HBV) screening should be performed in all patients before initiation of treatment with rituximab. At

minimum this should include HBsAg-status and HBcAb-status. These can be complemented with

other appropriate markers as per local guidelines. Patients with active hepatitis B disease should not

be treated with rituximab. Patients with positive hepatitis B serology (either HBsAg or HBcAb)

should consult liver disease experts before start of treatment and should be monitored and managed

following local medical standards to prevent hepatitis B reactivation.

Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during

post-marketing use of rituximab in NHL and CLL (see section 4.8). The majority of patients had

received rituximab in combination with chemotherapy or as part of a haematopoietic stem cell

transplant.

Immunisations

The safety of immunisation with live viral vaccines, following rituximab therapy has not been

studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended.

Patients treated with rituximab may receive non-live vaccinations. However, with non-live vaccines

response rates may be reduced. In a non-randomised study, patients with relapsed low-grade NHL

who received rituximab monotherapy when compared to healthy untreated controls had a lower rate

of response to vaccination with tetanus recall antigen (16% vs. 81%) and Keyhole Limpet

Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for >2-fold increase in antibody titer).

For CLL patients similar results are assumable considering similarities between both diseases but

that has not been investigated in clinical trials.

Mean pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, influenza

A, mumps, rubella, varicella) were maintained for at least 6 months after treatment with rituximab.

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson

Syndrome, some with fatal outcome, have been reported (see section 4.8). In case of such an event,

with a suspected relationship to rituximab, treatment should be permanently discontinued.

Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis

Methotrexate (MTX) naïve populations with rheumatoid arthritis

The use of rituximab is not recommended in MTX-naïve patients since a favourable benefit risk

relationship has not been established.

Infusion related reactions

Rituximab is associated with infusion related reactions (IRRs), which may be related to release of

cytokines and/or other chemical mediators. Premedication consisting of an analgesic/anti-pyretic

medicinal product and an anti-histaminic medicinal product, should always be administered before

each infusion of rituximab. In rheumatoid arthritis premedication with glucocorticoids should also be

administered before each infusion of rituximab in order to reduce the frequency and severity of IRRs

(see sections 4.2 and 4.8).

Severe IRRs with fatal outcome have been reported in rheumatoid arthritis patients in the

post-marketing setting. In rheumatoid arthritis most infusion-related events reported in clinical trials

were mild to moderate in severity. The most common symptoms were allergic reactions like headache,

pruritus, throat irritation, flushing, rash, urticaria, hypertension, and pyrexia. In general, the proportion

of patients experiencing any infusion reaction was higher following the first infusion than following

the second infusion of any treatment course. The incidence of IRR decreased with subsequent courses

(see section 4.8). The reactions reported were usually reversible with a reduction in rate, or

interruption, of rituximab infusion and administration of an anti-pyretic, an antihistamine, and,

occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Closely

monitor patients with pre-existing cardiac conditions and those who experienced prior

cardiopulmonary adverse reactions. Depending on the severity of the IRR and the required

interventions, temporarily or permanently discontinue rituximab. In most cases, the infusion can be

resumed at a 50 % reduction in rate (e.g. from 100 mg/h to 50 mg/h) when symptoms have completely

resolved.

Medicinal products for the treatment of hypersensitivity reactions, e.g. epinephrine (adrenaline),

antihistamines and glucocorticoids, should be available for immediate use in the event of an allergic

reaction during administration of rituximab.

There are no data on the safety of rituximab in patients with moderate heart failure (NYHA class III)

or severe, uncontrolled cardiovascular disease. In patients treated with rituximab, the occurrence of

pre-existing ischemic cardiac conditions becoming symptomatic, such as angina pectoris, has been

observed, as well as atrial fibrillation and flutter. Therefore, in patients with a known cardiac history,

and those who experienced prior cardiopulmonary adverse reactions the risk of cardiovascular

complications resulting from infusion reactions should be considered before treatment with rituximab

and patients closely monitored during administration. Since hypotension may occur during rituximab

infusion, consideration should be given to withholding anti-hypertensive medicinal product 12 hours

prior to the rituximab infusion.

IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to

those seen for rheumatoid arthritis patients in clinical trials (see section 4.8).

Cardiac disorders

Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or

myocardial infarction have occurred in patients treated with rituximab. Therefore patients with

a history of cardiac disease should be monitored closely (see Infusion related reactions, above).

Infections

Based on the mechanism of action of rituximab and the knowledge that B cells play an important

role in maintaining normal immune response, patients have an increased risk of infection following

rituximab therapy (see section 5.1). Serious infections, including fatalities, can occur during therapy

with rituximab (see section 4.8).Rituximab should not be administered to patients with an active,

severe infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or severely

immunocompromised patients (e.g. where levels of CD4 or CD8 are very low). Physicians should

exercise caution when considering the use of rituximab in patients with a history of recurring or

chronic infections or with underlying conditions which may further predispose patients to serious

infection, e.g. hypogammaglobulinaemia (see section 4.8). It is recommended that immunoglobulin

levels are determined prior to initiating treatment with rituximab.

Patients reporting signs and symptoms of infection following rituximab therapy should be promptly

evaluated and treated appropriately. Before giving a subsequent course of rituximab treatment,

patients should be re-evaluated for any potential risk for infections.

Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported

following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases

including Systemic Lupus Erythematosus (SLE) and vasculitis.

Hepatitis B Infections

Cases of hepatitis B reactivation, including those with a fatal outcome, have been reported in

rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis patients receiving

rituximab.

Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment

with rituximab. At minimum this should include HBsAg-status and HBcAb-status. These can be

complemented with other appropriate markers as per local guidelines. Patients with active hepatitis B

disease should not be treated with rituximab. Patients with positive hepatitis B serology (either

HBsAg or HBcAb) should consult liver disease experts before start of treatment and should be

monitored and managed following local medical standards to prevent hepatitis B reactivation.

Late neutropenia

Measure blood neutrophils prior to each course of rituximab, and regularly up to 6-months

after cessation of treatment, and upon signs or symptoms of infection (see section 4.8).

Skin reactions

Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell’s Syndrome) and

Stevens-Johnson Syndrome, some with fatal outcome, have been reported (see section 4.8). In

case of such an event with a suspected relationship to rituximab, treatment should be permanently

discontinued.

Immunisation

Physicians should review the patient’s vaccination status and follow current immunisation

guidelines prior to rituximab therapy. Vaccination should be completed at least 4 weeks prior to

first administration of rituximab.

The safety of immunisation with live viral vaccines following rituximab therapy has not been studied.

Therefore vaccination with live virus vaccines is not recommended whilst on rituximab or whilst

peripherally B cell depleted.

Patients treated with rituximab may receive non-live vaccinations. However, response rates to

non-live vaccines may be reduced. In a randomised trial, patients with rheumatoid arthritis treated

with rituximab and methotrexate had comparable response rates to tetanus recall antigen (39% vs.

42%), reduced rates to pneumococcal polysaccharide vaccine (43% vs. 82% to at least 2

pneumococcal antibody serotypes), and KLH neoantigen (47% vs. 93%), when given 6 months after

rituximab as compared to patients only receiving methotrexate. Should non-live vaccinations be

required whilst receiving rituximab therapy, these should be completed at least 4 weeks prior to

commencing the next course of rituximab.

In the overall experience of rituximab repeat treatment over one year in rheumatoid arthritis, the

proportions of patients with positive antibody titres against S. pneumoniae, influenza, mumps,

rubella, varicella and tetanus toxoid were generally similar to the proportions at baseline.

Concomitant/sequential use of other DMARDs in rheumatoid arthritis

The concomitant use of rituximab and anti-rheumatic therapies other than those specified under the

rheumatoid arthritis indication and posology is not recommended.

There are limited data from clinical trials to fully assess the safety of the sequential use of other

DMARDs (including TNF inhibitors and other biologics) following rituximab (see section 4.5).

The available data indicate that the rate of clinically relevant infection is unchanged when such

therapies are used in patients previously treated with rituximab, however patients should be closely

observed for signs of infection if biologic agents and/or DMARDs are used following rituximab

therapy.

Malignancy

Immunomodulatory medicinal products may increase the risk of malignancy. On the basis of

limited experience with rituximab in rheumatoid arthritis patients (see section 4.8) the present data

do not seem to suggest any increased risk of malignancy. However, the possible risk for the

development of solid tumours cannot be excluded at this time.

4.5

Interaction with other medicinal products and other forms of interaction

Currently, there are limited data on possible medicinal product interactions with rituximab.

In CLL patients, co-administration with rituximab did not appear to have an effect on the

pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of

fludarabine and cyclophosphamide on the pharmacokinetics of rituximab.

Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in

rheumatoid arthritis patients.

Patients with human anti-mouse antibody or human anti-chimeric antibody (HAMA/HACA)

titres may have allergic or hypersensitivity reactions when treated with other diagnostic or

therapeutic monoclonal antibodies.

In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic

DMARD following rituximab. In these patients the rate of clinically relevant infection while on

rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following

treatment with the biologic DMARD.

4.6

Fertility, pregnancy and lactation

Contraception in males and females

Due to the long retention time of rituximab in B cell depleted patients, women of childbearing

potential should use effective contraceptive methods during and for 12 months following

treatment with rituximab.

Pregnancy

IgG immunoglobulins are known to cross the placental barrier.

B cell levels in human neonates following maternal exposure to rituximab have not been studied in

clinical trials. There are no adequate and well-controlled data from studies in pregnant women,

however transient B-cell depletion and lymphocytopenia have been reported in some infants born to

mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies

(see section 5.3). For these reasons rituximab should not be administered to pregnant women unless

the possible benefit outweighs the potential risk.

Breast-feeding

Whether rituximab is excreted in human milk is not known. However, because maternal IgG is

excreted in human milk, and rituximab was detectable in milk from lactating monkeys, women

should not breastfeed while treated with rituximab and for 12 months following rituximab treatment.

Fertility

Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

4.7

Effects on ability to drive and use machines

No studies on the effects of rituximab on the ability to drive and use machines have been performed,

although the pharmacological activity and adverse reactions reported to date suggest that rituximab

would have no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile (non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia)

The overall safety profile of rituximab in non-Hodgkin’s lymphoma and CLL is based on data from

patients from clinical trials and from post-marketing surveillance. These patients were treated either

with rituximab monotherapy (as induction treatment or maintenance treatment following induction

treatment) or in combination with chemotherapy.

The most frequently observed adverse drug reactions (ADRs) in patients receiving rituximab were

IRRs which occurred in the majority of patients during the first infusion. The incidence of

infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after

eight doses of rituximab.

Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of

patients during clinical trials in patients with NHL and in 30-50% of patients during clinical trials

in patients with CLL

The most frequent reported or observed serious adverse drug reactions were:

IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4.

Infections, see section 4.4.

Cardiovascular events, see section 4.4.

Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4.)

Tabulated list of adverse reactions

The frequencies of ADRs reported with rituximab alone or in combination with chemotherapy

are summarised in Table 1. Within each frequency grouping, undesirable effects are presented in

order of decreasing seriousness. Frequencies are defined as very common (

1/10), common (

1/100 to < 1/10), uncommon (

1/1,000 to < 1/100), rare (

1/10,000 to < 1/1000), very rare (<

1/10,000) and not known (cannot be estimated from the available data).

The ADRs identified only during post-marketing surveillance, and for which a frequency could

not be estimated, are listed under “not known”.

Table 1

ADRs reported in clinical trials or during post-marketing surveillance in

patients with NHL and CLL disease treated with rituximab

monotherapy/maintenance or in combination with chemotherapy

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

Infections

and

infestations

bacterial

infection,

viral

infections,

bronchitis

sepsis,

pneumonia,

febrile

infection,

herpes zoster,

respiratory

tract

infection, fungal

infections,

infections of

unknown

aetiology,

acute

bronchitis,

sinusitis,

hepatitis B

serious viral

infection

Pneumocystis

jirovecii

Blood and

lymphatic

system

disorders

neutropenia,

leucopenia,

febrile

neutropenia,

thrombocyt

openia

anaemia,

pancytopenia,

granulocytopen

coagulation

disorders,

aplastic

anaemia,

haemolytic

anaemia,

lymphadenop

athy

transient

increase in

serum IgM

levels

late

neutropenia

Immune

system

disorders

infusion

related

reactions

angioedema

hypersensitivity

anaphylaxis

tumour lysis

syndrome,

cytokine

release

syndrome

serum

sickness

infusion-relate

d acute

reversible

thrombocytop

enia

Metabolism

and nutrition

disorders

hyperglycaemia,

weight

decrease,

peripheral

oedema, face

oedema,

increased LDH,

hypocalcaemia

Psychiatric

disorders

depression,

nervousness,

Nervous

system

disorders

paraesthesia,

hypoaesthesia,

agitation,

dysgeusia

peripheral

neuropathy,

facial nerve

cranial

neuropathy,

loss of other

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

insomnia,

vasodilatation,

dizziness,

anxiety

palsy

senses

Eye disorders

lacrimation

disorder,

conjunctivitis

severe vision

loss

Ear and

labyrinth

disorders

tinnitus, ear

pain

hearing loss

Cardiac

disorders

myocardial

infarction

and 6

arrhythmia,

atrial

fibrillation,

tachycardia,

cardiac

disorder

left

ventricular

failure,

supraventri-

cular

tachycardia,

+ventricular

tachycardia,

+angina,

+myocardial

ischaemia,

bradycardia

severe

cardiac

disoders

4 and 6

heart failure

and 6

Vascular

disorders

hypertension,

orthostatic

hypotension,

hypotension

vasculitis

(predominatel

y cutaneous),

leukocytoclast

ic vasculiti

Respiratory,

thoracic and

mediastinal

disorders

bronchospasm

respiratory

disease, chest

pain, dyspnoea,

increased

cough,

rhinitis

asthma,

bronchiolitis

obliterans,

lung disorder,

hypoxia

interstitial

lung disease

respiratory

failure

lung

infiltration

Gastrointesti

nal disorders

nausea

vomiting ,

diarrhoea,

abdominal pain,

dysphagia,

stomatitis,

constipation,

dyspepsia,

anorexia, throat

irritation

abdominal

enlargement

gastro-intestin

al perforation

Skin and

Subcutaneous

tissue

disorders

pruritus,

rash,

alopecia

urticaria,

sweating, night

sweats,

skin

disorder

severe bullous

skin reactions,

Stevens-Johns

on Syndrome

toxic

epidermal

necrolysis

(Lyell’s

Syndrome)

Musculoskele

tal,

connective

tissue and

bone

disorders

hypertonia,

myalgia,

arthralgia, back

pain, neck pain,

pain

Renal and

urinary

disorders

renal failure

General

disorders and

administratio

nsite

conditions

fever , chills,

asthenia,

headache

tumour pain,

flushing,

malaise,

cold syndrome,

fatigue,

shivering,

infusion site

pain

System organ

class

Very

common

Common

Uncommon

Rare

Very Rare

Not known

multi-organ

failure

Investigations

decreased

IgG levels

For each term, the frequency count was based on reactions of all grades (from mild to severe), except for terms marked

with "+" where the frequency count was based only on severe (

grade 3 NCI common toxicity criteria) reactions. Only

the highest frequency observed in the trials is reported

includes reactivation and primary infections; frequency based on R-FC regimen in relapsed/refractory CLL

see also section infection below

see also section haematologic adverse reactions below

see also section infusion-related reactions below. Rarely fatal cases reported

signs and symptoms of cranial neuropathy. Occurred at various times up to several months after completion of rituximab

therapy

observed mainly in patients with prior cardiac condition and/or cardiotoxic chemotherapy and were mostly associated

with infusion-related reactions

includes fatal cases

The following terms have been reported as adverse events during clinical trials, however,

were reported at a similar or lower incidence in the rituximab-arms compared to control

arms: haematotoxicity, neutropenic infection, urinary tract infection, sensory disturbance,

pyrexia.

Description of selected adverse reactions

Signs and symptoms suggestive of an infusion-related reaction were reported in more than 50%

of patients in clinical trials, and were predominantly seen during the first infusion, usually in the

first one to two hours. These symptoms mainly comprised fever, chills and rigors. Other

symptoms included flushing, angioedema, bronchospasm, vomiting, nausea, urticaria/rash,

fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension,

dyspnoea, dyspepsia, asthenia and features of tumour lysis syndrome. Severe infusion-related

reactions (such as bronchospasm, hypotension) occurred in up to 12% of the cases. Additional

reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary

oedema and acute reversible thrombocytopenia. Exacerbations of pre-existing cardiac conditions

such as angina pectoris or congestive heart failure or severe cardiac disorders (heart failure,

myocardial infarction, atrial fibrillation), pulmonary oedema, multi-organ failure, tumour lysis

syndrome, cytokine release syndrome, renal failure, and respiratory failure were reported at lower

or unknown frequencies. The incidence of infusion-related symptoms decreased substantially

with subsequent infusions and is <1% of patients by the eighth cycle of rituximab-containing

treatment.

Infections

Rituximab induces B-cell depletion in about 70-80% of patients, but was associated with

decreased serum immunoglobulins only in a minority of patients.

Localised candida infections as well as Herpes zoster were reported at a higher incidence in

the rituximab-containing arm of randomised studies. Severe infections were reported in about

4% of patients treated with rituximab monotherapy. Higher frequencies of infections overall,

including grade 3 or 4 infections, were observed during rituximab maintenance treatment up

to 2 years when compared to observation. There was no cumulative toxicity in terms of

infections reported over a 2 year treatment period. In addition, other serious viral infections

either new, reactivated or exacerbated, some of which were fatal, have been reported with

rituximab treatment. The majority of patients had received rituximab in combination with

chemotherapy or as part of a haematopoetic stem cell transplant. Examples of these serious

viral infections are infections caused by the herpes viruses (Cytomegalovirus, Varicella Zoster

Virus and Herpes Simplex Virus), JC virus (progressive multifocal leukoencephalopathy

(PML)) and hepatitis C virus. Cases of fatal PML that occurred after disease progression and

retreatment have also been reported in clinical trials. Cases of hepatitis B reactivation,have

been reported, the majority of which were in patients receiving rituximab in combination with

cytotoxic chemotherapy. In patients with relapsed/refractory CLL, the incidence of grade 3/4

hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% FC.

Progression of Kaposi’s sarcoma has been observed in rituximab-exposed patients with pre-

existing Kaposi’s sarcoma. These cases occurred in non-approved indications and the majority

of patients were HIV positive.

Haematologic adverse reactions

In clinical trials with rituximab monotherapy given for 4 weeks, haematological abnormalities

occurred in a minority of patients and were usually mild and reversible. Severe (grade 3/4)

neutropenia was reported in 4.2%, anaemia in 1.1% and thrombocytopenia in 1.7% of the patients.

During rituximab maintenance treatment for up to 2 years, leucopenia (5% vs. 2%, grade 3/4) and

neutropenia (10% vs. 4%, grade 3/4) were reported at a higher incidence when compared to

observation. The incidence of thrombocytopenia was low (<1% , grade 3/4) and was not different

between treatment arms. During the treatment course in studies with rituximab in combination with

chemotherapy, grade 3/4 leucopenia (R-CHOP 88% vs. CHOP 79%, R-FC 23% vs. FC 12%),

neutropenia (R-CVP 24% vs. CVP 14%; R-CHOP 97% vs. CHOP 88%, R-FC 30% vs. FC 19% in

previously untreated CLL), pancytopenia (R-FC 3% vs. FC 1% in previously untreated CLL) were

usually reported with higher frequencies when compared to chemotherapy alone. However, the

higher incidence of neutropenia in patients treated with rituximab and chemotherapy was not

associated with a higher incidence of infections and infestations compared to patients treated with

chemotherapy alone. Studies in previously untreated and relapsed/refractory CLL have established

that in up to 25% of patients treated with R-FC neutropenia was prolonged (defined as neutrophil

count remaining below 1x10

/L between day 24 and 42 after the last dose) or occurred with a late

onset (defined as neutrophil count below 1x10

/L later than 42 days after last dose in patients with

no previous prolonged neutropenia or who recovered prior to day 42) following treatment with

rituximab plus FC. There were no differences reported for the incidence of anaemia. Some cases of

late neutropenia occurring more than four weeks after the last infusion of rituximab were reported.

In the CLL first-line study, Binet stage C patients experienced more adverse events in the R-FC arm

compared to the FC arm (R-FC 83% vs. FC 71%). In the relapsed/refractory CLL study grade ¾

thrombocytopenia was reported in 11% of patients in the R-FC group compared to 9% of patients in

the FC group.

In studies of rituximab in patients with Waldenstrom’s macroglobulinaemia, transient increases in

serum IgM levels have been observed following treatment initiation, which may be associated with

hyperviscosity and related symptoms. The transient IgM increase usually returned to at least

baseline level within 4 months.

Cardiovascular adverse reactions

Cardiovascular reactions during clinical trials with rituximab monotherapy were reported in 18.8% of

patients with the most frequently reported events being hypotension and hypertension. Cases of grade

3 or 4 arrhythmia (including ventricular and supraventricular tachycardia) and angina pectoris during

infusion were reported. During maintenance treatment, the incidence of grade 3/4 cardiac disorders

was comparable between patients treated with rituximab and observation. Cardiac events were

reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular

failure, myocardial ischaemia) in 3% of patients treated with rituximab compared to <1% on

observation. In studies evaluating rituximab in combination with chemotherapy, the incidence of

grade 3 and 4 cardiac arrhythmias, predominantly supraventricular arrhythmias such as tachycardia

and atrial flutter/fibrillation, was higher in the R-CHOP group (14 patients, 6.9%) as compared to the

CHOP group (3 patients, 1.5%). All of these arrhythmias either occurred in the context of a rituximab

infusion or were associated with predisposing conditions such as fever, infection, acute myocardial

infarction or pre-existing respiratory and cardiovascular disease. No difference between the R-CHOP

and CHOP group was observed in the incidence of other grade 3 and 4 cardiac events including heart

failure, myocardial disease and manifestations of coronary artery disease. In CLL, the overall

incidence of grade 3 or 4 cardiac disorders was low both in the first-line study (4% R-FC, 3% FC) and

in the relapsed/refractory study (4% R-FC, 4% FC).

Respiratory system

Cases of interstitial lung disease, some with fatal outcome, have been reported.

Neurologic disorders

During the treatment period (induction treatment phase comprising of R-CHOP for at most eight

cycles), four patients (2 %) treated with R-CHOP, all with cardiovascular risk factors, experienced

thromboembolic cerebrovascular accidents during the first treatment cycle. There was no difference

between the treatment groups in the incidence of other thromboembolic events. In contrast, three

patients (1.5 %) had cerebrovascular events in the CHOP group, all of which occurred during the

follow-up period. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low

both in the first-line study (4% R-FC, 4% FC) and in the relapsed/refractory study (3% R-FC, 3%

FC).

Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

disturbance, headache, seizures and altered mental status, with or without associated hypertension. A

diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised

risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,

immunosuppressive therapy and/or chemotherapy.

Gastrointestinal disorders

Gastrointestinal perforation in some cases leading to death has been observed in patients receiving

rituximab for treatment of non-Hodgkin’s lymphoma. In the majority of these cases, rituximab was

administered with chemotherapy.

IgG levels

In the clinical trial evaluating rituximab maintenance treatment in relapsed/refractory follicular

lymphoma, median IgG levels were below the lower limit of normal (LLN) (<7 g/L) after induction

treatment in both the observation and the rituximab groups. In the observation group, the median IgG

level subsequently increased to above the LLN, but remained constant in the rituximab group. The

proportion of patients with IgG levels below the LLN was about 60% in the rituximab group

throughout the 2 year treatment period, while it decreased in the observation group (36% after 2

years).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been

observed in paediatric patients treated with rituximab, in some cases severe and requiring long-term

immunoglobulin substitution therapy. The consequences of long term B cell depletion in paediatric

patients are unknown.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Patient subpopulations - rituximab monotherapy

Elderly patients (

65 years):

The incidence of ADRs of all grades and grade 3 /4 ADR was similar in elderly patients compared

to younger patients (<65 years).

Bulky disease

There was a higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients

without bulky disease (25.6 % vs. 15.4 %). The incidence of ADRs of any grade was similar in

these two groups.

Re-treatment

The percentage of patients reporting ADRs upon re-treatment with further courses of rituximab was

similar to the percentage of patients reporting ADRs upon initial exposure (any grade and grade 3/4

ADRs).

Patient subpopulations - rituximab combination therapy

Elderly patients (

65 years)

The incidence of grade 3/4 blood and lymphatic adverse events was higher in elderly patients

compared to younger patients (<65 years), with previously untreated or relapsed/refractory

CLL.

Summary of the safety profile (rheumatoid arthritis)

The overall safety profile of rituximab in rheumatoid arthritis is based on data from patients from

clinical trials and from post-marketing surveillance.

The safety profile of rituximab in patients with moderate to severe rheumatoid arthritis (RA) is

summarised in the sections below. In clinical trials more than 3,100 patients received at least one

treatment course and were followed for periods ranging from 6 months to over 5 years;

approximately 2,400 patients received two or more courses of treatment with over 1,000 having

received 5 or more courses. The safety information collected during post-marketing experience

reflects the expected adverse reaction profile as seen in clinical trials for rituximab (see section 4.4).

Patients received 2 x 1,000 mg of rituximab separated by an interval of two weeks; in addition to

methotrexate (10-25 mg/week). Rituximab infusions were administered after an intravenous infusion

of 100 mg methylprednisolone; patients also received treatment with oral prednisone for 15 days.

Tabulated list of adverse reactions

Frequencies are defined as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000

to <1/100) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are

presented in order of decreasing seriousness.

The most frequent adverse reactions considered due to receipt of rituximab were IRRs. The overall

incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent

infusions. Serious IRRs were uncommon (0.5% of patients) and were predominantly seen during

the initial course. In addition to adverse reactions seen in RA clinical trials for rituximab,

progressive multifocal leukoencephalopathy (PML) (see section 4.4) and serum sickness-like

reaction have been reported during post marketing experience.

Table 2

Summary of adverse drug reactions reported in clinical trials or during post

marketing surveillance occurring in patients with rheumatoid arthritis receiving

rituximab

System organ class

Very common

Common

Uncommon

Rare

Very rare

Infections and

infestations

upper respiratory

tract infection,

urinary tract

infections

bronchitis,

sinusitis,

gastroenteritis,

tinea pedis

PML,

reactivation of

hepatitis B

Blood and

lymphatic

system

disorders

neutropenia

late neutropenia

serum sickness-

like reaction

Immune system

disorders

infusion related

reactions

(hypertension,

nausea, rash,

infusion related

reactions

(generalised

oedema,

System organ class

Very common

Common

Uncommon

Rare

Very rare

General

disorders and

administration

site conditions

pyrexia, pruritus,

urticaria, throat

irritation, hot

flush,

hypotension,

rhinitis, rigors,

tachycardia,

fatigue,

oropharyngeal

pain, peripheral

oedema,

erythma)

bronchospasm,

wheezing,

laryngeal

oedema,

angioneurotic

oedema,

generalised

pruritis,

anaphylaxis,

anaphylactoid

reaction)

Metabolism and

nutritional

Disorders

hypercholesterole

Psychiatric

disorders

depression,

anxiety

Nervous system

disorders

headache

paraesthesia,

migraine,

dizziness, sciatica

Cardiac disorders

angina pectoris,

atrial fibrillation,

heart failure,

myocardial

infarction

atrial flutter

Gastrointestinal

disorders

dyspepsia,

diarrhoea, gastro-

oesophageal

reflux, mouth

ulceration, upper

abdominal pain

Skin and

subcutaneous

tissue disorders

alopecia

toxic epidermal

necrolysis

(Lyell’s

Syndrome),

Stevens-Johnson

Syndrome

Musculo-

skeletal

disorders

arthralgia /

musculoskeletal

pain,

osteoarthritis,

bursitis

Investigations

decreased IgM

levels

decreased IgG

levels

Frequency category derived from laboratory values collected as part of routine laboratory monitoring in clinical trials

Frequency category derived from post-marketing data.

Reactions occurring during or within 24 hours of infusion. See also infusion-related reactions below. IRRs may occur as a

result of hypersensitivity and/or to the mechanism of action.

Includes observations collected as part of routine laboratory monitoring.

Includes fatal cases

Description of selected adverse reactions

Multiple courses

Multiple courses of treatment are associated with a similar ADR profile to that observed following

first exposure. The rate of all ADRs following first rituximab exposure was highest during the first

6 months and declined thereafter. This is mostly accounted for by IRRs (most frequent during the

first treatment course), RA exacerbation and infections all of which were more frequent in the first

6 months of treatment.

Infusion-related reactions

The most frequent ADRs following receipt of rituximab in clinical studies were IRRs. Among the

3189 patients treated with rituximab, 1,135 (36%) experienced at least one IRR with

733/3,189 (23%) of patients experiencing an IRR following first infusion of the first exposure to

rituximab. The incidence of IRRs declined with subsequent infusions. In clinical trials fewer than 1%

(17/3189) of patients experienced a serious IRR. There were no CTC Grade 4 IRRs and no deaths

due to IRRs in the clinical trials. The proportion of CTC Grade 3 events, and of IRRs leading to

withdrawal decreased by course and were rare from course 3 onwards. Premedication with

intravenous glucocorticoid significantly reduced the incidence and severity of IRRs (see sections 4.2

and 4.4). Severe IRRs with fatal outcome have been reported in the postmarketing setting.

In a trial designed to evaluate the safety of a more rapid rituximab infusion in patients with

rheumatoid arthritis, patients with moderate-to-severe active RA who did not experience a serious

IRR during or within 24 hours of their first studied infusion were allowed to receive a 2-hour

intravenous infusion of rituximab. Patients with a history of a serious infusion reaction to a biologic

therapy for RA were excluded from entry. The incidence, types and severity of IRRs were consistent

with that observed historically. No serious IRRs were observed.

Infections

The overall rate of infection was approximately 94 per 100 patient years in rituximab treated

patients. The infections were predominately mild to moderate and consisted mostly of upper

respiratory tract infections and urinary tract infections. The incidence of infections that were serious

or required IV antibiotics, was approximately 4 per 100 patient years. The rate of serious infections

did not show any significant increase following multiple courses of rituximab. Lower respiratory

tract infections (including pneumonia) have been reported during clinical trials, at a similar incidence

in the rituximab-arms compared to control arms.

Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported

following use of rituximab for the treatment of autoimmune diseases. This includes rheumatoid

arthritis and off-label autoimmune diseases, including Systemic Lupus Erythematosus (SLE) and

vasculitis.

In patients with non-Hodgkin’s lymphoma receiving rituximab in combination with cytotoxic

chemotherapy, cases of hepatitis B reactivation have been reported (see non-Hodgkin’s lymphoma).

Reactivation of hepatitis B infection has also been very rarely reported in rheumatoid arthritis patients

receiving rituximab (see section 4.4).

Cardiovascular adverse reactions

Serious cardiac reactions were reported at a rate of 1.3 per 100 patient years in the rituximab treated

patients compared to 1.3 per 100 patient years in placebo treated patients. The proportions of patients

experiencing cardiac reactions (all or serious) did not increase over multiple courses.

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual

disturbance, headache, seizures and altered mental status, with or without associated hypertension. A

diagnosis of PRES/RPLS requires confirmation by brain imaging. The reported cases had recognised

risk factors for PRES/RPLS, including the patients’ underlying disease, hypertension,

immunosuppressive therapy and/or chemotherapy.

Neutropenia

Events of neutropenia were observed with rituximab treatment, the majority of which were

transient and mild or moderate in severity. Neutropenia can occur several months after the

administration of rituximab (see section 4.4).

In placebo-controlled periods of clinical trials, 0.94% (13/1382) of rituximab treated patients and

0.27% (2/731) of placebo-treated patients developed severe neutropenia.

Neutropenic events, including severe late onset and persistent neutropenia, have been rarely reported

in the post-marketing setting, some of which were associated with fatal infections.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Laboratory abnormalities

Hypogammaglobulinaemia (IgG or IgM below the lower limit of normal) has been observed in RA

patients treated with rituximab. There was no increased rate in overall infections or serious infections

after the development of low IgG or IgM (see section 4.4).

A small number of spontaneous and literature cases of hypogammaglobulinaemia have been observed

in paediatric patients treated with rituximab, in some cases severe and requiring long-term

immunoglobulin substitution therapy. The consequences of long-term B cell depletion in paediatric

patients are unknown.

Summary of the Safety Profile (granulomatosis with polyangiitis and microscopic polyangiitis)

In the clinical trial in granulomatosis with polyangiitis and microscopic polyangitis, 99 patients were

treated with rituximab (375 mg/m

, once weekly for 4 weeks) and glucocorticoids (see section 5.1).

Tabulated list of adverse reactions

The ADRs listed in Table 3 were all adverse events which occurred at an incidence of ≥ 5% in the

rituximab group.

Table 3

Adverse drug reactions occurring at 6-months in ≥ 5% of patients receiving

rituximab, and at a higher frequency than the comparator group, in the

pivotal clinical study.

Body system

Adverse reaction

Rituximab (n=99)

Infections and infestations

Urinary tract infection

Bronchitis

Herpes zoster

Nasopharyngitis

Blood and lymphatic

system disorders

Thrombocytopenia

Immune system disorders

Cytokine release syndrome

Metabolism and nutrition disorders

Hyperkalaemia

Psychiatric disorders

Insomnia

Nervous system disorders

Dizziness

Tremor

Vascular disorders

Hypertension

Flushing

Body system

Adverse reaction

Rituximab (n=99)

Respiratory, thoracic and

mediastinal disorders

Cough

Dyspnoea

Epistaxis

Nasal congestion

Gastrointestinal

disorders

Diarrhoea

Dyspepsia

Constipation

Skin and subcutaneous

tissue disorders

Acne

Musculoskeletal and connective

tissue disorders

Muscle spasms

Arthralgia

Back pain

Muscle weakness

Musculoskeletal pain

Pain in extremities

General disorders and

administration site conditions

Peripheral oedema

Investigations

Decreased haemoglobin

Description of selected adverse drug reactions

Infusion related reactions

IRRs in the GPA and MPA clinical trial were defined as any adverse event occurring within 24

hours of an infusion and considered to be infusion-related by investigators in the safety population.

Ninety nine patients were treated with rituximab and 12% experienced at least one IRR. All IRRs

were CTC Grade 1 or 2. The most common IRRs included cytokine release syndrome, flushing,

throat irritation, and tremor. Rituximab was given in combination with intravenous glucocorticoids

which may reduce the incidence and severity of these events.

Infections

In the 99 rituximab patients, the overall rate of infection was approximately 237 per 100 patient years

(95% CI 197-285) at the 6-month primary endpoint. Infections were predominately mild to moderate

and consisted mostly of upper respiratory tract infections, herpes zoster and urinary tract infections.

The rate of serious infections was approximately 25 per 100 patient years. The most frequently

reported serious infection in the rituximab group was pneumonia at a frequency of 4%.

Malignancies

The incidence of malignancy in rituximab treated patients in the granulomatosis with polyangiitis and

microscopic polyangiitis clinical study was 2.00 per 100 patient years at the study common closing

date (when the final patient had completed the follow-up period). On the basis of standardised

incidence ratios, the incidence of malignancies appears to be similar to that previously reported in

patients with ANCA-associated vasculitis.

Cardiovascular adverse reactions

Cardiac events occurred at a rate of approximately 273 per 100 patient years (95% CI 149-470) at the

6-month primary endpoint. The rate of serious cardiac events was 2.1 per 100 patient years (95% CI

3-15). The most frequently reported events were tachycardia (4%) and atrial fibrillation (3%) (see

section 4.4).

Neurologic events

Cases of posterior reversible encephalopathy syndrome (PRES) reversible posterior

leukoencephalopathy syndrome (RPLS) have been reported in autoimmune conditions. Signs and

symptoms included visual disturbance, headache, seizures and altered mental status, with or without

associated hypertension. A diagnosis of PRES/RPLS requires confirmation by brain imaging. The

reported cases had recognised risk factors for PRES/RPLS, including the patients’ underlying disease,

hypertension, immunosuppressive therapy and/or chemotherapy.

Hepatitis B reactivation

A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported in

granulomatosis with polyangiitis and microscopic polyangiitis patients receiving rituximab in the post-

marketing setting.

Hypogammaglobulinaemia

Hypogammaglobulinaemia (IgA, IgG or IgM below the lower limit of normal) has been observed in

granulomatosis with polyangiitis and microscopic polyangiitis patients treated with rituximab. At 6

months, in the active-controlled, randomised, double-blind, multicentre, non-inferiority trial, in the

rituximab group, 27%, 58% and 51% of patients with normal immunoglobulin levels at baseline, had

low IgA, IgG and IgM levels, respectively compared to 25%, 50% and 46% in the

cyclophosphamide group. There was no increased rate in overall infections or serious infections in

patients with low IgA, IgG or IgM.

Neutropenia

In the active-controlled, randomised, double-blind, multicentre, non-inferiority trial of rituximab in

granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the rituximab

group (single course) and 23% of patients in the cyclophosphamide group developed CTC grade 3 or

greater neutropenia. Neutropenia was not associated with an observed increase in serious infection in

rituximab-treated patients. The effect of multiple rituximab courses on the development of

neutropenia in granulomatosis with polyangiitis and microscopic polyangiitis patients has not been

studied in clinical trials.

Skin and subcutaneous tissue disorders

Toxic Epidermal Necrolysis (Lyell’s Syndrome) and Stevens-Johnson Syndrome, some with fatal

outcome, have been reported very rarely.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare

professionals are asked to report any suspected adverse reactions via the national reporting system

listed in Appendix V.

4.9

Overdose

Limited experience with doses higher than the approved dose of intravenous rituximab formulation

is available from clinical trials in humans. The highest intravenous dose of rituximab tested in

humans to date is 5000 mg (2250 mg/m

), tested in a dose escalation study in patients with CLL. No

additional safety signals were identified.

Patients who experience overdose should have immediate interruption of their infusion and be closely

monitored.

In the post-marketing setting five cases of rituximab overdose have been reported. Three cases had

no reported adverse event. The two adverse events that were reported were flu-like symptoms, with

a dose of 1.8 g of rituximab and fatal respiratory failure, with a dose of 2 g of rituximab.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies

,

ATC code: L01XC02

Rituzena is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu

Rituximab binds specifically to the transmembrane antigen, CD20, a non-glycosylated

phosphoprotein, located on pre-B and mature B lymphocytes. The antigen is expressed on >95 % of

all B cell non-Hodgkin’s lymphomas.

CD20 is found on both normal and malignant B cells, but not on haematopoietic stem cells,

pro-B cells, normal plasma cells or other normal tissue. This antigen does not internalize

upon antibody binding and is not shed from the cell surface. CD20 does not circulate in the

plasma as a free antigen and, thus, does not compete for antibody binding.

The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can

recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated

cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and

antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on

the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B

lymphocytes has also been demonstrated to induce cell death via apoptosis.

Peripheral B cell counts declined below normal following completion of the first dose of rituximab.

In patients treated for haematological malignancies, B cell recovery began within 6 months of

treatment and generally returned to normal levels within 12 months after completion of therapy,

although in some patients this may take longer (up to a median recovery time of 23 months

post-induction therapy). In patients with granulomatosis with polyangiitis or microscopic

polyangiitis, the number of peripheral blood B cells decreased to <10 cells/μL after two weekly

infusions of rituximab 375 mg/m

, and remained at that level in most patients up to the 6 month time

point. The majority of patients (81%) showed signs of B cell return, with counts >10 cells/μL by

month 12, increasing to 87% of patients by month 18.

Clinical experience in non-Hodgkin’s lymphoma and in chronic lymphocytic leukaemia

Follicular lymphoma

Monotherapy

Initial treatment, weekly for 4 doses

In the pivotal trial, 166 patients with relapsed or chemoresistant low-grade or follicular B cell NHL

received 375 mg/m

of rituximab as an intravenous infusion once weekly for four weeks. The overall

response rate (ORR) in the intent-to-treat (ITT) population was 48 % (CI

% 41% - 56%) with a 6%

complete response (CR) and a 42% partial response (PR) rate. The projected median time to

progression (TTP) for responding patients was 13.0 months. In a subgroup analysis, the ORR was

higher in patients with IWF B, C, and D histological subtypes as compared to IWF A subtype (58%

vs. 12%), higher in patients whose largest lesion was < 5 cm vs. > 7 cm in greatest diameter (53% vs.

38%), and higher in patients with chemosensitive relapse as compared to chemoresistant (defined as

duration of response < 3 months) relapse (50% vs. 22%). ORR in patients previously treated with

autologous bone marrow transplant (ABMT) was 78% versus 43% in patients with no ABMT.

Neither age, sex, lymphoma grade, initial diagnosis, presence or absence of bulky disease, normal or

high LDH nor presence of extranodal disease had a statistically significant effect (Fisher’s exact test)

on response to rituximab. A statistically significant correlation was noted between response rates and

bone marrow involvement. 40% of patients with bone marrow involvement responded compared to

59% of patients with no bone marrow involvement (p=0.0186). This finding was not supported by a

stepwise logistic regression analysis in which the following factors were identified as prognostic

factors: histological type, bcl-2 positivity at baseline, resistance to last chemotherapy and bulky

disease.

Initial treatment, weekly for 8 doses

In a multicentre, single-arm trial, 37 patients with relapsed or chemoresistant, low grade or follicular

B cell NHL received 375 mg/m

of rituximab as intravenous infusion weekly for eight doses. The

ORR was 57% (95% Confidence interval (CI); 41% – 73%; CR 14%, PR 43%) with a projected

median TTP for responding patients of 19.4 months (range 5.3 to 38.9 months).

Initial treatment, bulky disease, weekly for 4 doses

In pooled data from three trials, 39 patients with relapsed or chemoresistant, bulky disease (single

lesion ≥ 10 cm in diameter), low grade or follicular B cell NHL received 375 mg/m

of rituximab as

intravenous infusion weekly for four doses. The ORR was 36 % (CI

% 21% – 51%; CR 3%, PR

33%) with a median TTP for responding patients of 9.6 months (range 4.5 to 26.8 months).

Re-treatment, weekly for 4 doses

In a multicentre, single-arm trial, 58 patients with relapsed or chemoresistant low grade or follicular

B cell NHL, who had achieved an objective clinical response to a prior course of rituximab, were

re-treated with 375 mg/m

of rituximab as intravenous infusion weekly for four doses. Three of the

patients had received two courses of rituximab before enrolment and thus were given a third course

in the study. Two patients were re-treated twice in the study. For the 60 re-treatments on study, the

ORR was 38% (CI

% 26% – 51%; 10% CR, 28% PR) with a projected median TTP for

responding patients of 17.8 months (range 5.4 – 26.6). This compares favourably with the TTP

achieved after the prior course of rituximab (12.4 months).

Initial treatment, in combination with chemotherapy

In an open-label randomised trial, a total of 322 previously untreated patients with follicular

lymphoma were randomised to receive either CVP chemotherapy (cyclophosphamide 750 mg/m

vincristine 1.4 mg/m

up to a maximum of 2 mg on day 1, and prednisolone 40 mg/m

/day on

days 1 -5) every 3 weeks for 8 cycles or rituximab 375 mg/m

in combination with CVP (R-

CVP). Rituximab was administered on the first day of each treatment cycle. A total of 321

patients (162 R-CVP, 159 CVP) received therapy and were analysed for efficacy. The median

follow up of patients was 53 months. R-CVP led to a significant benefit over CVP for the

primary endpoint, time to treatment failure (27 months vs. 6.6 months, p < 0.0001, log-rank test).

The proportion of patients with a tumour response (CR, CRu, PR) was significantly higher (p<

0.0001 Chi-Square test) in the R-CVP group (80.9%) than the CVP group (57.2%). Treatment

with R-CVP significantly prolonged the time to disease progression or death compared to CVP,

33.6 months and 14.7 months, respectively (p < 0.0001, log-rank test). The median duration of

response was 37.7 months in the R-CVP group and was 13.5 months in the CVP group (p <

0.0001, log-rank test).

The difference between the treatment groups with respect to overall survival showed a significant

clinical difference (p=0.029, log-rank test stratified by centre): survival rates at 53 months were

80.9% for patients in the R-CVP group compared to 71.1 % for patients in the CVP group

Results from three other randomised trials using rituximab in combination with chemotherapy

regimen other than CVP (CHOP, MCP, CHVP/Interferon-α) have also demonstrated significant

improvements in response rates, time-dependent parameters as well as in overall survival. Key

results from all four studies are summarised in table 4.

Table 4

Summary of key results from four phase III randomised studies evaluating

the benefit of rituximab with different chemotherapy regimens in follicular

lymphoma

Study

Treatment,

N

Median

FU,

months

ORR, %

CR,%

Median

TTF/PFS/ EFS

mo

OS

rates,

%

M39021

CVP, 159

R-CVP, 162

Median TTP:

14.7

33.6

P<0.0001

53-months

71.1

80.9

p=0.029

GLSG’00

CHOP, 205

R-CHOP,

Median TTF:

years

Not reached

p < 0.001

18-months

p = 0.016

OSHO

39

MCP, 96

R-MCP,

Median PFS:

28.8 Not

reached

p < 0.0001

48-months

p = 0.0096

FL2000

CHVP-IFN,

R-CHVP-

IFN, 175

Median EFS: 36

Not reached

p < 0.0001

42-months

p = 0.029

EFS – Event Free Survival

TTP – Time to progression or death

PFS – Progression-Free Survival

TTF – Time to Treatment Failure

OS rates – survival rates at the time of the analyses

Diffuse large B cell non-Hodgkin’s lymphoma

In a randomised, open-label trial, a total of 399 previously untreated elderly patients (age 60 to 80

years) with diffuse large B cell lymphoma received standard CHOP chemotherapy

(cyclophosphamide 750 mg/m

, doxorubicin 50 mg/m

, vincristine 1.4 mg/m

up to a maximum of 2

mg on day 1, and prednisolone 40 mg/m

/day on days 1-5) every 3 weeks for eight cycles, or

rituximab 375 mg/m

plus CHOP (R-CHOP). Rituzena was administered on the first day of the

treatment cycle.

The final efficacy analysis included all randomised patients (197 CHOP, 202 R-CHOP), and had a

median follow-up duration of approximately 31 months. The two treatment groups were well

balanced in baseline disease characteristics and disease status. The final analysis confirmed that R-

CHOP treatment was associated with a clinically relevant and statistically significant improvement in

the duration of event-free survival (the primary efficacy parameter; where events were death, relapse

or progression of lymphoma, or institution of a new anti-lymphoma treatment) (p = 0.0001). Kaplan

Meier estimates of the median duration of event-free survival were 35 months in the R-CHOP arm

compared to 13 months in the CHOP arm, representing a risk reduction of 41 %. At 24 months,

estimates for overall survival were 68.2 % in the R-CHOP arm compared to 57.4 % in the CHOP arm.

A subsequent analysis of the duration of overall survival, carried out with a median follow-up

duration of 60 months, confirmed the benefit of R-CHOP over CHOP treatment (p=0.0071),

representing a risk reduction of 32 %.

The analysis of all secondary parameters (response rates, progression-free survival, disease-free

survival, duration of response) verified the treatment effect of R-CHOP compared to CHOP. The

complete response rate after cycle 8 was 76.2 % in the R-CHOP group and 62.4 % in the CHOP

group (p=0.0028). The risk of disease progression was reduced by 46 % and the risk of relapse by

51 %. In all patients subgroups (gender, age, age adjusted IPI, Ann Arbor stage, ECOG, β2

microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow

involvement), the risk ratios for event-free survival and overall survival (R-CHOP compared with

CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improvements in

outcome for both high- and low-risk patients according to age adjusted IPI.

Clinical laboratory findings

Of 67 patients evaluated for human anti-mouse antibody (HAMA), no responses were noted. Of

356 patients evaluated for HACA, 1.1 % (4 patients) were positive.

Chronic lymphocytic leukaemia

In two open-label randomised trials, a total of 817 previously untreated patients and 552 patients

with relapsed/refractory CLL were randomised to receive either FC chemotherapy (fludarabine 25

mg/m

, cyclophosphamide 250 mg/m

, days 1-3) every 4 weeks for 6 cycles or rituximab in

combination with FC (R-FC). Rituximab was administered at a dosage of 375 mg/m

during the first

cycle one day prior to chemotherapy and at a dosage of 500 mg/m

on day 1 of each subsequent

treatment cycle. Patients were excluded from the study in relapsed/refractory CLL if they had

previously been treated with monoclonal antibodies or if they were refractory (defined as failure to

achieve a partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total

of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 5a and Table 5b) and 552 patients

(276 R-FC, 276 FC) for the relapsed/refractory study (Table 6) were analysed for efficacy.

In the first-line study, after a median observation time of 48.1 months, the median PFS was 55

months in the R-FC group and 33 months in the FC group (p < 0.0001, log-rank test). The analysis of

overall survival showed a significant benefit of R-FC treatment over FC chemotherapy alone (p =

0.0319, log-rank test) (Table 5a). The benefit in terms of PFS was consistently observed in most

patient subgroups analysed according to disease risk at baseline (i.e. Binet stages A-C) (Table 5b).

Table 5a

First-line treatment of chronic lymphocytic leukaemia

Overview of efficacy results for rituximab plus FC vs. FC alone - 48.1 months

median observation time

Efficacy parameter

Kaplan-Meier estimate of median time

to event (months)

Risk

reduction

FC

(N = 409)

R-FC

(N=408)

Log-rank

p value

Progression

free survival (PFS)

32.8

55.3

<0.0001

Overall survival

0.0319

Event free survival

31.3

51.8

<0.0001

Response rate (CR, nPR, or PR)

CR rates

72.6%

16.9%

85.8%

36.0%

<0.0001

<0.0001

n.a.

n.a.

Duration of response*

36.2

57.3

<0.0001

Disease free survival (DFS)**

48.9

60.3

0.0520

Time to new treatment

47.2

69.7

<0.0001

Response rate and CR rates analysed using Chi-squared Test. NR: not reached; n.a.: not applicable

*: only applicable to patients achieving a CR, nPR, PR

**: only applicable to patients achieving a CR

Table 5b

First-line treatment of chronic lymphocytic leukaemia

Hazard ratios of progression-free survival according to Binet stage

(ITT) - 48.1 months median observation time

Number of

patients

Hazard ratio

(95% CI)

p-value (Wald

test, not

Progression

free survival (PFS)

FC

R

FC

adjusted)

Binet stage A

0.39 (0.15; 0.98)

0.0442

Binet stage B

0.52 (0.41; 0.66)

<0.0001

Binet stage C

0.68 (0.49; 0.95)

0.0224

CI: Confidence Interval

In the relapsed/refractory study, the median progression-free survival (primary endpoint) was 30.6

months in the R-FC group and 20.6 months in the FC group (p=0.0002, log-rank test). The benefit in

terms of PFS was observed in almost all patient subgroups analysed according to disease risk at

baseline. A slight but not significant improvement in overall survival was reported in the R-FC

compared to the FC arm.

Table 6

Treatment of relapsed/refractory chronic lymphocytic leukaemia - overview

of efficacy results for rituximab plus FC vs. FC alone (25.3 months median

observation time)

Efficacy parameter

Kaplan-Meier estimate of

median time to event (months)

Risk

reduction

FC

(N = 276)

R-FC

(N=276

Log-

Rank p

Progression-free survival (PFS)

20.6

30.6

0.0002

Overall survival

51.9

0.2874

Event free survival

19.3

28.7

0.0002

Response rate (CR, nPR, or PR)

CR rates

Duration of response *

Disease free survival (DFS)**

Time to new CLL treatment

58.0%

13.0%

27.6

42.2

34.2

69.9%

24.3%

39.6

39.6

0.0034

0.0007

0.0252

0.8842

0.0024

n.a.

n.a.

Response rate and CR rates analysed using Chi-squared Test.

NR: not reached n.a. not applicable

*: only applicable to patients achieving a CR, nPR, PR;

**: only applicable to patients achieving a CR;

Results from other supportive studies using rituximab in combination with other chemotherapy

regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of

previously untreated and/or relapsed/refractory CLL patients have also demonstrated high

overall response rates with benefit in terms of PFS rates, albeit with modestly higher toxicity

(especially myelotoxicity). These studies support the use of rituximab with any chemotherapy.

Data in approximately 180 patients pre-treated with rituximab have demonstrated clinical

benefit (including CR) and are supportive for rituximab re-treatment.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with

rituximab in all subsets of the paediatric population with follicular lymphoma and chronic

lymphocytic leukaemia. See section 4.2 for information on paediatric use.

Clinical experience in granulomatosis with polyangiitis (Wegener’s) and microscopic polyangiitis

A total of 197 patients aged 15 years or older with severely, active granulomatosis with polyangiitis

(75%) and microscopic polyangiitis (24%) were enrolled and treated in an active-comparator,

randomised, double-blind, multicentre, non-inferiority trial.

Patients were randomised in a 1:1 ratio to receive either oral cyclophosphamide daily (2mg/kg/day)

for 3-6 months or rituximab (375 mg/m

) once weekly for 4 weeks. All patients in the

cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both

arms received 1000mg of pulse intravenous (IV) methylprednisolone (or another equivalent-dose

glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg/kg/day, not exceeding 80

mg/day). Prednisone tapering was to be completed by 6 months from the start of study treatment.

The primary outcome measure was achievement of complete remission at 6 months defined as a

Birmingham Vasculitis Activity Score for Wegener’s granulomatosis (BVAS/WG) of 0, and off

glucocorticoid therapy. The prespecified non-inferiority margin for the treatment difference was 20%.

The trial demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission

(CR) at 6 months (Table 7).

Efficacy was observed both for patients with newly diagnosed disease and for patients with relapsing

disease (Table 8).

Table 7

Percentage of patients who achieved complete remission at 6 months

(Intent-to-treat population*)

Rituximab

(n

99)

Cyclophosphamide

(n

98)

Treatment difference

(Rituximab

--cyclophosphamide)

Rate

63.6%

53.1%

10.6%

95.1%

(−3.2%, 24.3%)

CI = confidence interval.

* Worst case imputation

Non-inferiority was demonstrated since the lower bound (−3.2%) was higher than the pre-determined

non-inferiority margin ( − 20%).

The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis.

Table 8

Complete remission at 6-months by disease status

Rituximab

Cyclophosphamide

Difference (CI 95%)

All patients

Newly

diagnosed

n=99

n=48

n=51

n=98

n=48

n=50

Complete remission

All Patients

63.6%

53.1%

10.6% (

3.2, 24.3)

Newly diagnosed

60.4%

64.6%

− 4.2% (− 23.6, 15.3)

Relapsing

66.7%

42.0%

24.7% (5.8, 43.6)

Worst case imputation is applied for patients with missing data

Complete remission at 12 and 18 months

In the rituximab group, 48% of patients achieved CR at 12 months, and 39% of patients achieved

CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for

maintenance of complete remission), 39% of patients achieved CR at 12 months, and 33% of

patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the

rituximab group compared with four in the cyclophosphamide group.

Retreatment with rituximab

Based upon investigator judgment, 15 patients received a second course of rituximab therapy for

treatment of relapse of disease activity which occurred between 6 and 18 months after the first

course of rituximab. The limited data from the present trial preclude any conclusions regarding the

efficacy of subsequent courses of rituximab in patients with granulomatosis with polyangiitis and

microscopic polyangiitis.

Continued immunosuppressive therapy may be especially appropriate in patients at risk for relapses

(i.e. with history of earlier relapses and granulomatosis with polyangiitis, or patients with

reconstitution of B-lymphocytes in addition to PR3-ANCA at monitoring). When remission with

rituximab has been achieved, continued immunosuppressive therapy may be considered to prevent

relapse. The efficacy and safety of rituximab in maintenance therapy has not been established.

Laboratory evaluations

A total of 23/99 (23%) rituximab-treated patients in the trial tested positive for HACA by 18 months.

None of the 99 rituximab-treated patients were HACA positive at screening. The clinical relevance of

HACA formation in rituximab-treated patients is unclear.

5.2

Pharmacokinetic properties

Non-Hodgkin’s lymphoma

Based on a population pharmacokinetic analysis in 298 NHL patients who received single or

multiple infusions of rituximab as a single agent or in combination with CHOP therapy (applied

rituximab doses ranged from 100 to 500 mg/m

), the typical population estimates of nonspecific

clearance (CL

), specific clearance (CL

) likely contributed by B cells or tumour burden, and

central compartment volume of distribution (V

) were 0.14 L/day, 0.59 L/day, and 2.7 L,

respectively. The estimated median terminal elimination half-life of rituximab was 22 days (range,

6.1 to 52 days). Baseline CD19-positive cell counts and size of measurable tumour lesions

contributed to some of the variability in CL

of rituximab in data from 161 patients given 375

mg/m

as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell

counts or tumour lesions had a higher CL

. However, a large component of inter-individual

variability remained for CL

after correction for CD19-positive cell counts and tumour lesion size.

varied by body surface area (BSA) and CHOP therapy. This variability in V

(27.1% and 19.0%)

contributed by the range in BSA (1.53 to 2.32 m

) and concurrent CHOP therapy, respectively, were

relatively small. Age, gender and WHO performance status had no effect on the pharmacokinetics of

rituximab. This analysis suggests that dose adjustment of rituximab with any of the tested covariates

is not expected to result in a meaningful reduction in its pharmacokinetic variability.

Rituximab, administered as an intravenous infusion at a dose of 375 mg/m

at weekly intervals for 4

doses to 203 patients with NHL naive to rituximab, yielded a mean C

following the fourth

infusion of 486 µg/mL (range, 77.5 to 996.6 µg/mL). Rituximab was detectable in the serum of

patients 3 – 6 months after completion of last treatment.

Upon administration of rituximab at a dose of 375 mg/m

as an intravenous infusion at weekly

intervals for 8 doses to 37 patients with NHL, the mean C

increased with each successive

infusion, spanning from a mean of 243 µg/mL (range, 16 – 582 µg/mL) after the first infusion to 550

µg/mL (range, 171 – 1177 µg/mL) after the eighth infusion.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m

combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Chronic lymphocytic leukaemia

Rituximab was administered as an intravenous infusion at a first-cycle dose of 375 mg/m

increased

to 500 mg/m

each cycle for 5 doses in combination with fludarabine and cyclophosphamide in CLL

patients. The mean C

(N=15) was 408 µg/mL (range, 97 – 764 µg/mL) after the fifth 500 mg/

infusion and the mean terminal half-life was 32 days (range, 14 – 62 days).

Rheumatoid arthritis

Following two intravenous infusions of rituximab at a dose of 1000 mg, two weeks apart, the mean

terminal half-life was 20.8 days (range, 8.58 to 35.9 days), mean systemic clearance was 0.23 L/day

(range, 0.091 to 0.67 L/day), and mean steady-state distribution volume was 4.6 L (range, 1.7 to 7.51

L). Population pharmacokinetic analysis of the same data gave similar mean values for systemic

clearance and half-life, 0.26 L/day and 20.4 days, respectively. Population pharmacokinetic analysis

revealed that BSA and gender were the most significant covariates to explain inter-individual

variability in pharmacokinetic parameters. After adjusting for BSA, male subjects had a larger volume

of distribution and a faster clearance than female subjects. The gender- related pharmacokinetic

differences are not considered to be clinically relevant and dose adjustment is not required. No

pharmacokinetic data are available in patients with hepatic or renal impairment.

The pharmacokinetics of rituximab were assessed following two intravenous (IV) doses of 500 mg

and 1000 mg on Days 1 and 15 in four studies. In all these studies, rituximab pharmacokinetics were

dose proportional over the limited dose range studied. Mean Cmax for serum rituximab following first

infusion ranged from 157 to 171 µg/mL for 2 x 500 mg dose and ranged from 298 to 341 µg/mL for 2

x 1000 mg dose. Following second infusion, mean Cmax ranged from 183 to 198 µg/mL for the2 x

500 mg dose and ranged from 355 to 404 µg/mL for the 2 x 1000 mg dose. Mean terminal elimination

half-life ranged from 15 to 16 days for the 2 x 500 mg dose group and 17 to 21 days for the 2 x 1000

mg dose group. Mean Cmax was 16 to 19% higher following second infusion compared to the first

infusion for both doses.

The pharmacokinetics of rituximab were assessed following two IV doses of 500 mg and 1000 mg

upon re-treatment in the second course. Mean Cmax for serum rituximab following first infusion was

170 to 175 µg/mL for 2 x 500 mg dose and 317 to 370 µg/mL for 2 x 1000 mg dose. Cmax following

second infusion, was 207 µg/mL for the 2 x 500 mg dose and ranged from 377 to 386 µg/mL for the 2

x 1000 mg dose. Mean terminal elimination half-life after the second infusion, following the second

course, was 19 days for 2 x 500 mg dose and ranged from 21 to 22 days for the 2 x 1000 mg dose.

PK parameters for rituximab were comparable over the two treatment courses.

The pharmacokinetic (PK) parameters in the anti-TNF inadequate responder population, following the

same dosage regimen (2 x 1000 mg, IV, 2 weeks apart), were similar with a mean maximum serum

concentration of 369 µg/mL and a mean terminal half-life of 19.2 days.

Granulomatosis with polyangiitis and microscopic polyangiitis

Based on the population pharmacokinetic analysis of data in 97 patients with granulomatosis with

polyangiitis and microscopic polyangiitis who received 375 mg/m

rituximab once weekly for four

doses, the estimated median terminal elimination half-life was 23 days (range, 9 to 49 days).

Rituximab mean clearance and volume of distribution were 0.313 L/day (range, 0.116 to 0.726

L/day) and 4.50 L (range 2.25 to 7.39 L) respectively. The PK parameters of rituximab in these

patients appear similar to what has been observed in rheumatoid arthritis patients.

5.3

Preclinical safety data

Rituximab has shown to be highly specific to the CD20 antigen on B cells. Toxicity studies in

cynomolgus monkeys have shown no other effect than the expected pharmacological depletion

of B cells in peripheral blood and in lymphoid tissue.

Developmental toxicity studies have been performed in cynomolgus monkeys at doses up to

100 mg/kg (treatment on gestation days 20-50) and have revealed no evidence of toxicity to the

foetus due to rituximab. However, dose-dependent pharmacologic depletion of B cells in the

lymphoid organs of the foetuses was observed, which persisted post natally and was accompanied

by a decrease in IgG level in the newborn animals affected. B cell counts returned to normal in these

animals within 6 months of birth and did not compromise the reaction to immunisation.

Standard tests to investigate mutagenicity have not been carried out, since such tests are not relevant

for this molecule. No long-term animal studies have been performed to establish the carcinogenic

potential of rituximab.

Specific studies to determine the effects of rituximab on fertility have not been performed. In general

toxicity studies in cynomolgus monkeys no deleterious effects on reproductive organs in males or

females were observed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Tri-sodium citrate dihydrate

Polysorbate 80

Water for injections

6.2

Incompatibilities

No incompatibilities between rituximab and polyvinyl chloride or polyethylene bags or infusion sets

have been observed.

6.3

Shelf life

Unopened vial

4 years

Diluted product

The prepared infusion solution of rituximab is physically and chemically stable for 24 hours

at 2 °C - 8 °C and subsequently 12 hours at room temperature (not more than 30 °C).

From a microbiological point of view, the prepared infusion solution should be used immediately. If

not used immediately, in-use storage times and conditions prior to use are the responsibility of the

user and would normally not be longer than 24 hours at 2 °C – 8 °C, unless dilution has taken place

in controlled and validated aseptic conditions.

6.4

Special precautions for storage

Store in a refrigerator (2 °C – 8 °C). Keep the container in the outer carton in order to protect from

light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5

Nature and contents of container

Clear Type I glass vials with butyl rubber stopper containing 500 mg of rituximab in 50 mL. Pack of 1

vial.

6.6

Special precautions for disposal and other handling

Rituzena is provided in sterile, preservative-free, non-pyrogenic, single use vials.

Aseptically withdraw the necessary amount of Rituzena, and dilute to a calculated concentration of

1 to 4 mg/mL rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride9

mg/mL (0.9%) solution for injection or 5 % D-Glucose in water. For mixing the solution, gently

invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared

solutions. Since the medicinal product does not contain any anti-microbial preservative or

bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products should be

inspected visually for particulate matter and discolouration prior to administration.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

MARKETING AUTHORISATION HOLDER

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B torony

Hungary

8.

MARKETING AUTHORISATION NUMBER(S)

EU/1/17/1206/001

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 13 July 2017

Date of latest renewal:

10.

DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/

Read the complete document

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Telephone

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© European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged.

EMA/537274/2017

EMEA/H/C/004724

EPAR summary for the public

Rituzena

rituximab

This is a summary of the European public assessment report (EPAR) for Rituzena. It explains how the

Agency assessed the medicine to recommend its authorisation in the EU and its conditions of use. It is

not intended to provide practical advice on how to use Rituzena.

For practical information about using Rituzena, patients should read the package leaflet or contact their

doctor or pharmacist.

What is Rituzena and what is it used for?

Rituzena is a medicine used in adults to treat the following blood cancers and inflammatory conditions:

follicular lymphoma and diffuse large B cell non-Hodgkin’s lymphoma (two types of non-Hodgkin’s

lymphoma, a blood cancer);

chronic lymphocytic leukaemia (CLL, another blood cancer affecting white blood cells);

granulomatosis with polyangiitis (GPA or Wegener’s granulomatosis) and microscopic polyangiitis

(MPA), which are inflammatory conditions of the blood vessels.

Depending on the condition it is used to treat, Rituzena may be given with chemotherapy (other cancer

medicines) or medicines used for inflammatory disorders (corticosteroids). Rituzena contains the active

substance rituximab.

Rituzena is a ‘biosimilar medicine’. This means that Rituzena is highly similar to a biological medicine

(also known as the ‘reference medicine’) that is already authorised in the European Union (EU). The

reference medicine for Rituzena is MabThera. For more information on biosimilar medicines, see here

Previously known as Tuxella.

Rituzena0F

EMA/537274/2017

Page 2/3

How is Rituzena used?

Rituzena can only be obtained with a prescription. It is available as a concentrate for making a solution

that must be given by infusion (drip) into a vein. Before each infusion, the patient should be given an

antihistamine (to prevent allergic reactions) and an anti-pyretic (a medicine to reduce fever). Rituzena

should be given under the close supervision of an experienced healthcare professional and in a place

where facilities for resuscitating patients are immediately available.

For further information, see the package leaflet.

How does Rituzena work?

The active substance in Rituzena, rituximab, is a monoclonal antibody (a type of protein) designed to

recognise and attach to a protein called CD20 present on the surface of B cells (types of white blood

cells). When rituximab attaches to CD20, it causes the death of B cells, which helps in lymphoma and

CLL, where B cells have become cancerous. In GPA and MPA, destroying the B cells lowers the

production of antibodies thought to play an important role in attacking the blood vessels and causing

inflammation.

What benefits of Rituzena have been shown in studies?

Laboratory studies comparing Rituzena with MabThera have shown that the active substance in

Rituzena is highly similar to that in MabThera in terms of structure, purity and biological activity.

Studies have also shown that giving Rituzena produces similar levels of the active substance in the

body to giving MabThera.

In addition, Rituzena has been compared with MabThera given into a vein in a main study involving

372 patients with active rheumatoid arthritis (an inflammatory disease). The study showed that

Rituzena and MabThera had comparable effects on arthritis symptoms: after 24 weeks, the proportion

of patients with a 20% improvement in symptom score (called ACR20) was 74% (114 of 155 patients)

with Rituzena and 73% (43 of 59 patients) with MabThera.

Further evidence came from supportive studies, including one involving 121 patients with advanced

follicular lymphoma, where adding Rituzena to chemotherapy medicines was at least as effective as

adding Rituxan, the US version of MabThera. In this study improvement was seen in 96% of cases (67

of 70 patients) with Rituzena and 90% (63 of 70 patients) with Rituxan.

Because Rituzena is a biosimilar medicine, the studies on effectiveness and safety of rituximab carried

out with MabThera do not all need to be repeated for Rituzena.

What are the risks associated with Rituzena?

The most common side effects with rituximab are reactions related to the infusion (such as fever, chills

and shivering) which occur in most cancer patients and in more than 1 in 10 GPA or MPA patients at

the time of the first infusion. The risk of such reactions decreases in subsequent infusions. The most

common serious side effects are infusion reactions, infections and, in cancer patients, heart-related

problems. Other serious side effects include hepatitis B reactivation (return of previous active liver

infection with hepatitis B virus) and a rare and severe brain infection known as progressive multifocal

leukoencephalopathy (PML). For the full list of side effects reported with Rituzena, see the package

leaflet.

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EMA/537274/2017

Page 3/3

Rituzena must not be used in people who are hypersensitive (allergic) to rituximab, mouse proteins or

any of the other ingredients. It must also not be used in patients with a severe infection or a severely

weakened immune system. Patients with GPA or MPA must also not receive Rituzena if they have

severe heart problems.

Why is Rituzena approved?

The European Medicines Agency decided that, in accordance with EU requirements for biosimilar

medicines, Rituzena has a highly similar structure, purity and biological activity to MabThera and is

distributed in the body in the same way. In addition, a study comparing Rituzena to MabThera in

patients with rheumatoid arthritis (which can support its use in other inflammatory disorders such as

GPA and MPA) showed that both medicines are similarly effective, and a supportive study in follicular

lymphoma showed effectiveness in cancer. Thus, all these data were considered sufficient to conclude

that Rituzena will behave in the same way in terms of effectiveness as MabThera in its approved

indications. Therefore, the Agency’s view was that, as for MabThera, the benefit outweighs the

identified risk and it recommended that Rituzena be given marketing authorisation.

What measures are being taken to ensure the safe and effective use of

Rituzena?

The company that markets Rituzena will provide doctors and patients using the medicine for non-

cancer conditions with educational material including information on the need to give the medicine

where facilities for resuscitation are available and on the risk of infection, including PML. Patients are

also to receive an alert card, which they are to carry at all times, instructing them to contact their

doctor immediately if they have any of the listed symptoms of infection.

Doctors prescribing Rituzena for cancer will be provided with educational material reminding them of

the need to use the medicine only by infusion into a vein.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe

and effective use of Rituzena have also been included in the summary of product characteristics and

the package leaflet.

Other information about Rituzena

The European Commission granted a marketing aithorisation valid throughout the European Union for

Tuxella on 13 July 2017. The name of the product was changed to Rituzena on 4 August 2017.

The full EPAR for Rituzena can be found on the Agency’s website:

ema.europa.eu/Find

medicine/Human medicines/European public assessment reports. For more information about

treatment with Rituzena, read the package leaflet (also part of the EPAR) or contact your doctor or

pharmacist.

This summary was last updated in 08-2017.

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