Mabthera 500 mg concentrate for solution for infusion

Package leaflet: Information for the user

Introduction

Package leaflet: Information for the patient

MabThera 100mg concentrate for solution for infusion

MabThera 500mg concentrate for solution for infusion

rituximab

Read the entire leaflet carefully before you start using this medicine, as it contains important information for you.

• Keep this leaflet, as you may need to read it again.
• If you have any questions, consult your doctor, pharmacist, or nurse.
• If you experience any side effects, consult your doctor, pharmacist, or nurse, even if they are side effects not listed in this leaflet. See section 4.

Leaflet contents

1. What MabThera is and what it is used for
2. What you need to know before using MabThera
3. How to use MabThera
4. Possible side effects
5. How to store MabThera
6. Contents of the pack and other information

1. What MabThera is and what it is used for

What MabThera is

MabThera contains the active substance “rituximab”. This is a type of protein called a “monoclonal antibody”. It binds to the surface of a type of white blood cell called “B-lymphocytes”. When rituximab binds to the surface of these cells, it causes their death.

What MabThera is used for

MabThera can be used in adults and children for the treatment of several different diseases. Your doctor may prescribe MabThera for the treatment of:

1. Non-Hodgkin’s Lymphoma

This is a disease of the lymphatic system (part of the immune system) that affects a type of white blood cell called B-lymphocytes.

MabThera may be given to adults alone or in combination with other medicines called “chemotherapy”.

In adult patients who have responded to initial treatment, MabThera may be used as maintenance therapy for 2 years following completion of the initial treatment.

In children and adolescents, MabThera is administered in combination with “chemotherapy”.

2. Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. B-lymphocytes are involved, which are produced in the bone marrow and mature in lymph nodes. Patients with CLL have too many abnormal lymphocytes that accumulate mainly in the bone marrow and blood. The proliferation of these abnormal lymphocytes may be responsible for some of the symptoms you may experience. MabThera, in combination with chemotherapy, destroys these cells, which gradually disappear from the body through biological processes.

3. Rheumatoid Arthritis

MabThera is used in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a disease affecting the joints. B-lymphocytes are involved and contribute to some of the symptoms you may experience. MabThera is used to treat rheumatoid arthritis in people who have already been treated with other medicines that either stopped working, did not work well enough, or caused adverse effects. MabThera is usually used in combination with another medicine called methotrexate.

MabThera reduces joint damage caused by rheumatoid arthritis and improves the ability to perform normal daily activities.

The best responses to MabThera are observed when the blood test for rheumatoid factor (RF) and/or the anti–Cyclic Citrullinated Peptide (anti-CCP) test is positive. Both tests are usually positive in patients with rheumatoid arthritis and help confirm the diagnosis.

4. Granulomatosis with polyangiitis or microscopic polyangiitis

MabThera is used to treat adult and pediatric patients aged 2 years and older with granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) or microscopic polyangiitis, administered in combination with corticosteroids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of blood vessel inflammation that primarily affect the lungs and kidneys, but may also affect other organs. B-lymphocytes are involved in the cause of these diseases.

5. Pemphigus vulgaris

MabThera is used for the treatment of patients with moderate to severe pemphigus vulgaris.

Pemphigus vulgaris is an autoimmune disease that causes painful blisters on the skin and mucous membranes of the mouth, nose, throat, and genitals.

2. What you need to know before using MabThera

Do not use MabThera

• if you are allergic to rituximab, to other proteins similar to rituximab, or to any of the other ingredients of this medicine (listed in section 6)
• if you have a serious active infection
• if you have a weakened immune system
• if you have severe heart failure or uncontrolled severe heart disease and have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris.

Do not use MabThera if any of the above apply to you. If you are unsure, ask your doctor, pharmacist, or nurse before receiving MabThera.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before using MabThera:

• if you think you have, or have previously had, infectious hepatitis. This is because, in a few cases, patients who have previously had hepatitis B may experience a reactivation of the disease, which can be fatal in very rare cases. Patients with a history of hepatitis B infection will be closely monitored by their doctor for possible signs of hepatitis B.
• if you have had any heart conditions (such as angina, palpitations, or heart failure) or breathing problems.

If any of the above apply to you (or if you are unsure), ask your doctor, pharmacist, or nurse before receiving MabThera. Your doctor may need to monitor you during your treatment with MabThera.

Also ask your doctor if you think you may need vaccinations in the near future, including travel vaccines. Some vaccines should not be given at the same time as MabThera or in the months following its administration. Your doctor will check whether you need any vaccinations before you receive MabThera.

If you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris, you should also tell your doctor:

• if you think you may have an infection, even if it is mild, such as a cold. The cells targeted by MabThera help fight infections, so you should wait until the infection has resolved before using MabThera. Also inform your doctor if you have had frequent infections in the past or if you have a serious infection.

Children and adolescents

Non-Hodgkin's lymphoma

MabThera can be used to treat children and adolescents aged 6 months and older with non-Hodgkin's lymphoma, specifically CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL) / Burkitt leukemia (mature B-acute lymphoblastic leukemia) (B-ALL), or Burkitt-like lymphoma (BLL).

Talk to your doctor, pharmacist, or nurse before receiving this medicine if you or your child are under 18 years of age.

Granulomatosis with polyangiitis or microscopic polyangiitis

MabThera can be used to treat children and adolescents aged 2 years and older with granulomatosis with polyangiitis (previously called Wegener's granulomatosis) or microscopic polyangiitis. There is limited information on the use of MabThera in children and adolescents with other diseases.

Inform your doctor, pharmacist, or nurse before receiving MabThera if you or your child is under 18 years of age.

Other medicines and MabThera

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription or herbal medicines. This is because MabThera may affect how other medicines work. Likewise, other medicines may affect how MabThera works.

In particular, tell your doctor:

• if you are being treated for high blood pressure. You may be advised not to take your blood pressure medication during the 12 hours before receiving MabThera. This is because some people experience a drop in blood pressure during MabThera infusion.
• if you have ever taken medicines that affect your immune system—such as chemotherapy or immunosuppressive medicines.

If any of the above apply to you (or if you are unsure), ask your doctor, pharmacist, or nurse before receiving MabThera.

Pregnancy and breastfeeding

You must inform your doctor or nurse if you are pregnant, think you might be pregnant, or plan to become pregnant. This is because MabThera can cross the placental barrier and may affect your unborn baby.

If you are of childbearing age, you and your partner should use an effective method of contraception during treatment with MabThera and for 12 months after the last dose of MabThera. MabThera passes into breast milk in very small amounts. As the long-term effects on infants are unknown, breastfeeding is not recommended during treatment with MabThera and for 6 months after treatment, as a precaution.

Driving and using machines

It is unknown whether MabThera has any effect on the ability to drive vehicles or operate machinery.

MabThera contains sodium

This medicine contains 52.6 mg of sodium (a main component of household/table salt) per 10 ml vial and 263.2 mg of sodium per 50 ml vial.

This is equivalent to 2.6% (per 10 ml vial) and 13.2% (per 50 ml vial) of the maximum daily recommended sodium intake for an adult.

3. How to use MabThera

How MabThera is used

MabThera will be administered to you by a doctor or nurse experienced in the use of this medicine. You will be closely monitored during the administration of MabThera in case you experience any adverse reactions.

MabThera will always be given as an intravenous infusion (drip).

Medications given before each MabThera infusion

Before administration of MabThera, you will be given other medications (premedication) to prevent or reduce possible adverse reactions.

Dose and frequency of treatment

1. If you are being treated for non-Hodgkin's lymphoma

• If you are receiving MabThera as a single treatment

MabThera will be administered once weekly for 4 weeks. Treatment cycles with MabThera may be repeated.

• If you are receiving MabThera with chemotherapy

MabThera will be administered on the same day as chemotherapy. It is usually given every 3 weeks up to 8 times.

• If you respond well to treatment, you may continue MabThera as maintenance therapy every 2 or 3 months for up to 2 years. Your doctor may adjust this depending on your response to the medicine.
• If you are under 18 years of age, you will receive MabThera with chemotherapy. You will receive MabThera up to 6 times over a period of 3.5 to 5.5 months.

b) If you are being treated for chronic lymphocytic leukemia

When you are receiving MabThera in combination with chemotherapy, you will receive MabThera infusions on Day 0 of Cycle 1, then on Day 1 of each subsequent cycle, for a total of 6 cycles. Each cycle lasts 28 days. Chemotherapy should be administered after the MabThera infusion. Your doctor will decide whether you should receive maintenance therapy.

c) If you are being treated for rheumatoid arthritis

Each treatment cycle consists of two infusions, both given 2 weeks apart. MabThera treatment cycles may be repeated. Depending on the signs and symptoms of your disease, your doctor may decide at some point to give you a higher dose of MabThera, which may occur several months after starting treatment.

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

MabThera treatment consists of four infusions given one week apart. Corticosteroids are usually administered by injection before starting MabThera treatment. To treat your disease, your doctor may start oral corticosteroids at any time.

If you are 18 years of age or older and respond well to treatment, you may receive MabThera as maintenance therapy. This will be given as two infusions 2 weeks apart, followed by one infusion every 6 months for at least 2 years. Your doctor may decide to continue your treatment with MabThera for a longer period (up to 5 years), depending on your response to the medicine.

e) If you are being treated for pemphigus vulgaris

Each treatment cycle consists of two infusions, both given 2 weeks apart. If you respond well to treatment, you may receive MabThera as maintenance therapy. This will be given 1 year and 18 months after the initial treatment, and then every 6 months as needed. Your doctor may adjust this depending on your response to the medicine.

If you have any further questions about how to use this medicine, ask your doctor, pharmacist, or nurse.

4. Possible adverse effects

Like all medicines, MabThera can cause adverse effects, although not everyone experiences them.

Most of these adverse effects are mild to moderate in intensity, but some may be serious and require treatment. In rare cases, some of these reactions have been fatal.

Infusion reactions

During or within 24 hours after the first infusion, you may experience fever, chills, and shivering. Other less common adverse effects that some patients may experience include: pain at the infusion site, skin blisters and itching, nausea and vomiting, fatigue, headache, difficulty breathing, increased blood pressure, wheezing, throat discomfort, swelling of the tongue or throat, nasal itching or congestion, vomiting, flushing, or palpitations, heart attack, or low platelet count. If you have heart disease or angina, these reactions could worsen. Inform immediately the person administering the infusion if you or your child experience any of these symptoms, as you may need a slower infusion rate or interruption of the infusion. You may require additional treatment with antihistamines or paracetamol. Once symptoms have subsided or improved, the infusion may continue. These reactions are less likely after the second infusion. Your doctor may decide to discontinue your treatment with MabThera if you experience severe infusion reactions.

Infections

Inform your doctor immediately if, after treatment with MabThera, you or your child develop any symptoms of infection, such as:

• fever, cough, sore throat, burning sensation when urinating, or onset of fatigue or general malaise,
• memory loss, difficulty concentrating, difficulty walking, or vision loss. This may be due to a very rare, serious brain infection (Progressive Multifocal Leukoencephalopathy or PML), which has been fatal,
• fever, headache, neck stiffness, lack of coordination (ataxia), personality changes, hallucinations, altered consciousness, seizures, or coma – this could be due to a serious brain infection (enteroviral meningoencephalitis), which may be fatal.

You may be more susceptible to infections after treatment with MabThera. These are usually colds, but cases of pneumonia, urinary tract infections, or serious viral infections have been reported. All of these are listed below under "Other adverse effects".

If you are being treated for rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris, your doctor should have provided you with a Patient Alert Card, which also contains this information. It is important that you carry this card and show it to your partner or caregiver.

Skin reactions

Very rarely, severe blistering of the skin may occur, which can be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may occur with fever. Inform your doctor immediately if you experience any of these symptoms.

Other adverse effects

1. If you or your child are being treated for non-Hodgkin’s lymphoma or chronic lymphocytic leukemia

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

• bacterial or viral infections, bronchitis,
• low white blood cell count with or without fever, or low levels of blood cells called "platelets",
• nausea,
• hair loss, chills, headache,
• reduced immunity due to decreased levels of antibodies called "immunoglobulins" (IgG) in the blood, which help protect against infection.

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

• blood infections (sepsis), pneumonia, herpes, colds, bronchial infections, fungal infections, infections of unknown origin, sinusitis, hepatitis B,
• low red blood cell count (anemia), low levels of all blood cells,
• allergic reactions (hypersensitivity),
• high blood sugar levels, weight loss, peripheral and facial edema, increased levels of LDH enzyme in blood, decreased blood calcium levels,
• abnormal skin sensations such as numbness, tingling, prickling, burning, progressive increase in these sensations, reduced sense of touch,
• restlessness, difficulty falling asleep,
• facial flushing and redness in other skin areas due to blood vessel dilation,
• dizziness or anxiety,
• increased tearing, lacrimal duct disorders, eye inflammation (conjunctivitis),
• ringing in the ears (tinnitus), ear pain,
• cardiac disorders such as myocardial infarction, irregular heartbeat, abnormally rapid heartbeat,
• increased or decreased blood pressure (especially low blood pressure upon standing),
• muscle tension in the airways causing breathing difficulty (bronchospasm), inflammation, irritation in the lungs, throat and/or nasal cavities, shortness of breath, runny nose,
• vomiting, diarrhea, abdominal pain, throat or mouth irritation or ulcers, difficulty swallowing, constipation, indigestion,
• eating disorders: insufficient food intake leading to weight loss,
• hives, increased sweating, night sweats,
• muscle problems such as muscle tension, joint or muscle pain, back and neck pain,
• tumor pain,
• general malaise or restlessness, fatigue, agitation, cold-like symptoms,
• multiorgan failure.

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

• coagulation disorders, decreased red blood cell production, increased destruction of red blood cells (aplastic hemolytic anemia), inflammation/swelling of lymph nodes,
• lethargy, loss of interest in usual activities, nervousness,
• taste disturbances, such as changes in food taste,
• heart problems such as reduced heart rate or chest pain (angina),
• asthma, low oxygen supply to organs,
• stomach swelling.

Rare (may affect up to 1 in 10,000 people):

• temporary increase in a type of antibody in the blood (called immunoglobulins – IgM), chemical changes in the blood due to breakdown of cancer cells,
• nerve damage in arms and legs, facial paralysis,
• heart failure,
• inflammation of blood vessels, including those causing skin symptoms,
• respiratory failure,
• intestinal wall damage (perforation),
• serious skin problems causing blisters that may be potentially fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may occur with fever,
• kidney problems,
• severe vision loss.

Frequency not known (frequency cannot be estimated from available data):

• delayed decrease in white blood cells in the blood,
• reduced platelet count after infusion – reversible, but in rare cases may be fatal,
• hearing loss, loss of other senses,
• infection/inflammation of the brain and meninges (enteroviral meningoencephalitis).

Children and adolescents with non-Hodgkin’s lymphoma:

In general, adverse effects in children and adolescents with non-Hodgkin’s lymphoma were similar to those in adults with non-Hodgkin’s lymphoma or chronic lymphocytic leukemia. The most commonly observed adverse effects were fever associated with low levels of a type of white blood cells (neutrophils), inflammation or sores in the mouth, and allergic reactions (hypersensitivity).

• If you are being treated for rheumatoid arthritis

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

• infections such as pneumonia (bacterial),
• pain when urinating (urinary tract infection),
• allergic reactions, most likely to occur during infusion but may occur up to 24 hours after infusion,
• changes in blood pressure, nausea, rashes, fever, hot flushes, nasal congestion, sneezing, shivering, rapid heartbeat, and fatigue,
• headache,
• changes in laboratory tests performed by your doctor. These include a decrease in certain specific proteins in the blood (immunoglobulins) that help protect against infection.

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

• infections such as bronchial inflammation (bronchitis),
• feeling of warmth, intermittent pain in the nose, cheeks, and eyes (sinusitis), abdominal pain, vomiting, diarrhea, breathing problems,
• fungal infection in the feet (athlete’s foot),
• increased blood cholesterol levels,
• abnormal skin sensations such as numbness, tingling, pricking, or burning, sciatica, headache, dizziness,
• hair loss,
• anxiety, depression,
• indigestion, diarrhea, acid reflux, throat and/or mouth irritation and/or ulceration,
• abdominal, back, muscle, and/or joint pain.

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

• fluid retention in the face and body,
• inflammation, irritation, and/or pressure in the lungs and throat, cough,
• skin reactions including hives, itching, and skin rashes,
• allergic reactions including wheezing or difficulty breathing, facial and tongue swelling, collapse.

Rare (may affect up to 1 in 10,000 people):

• a group of symptoms occurring a few weeks after MabThera infusion, including allergic reactions such as rash, itching, joint pain, swollen lymph nodes, and fever,
• formation of severe blisters on the skin that may be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may occur with fever.

Frequency not known (frequency cannot be estimated from available data):

• serious viral infection,
• infection/inflammation of the brain and meninges (enteroviral meningoencephalitis).

Other rare adverse effects reported with MabThera include a decrease in white blood cells (neutrophils) in the blood, which help fight infections. Some infections may be serious (see information on Infections in this section).

c) If you or your child are being treated for granulomatosis with polyangiitis or microscopic polyangiitis.

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

• infections, such as chest infections, urinary tract infections (pain when urinating), colds, or herpes infections,
• allergic reactions, more likely to occur during infusion but may occur up to 24 hours after,
• diarrhea,
• cough or difficulty breathing,
• nosebleeds,
• hypertension,
• joint or back pain,
• muscle spasms or tremors, dizziness,
• tremors (especially in the hands),
• difficulty sleeping (insomnia),
• swelling of the hands or ankles.

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

• indigestion,
• constipation,
• skin rash, including acne or spots,
• flushing or skin redness,
• fever,
• stuffy or runny nose,
• tense or sore muscles,
• muscle, hand, or foot pain,
• low red blood cell count (anemia),
• low platelet count in blood,
• increased blood potassium levels,
• changes in heart rhythm or abnormally fast heartbeat.

Rare (may affect up to 1 in 10,000 people):

• formation of severe blisters on the skin that may be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may occur with fever,
• reactivation of previous hepatitis B infection.

Frequency not known (frequency cannot be estimated from available data):

• serious viral infection,
• infection/inflammation of the brain and meninges (enteroviral meningoencephalitis).

Children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis

In general, side effects in children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis were similar in type to those in adults with granulomatosis with polyangiitis or microscopic polyangiitis. The most commonly observed side effects were infections, allergic reactions, and malaise (nausea).

d) If you are being treated for pemphigus vulgaris

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

• allergic reactions, more likely to occur during infusion but may occur up to 24 hours after,
• headache,
• infections such as chest infections,
• persistent depression,
• hair loss.

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

• infections such as common cold, herpes infections, eye infections, oral candidiasis, and urinary tract infections (pain when urinating),
• mood disorders such as irritability and depression,
• skin disorders such as itching, hives, and benign lumps,
• feeling of fatigue or dizziness,
• fever,
• joint or muscle pain,
• stomach pain,
• muscle pain,
• abnormally fast heartbeat.

Frequency not known (frequency cannot be estimated from available data):

• serious viral infection,
• infection/inflammation of the brain and meninges (enteroviral meningoencephalitis).

MabThera may also cause changes in laboratory tests performed by your doctor.

If you are being treated with MabThera in combination with other medicines, some of the possible adverse effects may be due to the other medicines.

Reporting of adverse effects

If you experience any adverse effect, consult your doctor, pharmacist, or nurse, even if it is an effect not listed in this leaflet. You may also report them directly through the national reporting system listed in Appendix V. By reporting adverse effects, you can help provide more information on the safety of this medicine.

5. Storage of MabThera

Keep out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the container after EXP. The expiry date refers to the last day of the month indicated.

Store in a refrigerator (between 2 °C and 8 °C). Do not freeze. Keep the vial in the outer packaging to protect it from light.

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging you no longer need. This will help protect the environment.

6. Contents of the pack and other information

Composition of MabThera

• The active substance is rituximab. The 10 ml vial contains 100 mg of rituximab (10 mg/ml). The 50 ml vial contains 500 mg of rituximab (10 mg/ml).
• The other components are sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid and water for injections. See section 2 “MabThera contains sodium”.

Nature and contents of the container

MabThera is a clear, colourless solution supplied as a concentrate for infusion solution.

10 ml vials – Pack containing 2 vials

50 ml vials – Pack containing 1 vial

Marketing Authorization Holder

Roche Registration GmbH
Emil-Barell-Strasse 1
79639 Grenzach-Wyhlen
Germany

Manufacturer

Roche Pharma AG
Emil-Barrell-Str. 1
79639 Grenzach-Wyhlen
Germany

Further information on this medicinal product is available upon request from the local representative of the Marketing Authorization Holder.

Belgium/Belgium/Belgium, N.V. Roche S.A. Tel/Tel: +32 (0) 2 525 82 11	Lithuania UAB “Roche Lietuva” Tel: +370 5 2546799
	Luxembourg/Luxembourg (See/siehe Belgium/Belgium)
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Denmark Roche Pharmaceutical A/S Tlf: +45 - 36 39 99 99	Malta (See Ireland)
Germany Roche Pharma AG Tel: +49 (0) 7624 140	Netherlands Roche Nederland B.V. Tel: +31 (0) 348 438050
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Date of the most recent review of this leaflet

Other sources of information

Detailed information on this medicine is available on the website of the European Medicines Agency: http://www.ema.europa.eu.

This leaflet can be found on the European Medicines Agency website in all languages of the European Union.