MABTHERA 500 MG CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

MabThera 100mg concentrate for solution for infusion

MabThera 500mg concentrate for solution for infusion

rituximab

Read all of this leaflet carefully before you start using 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.

Contents of the pack

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

1. What is MabThera and what is it used for

What is MabThera

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 them to die.

What is MabThera 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 can be given to adults alone or with other medicines called “chemotherapy”.

In adult patients who have responded to treatment, MabThera can be used as maintenance treatment for 2 years after completing initial treatment.

In children and adolescents, MabThera is given in combination with "chemotherapy".

1. Chronic Lymphocytic Leukemia

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

1. Rheumatoid Arthritis

MabThera is used to treat rheumatoid arthritis. Rheumatoid arthritis is a disease of the joints. It affects B lymphocytes, causing 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 have either stopped working, not worked well enough, or have caused side effects. MabThera is usually given with another medicine called methotrexate.

MabThera reduces the damage that rheumatoid arthritis causes to the joints and improves the ability to perform normal daily activities.

The best responses to MabThera are seen when the blood test for rheumatoid factor (RF) and/or the test for anti-cyclic citrullinated peptide (anti-CCP) is positive. Both tests are usually positive in patients with rheumatoid arthritis and help confirm the diagnosis.

1. Granulomatosis with Polyangiitis or Microscopic Polyangiitis

MabThera is used to treat adult and pediatric patients 2 years of age and older with granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) or microscopic polyangiitis, given in combination with corticosteroids. Granulomatosis with polyangiitis or microscopic polyangiitis are two forms of blood vessel inflammation that mainly affect the lungs and kidneys but can also affect other organs. B lymphocytes are involved in the cause of these diseases.

1. Pemphigus Vulgaris

MabThera is used to treat patients with moderate to severe pemphigus vulgaris.

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

2. What you need to know before you use 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 any severe active infection
• if you have a weak immune system
• if you have severe heart failure or uncontrolled severe heart disease and you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris.

Do not use MabThera if you have any of the above. If you are not sure, ask your doctor, pharmacist, or nurse before you are given MabThera.

Warnings and precautions

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

• if you think you have an infectious hepatitis or have had it in the past. This is because in a few cases, patients who had hepatitis B may suffer a relapse that 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 disease (such as chest pain, palpitations, or heart failure) or respiratory problems.

If any of the above apply to you (or you are not sure), ask your doctor, pharmacist, or nurse before you are given MabThera. Your doctor may need to monitor you during your treatment with MabThera.

Also, ask your doctor if you think you may need to be vaccinated in the near future, including vaccinations needed for travel to other countries. Some vaccinations should not be given at the same time as MabThera or in the months following its administration. Your doctor will check if you need any vaccinations before receiving 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 any infection, even if it is mild, such as a cold. The cells that MabThera targets help fight infections, so you should wait until the infection has passed before using MabThera. Also, tell your doctor if you have had many infections in the past or if you have a severe infection.

Children and adolescents

Non-Hodgkin's Lymphoma

MabThera can be used to treat children and adolescents from 6 months of age and older with non-Hodgkin's lymphoma, specifically CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL) / Burkitt leukemia (mature B-cell acute leukemia) (MBAL), or lymphoma similar to Burkitt (BL).

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

Granulomatosis with Polyangiitis or Microscopic Polyangiitis.

MabThera can be used to treat children and adolescents 2 years of age and older with granulomatosis with polyangiitis (formerly called Wegener's granulomatosis) or microscopic polyangiitis. There is not much information on the use of MabThera in children and young people with other diseases.

Tell your doctor, pharmacist, or nurse before you are given MabThera if you or your child are under 18 years old.

Other medicines and MabThera

Tell your doctor or pharmacist if you are using or have recently used other medicines, including those bought without a prescription or herbal medicines. This is because MabThera can affect how other medicines work. Also, other medicines can affect how MabThera works.

In particular, tell your doctor:

• if you are being treated for high blood pressure. You may be told not to take your blood pressure medicines during the 12 hours before you are given MabThera. This is because some people experience a drop in blood pressure during the infusion of MabThera.
• 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 you are not sure), ask your doctor, pharmacist, or nurse before you are given MabThera.

Pregnancy and breastfeeding

You should tell your doctor or nurse if you are pregnant, think you may be pregnant, or plan to become pregnant. This is because MabThera can cross the placenta and affect your baby.

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

Driving and using machines

It is not known if MabThera has any effects on the ability to drive or use machines.

MabThera contains sodium

This medicine contains 52.6 mg of sodium (the main component of kitchen/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 recommended daily intake of sodium for an adult.

3. How to use MabThera

How MabThera is given

MabThera will be given to you by a doctor or nurse who is experienced in the use of this medicine. They will keep you under observation during the infusion of MabThera in case you experience any side effects.

MabThera will always be given by intravenous infusion (drip).

Medicines given before each MabThera infusion

Before the infusion of MabThera, you will be given other medicines (pre-medication) to prevent or reduce possible side effects.

Dose and frequency of treatment

• If you are being treated for non-Hodgkin's lymphoma
  • If you are being treated with MabThera alone

MabThera will be given to you once a week for 4 weeks. You can have more cycles of treatment with MabThera.

• If you are being treated with MabThera and chemotherapy

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

• If you are being treated for chronic lymphocytic leukemia

When you are being treated with MabThera in combination with chemotherapy, you will receive infusions of MabThera on Day 0 of cycle 1, then on Day 1 of each cycle up to a total of 6 cycles. Each cycle lasts 28 days. Chemotherapy should be given after the infusion of MabThera. Your doctor will decide if you should receive supportive therapy.

• If you are being treated for rheumatoid arthritis

Each treatment cycle consists of two infusions, given 2 weeks apart. You can have more cycles of treatment with MabThera. Depending on the signs and symptoms of your disease, your doctor may decide if you should receive a higher dose of MabThera at some point, which may be given after a few months.

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

Treatment with MabThera uses four infusions, given weekly. You will usually be given corticosteroids by injection before starting treatment with MabThera. To treat your disease, your doctor may start giving you corticosteroids by mouth at any time.

If you are 18 years or older and respond well to treatment, you may be given MabThera as maintenance treatment. This will be given as 2 infusions, 2 weeks apart, followed by 1 infusion every 6 months for at least 2 years. Your doctor may decide to treat you for longer with MabThera (up to 5 years), depending on your response to the medicine.

• If you are being treated for pemphigus vulgaris

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

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

4. Possible Adverse Effects

Like all medicines, MabThera can cause adverse effects, although not all people will experience them.

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

Infusion Reactions

During or after the first 24 hours following the first infusion, you may experience fever, chills, and tremors. Other less frequent adverse effects that some patients may experience include: pain at the infusion site, blisters, and itching of the skin, nausea and vomiting, fatigue, headache, difficulty breathing, increased blood pressure, wheezing, discomfort in the throat, swelling of the tongue or throat, itching or nasal congestion, vomiting, flushing or palpitations, heart attack or low platelet count. If you have a history of heart disease or angina, these reactions could worsen. Inform the person administering the infusion immediatelyif you or your child experience any of these symptoms, as you may need a slower infusion or to interrupt it. You may need additional treatment with antihistamines or paracetamol. When the symptoms disappear or improve, the infusion can continue. After the second infusion, it is less likely that these reactions will occur. Your doctor may decide to discontinue your treatment with MabThera if you have severe infusion reactions.

Infections

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

• fever, cough, sore throat, burning sensation while urinating, or if you start to feel tired or unwell,
• memory loss, concentration problems, difficulty walking, or vision loss. This may be due to a very rare and serious brain infection (Progressive Multifocal Leukoencephalopathy or PML), which can be fatal,
• fever, headache, stiff neck, lack of coordination (ataxia), personality changes, hallucinations, altered consciousness, seizures, or coma – this could be due to a serious brain infection (enteroviral meningoencephalitis), which can be fatal.

You may be more prone to infections after treatment with MabThera. These are usually colds, but cases of pneumonia, urinary tract infections, or severe viral infections have been reported. All of these are included below as "Other Adverse Effects".

If you are being treated for rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris, your doctor should have given you a Patient Information Card, where you will also find this information. It is essential that you carry this card and show it to your partner or caregiver.

Skin Reactions

Very rarely, severe blisters can form on the skin, which can be fatal. Redness may appear, usually associated with blisters, 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

• If you or your child are being treated for non-Hodgkin's lymphoma or chronic lymphatic 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 blood cells called "platelets",
• nausea,
• hair loss on the scalp, chills, headache,
• reduced immunity due to decreased levels of antibodies called "immunoglobulins" (IgG) in the blood that 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, nasal sinus inflammation, hepatitis B,
• low red blood cell count (anemia), low blood cell count,
• allergic reactions (hypersensitivity),
• high blood sugar levels, weight loss, peripheral and facial edema, increased levels of the enzyme LDH in the blood, decreased calcium levels in the blood,
• abnormal sensations on the skin, such as numbness, tingling, pinching, burning, progressive increase in these sensations on the skin, decreased sense of touch,
• agitation, difficulty staying asleep,
• flushing of the face and other areas of the skin due to dilation of blood vessels,
• feeling of dizziness or anxiety,
• increased tearing, alterations in the tear duct, eye inflammation (conjunctivitis),
• ringing in the ears, ear pain,
• cardiac disorders, such as myocardial infarction, irregular heartbeat, abnormally rapid heartbeats,
• increased or decreased blood pressure (decreased blood pressure, especially when standing up),
• bronchospasm, inflammation, irritation in the lungs, throat, and/or nasal cavities, shortness of breath, nasal congestion,
• vomiting, diarrhea, abdominal pain, irritation or ulcers in the throat and mouth, difficulty swallowing, constipation, indigestion,
• eating disorders: not eating enough, leading to weight loss,
• hives, increased sweating, night sweats,
• muscle problems, such as muscle tension, pain in the joints or muscles, back and neck pain,
• tumor pain,
• general discomfort or feeling of restlessness or fatigue, agitation, cold symptoms,
• multi-organ 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,
• exhaustion, loss of interest in usual activities, nervousness,
• alterations in taste, such as changes in the taste of food,
• heart problems, such as reduced heart rate or chest pain (angina),
• asthma, low oxygen levels in the blood,
• stomach swelling.

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

• temporary increase in the amount of a type of antibody in the blood (called immunoglobulins – IgM), chemical alterations in the blood caused by the rupture of cancer cells,
• nerve damage in arms and legs, facial paralysis,
• heart failure,
• inflammation of blood vessels, including those that lead to skin symptoms,
• respiratory failure,
• damage to the intestinal wall (perforation),
• severe skin problems that cause blisters that can be potentially fatal. Redness may appear, usually associated with blisters, 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 (the frequency cannot be estimated from the available data):

• delayed decrease in white blood cells in the blood,
• reduction in platelet count after infusion – reversible, but in rare cases can 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, the adverse effects in children and adolescents with non-Hodgkin's lymphoma were similar to those in adults with non-Hodgkin's lymphoma or chronic lymphatic leukemia. The most common adverse effects observed were fever associated with low levels of a type of white blood cell (neutrophils), inflammation or ulcers 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 while urinating (urinary tract infection),
• allergic reactions, which are most likely to occur during the infusion but can occur up to 24 hours after the infusion,
• changes in blood pressure, nausea, rash, fever, feeling of warmth, nasal congestion, sneezing, tremors, rapid heartbeat, and fatigue,
• headache,
• changes in laboratory tests performed by your doctor. These include a decrease in the amount of certain specific proteins in the blood (immunoglobulins) that help protect against infection.

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

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

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

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

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

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

Frequency Not Known (the frequency cannot be estimated from the available data):

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

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

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

Reporting of Adverse Effects

If you experience any type of adverse effect, consult your doctor, pharmacist, or nurse, even if it is a possible adverse effect that is not listed in this leaflet. You can also report them directly through the national reporting system included in Appendix V. By reporting adverse effects, you can contribute to providing more information on the safety of this medication.

• 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 while urinating), colds, or herpes infections,
• allergic reactions, which are more likely to occur during the infusion but can occur up to 24 hours after the infusion,
• diarrhea,
• cough or difficulty breathing,
• nasal bleeding,
• high blood pressure,
• joint or back pain,
• muscle spasms or tremors,
• feeling of dizziness,
• tremors (especially in the hands),
• difficulty sleeping (insomnia),
• inflammation of the hands or ankles.

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

• indigestion,
• constipation,
• skin rash, including acne or spots,
• flushing or redness of the skin,
• fever,
• stuffy nose or runny nose,
• muscle tension or pain,
• pain in the muscles or hands or feet,
• low red blood cell count (anemia),
• low platelet count in the blood,
• increased potassium levels in the blood,
• changes in heart rhythm or faster than normal heartbeat.

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

• severe blisters on the skin that can be fatal. Redness may appear, usually associated with blisters, 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 (the frequency cannot be estimated from the available data):

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

Children and Adolescents with Granulomatosis with Polyangiitis or Microscopic Polyangiitis

In general, the adverse effects in children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis were similar to those in adults with granulomatosis with polyangiitis or microscopic polyangiitis. The most common adverse effects observed were infections, allergic reactions, and discomfort (nausea).

• If you are being treated for pemphigus vulgaris

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

• allergic reactions, which are more likely to occur during the infusion but can occur up to 24 hours after the infusion,
• headache,
• infections such as chest infections,
• prolonged 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 while urinating),
• mood disorders, such as irritability and depression,
• skin disorders, such as itching, hives, and benign bumps,
• feeling of fatigue or dizziness,
• fever,
• joint or muscle pain,
• stomach pain,
• muscle pain,
• faster than normal heartbeat.

Frequency Not Known (the frequency cannot be estimated from the available data):

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

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

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

5. Storage of MabThera

Keep out of sight and reach of children.

Do not use this medication after the expiration date stated on the packaging after EXP. The expiration date is 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 should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medication. This will help protect the environment.

6. Container contents and additional information

MabThera composition

• The active ingredient 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 injectable preparations. See section 2 "MabThera contains sodium".

Appearance and container contents of the product

MabThera is a clear and colorless solution presented as a concentrate for solution for infusion.

vials of 10 ml – Packaging with 2 vials

vials of 50 ml – Packaging with 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

You can request more information about this medication by contacting the local representative of the marketing authorization holder.

Date of the last revision of this prospectus

Other sources of information

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

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