Prospect: Information for the Patient

MabThera 100mg Concentrate for Infusion Solution

MabThera 500mg Concentrate for Infusion Solution

rituximab

Read this prospect thoroughly before starting to use the medication, as it contains important information for you.

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

What is MabThera

MabThera contains the active ingredient “rituximab”. This is a type of protein called “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 is MabThera used for

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

1. NH Hodgkin 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 administered in adults alone or with other medications called “chemotherapy”.

In adult patients in whom the initial treatment has been effective, MabThera may be used as maintenance therapy for 2 years after completing the initial treatment.

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

1. Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. B lymphocytes, which are produced in the bone marrow and develop in lymph nodes, are involved. 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 the cause of 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 in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a joint disease. B lymphocytes are involved, causing some of the symptoms you may experience. MabThera is used in the treatment of rheumatoid arthritis in people who have already been treated with other medications, which have either stopped working, not worked well enough, or caused side effects. MabThera is usually used in combination with another medication called methotrexate.

MabThera reduces the damage caused by rheumatoid arthritis to the joints 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 are 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 for the treatment of adult and pediatric patients 2 years of age or older with granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) or microscopic polyangiitis, administered in combination with corticosteroids. Granulomatosis with polyangiitis or microscopic polyangiitis are two forms of blood vessel inflammation that primarily affect 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 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.

Do not use MabThera

• if you are allergic to rituximab, other proteins similar to rituximab, or any of the other components of this medication (listed in section 6)
• if you have any active severe 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 you have any of the above. If you are unsure, ask your doctor, pharmacist, or nurse before MabThera is administered to you.

Warnings and precautions

Consult your doctor, pharmacist, or nurse before usingMabThera:

• 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 rare occasions. Patients with a history of hepatitis B infection will be closely monitored by their doctor to detect possible signs of hepatitis B
• if you have had any heart disease (such as angina, palpitations, or heart failure) or respiratory problems.

If you are affected by any of the above (or are unsure), ask your doctor, pharmacist, or nurse before MabThera is administered to you. 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 travel vaccines. Some vaccines should not be administered at the same time as MabThera or in the months following its administration. Your doctor will check if you need any vaccine before receiving MabThera.

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

• if you think you may have any infection, even if it is mild such as a cold. The cells targeted by MabThera help fight infections, so you should wait for the infection to pass before using MabThera. Also inform your doctor if you have had many infections in the past or if you have a severe infection.

Children and adolescents

Non-Hodgkin lymphoma

MabThera can be used for the treatment of children and adolescents, 6 months of age and older, with non-Hodgkin lymphoma, specifically diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL) / Burkitt leukemia (BLA-B) or Burkitt-like lymphoma (LBL).

Speak with your doctor, pharmacist, or nurse before receiving this medication if you or your child are under 18 years old.

Granulomatosis with polyangiitis or microscopic polyangiitis.

MabThera can be used for the treatment of children and adolescents, 2 years of age and older, with granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) or microscopic polyangiitis. There is little information on the use of MabThera in children and young people with other diseases.

Inform your doctor, pharmacist, or nurse before MabThera is administered to you if you or your child is under 18 years old.

Other medications and MabThera

Inform your doctor or pharmacist if you are using or have recently used other medications, even those purchased without a prescription or herbal medications. This is because MabThera may affect how other medications work. Other medications may also affect how MabThera works.

Particularly inform your doctor if:

• if you are being treated for hypertension. You may be told not to take your medications for 12 hours before MabThera is administered. This is because some people experience a drop in blood pressure during MabThera infusion.
• if you have ever taken medications that affect your immune system – such as chemotherapy or immunosuppressive medications.

If you are affected by any of the above (or are unsure), ask your doctor, pharmacist, or nurse before MabThera is administered to you.

Pregnancy and breastfeeding

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

If you are of childbearing age, you and your partner must use an effective contraceptive method during treatment with MabThera and for 12 months after the last treatment with 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 or in the 6 months following treatment.

Driving and operating machinery

The effect of MabThera on the ability to drive vehicles or operate machinery is unknown.

MabThera contains sodium

This medication contains 52.6 mg of sodium (main component of 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 sodium intake for an adult.

How to Use MabThera

MabThera will be administered by a doctor or nurse experienced in the use of this medication. You will be kept under observation during the administration of MabThera in case you experience any adverse effects.

MabThera will be administered to you always through intravenous infusion (drip).

Medications Administered Before Each Infusion of MabThera

Before the administration of MabThera, other medications (pre-medication) will be administered to you to prevent or reduce possible adverse effects.

Quantity and Frequency of Treatment

a)If You Are Being Treated for Non-Hodgkin Lymphoma

• If You Are Being Treated with MabThera Alone

MabThera will be administered once a week for 4 weeks. MabThera treatment cycles can be repeated.

• If You Are Being Treated with MabThera and Chemotherapy

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

• If You Respond Well to Treatment, You May Continue Treatment with MabThera as Maintenance Every 2 or 3 Months for 2 Years. Your Doctor May Modify This Depending on Your Response to the Medication.
• If You Are Under 18 Years Old, 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 Being Treated with MabThera in Combination with Chemotherapy, You Will Receive MabThera Infusions on Day 0 of Cycle 1, Then on Day 1 of Each Cycle Until a Total of 6 Cycles Are Completed. Each Cycle Lasts 28 Days. Chemotherapy Must Be Administered After the MabThera Infusion. Your Doctor Will Decide If You Should Receive Supportive Therapy.

c)If You Are Being Treated for Rheumatoid Arthritis

Each Treatment Cycle Consists of Two Infusions, Both Separated by a 2-Week Interval. MabThera Treatment Cycles Can Be Repeated. Depending on the Signs and Symptoms of Your Disease, Your Doctor May Decide to Administer a Higher Dose of MabThera at Some Point, Which May Occur Several Months Later.

d)If You Are Being Treated for Granulomatosis with Polyangiitis or Microscopic Polyangiitis

MabThera Treatment Uses Four Separate Infusions, Administered at Weekly Intervals. Corticosteroids Are Usually Injected Before Starting MabThera Treatment. To Treat Your Disease, Your Doctor May Start Administering Corticosteroids by Mouth at Any Time.

If You Are 18 Years Old or Older and Respond Well to Treatment, You May Receive MabThera as Maintenance Treatment. This Will Be Administered in the Form of 2 Separate Infusions, 2 Weeks Apart, Followed by 1 Infusion Every 6 Months for at Least 2 Years. Your Doctor May Decide to Treat You for a Longer Period with MabThera (Up to 5 Years), Depending on Your Response to the Medication.

e)If You Are Being Treated for Pemphigus Vulgaris

Each Treatment Cycle Consists of Two Infusions, Both Separated by a 2-Week Interval. If You Respond Well to Treatment, You May Receive MabThera as Maintenance Treatment. This Will Be Administered 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 Medication.

If You Have Any Other Questions About the Use of This Medication, Ask Your Doctor, Pharmacist, or Nurse.

Like all medicines, MabThera can cause side effects, although not everyone will experience them.

The majority of these side effects are of mild to moderate intensity, but some of them can be severe 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 side effects that some patients may experience include: pain at the infusion site, blisters, and itching on the skin, nausea and vomiting, fatigue, headache, difficulty breathing, increased blood pressure, wheezing, throat discomfort, swelling of the tongue or throat, itching or congestion in the nose, vomiting, flushing or palpitations, heart attack, or low platelet count. If you have any heart disease or angina, these reactions may 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 stop 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 stop your treatment with MabThera if you experience 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 when urinating, or if you start feeling tired or generally unwell,
• memory loss, concentration problems, difficulty walking, or loss of vision. This may be due to a rare and severe brain infection (Progressive Multifocal Leukoencephalopathy or PML),
• fever, headache, stiff neck, discoordination (ataxia), personality change, hallucinations, altered consciousness, seizures, or coma – this may be due to a severe brain infection (enteroviral meningitis), which can be fatal.

You may be more susceptible to infections after treatment with MabThera. These are usually colds, but there have been reported cases of pneumonia, urinary tract infections, or severe viral infections. All of these are included below as “Other side 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 Leaflet, where you will also find this information. It is essential that you carry this leaflet and show it to your partner or caregiver.

Skin Reactions

Very rarely, severe blisters can form on the skin that can be fatal. You may experience redness, usually associated with blisters, on the skin or mucous membranes, such as in the mouth, genital area, or eyelids, and may be accompanied by fever.Inform your doctor immediately if you experience any of these symptoms.

Other Side Effects

a)If you or your child are being treated for non-Hodgkin 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 platelet count,
• nausea,
• hair loss,
• chills, headache,
• weakened 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, common cold, bronchitis infections, fungal infections, unknown origin infections, nasal congestion, hepatitis B,
• low red blood cell count (anemia), low count of all blood cells,
• allergic reactions (hypersensitivity),
• high blood sugar levels, weight loss, peripheral and facial edema, increased levels of LDH enzyme in the blood, decreased levels of calcium in the blood,
• abnormal sensations in the skin, such as numbness, tingling, pins and needles, progressive increase in these sensations in the skin, decreased sense of touch,
• agitation, difficulty falling asleep,
• flushing of the face and other areas of the skin due to vasodilation,
• feeling of dizziness or anxiety,
• excessive tearing, alterations in the tear duct, conjunctivitis (inflammation of the eyes),
• ringing in the ears, ear pain,
• cardiac alterations, such as myocardial infarction, irregular heart rate,
• increased or decreased blood pressure,
• muscle tension in the respiratory tract causing difficulty breathing, (bronchospasm), inflammation, irritation in the lungs, throat, and/or nasal cavities, shortness of breath, nasal discharge,
• vomiting, diarrhea, abdominal pain, irritation or ulceration in the throat and mouth, difficulty swallowing, constipation, indigestion,
• food-related alterations: not eating enough, leading to weight loss,
• hiccups, excessive sweating, nocturnal sweating,
• muscle problems, such as muscle tension, joint or muscle pain, back and neck pain,
• tumor pain,
• general discomfort or feeling of restlessness or fatigue, agitation, cold symptoms,
• multi-organ insufficiency.

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

• coagulation disorders, decreased production of red blood cells, increased destruction of red blood cells (aplastic anemia), lymph node inflammation/hypertrophy,
• weakness, loss of interest in usual activities, nervousness,
• alterations in the sense of taste, such as changes in the taste of food,
• cardiac problems, such as reduced heart rate or chest pain (angina),
• asthma, insufficient oxygen supply to organs,
• gastric distension.

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

• temporary increase in the amount of a type of antibody in the blood (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 cause skin symptoms,
• respiratory insufficiency,
• intestinal wall damage (perforation),
• severe skin problems that can be potentially fatal. You may experience redness, usually associated with blisters, on the skin or mucous membranes, such as in the mouth, genital area, or eyelids, and may be accompanied by fever,
• renal problems, severe vision loss.

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

• delayed decrease in white blood cell count in the blood,
• reversible decrease in platelet count after infusion, but in rare cases, it can be fatal,
• loss of hearing, loss of other senses,
• brain and meninges infection/inflammation (enteroviral meningitis).

Children and adolescents with non-Hodgkin lymphoma:

In general, the side effects in children and adolescents with non-Hodgkin lymphoma were similar to those in adults with non-Hodgkin lymphoma or chronic lymphocytic leukemia. The most common side effects observed were fever associated with low white blood cell count (neutropenia), inflammation or ulcers in the oral cavity, and allergic reactions (hypersensitivity).

b)If you are being treated for rheumatoid arthritis

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

• infections, such as pneumonia (bacterial),
• urinary tract infections (painful urination),
• allergic reactions, which are more likely to occur during infusion, but can occur up to 24 hours after infusion,
• changes in blood pressure, nausea, rashes, fever, hot flashes, nasal congestion, sneezing, chills, 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 infections,
• sensation of heat, intermittent pain in the nose, cheeks, and eyes (sinusitis), abdominal pain, vomiting, and diarrhea, respiratory problems,
• foot fungal infections (athlete's foot),
• increased cholesterol levels in the blood,
• abnormal sensations in the skin, such as numbness, tingling, pins and needles, or burning, sciatica, headache, dizziness,
• hair loss,
• anxiety, depression,
• indigestion, diarrhea, acid reflux, irritation, or ulceration of the throat and mouth,
• abdominal, back, muscle, or joint pain.

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

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

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

• a group of symptoms that occur a few weeks after MabThera infusion, including allergic reactions such as hives, itching, joint pain, lymph node inflammation, and fever,
• severe skin blisters that can be fatal. You may experience redness, usually associated with blisters, on the skin or mucous membranes, such as in the mouth, genital area, or eyelids, and may be accompanied by fever.

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

• severe viral infection,
• brain and meninges infection/inflammation (enteroviral meningitis).

Other rare side effects reported due to MabThera include a decrease in white blood cell count in the blood (neutropenia) that helps fight infections. Some infections may be severe (see information on “Infections” within 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 pneumonia, urinary tract infections (painful urination), common cold, or herpes infections,
• allergic reactions, which are more likely to occur during infusion, but can occur up to 24 hours after infusion,
• diarrhea,
• cough or difficulty breathing,
• nasal bleeding,
• high blood pressure,
• joint or back pain,
• muscle spasms or chills,
• dizziness,
• chills (especially in the hands),
• difficulty sleeping (insomnia),
• inflammation of the hands or feet.

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

• indigestion,
• constipation,
• skin rash, including acne or spots,
• flushing or redness of the skin,
• fever,
• nasal congestion,
• muscle tension or pain,
• joint or muscle pain,
• low red blood cell count (anemia),
• low platelet count in the blood,
• increased potassium levels in the blood,
• changes in heart rate or rapid heartbeat.

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

• severe skin blisters that can be fatal. You may experience redness, usually associated with blisters, on the skin or mucous membranes, such as in the mouth, genital area, or eyelids, and may be accompanied by fever,
• reappearance of previous Hepatitis B infection.

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

• severe viral infection,
• brain and meninges infection/inflammation (enteroviral meningitis).

Children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis

In general, the side 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 side effects observed were infections, allergic reactions, and general discomfort (nausea).

d)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 infusion, but can occur up to 24 hours after infusion,
• headache,
• infections, such as pneumonia,
• prolonged depression,
• hair loss.

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

• infections, such as common cold, herpes infections, eye infections, oral candidiasis, or urinary tract infections (painful urination),
• mood disorders, such as irritability and depression,
• skin disorders, such as itching, urticaria, and benign growths,
• feeling tired or dizzy,
• fever,
• joint or muscle pain,
• abdominal pain,
• muscle pain,
• rapid heartbeat.

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

• severe viral infection,
• brain and meninges infection/inflammation (enteroviral meningitis).

MabThera may 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 side effects may be due to the other medications.

Reporting of side effects

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

Keep out of sight and reach of children.

Do not use this medication after the expiration date that appears on the packaging after EXP. The expiration date is the last day of the month indicated.

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

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications you no longer need. This will help protect the environment.

Composition of MabThera

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

Appearance of the product and contents of the pack

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

10ml vials – Pack with 2 vials

50ml vials – Pack with 1 vial

Marketing Authorization Holder

Roche Registration GmbH

Emil-Barell-Strasse 1

79639 Grenzach-Wyhlen

Germany

Manufacturer

Roche PharmaAG

Emil-Barrell-Str. 1

79639 Grenzach-Wyhlen

Germany

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

Last update of this leaflet

Other sources of information

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

This leaflet is available in all languages of the European Union on the website of the European Medicines Agency.