TRUXIMA 500 mg CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Truxima 100 mg concentrate for solution for infusion

Truxima 500 mg 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 Truxima and what is it used for
2. What you need to know before you use Truxima
3. How to use Truxima
4. Possible side effects
5. Storage of Truxima
6. Contents of the pack and other information

1. What is Truxima and what is it used for

What is Truxima

Truxima 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 is Truxima used for

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

• 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.

Truxima can be given to adults alone or with other medicines called “chemotherapy”. In adult patients who have responded to treatment, Truxima can be continued for 2 years after completing the initial treatment.

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

• Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia (CLL) is the most common type of leukaemia 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 lymphocytes that accumulate mainly in the bone marrow and in the blood. The proliferation of these abnormal lymphocytes can cause some of the symptoms you may experience. Truxima in combination with chemotherapy destroys these cells, which gradually disappear from the body through biological processes.

• Rheumatoid arthritis

Truxima 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. Truxima 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. Truxima is usually given with another medicine called methotrexate. Truxima reduces the damage that rheumatoid arthritis causes to the joints and improves the ability to perform normal daily activities.

The best responses to Truxima 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.

• Granulomatosis with polyangiitis or microscopic polyangiitis

Truxima is used to treat adult and child patients aged 2 years and older with granulomatosis with polyangiitis (formerly called 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.

• Pemphigus vulgaris

Truxima 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 Truxima

Do not use Truxima

• if you are allergic to rituximab, to other similar proteins 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, uncontrolled heart failure or severe, uncontrolled heart disease and you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris.

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

Warnings and precautions

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

• 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 angina, 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 Truxima. Your doctor may need to monitor you during your treatment with Truxima.

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

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

Children and adolescents

Non-Hodgkin's lymphoma

Truxima can be used to treat children and adolescents from 6 months of age and older with non-Hodgkin's lymphoma, specifically diffuse large B-cell lymphoma (DLBCL) or Burkitt lymphoma/leukaemia (BL/B-ALL) or Burkitt-like lymphoma (BLL).

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

Granulomatosis with polyangiitis or microscopic polyangiitis.

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

Tell your doctor, pharmacist or nurse before you or your child are given Truxima if you or your child are under 18 years of age.

Using Truxima with other medicines

Tell your doctor or pharmacist if you are using or have recently used other medicines, including those obtained without a prescription or herbal medicines. This is because Truxima may affect the way other medicines work. Also, other medicines may affect the way Truxima 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 Truxima. This is because some people have low blood pressure during the infusion of Truxima
• 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 Truxima.

Pregnancy and breast-feeding

You must tell your doctor or nurse if you are pregnant, think you may be pregnant or are planning to have a baby. This is because Truxima may pass into the placenta and affect your baby.

If you are of childbearing potential, you and your partner should use an effective method of contraception during treatment with Truxima and for up to 12 months after the last treatment with Truxima.

Truxima passes into breast milk in very small amounts. As the long-term effects on breast-fed infants are not known, breast-feeding is not recommended during treatment with Truxima and for 6 months after treatment.

Driving and using machines

Rituximab has no or negligible influence on the ability to drive and use machines.

Truxima contains sodium

This medicine contains 52.6 mg of sodium (main component of cooking/table salt) per 10 ml vial and 263.2 mg of sodium (main component of cooking/table salt) 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 Truxima

How to use Truxima

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

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

Medicines given before each Truxima infusion

Before the infusion of Truxima, 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 only being treated with Truxima

Truxima will be given once a week for 4 weeks. Treatment cycles with Truxima can be repeated.

• If you are being treated with Truxima and chemotherapy

Truxima will be given 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 Truxima 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 of age, you will be given Truxima with chemotherapy. You will receive Truxima up to 6 times over a period of 3.5 to 5.5 months.

• If you are being treated for chronic lymphocytic leukaemia

When you are being treated with Truxima in combination with chemotherapy, you will receive Truxima infusions on day 0 of cycle 1 and 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 Truxima infusion. 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. Treatment cycles with Truxima can be repeated. Depending on the signs and symptoms of your disease, your doctor may decide if you should receive a higher dose of Truxima at some point, which may be after a few months.

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

Treatment with Truxima uses four infusions, given one week apart. Corticosteroids are usually given by injection before starting treatment with Truxima. 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 Truxima 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 Truxima (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 Truxima as maintenance treatment. This will be given 1 year and 18 months after the 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, Truxima can cause adverse effects, although not all people suffer from them.

Most of these adverse effects are of mild to moderate 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 are: pain at the infusion site, blisters, and itching of the skin, nausea and vomiting, fatigue, headache, difficulty breathing, increased blood pressure, wheezing, throat irritation, 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. Immediately inform the person administering the infusionif 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 interrupt your treatment with Truxima if you experience severe infusion reactions.

Infections

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

• fever, cough, sore throat, burning sensation when 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, which can be fatal (Progressive Multifocal Leukoencephalopathy or PML).

You may be more prone to infections after treatment with Truxima.

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 alert card, which also contains 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 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 count of all blood cells.
• allergic reactions (hypersensitivity).
• high blood sugar levels, weight loss, peripheral and facial edema, increased levels of lactate dehydrogenase enzyme (LDH) in blood, decreased calcium levels in blood.
• abnormal sensations on the skin, such as numbness, tingling, pinching, burning, progressive increase of these sensations on the skin, decreased sense of touch.
• agitation, difficulty staying asleep.
• redness of the face and other areas of the skin due to dilation of blood vessels.
• dizziness or anxiety sensation.
• increased tearing, alterations in the tear duct, eye inflammation (conjunctivitis).
• ringing in the ear, ear pain.
• cardiac alterations, such as myocardial infarction and irregular heartbeat or abnormally rapid heartbeats.
• increased or decreased tension (decreased tension especially when standing up).
• muscle tension in the airways that causes difficulty breathing (bronchospasm), inflammation, irritation in the lungs, throat, and/or nasal cavities, shortness of breath, nasal congestion.
• vomiting, diarrhea, abdominal pain, irritation and/or ulceration of 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, joint or muscle pain, back and neck pain.
• general discomfort or feeling of restlessness or fatigue, agitation, cold-like symptoms.
• multi-organ failure.

Uncommon (may affect up to 1 in 100 people)

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

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.

Children and Adolescents with Non-Hodgkin Lymphoma

In general, the adverse effects in children and adolescents with non-Hodgkin lymphoma were similar to those in adults with non-Hodgkin 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 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).
• urinary tract infections (pain when urinating).
• allergic reactions 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, sensation of hot flashes, 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.
• sensation of warmth, intermittent pain, in the nose, cheeks, and eyes (sinusitis), abdominal pain, vomiting, and diarrhea, respiratory problems.
• athlete's foot (fungal infection of the feet).
• 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 ulceration of the throat and mouth.
• abdominal, back, 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.

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

• a group of symptoms that occurs a few weeks after Truxima 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.

Other rare adverse effects reported due to Truxima include a decrease in the number of white blood cells in the blood (neutrophils) that help fight infections. Some infections can be severe (see information on "Infections" within this section).

• 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, 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.
• dizziness sensation.
• 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.
• muscle or hand or foot pain.
• low red blood cell count (anemia).
• low platelet count in blood.
• increased potassium levels in blood.
• changes in heart rhythm or faster than normal heartbeat.

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.

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, and 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 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.

Truxima may also cause changes in laboratory tests performed by your doctor. If you are being treated with Truxima 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 prospectus. 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.

5. Storage of Truxima

Keep out of sight and reach of children.

Do not use this medication after the expiration date shown on the packaging after CAD. The expiration date is the last day of the month indicated.

Store in the refrigerator (between 2°C and 8°C). Keep the vial inside the outer packaging to protect it from light.

Medicines should not be disposed of through 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

Composition of Truxima

• The active substance of Truxima 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 chloride, disodium citrate dihydrate, polysorbate 80, and water for injectable preparations. (see section 2 "Truxima contains sodium").

Appearance of the product and container contents

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

vials of 10 ml – Pack with 2 vials

vials of 50 ml – Pack with 1 vial

Marketing authorization holder

Celltrion Healthcare Hungary Kft.

1062 Budapest

Váci út 1-3. WestEnd Office Building B tower

Hungary

Manufacturer

Millmount Healthcare Ltd.

Block 7, City North Business Campus,

Stamullen, Co. Meath K32 YD60, Ireland

Nuvisan GmbH

Wegenerstrasse 13,

89231 Neu-Ulm,

Germany

Nuvisan France SARL

2400, Route des Colles, 06410, Biot,

France

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

Date of last revision of this leaflet

Other sources of information

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