RIXATHON 500 MG CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Rixathon 100mg concentrate for solution for infusion

Rixathon 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 experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are not listed in this leaflet. See section 4.

Contents of the pack

1. What is Rixathon and what is it used for
2. What you need to know before you are given Rixathon
3. How Rixathon is given
4. Possible side effects
5. Storage of Rixathon
6. Contents of the pack and further information

1. What is Rixathon and what is it used for

What is Rixathon

Rixathon 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 Rixathon used for

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

• Non-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.

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

In children and adolescents, rituximab is given in combination with “chemotherapy”.

• Chronic lymphocytic leukaemia (CLL)

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 B 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. Rixathon, in combination with chemotherapy, destroys these cells, which gradually disappear from the body through biological processes.

• Rheumatoid arthritis

Rixathon 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. Rixathon 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. Rixathon is usually given with another medicine called methotrexate.

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

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

• Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Rixathon is used to treat adult and child patients aged 2 years and older with GPA (formerly known as Wegener's granulomatosis) or MPA, given in combination with corticosteroids.

GPA and MPA 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 (PV)

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

PV 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 are given Rixathon

Do not use Rixathon

• 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 active, severe infection
• if you have a weakened 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 Rixathon if you have any of the above. If you are not sure, ask your doctor, pharmacist, or nurse before you are given Rixathon.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before you start using Rixathon:

• 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 life-threatening 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 Rixathon. Your doctor may need to monitor you during your treatment with Rixathon.

Also, ask your doctor if you think you may need to be vaccinated in the near future, including vaccines needed for travel to other countries. Some vaccines should not be given at the same time as Rixathon or in the months following its administration. Your doctor will check if you need any vaccine before receiving Rixathon.

If you have rheumatoid arthritis, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), or pemphigus vulgaris (PV), 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 Rixathon targets help fight infections, so you should wait until the infection has passed before using Rixathon. 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 lymphoma

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

Granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Rituximab can be used to treat children and adolescents aged 2 years and older with GPA (formerly known as Wegener's granulomatosis) or MPA. There is limited information on the use of rituximab in children and young people with other diseases.

There is limited information on the use of rituximab in children and adolescents with other diseases.

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

Other medicines and Rixathon

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 Rixathon may affect the way other medicines work. Also, other medicines may affect the way Rixathon works.

In particular, tell your doctor:

• if you are being treated for high blood pressure. You may be told not to take your medicines during the 12 hours before you are given Rixathon. This is because some people experience a drop in blood pressure during the infusion of Rixathon.
• 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 Rixathon.

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 Rixathon may pass into 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 Rixathon and for up to 12 months after the last treatment with Rixathon. Rixathon passes into breast milk in small amounts. As the long-term effects on breastfed infants are unknown, breastfeeding is not recommended during treatment with Rixathon or for 6 months after treatment.

Driving and using machines

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

Rixathon contains sodium

This medicine contains 52.6 mg of sodium 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.

Rixathon contains polysorbate

This medicine contains 7.0 mg of polysorbate 80 (E 433) in each 10 ml vial and 35.0 mg of polysorbate 80 (E 433) in each 50 ml vial, equivalent to 0.7 mg/ml.

Polysorbates may cause allergic reactions. Tell your doctor if you or your child has any known allergy.

3. How Rixathon is given

How Rixathon is given

Rixathon 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 administration of Rixathon in case you experience any side effects.

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

Medicines given before each Rixathon infusion

Before the administration of Rixathon, you will be given other medicines (premedication) to prevent or reduce possible side effects.

Dose and frequency of treatment

• If you are being treated for non-Hodgkin lymphoma
  • If you are being treated with Rixathon alone

Rixathon will be given to you once a week for 4 weeks. Treatment cycles with Rixathon can be repeated.

• If you are being treated with Rixathon and chemotherapy

Rixathon 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 continue to receive Rixathon as maintenance treatment 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 Rixathon with chemotherapy. You will receive Rixathon up to 6 times over a period of 3.5 to 5.5 months.

• If you are being treated for chronic lymphocytic leukaemia (CLL)

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

• If you are being treated for granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)

Treatment with Rixathon uses four infusions, given at weekly intervals. Corticosteroids are usually given by injection before starting treatment with Rixathon. 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 receive Rixathon 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 Rixathon (up to 5 years), depending on your response to the medicine.

• If you are being treated for pemphigus vulgaris (PV)

Each treatment cycle consists of two infusions, given 2 weeks apart. If you respond well to treatment, you may receive Rixathon 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, this medicine 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 24 hours following the 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 heart condition 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 interruption. 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 appear. Your doctor may decide to discontinue your treatment with Rixathon if you have severe infusion reactions.

Infections

Inform your doctor immediately if after treatment with Rixathon you or your childhave 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 (progressive multifocal leukoencephalopathy or PML),
• 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 Rixathon.

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 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. 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 (NHL) or Chronic Lymphatic Leukemia (CLL)

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 LDH enzyme levels in blood, decreased calcium levels in 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 ear, ear pain,
• cardiac alterations, such as myocardial infarction, irregular heartbeat, 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 discharge,
• 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, joint or muscle pain, back and neck 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,
• decline, 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 (frequency cannot be estimated from available data):

• delayed decrease in white blood cells in the blood
• reversible reduction in platelet count after infusion, 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 Lymphoma (NHL):

In general, adverse effects in children and adolescents with non-Hodgkin lymphoma were similar to those in adults with NHL or CLL. 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 when urinating (urinary tract infection),
• 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, 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,
• fungal infection of 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 rituximab infusion and includes allergic reactions such as rash, itching, joint pain, lymph node inflammation, and fever,
• severe blistering of 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 (frequency cannot be estimated from available data):

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

Rixathon may also cause changes in laboratory tests performed by your doctor. If you are being treated with Rixathon 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 adverse effects, consult your doctor, pharmacist, or nurse, even if they are possible adverse effects 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 help provide more information on the safety of this medicine.

5. Storage of Rixathon

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

Do not use this medicine after the expiration date stated on the packaging and label of the vial after CAD. 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.

This medicine can also be stored in the original box outside the refrigerator for up to 30°C for a single period of up to seven days, but not beyond the initial expiration date. In this situation, it should not be refrigerated again. Write the new expiration date on the box, including day/month/year. Discard this medicine if it has not been used by the new expiration date or the expiration date printed on the box, whichever occurs first.

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of the packaging and any unused medicine. This will help protect the environment.

6. Container contents and additional information

Rixathon composition

• The active ingredient of Rixathon 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 (E 433), sodium chloride, sodium hydroxide, hydrochloric acid, and water for injectable preparations. See section 2 "Rixathon contains sodium".

Appearance of the product and container contents

Rixathon is a clear, colorless to slightly yellowish solution presented as a concentrate for solution for infusion (sterile concentrate).

10 ml vial: packaging of 2 or 3 vials.

50 ml vial: packaging of 1 or 2 vials.

Marketing authorization holder

Sandoz GmbH

Biochemiestr. 10

6250 Kundl

Austria

Manufacturer

Sandoz GmbH Schaftenau

Biochemiestr. 10

6336 Langkampfen

Austria

Lek Pharmaceuticals d.d. Ljubljana

Verovškova 57

1526 Ljubljana

Slovenia

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.

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