ITUXREDI 500 mg CONCENTRATE FOR INFUSION SOLUTION

Introduction

Package Leaflet: Information for the Patient

Ituxredi 100 mg Concentrate for Solution for Infusion

Ituxredi 500 mg Concentrate for Solution for Infusion

rituximab

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

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

1. What is Ituxredi and what is it used for

What is Ituxredi

Ituxredi 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 Ituxredi used for

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

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

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

1. Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. It involves 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. Rituximab, in combination with chemotherapy, destroys these cells, which gradually disappear from the body through biological processes.

1. Rheumatoid Arthritis

Rituximab is used to treat rheumatoid arthritis. Rheumatoid arthritis is a disease of the joints. It involves B lymphocytes, causing some of the symptoms you may experience. Rituximab 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. Rituximab is usually given with another medicine called methotrexate.

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

The best responses to rituximab 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.

1. Granulomatosis with Polyangiitis or Microscopic Polyangiitis

Rituximab 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

Rituximab 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 Ituxredi

Do not use Ituxredi

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

Warnings and precautions

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

• 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 rituximab. Your doctor may need to monitor you during your treatment with rituximab.

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 rituximab or in the months following its administration. Your doctor will check if you need any vaccination before receiving rituximab.

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 rituximab targets help fight infections, so you should wait until the infection has passed before using rituximab. Also, tell your doctor if you have had many infections in the past or if you have any severe infection.

Children and adolescents

Non-Hodgkin's Lymphoma

Rituximab 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 Burkitt-like lymphoma (BLL).

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.

Rituximab 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 rituximab in children and young people with other diseases.

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

Other medicines and Ituxredi

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 rituximab may affect the way other medicines work. Also, other medicines may affect the way rituximab 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 rituximab. This is because some people experience a drop in blood pressure during the infusion of rituximab.
• 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 rituximab.

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 rituximab can cross 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 rituximab and for up to 12 months after the last treatment with rituximab. Rituximab 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 rituximab and for 6 months after treatment.

Driving and using machines

It is not known if Ituxredi affects the ability to drive or use machines.

Ituxredi contains sodium

This medicine contains 52.2 mg of sodium (main component of cooking/table salt) in each 10 ml vial and 261.2 mg of sodium in each 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 Ituxredi

How Ituxredi is used

Rituximab will be given to you by a doctor or nurse with experience in the use of this medicine. They will keep you under observation during the administration of rituximab in case you experience any side effects. Rituximab will always be given as an intravenous infusion (drip).

Medicines given before each Ituxredi infusion

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

Dose and frequency of treatment

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

• If you are being treated with rituximab alone

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

• If you are being treated with rituximab with chemotherapy

Rituximab 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 treatment with rituximab 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 rituximab with chemotherapy. You will receive rituximab up to 6 times over a period of 3.5 to 5.5 months.

1. If you are being treated for chronic lymphocytic leukemia

When you are being treated with rituximab in combination with chemotherapy, you will receive rituximab 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 rituximab infusion. Your doctor will decide if you should receive supportive therapy.

1. If you are being treated for rheumatoid arthritis

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

1. If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis

Treatment with rituximab uses four infusions, given at weekly intervals. Corticosteroids are usually given by injection before starting treatment with rituximab. To treat your disease, your doctor may start giving you oral corticosteroids at any time.

If you are 2 years or older and respond well to treatment, you may be given rituximab 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 rituximab (up to 5 years), depending on your response to the medicine.

1. 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 rituximab 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, rituximab 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 up to 24 hours after 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 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 appear. Your doctor may decide to discontinue your treatment with rituximab if you have severe infusion reactions.

Infections

Immediately inform your doctor if, after treatment with rituximab, you or your childexperience 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).
• fever, headache, neck stiffness, discoordination (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 rituximab. 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

1. 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 low platelet count
• 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 overall blood cell count
• allergic reactions (hypersensitivity)
• high blood sugar levels, weight loss, peripheral and facial edema, increased LDH enzyme levels in the blood, decreased calcium levels in the blood
• abnormal skin sensations, such as numbness, tingling, pinching, burning, progressive increase in these skin sensations, decreased sense of touch
• agitation, difficulty staying asleep
• flushing of the face and other skin areas due to dilation of blood vessels
• 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)
• 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 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
• tumor pain
• general discomfort or feeling of unease or fatigue, agitation, cold-like 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
• taste disorders, such as changes in food taste
• 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 cell count 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 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 ulcers in the mouth, and allergic reactions (hypersensitivity).

1. If you are being treated for Rheumatoid Arthritis

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

• Infections such as pneumonia (bacterial)
• Pain when urinating (urinary tract infection)
• Allergic reactions, most likely to occur during infusion, but can occur up to 24 hours after 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
• 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, 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

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 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)

Rituximab may also cause changes in laboratory tests performed by your doctor. If you are being treated with rituximab 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 or pharmacist, even if they are 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 medication.

5. Storage of Ituxredi

Keep out of sight and reach of children.

Do not use this medicine after the expiration date stated on the packaging 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 container in the outer packaging to protect it from light.

• After aseptic dilution in sodium chloride solution

The prepared Ituxredi infusion solution in 0.9% sodium chloride solution is physically and chemically stable for 60 days at 5 ± 3°C and 30 days at 25 ± 2°C.

• After aseptic dilution in dextrose solution

The prepared Ituxredi infusion solution in 5% dextrose solution is physically and chemically stable for 48 hours at 2°C - 8°C and 25 ± 2°C.

From a microbiological point of view, the prepared infusion solution should be used immediately. If not used immediately, the storage times and conditions before use are the responsibility of the user and should not normally exceed 24 hours at 2°C - 8°C.

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

Composition of Ituxredi

• The active substance of Ituxredi 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 (E331), citric acid (E330), polysorbate 80 (E433), sodium chloride, and water for injectable preparations.

Appearance of the product and container contents

Ituxredi is a clear to opalescent, colorless to yellowish solution, presented as a concentrate for solution for infusion in glass vials.

Each container contains one or two vials of Ituxredi.

Not all pack sizes may be marketed.

Marketing authorization holder

Reddy Holding GmbH

Kobelweg 95

Augsburg 86156

Germany

Manufacturer

Betapharm Arzneimittel GmbH

Kobelweg 95

Augsburg 86156

Germany

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

Date of the last revision of this leaflet:

Ituxredi contains the same active substance and works in the same way as the "reference medicinal product" already authorized in the EU.