Ituxredi 100 mg concentrate for solution for infusion: detailed information

Patient Information Leaflet

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 for rapid identification of new safety information. Healthcare professionals are requested to report any suspected adverse reactions. See section 4.8 for information on how to report adverse reactions.

Read the entire leaflet carefully before starting to use this medicine, as it contains important information for you.

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

Leaflet Contents

What Ituxredi is and what it is used for
What you need to know before using Ituxredi
How to use Ituxredi
Possible side effects
How to store Ituxredi
Contents of the pack and other information

1. What Ituxredi is and what it is used for

What Ituxredi is

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 cells called “B-lymphocytes”. When rituximab binds to the surface of these cells, it causes their death.

What Ituxredi is 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:

Non-Hodgkin’s lymphoma

This is a disease of the lymphatic system (part of the immune system) that affects a type of white blood cells called B-lymphocytes.

Rituximab may be given to adults alone or in combination with other medicines called “chemotherapy”. In adult patients who have responded to initial treatment, rituximab may be used as maintenance treatment for 2 years after completion of the initial therapy.

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

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults. B-lymphocytes are involved, which are produced in the bone marrow and mature in lymph nodes. 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 responsible for some of the symptoms experienced. Rituximab, in combination with chemotherapy, destroys these cells, which gradually disappear from the body through biological processes.

Rheumatoid arthritis

Rituximab is used in the treatment of rheumatoid arthritis. Rheumatoid arthritis is a disease affecting the joints. B-lymphocytes are involved and contribute to some of the symptoms experienced. Rituximab is used to treat rheumatoid arthritis in patients who have already been treated with other medicines that either stopped working, were not effective enough, or caused adverse effects. Rituximab is usually used in combination with another medicine called methotrexate.

Rituximab reduces joint damage caused by rheumatoid arthritis and improves the ability to perform normal daily activities.

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

Granulomatosis with polyangiitis or microscopic polyangiitis

Rituximab is used for the treatment of adult and pediatric patients 2 years of age and older with granulomatosis with polyangiitis (previously known as Wegener's granulomatosis) or microscopic polyangiitis, administered in combination with corticosteroids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of blood vessel inflammation that primarily affect the lungs and kidneys, but may also involve other organs. B-lymphocytes are involved in the cause of these diseases.

Pemphigus vulgaris

Rituximab 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.

2. What you need to know before using Ituxredi

Do not use Ituxredi

if you are allergic to rituximab, to other proteins similar to rituximab, or to any of the other components of this medicine (listed in section 6)
if you have any active serious infection
if you have a weakened immune system
if you have severe heart failure or severe uncontrolled heart disease and have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris.

Do not use rituximab if any of the above apply to you. If you are unsure, ask your doctor, pharmacist, or nurse before receiving rituximab.

Warnings and precautions

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

if you think you have infectious hepatitis or have had it in the past. This is because, in some cases, patients who previously had hepatitis B may experience a reactivation, which 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 reactivation.
if you have had any heart disease (such as chest pain, palpitations, or heart failure) or breathing problems.

If any of the above apply to you (or if you are unsure), consult your doctor, pharmacist, or nurse before receiving rituximab. Your doctor may need to monitor you during treatment with rituximab.

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

If you have rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis, or pemphigus vulgaris, you should 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 rituximab help fight infections, so you should wait until the infection has resolved before using rituximab. Also inform your doctor if you have had frequent infections in the past or if you have a serious infection.

Children and adolescents

Non-Hodgkin’s lymphoma

Rituximab can be used to treat children and adolescents aged 6 months and older with non-Hodgkin’s lymphoma, specifically CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt leukemia (mature B-acute lymphoblastic leukemia) (B-ALL), 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 of age.

Granulomatosis with polyangiitis or microscopic polyangiitis

Rituximab can be used to treat children and adolescents aged 2 years and older with granulomatosis with polyangiitis (previously known as Wegener’s granulomatosis) or microscopic polyangiitis. There is limited information on the use of rituximab in children and adolescents with other diseases.

Inform your doctor, pharmacist, or nurse before receiving rituximab if you or your child is under 18 years of age.

Other medicines and Ituxredi

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription or herbal medicines. This is because rituximab may affect how other medicines work. Likewise, other medicines may affect how rituximab works.

In particular, inform your doctor if:

you are being treated for high blood pressure. You may be advised not to take your blood pressure medications during the 12 hours before receiving rituximab. This is because some people experience a drop in blood pressure during rituximab infusion.
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 if you are unsure), consult your doctor, pharmacist, or nurse before receiving rituximab.

Pregnancy and breastfeeding

You must inform your doctor or nurse if you are pregnant, think you might be pregnant, or plan to become pregnant. This is because rituximab can cross the placental barrier 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 at least 12 months after the last dose of rituximab. Rituximab passes into breast milk in very small amounts. As the long-term effects on infants are unknown, breastfeeding is not recommended during treatment with rituximab and for 6 months after treatment as a precaution.

Driving and using machines

It is unknown whether Ituxredi has any effect on the ability to drive vehicles or operate machinery.

Ituxredi contains sodium

This medicine contains 52.2 mg of sodium (the main component of table/cooking salt) in each 10 ml vial and 261.2 mg of sodium in each 50 ml vial.

This corresponds to 2.6% (per 10 ml vial) and 13.2% (per 50 ml vial) of the maximum recommended daily sodium intake for an adult.

3. How to use Ituxredi

How Ituxredi is used

Rituximab will be administered by a physician or nurse experienced in the use of this medicine. You will be monitored during the administration of rituximab in case you experience any adverse effects. Rituximab is always administered as an intravenous infusion (drip).

Medications given before each Ituxredi infusion

Before receiving rituximab, you will be given other medicines (pre-medication) to prevent or reduce possible adverse effects.

Dose and frequency of treatment

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

If you are receiving rituximab as monotherapy

Rituximab will be administered once weekly for 4 weeks. Treatment cycles with rituximab may be repeated.

If you are receiving rituximab with chemotherapy

Rituximab will be administered on the same day as chemotherapy. It is generally given every 3 weeks up to 8 times.

If you respond well to treatment, you may continue rituximab as maintenance therapy every 2 or 3 months for up to 2 years. Your doctor may adjust this depending on your response to the medicine.
If you are under 18 years of age, you will receive rituximab with chemotherapy. You will receive rituximab up to 6 times over a period of 3.5 to 5.5 months.

If you are being treated for chronic lymphocytic leukemia

When receiving rituximab in combination with chemotherapy, you will receive rituximab 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 should be administered after the rituximab infusion. Your doctor will decide whether you should receive supportive therapy.

If you are being treated for rheumatoid arthritis

Each treatment cycle consists of two infusions, both separated by an interval of 2 weeks. Treatment cycles with rituximab may be repeated. Depending on the signs and symptoms of your disease, your doctor may decide at some point to administer a higher dose of rituximab, which may occur several months later.

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

Rituximab treatment consists of four separate infusions administered at weekly intervals. Corticosteroids are usually given by injection before starting rituximab treatment. To treat your disease, your doctor may start oral corticosteroids at any time.

If you are 2 years of age or older and respond well to treatment, you may receive rituximab as maintenance therapy. This will be administered as two infusions separated by 2 weeks, followed by one infusion every 6 months for at least 2 years. Your doctor may decide to treat you for a longer period with rituximab (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, both separated by an interval of 2 weeks. If you respond well to treatment, you may receive rituximab as maintenance therapy. This will be administered 1 year and 18 months after initial treatment, and then every 6 months as needed. Your doctor may adjust this depending on your response to the medicine.

If you have any further questions about 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 everyone experiences them.

Most of these adverse effects are mild to moderate in intensity, but some may be serious 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 adverse effects that some patients may experience include: pain at the infusion site, blisters and itching of the skin, nausea and vomiting, fatigue, headache, difficulty breathing, increased blood pressure, wheezing, throat discomfort, swelling of the tongue or throat, nasal itching or congestion, vomiting, flushing, or palpitations, heart attack, or low platelet count. If you have heart disease or angina, these reactions could worsen. Inform immediately the person administering the infusion if you or your child experience any of these symptoms, as the infusion may need to be slowed down or stopped. You may require additional treatment with antihistamines or paracetamol. Once symptoms disappear or improve, the infusion may continue. These reactions are less likely after the second infusion. Your doctor may decide to discontinue your treatment with rituximab if you experience severe infusion reactions.

Infections

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

fever, cough, sore throat, burning sensation when urinating, or if you begin to feel tired or generally unwell.
memory loss, difficulty concentrating, difficulty walking, or vision loss. This could be due to a very rare, serious brain infection (Progressive Multifocal Leukoencephalopathy or PML), which has been fatal.
fever, headache, neck stiffness, 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 susceptible to infections after treatment with rituximab. These are usually colds, but cases of pneumonia, urinary tract infections, or serious viral infections have been reported. All of these are listed below under "Other adverse effects".

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

Skin reactions

Very rarely, severe blistering of the skin may occur, which can be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may be accompanied by fever. Inform your doctor immediately if you experience any of these symptoms.

Other adverse effects

If you or your child is being treated for non-Hodgkin's 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 levels of blood cells called "platelets"
nausea
hair loss from the scalp, chills, headache
reduced immunity due to decreased levels of antibodies called "immunoglobulins" (IgG) in the blood, which 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, sinusitis, hepatitis B
low red blood cell count (anemia), low levels of all blood cells
allergic reactions (hypersensitivity)
high blood sugar levels, weight loss, peripheral and facial edema, increased levels of LDH enzyme in blood, decreased blood calcium levels
abnormal skin sensations such as numbness, tingling, pricking, burning, progressive increase in these sensations, reduced sense of touch
restlessness, difficulty falling asleep
facial redness and redness in other skin areas due to blood vessel dilation
dizziness or anxiety
increased tearing, lacrimal duct disorders, eye inflammation (conjunctivitis)
ringing in the ears (tinnitus), ear pain
heart disorders, such as myocardial infarction, irregular heartbeat, abnormally rapid heartbeat
increased or decreased blood pressure (especially low blood pressure upon standing)
muscle tension in the airways causing breathing difficulty (bronchospasm), lung, throat, and/or nasal cavity inflammation or irritation, shortness of breath, nasal discharge
vomiting, diarrhea, abdominal pain, throat or mouth irritation or ulcers, difficulty swallowing, constipation, indigestion
eating disorders: insufficient food intake 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 malaise or restlessness, 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), lymph node inflammation/swelling
lethargy, loss of interest in usual activities, nervousness
taste disturbances, such as changes in food taste
heart problems such as reduced heart rate or chest pain (angina)
asthma, low oxygen supply to organs
stomach swelling

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

temporary increase in a type of antibody in the blood (called immunoglobulins – IgM), chemical imbalances in blood caused by the breakdown of cancer cells
nerve damage in arms and legs, facial paralysis
heart failure
inflammation of blood vessels, including those causing skin symptoms
respiratory failure
damage to the intestinal wall (perforation)
severe skin problems causing blisters that can be potentially fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may be accompanied by 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
reduced platelet count after infusion – reversible, but in rare cases may be fatal
hearing loss, loss of other senses
infection/inflammation of the brain and meninges (enteroviral meningoencephalitis)

Children and adolescents with non-Hodgkin's lymphoma:

In general, adverse effects in children and adolescents with non-Hodgkin's lymphoma were similar to those in adults with non-Hodgkin's lymphoma or chronic lymphocytic leukemia. The most commonly observed adverse effects were fever associated with low levels of a type of white blood cells (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)
Pain when urinating (urinary tract infection)
Allergic reactions, most likely to occur during infusion, but may occur up to 24 hours after infusion
Changes in blood pressure, nausea, rashes, fever, feeling of flushing, nasal congestion, sneezing, chills, rapid heartbeat, and fatigue
Headache
Changes in laboratory tests performed by your doctor. These include a decrease in specific proteins in the blood (immunoglobulins) that help protect against infection.

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

Infections such as bronchial inflammation (bronchitis)
Feeling of warmth, intermittent pain in the nose, cheeks, and eyes (sinusitis), abdominal pain, vomiting, and diarrhea, breathing problems
Fungal infection in the feet (athlete's foot)
Increased blood cholesterol levels
Abnormal skin sensations such as numbness, tingling, pricking, or burning, sciatica, headache, dizziness
Hair loss
Anxiety, depression
Indigestion, diarrhea, acid reflux, throat and mouth irritation and/or ulceration
Abdominal, back, muscle, and/or joint pain

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

Fluid retention in the face and body
Inflammation, irritation, and/or pressure in the lungs and throat, cough
Skin reactions including hives, pruritus, and skin rashes
Allergic reactions including wheezing or difficulty breathing, facial and tongue swelling, collapse

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

A group of symptoms occurring a few weeks after rituximab infusion, including allergic reactions such as rash, pruritus, joint pain, lymph node swelling, and fever
Formation of severe blisters on the skin that can be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may be accompanied by fever.

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

Severe viral infection
infection/inflammation of the brain and meninges (enteroviral meningoencephalitis)

Other rare adverse effects reported with rituximab include a decrease in white blood cells (neutrophils) that help fight infections. Some infections may 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, more likely to occur during infusion, but may occur up to 24 hours after infusion
diarrhea
cough or difficulty breathing
nosebleeds
hypertension
joint or back pain
muscle spasms or tremors
dizziness
tremors (especially in the hands)
difficulty sleeping (insomnia)
swelling of the hands or ankles

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

indigestion
constipation
skin rash, including acne or spots
flushing or skin redness
fever
nasal congestion or discharge
tense or painful muscles
muscle pain or pain in hands or feet
low red blood cell count (anemia)
low platelet count in blood
increased blood potassium levels
changes in heart rhythm or abnormally fast heartbeat

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

formation of severe blisters on the skin that can be fatal. Redness, usually associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area, or eyelids, and may be accompanied by fever.
reactivation of previous hepatitis B infection

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

Severe viral infection
infection/inflammation of the brain and meninges (enteroviral meningoencephalitis)

Children and adolescents with granulomatosis with polyangiitis or microscopic polyangiitis

In general, 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 commonly observed side effects were infections, allergic reactions, and malaise (nausea).

If you are being treated for pemphigus vulgaris

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

allergic reactions, most likely to occur during infusion, but may occur up to 24 hours afterward
headache
infections such as chest infections
prolonged depression
hair loss

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

infections such as common cold, herpes infections, eye infections, oral candidiasis, and urinary tract infections (pain when urinating)
mood disorders such as irritability and depression
skin disorders such as itching, hives, and benign lumps
feeling of fatigue or dizziness
fever
joint or muscle pain
stomach pain
muscle pain
abnormally fast heartbeat

Frequency not known (frequency cannot be estimated from 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 medicines, some of the possible adverse effects may be due to the other medicines.

Reporting of adverse effects

If you experience any adverse effect, consult your doctor or pharmacist, even if it is an effect not listed in this leaflet. You may 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 Ituxredi

Keep out of the sight and reach of children.

Do not use this medicinal product after the expiry date stated on the packaging after EXP. The expiry date refers to 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 infusion solution of Ituxredi in 0.9 % sodium chloride solution is physically and chemically stable for 60 days at 5 ± 3 °C and for 30 days at 25 ± 2 °C.

After aseptic dilution in dextrose solution

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

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

Medicines must not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines and packaging that you no longer need. This will help protect the environment.

6. Contents of the pack and other 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 (50 mg/ml).

The other components are sodium citrate (E331), citric acid (E330), polysorbate 80 (E433), sodium chloride, and water for injections.

Appearance of the product and contents of the container

Ituxredi is a solution ranging from clear to opalescent, colourless to slightly yellowish, supplied as a concentrate for infusion solution in glass vials.

Each pack 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 responsible for batch release

Betapharm Arzneimittel GmbH
Kobelweg 95
Augsburg 86156
Germany

Further information on this medicinal product is available upon request by contacting the local representative of the Marketing Authorization Holder.

Belgium/Belgium/Belgium

betapharm Arzneimittel GmbH

Tel/Tel: + 49 821 74881 0