Active ingredients: Rituximab
MabThera 100 mg concentrate for solution for infusion
Mabthera package inserts are available for pack sizes:- MabThera 100 mg concentrate for solution for infusion
- MabThera 500 mg concentrate for solution for infusion
- MabThera 1400 mg solution for subcutaneous injection
Indications Why is Mabthera used? What is it for?
What is MabThera
MabThera contains the active substance 'rituximab', a type of protein called a 'monoclonal antibody' that binds to the surface of particular white blood cells, called B lymphocytes. When rituximab binds to the surface of these cells, it kills them.
What is MabThera used for
MabThera can be used to treat many different conditions in adults. Your doctor may prescribe MabThera to treat:
a) Non-Hodgkin's lymphoma
Non-Hodgkin's lymphoma is a disease of the lymphatic tissue (part of the immune system) that involves B lymphocytes, a special type of white blood cell.
MabThera can be given as monotherapy (alone) or with other medicines collectively called 'chemotherapy'.
In patients whose treatment proves effective, MabThera can be used as maintenance therapy for 2 years after completion of the initial treatment.
b) Chronic lymphatic leukemia
Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia. CLL involves a particular lymphocyte, the B cell, which originates in the bone marrow and matures in the lymph nodes. Patients with CLL have too many abnormal lymphocytes, which become they accumulate mainly in the bone marrow and in the blood. The proliferation of these abnormal B lymphocytes is the cause of the symptoms you may have. MabThera in combination with chemotherapy destroys these cells which are gradually removed from the body by biological processes.
c) Rheumatoid arthritis
MabThera is used to treat rheumatoid arthritis. Rheumatoid arthritis is a disease that affects the joints. B lymphocytes are responsible for some of the symptoms you have. MabThera is used to treat rheumatoid arthritis in people who have tried other medicines but have stopped working, did not work well enough, or caused side effects. MabThera is usually taken with another medicine called methotrexate. MabThera slows down the joint damage caused by rheumatoid arthritis and increases the ability to perform normal daily activities.
The best response to MabThera has been seen in those who have a positive blood test for rheumatoid factor (RF) and / or anti-cyclic citrullinated peptide (anti-CCP). Both tests are commonly positive in rheumatoid arthritis and help confirm the diagnosis.
d) Granulomatosis with polyangiitis and microscopic polyangiitis
MabThera is used for the induction of remission of granulomatosis with polyangiitis (formally called Wegener's disease) or microscopic polyangiitis, in association with glucocorticoids. Granulomatosis with polyangiitis and microscopic polyangiitis are two forms of inflammation of the blood vessels that mainly affect the lung and kidneys, but can affect other organs as well.B lymphocytes are involved in the cause of these conditions.
Contraindications When Mabthera should not be used
Do not take MabThera:
- if you are allergic to rituximab, other proteins similar to rituximab or any of the other ingredients of this medicine (listed in section 6);
- if you currently have a "severe active infection;
- if your immune system is weak;
- if you have severe heart failure or severe uncontrolled heart disease and have rheumatoid arthritis, granulomatosis with polyangiitis or microscopic polyangiitis.
Do not take MabThera if any of the above apply to you. If you are not sure, talk to your doctor, pharmacist or nurse before you are given MabThera.
Precautions for use What you need to know before taking Mabthera
Talk to your doctor, pharmacist or nurse before you are given MabThera:
- if you have had a hepatitis infection in the past or may have it now, as in a small number of cases MabThera could cause hepatitis B to become reactivated, which in very rare cases can be fatal. Patients with a history of hepatitis B infection will be closely monitored by the doctor for any signs of this infection;
- if you have ever suffered from heart problems (such as angina, palpitations or heart failure) or have had breathing problems.
If any of the above apply to you (or if you are unsure), talk to your doctor, pharmacist or nurse before you are given MabThera. Your doctor may need to pay special attention to you while taking MabThera.
If you have rheumatoid arthritis, granulomatosis with polyangiitis or microscopic polyangiitis talk to your doctor
- if you think you have an infection, even a mild one such as a cold. The cells that are affected by MabThera are used to fight infections and you need to wait for the infection to clear before taking MabThera. Also, tell your doctor if you have had numerous infections in the past or if you suffer from severe infections;
- if you think you need any vaccinations in the immediate future, including vaccinations needed to travel to other countries. Some vaccines should not be given at the same time as MabThera or in the months after taking MabThera. Your doctor will consider whether you can have any vaccines before taking MabThera.
Children and adolescents
Talk to your doctor, pharmacist or nurse before giving this medicine if you or your child is under 18 years of age, as not much information is currently available regarding the use of MabThera in children and adolescents.
Interactions Which drugs or foods may change the effect of Mabthera
Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other medicines, including non-prescription and herbal medicines, as MabThera can affect the way some medicines work and vice versa.
In particular, tell your doctor:
- if you are taking medicines to treat hypertension. You may be asked to stop taking these medicines for 12 hours before taking MabThera, as some people experience a drop in blood pressure while taking MabThera;
- if you have taken medicines in the past that affect the immune system - such as chemotherapy or immunosuppressive medicines.
If any of the above apply to you (or if you are unsure), talk to your doctor, pharmacist or nurse before you are given MabThera.
Warnings It is important to know that:
Pregnancy, breastfeeding and fertility
You should tell your doctor or nurse if you are pregnant, suspect or are planning to become pregnant, as MabThera can cross the placenta and affect the baby.
If there is a possibility that you may become pregnant, you and your partner will need to use effective contraception during MabThera therapy and within 12 months of receiving the last MabThera treatment.
MabThera can pass into breast milk, so you should not breast-feed during therapy with this medicine, nor for 12 months after receiving your last treatment with MabThera.
Driving and using machines
It is not known whether MabThera affects the ability to drive and use tools or machines.
Dosage and method of use How to use Mabthera: Dosage
Administration
MabThera will be given to you by a doctor or nurse experienced in the use of this treatment. They will closely monitor you during the administration of this medicine to detect any side effects.
MabThera will always be given as a drop-by-drop infusion into a vein (intravenous infusion).
Medicines given before each MabThera infusion
You will be given other medicines (premedication) before the MabThera infusion to avoid or reduce the occurrence of possible side effects.
How much and how often you will receive therapy
a) If you are being treated for non-Hodgkin's lymphoma
- If you are given only MabThera
MabThera will be given to you once a week for 4 weeks. Repeated courses of treatment with MabThera are possible.
- If you are given MabThera in combination with chemotherapy
You will receive MabThera the same day you receive chemotherapy; their administration generally takes place every 3 weeks for a maximum of 8 times
- If you respond well to treatment, MabThera may be given to you as maintenance therapy every 2 to 3 months for two years. Based on your response to the medicine, your doctor may change this administration regimen.
b) If you are being treated for chronic lymphocytic leukemia
If you are being treated with MabThera in combination with chemotherapy, you will receive MabThera infusions on day 0 of cycle 1, then on day 1 of each cycle for a total of 6 cycles. Each cycle lasts for 28 days. Chemotherapy should be given after the MabThera infusion. Your doctor will decide if you should receive concomitant supportive therapy.
c) If you are being treated for rheumatoid arthritis
Each treatment cycle consists of two separate infusions, administered at a 2-week interval between each other. Repeated courses of treatment with MabThera are possible. Based on the signs and symptoms of your disease, your doctor will decide when to give you further courses. This could happen in several months.
d) If you are being treated for granulomatosis with polyangiitis or microscopic polyangiitis
Treatment with MabThera involves four separate infusions given at weekly intervals. Corticosteroids will be given by injection before starting treatment with MabThera. Oral corticosteroid administration can be started at any time by your doctor to treat your condition.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Side Effects What are the side effects of Mabthera
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Most side effects are mild or moderate, but in some cases they can be severe and require treatment. Rarely, some of these reactions have been fatal.
Infusion reactions
During or within the first 2 hours after the first infusion you may develop fever, chills and tremor.Less frequently, some patients may have pain at the infusion site, blistering, itchy skin, malaise, tiredness, headache, difficulty breathing, swollen tongue or throat, irritation or runny nose, vomiting, feeling warm or warm. palpitations, heart attack or reduction in the number of platelets. If you have heart disease or angina, these reactions may get worse. If you experience any of these symptoms, tell the person giving you the infusion immediately, as the rate of infusion may need to be slowed down or stopped. Additional treatment may be needed, for example with an antihistamine or paracetamol. When these symptoms are resolved or improved, the infusion can be resumed. These reactions are less likely to occur after the second infusion. Your doctor may decide to stop treatment with MabThera if these reactions are severe.
Infections
Tell your doctor immediately if you have any signs of an infection, including:
- fever, cough, sore throat, burning when urinating, feeling weak or generally unwell;
- memory loss, troubled thinking, difficulty walking or loss of vision - these may be due to a very rare "serious infection which has been fatal (progressive multifocal leukoencephalopathy or PML). You may develop infections more easily during treatment. with MabThera.
- These are often colds, but there have been cases of pneumonia or urinary tract infections. These conditions are listed in the "list under" Other undesirable effects "below.
If you are being treated for rheumatoid arthritis, you will also find this information in the Patient Alert Card that will be given to you by your doctor. It is important that you carry this alert card with you and show it to your family member or anyone else take care of her.
Skin reactions
Very rarely, severe skin reactions with blistering can occur, which can be life-threatening. Redness, often associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area or eyelid area, and fever may be present. Tell your doctor immediately if you get any of these symptoms.
Other side effects
a) If you are being treated for non-Hodgkin's lymphoma or chronic lymphocytic leukemia
Very common side effects (may affect more than 1 in 10 people):
- bacterial or viral infections, bronchitis
- low number of white blood cells, with or without fever, or platelets (blood cells)
- nausea
- areas of baldness on the scalp, chills, headache
- lowering of the immune system - due to a reduction in the amount of certain antibodies called 'immunoglobulins' (IgG) in the blood which help the body protect itself from infections.
Common side effects (may affect up to 1 in 10 people):
- blood infections (sepsis), pneumonia, shingles, colds, bronchial infection, fungal infections, infections of unknown origin, sinusitis, hepatitis B
- low number of red blood cells (anemia), low number of all blood cells
- allergic reactions (hypersensitivity)
- high blood sugar, weight loss, swelling of the face and body, high levels of the "enzyme" LDH "in the blood, low levels of calcium in the blood
- abnormal sensations in the skin - such as numbness, tingling, tingling, burning, feeling of stretched skin, decreased sense of touch
- sense of restlessness, difficulty falling asleep
- marked redness of the face and other skin areas as a consequence of the dilation of blood vessels
- dizziness or anxiety
- increased lacrimation, tear duct problems, eye inflammation (conjunctivitis)
- continuous ringing in the ears, pain in the ear
- heart problems - such as heart attack, irregular or fast heart rate
- high or low blood pressure (decrease in blood pressure particularly when standing)
- contraction of the muscles in the airways causing wheezing (bronchospasm), inflammation, irritation in the lungs, throat and sinuses, shortness of breath, runny nose
- vomiting, diarrhea, stomach pain, throat and mouth irritation or ulceration, swallowing problems, constipation, indigestion
- eating disorders: insufficient food intake resulting in weight loss
- hives, increased sweating, night sweats
- muscle problems - such as muscle stiffness, joint or muscle pain, back and neck pain
- general malaise, restlessness or tiredness, tremors, signs of flu
- multi-organ failure.
Uncommon side effects (may affect up to 1 in 100 people):
- bleeding problems, decreased production of red blood cells and increased destruction of red blood cells (haemolytic and aplastic anemia), swelling or enlargement of the lymph nodes
- low mood and loss of interest or pleasure in doing activities, nervousness
- problems related to taste - such as changes in the sense of taste
- heart problems - such as slow heart rate or chest pain (angina)
- asthma, insufficient amount of oxygen reaching the body's organs
- bloating of the stomach.
Very rare side effects (may affect up to 1 in 10,000 people):
- short-lived increase in the amount of certain types of antibodies (immunoglobulins - IgM) in the blood, chemical change in the blood due to the breakdown of dying cancer cells
- damage to the nerves of the arms and legs, paralysis of the face
- heart failure
- inflammation of blood vessels, including those causing skin symptoms
- respiratory failure
- damage to the intestinal wall (perforation)
- severe skin problems with blistering, potentially fatal. Redness, often associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area or eyelid area, and fever may be present.
- kidney failure
- severe vision loss.
Not known (the frequency with which these side effects occur is not known):
- non-immediate reduction of white blood cells
- reduction in the number of platelets soon after infusion - reversible condition, but in rare cases life-threatening
- loss of hearing, loss of other senses.
b) If you are being treated for rheumatoid arthritis
Very common side effects (may affect more than 1 in 10 people):
- infections such as pneumonia (bacterial)
- pain when passing urine (urinary tract infection)
- allergic reactions that are likely to occur during the infusion but can occur up to 24 hours after the infusion
- changes in blood pressure, nausea, rash, fever, itchy feeling, runny or stuffy nose, sneezing, shaking, fast heartbeat and tiredness
- headache
- changes in the laboratory tests required by the doctor. These include a reduction in the amount of certain specific proteins in the blood (immunoglobulins) that help protect against infection.
Common side effects (may affect up to 1 in 10 people):
- infections such as bronchial inflammation (bronchitis)
- a feeling of pain and fullness behind the nose, cheeks and eyes (sinusitis), pain in the abdomen, vomiting and diarrhea, trouble breathing
- foot fungal infection (athlete's foot)
- high blood cholesterol levels
- abnormal sensations on the skin, such as numbness, tingling, tingling or burning, sciatica, migraine, dizziness
- hair loss
- anxiety, depression
- indigestion, diarrhea, acid reflux, irritation and / or ulceration of the throat and mouth
- pain in the belly, back, muscles and / or joints.
Uncommon side effects (may affect up to 1 in 100 people):
- excess fluid retention in the face and body
- inflammation, irritation and / or tension in the lungs, throat, cough
- skin reactions, including hives, itching, rash
- allergic reactions including wheezing or shortness of breath, swelling of the face and tongue, collapse.
Very rare side effects (may affect up to 1 in 10,000 people):
- a complex of symptoms occurring within a few weeks of the infusion of MabThera including allergic-type reactions such as rash, itching, painful joints, swollen lymph glands and fever
- severe skin reactions with blistering which can be life-threatening. Redness, often associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genital area or eyelid area, and fever may be present.
Other rarely reported side effects from treatment with MabThera include a reduction in the number of white blood cells (neutrophils) which are used to fight infections. Some infections can be serious (please see the Infections information in this section).
c) If you are being treated for granulomatosis with polyangiitis or for microscopic polyangiitis
Very common side effects (may affect more than 1 in 10 people):
- infections, such as lung infections, urinary tract infections (painful urination), colds and herpes infections
- allergic reactions that are likely to occur during the infusion but can occur up to 24 hours after the infusion
- diarrhea
- cough or shortness of breath
- nose bleeding
- increased blood pressure
- pain in the joints or back
- muscle twitching or shaking
- feeling dizzy
- tremors (tremor, often in the hands)
- sleep disturbances (insomnia)
- swelling of the hands and ankles.
Common side effects (may affect up to 1 in 10 people):
- indigestion
- constipation
- skin rashes, including acne or blemishes
- flushing or redness of the skin
- stuffy nose
- muscle stiffness or muscle aches
- pain in the muscles or hands or feet
- low number of red blood cells (anemia)
- low number of platelets in the bloodincrease in the amount of potassium in the blood
- changes in heart rhythm or heart rate faster than normal.
Very rare side effects (may affect up to 1 in 10,000 people):
- severe skin reactions with blistering which can be life-threatening. Redness, often associated with blisters, may appear on the skin or mucous membranes, such as inside the mouth, genitals or eyelids, and fever may be present.
- recurrence of a previous hepatitis B infection.
MabThera can also cause changes in the laboratory tests required by your doctor.
If you are taking MabThera in combination with other medicines, some of the side effects you experience may be due to the other medicines.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of the month.
Store in a refrigerator (2 ° C - 8 ° C). Keep the container in the outer packaging to protect it from light.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
What MabThera contains
- The active substance in MabThera is rituximab. The vial contains 100 mg of rituximab (10 mg / ml).
- The other ingredients are sodium citrate, polysorbate 80, sodium chloride, sodium hydroxide, hydrochloric acid and water for injections.
What MabThera looks like and contents of the pack
MabThera is a clear and colorless solution, supplied as a concentrate for solution for infusion. The 10 ml vials are available in packs of 2 vials.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
MABTHERA 100 MG CONCENTRATE FOR SOLUTION FOR INFUSION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 10 mg of rituximab.
Each vial contains 100 mg of rituximab.
Rituximab is a genetically engineered chimeric mouse / human monoclonal antibody consisting of a glycosylated immunoglobulin with human IgG1 constant regions and murine light chain and heavy chain variable region sequences.
The antibody is produced using a mammalian cell suspension culture (Chinese Hamster ovary) and purified by affine chromatography and ion exchange, including specific viral inactivation and removal procedures.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear and colorless liquid.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
MabThera is indicated in adults for the following indications:
Non-Hodgkin's lymphoma (NHL)
MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy.
MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy.
MabThera monotherapy is indicated for the treatment of patients with stage III-IV follicular lymphoma who are chemoresistant or are in second or subsequent relapse after chemotherapy.
MabThera is indicated for the treatment of patients with CD20 positive diffuse large B cell non-Hodgkin's lymphoma in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone).
Chronic lymphocytic leukemia (CLL)
MabThera in combination with chemotherapy is indicated for the treatment of patients with previously untreated and relapsed / refractory chronic lymphocytic leukemia. Only limited data on efficacy and safety are available for patients previously treated with monoclonal antibodies, including MabThera, or for patients refractory to previous treatment with MabThera plus chemotherapy.
See section 5.1 for further information.
Rheumatoid arthritis
MabThera in combination with methotrexate is indicated for the treatment of severe active rheumatoid arthritis in adult patients who have shown an "inadequate response or" intolerance to other disease-modifying antirheumatic drugs (DMARDs), including one or more inhibitors of the factor of tumor necrosis (TNF).
MabThera has been shown to reduce the rate of joint damage progression as assessed by X-rays and to improve physical function when given in combination with methotrexate.
Granulomatosis with polyangiitis and microscopic polyangiitis
MabThera in combination with glucocorticoids is indicated for the induction of remission in adult patients with granulomatosis with (Wegener's) polyangiitis (GPA) and severe active microscopic polyangiitis (MPA).
04.2 Posology and method of administration
MabThera should be administered under the close supervision of an experienced healthcare professional and in an environment with immediate availability of resuscitation equipment (see section 4.4).
Premedication with an antipyretic drug and an antihistamine, for example paracetamol and diphenhydramine, should always be taken before each administration of MabThera.
In patients with non-Hodgkin's lymphoma and chronic lymphocytic leukemia (CLL), premedication with glucocorticoids should be considered if MabThera is not given in combination with glucocorticoid-containing chemotherapy.
In patients with rheumatoid arthritis, premedication with intravenous methylprednisolone 100 mg should be completed 30 minutes prior to the infusion of MabThera in order to reduce the incidence and severity of infusion-related reactions (IRRs).
In patients suffering from granulomatosis with (Wegener's) polyangiitis or microscopic polyangiitis, intravenous methylprednisolone at a dose of 1000 mg / day is recommended for 1 to 3 days prior to the first infusion of MabThera (the last dose of methylprednisolone can be administered on the same day as the first infusion of MabThera) This should be followed by oral prednisone at a dose of 1 mg / kg / day (80 mg / day should not be exceeded and tapering should be done as quickly as possible depending on the clinical condition) during and after treatment with MabThera.
Dosage
& EGRAVE; It is important to check the medicine label to ensure that the appropriate formulation (intravenous or subcutaneous) is administered to the patient as prescribed.
Non-Hodgkin's lymphoma
Follicular non-Hodgkin's lymphoma
Association therapy
The recommended dose of MabThera in combination with chemotherapy for induction treatment of previously untreated or relapsed / refractory patients with follicular lymphoma is 375 mg / m2 body surface area per cycle, for up to 8 cycles.
MabThera should be administered on day 1 of each chemotherapy cycle, following i.v. the glucocorticoid component of chemotherapy, if applicable.
Maintenance therapy
• Previously untreated follicular lymphoma
The recommended dose of MabThera used as maintenance treatment for previously untreated follicular lymphoma patients who have responded to induction treatment is: 375 mg / m2 body surface area once every two months (starting 2 months after the last dose of therapy). induction) until disease progression or for a maximum period of two years.
• Relapsed / refractory follicular lymphoma
The recommended dose of MabThera used as maintenance treatment for patients with relapsed / resistant follicular lymphoma who have responded to induction treatment is 375 mg / m2 body surface area once every 3 months (starting 3 months after the last dose of therapy). induction) until disease progression or for a maximum period of two years.
Monotherapy
• Relapsed / refractory follicular lymphoma
The recommended dose of MabThera monotherapy used as induction treatment for adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy is 375 mg / m2 body surface area, administered as an i.v. infusion. once a week for four weeks.
For retreatment with MabThera monotherapy for patients who have responded to previous treatment with MabThera monotherapy for relapsed / refractory follicular lymphoma, the recommended dose is 375 mg / m2 body surface area, administered as an intravenous infusion once weekly for four weeks. (see section 5.1).
Diffuse large B-cell non-Hodgkin's lymphoma
MabThera must be used in combination with CHOP chemotherapy. The recommended dosage is 375 mg / m2 body surface area, administered on day 1 of each chemotherapy cycle for 8 cycles following intravenous infusion of the glucocorticoid component of CHOP. The safety and efficacy of MabThera in combination with other chemotherapies in diffuse large B cell non-Hodgkin's lymphoma have not yet been established.
Dosage adjustments during treatment
No dose reductions of MabThera are recommended. When MabThera is given in combination with chemotherapy, standard dose reductions for chemotherapy medicinal products should be applied.
Chronic lymphocytic leukemia
For patients with CLL, prophylaxis with adequate hydration and administration of uricostats starting 48 hours prior to initiation of therapy is recommended to reduce the risk of tumor lysis syndrome. For CLL patients whose lymphocyte count is> 25 x 109 / L it is recommended to administer prednisone / prednisolone 100 mg intravenously immediately prior to the MabThera infusion to decrease the rate and severity of acute infusion reactions and / or cytokine release syndrome.
The recommended dosage of MabThera in combination with chemotherapy in previously untreated and relapsed / refractory patients is 375 mg / m2 body surface area given on day 0 of the first treatment cycle followed by 500 mg / m2 body surface area given on day 1 of each subsequent cycle for 6 total cycles. Chemotherapy should be given after MabThera infusion.
Rheumatoid arthritis
Patients receiving MabThera should be given the patient alert card with each infusion.
A course of MabThera consists of two intravenous infusions of 1000 mg each. The recommended dosage of MabThera is 1000 mg by intravenous infusion, followed by a second 1000 mg intravenous infusion two weeks later.
The need for further treatment should be assessed 24 weeks after the previous cycle. Retreatment should be done at that time if residual disease activity remains, otherwise retreatment should be delayed until residual disease activity reappears.
Available data suggest that clinical response is usually achieved within 16 to 24 weeks of an initial treatment course. In patients who do not see therapeutic benefit within this time period, careful consideration should be given to whether to continue therapy.
Granulomatosis with polyangiitis and microscopic polyangiitis
Patients treated with MabThera should be given the patient alert card with each infusion.
The recommended dosage of MabThera for induction therapy of remission of granulomatosis with polyangiitis and microscopic polyangiitis is 375 mg / m2 of body surface area, administered by intravenous infusion once weekly for 4 weeks (4 total infusions).
For patients with granulomatosis with polyangiitis and microscopic polyangiitis, during and after treatment with MabThera, prophylaxis for pneumonia is recommended. Pneumocystis jiroveci, (PCP), as appropriate.
Special populations
Pediatric population
The safety and efficacy of MabThera in children and adolescents below 18 years of age have not yet been established. There are no data available.
Elderly patients
No dosage adjustment is necessary in elderly patients (aged> 65 years).
Method of administration
The prepared MabThera solution should be administered by intravenous infusion through a dedicated line. It should not be administered as an intravenous push or bolus. Patients should be carefully monitored for the onset of cytokine release syndrome (see section 4.4). Patients who develop severe reactions, especially severe dyspnoea, bronchospasm or hypoxia, should have the infusion stopped immediately. Patients with non-Hodgkin's lymphoma should then be evaluated for the presence of tumor lysis syndrome by performing appropriate laboratory tests and for the presence of pulmonary infiltration by chest X-ray. In all patients, the infusion should not be resumed until complete resolution of all symptoms and normalization of laboratory values and chest X-ray. Only then can the infusion be resumed at an initial rate reduced by half that previously used. Should the same serious adverse reactions occur again, the decision to discontinue treatment should be carefully considered on a case-by-case basis.
Mild or moderate infusion-related reactions (IRRs) (see section 4.8) generally respond to a reduction in the rate of infusion. As symptoms improve, the rate of infusion may be increased.
First infusion
The recommended initial infusion rate is 50 mg / h; after the first 30 minutes, it can be increased in increments of 50 mg / h every 30 minutes, up to a maximum of 400 mg / h.
Subsequent infusions
For all indications
Subsequent doses of MabThera can be administered at an initial infusion rate of 100 mg / h and increased by 100 mg / h at 30 minute intervals, up to a maximum of 400 mg / h.
For rheumatoid arthritis only
Alternative scheme for faster administration of subsequent infusions
If with the first or subsequent infusions given at the 1000 mg dose of MabThera according to the standard infusion schedule, patients have not experienced a severe infusion-related reaction, the second and subsequent infusions can be given at a faster rate, at the same rate. concentration of the previous infusions (4 mg / ml for a volume of 250 ml).
Start the infusion at a rate of 250 mg / h for the first 30 minutes and then at 600 mg / h for the next 90 minutes. If the faster infusion is well tolerated, the same infusion schedule can be used for the administration of subsequent infusions.
The faster infusion should not be given to patients with clinically significant cardiovascular disease, including arrhythmias, or who have experienced severe reactions to the infusion of rituximab or any previous biologic therapy in the past.
04.3 Contraindications
Contraindications for use in non-Hodgkin's lymphoma and chronic lymphocytic leukemia
Hypersensitivity to the active substance, to murine proteins or to any of the other excipients listed in section 6.1.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state.
Contraindications to use in rheumatoid arthritis, in granulomatosis with polyangiitis and microscopic polyangiitis
Hypersensitivity to the active substance, to murine proteins or to any of the other excipients listed in section 6.1.
Active, severe infections (see section 4.4).
Patients in a severely immunocompromised state.
Severe heart failure (New York Heart Association class IV) or severe and uncontrolled heart disease (see section 4.4 for other cardiac disorders).
04.4 Special warnings and appropriate precautions for use
To improve the traceability of biological medicinal products, the product name MabThera should be clearly recorded in the patient record.
Progressive multifocal leukoencephalopathy
All patients treated with MabThera for rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding the risk potentially major infections, including progressive multifocal leukoencephalopathy (PML).
Very rare fatal cases of PML have been reported following the use of MabThera. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or for signs suggestive of PML. If PML is suspected, further administrations should be made. be suspended until the diagnosis of PML has been ruled out. The physician should evaluate the patient to determine whether the symptoms are indicative of neurological dysfunction and, if so, whether these symptoms are possibly suggestive of PML. Neurological counseling should be sought if clinically indicated.
If in doubt, further evaluation should be considered, including tests such as MRI preferably with contrast, cerebrospinal fluid (CSF) testing to evaluate JC virus DNA, and repeated neurological evaluations.
Physicians should be especially alert to symptoms suggestive of PML that the patient may not notice (for example, cognitive, neurological, or psychiatric symptoms). The patient should also be advised to inform their partner or caregiver about the treatment, as they may notice symptoms of which the patient is unaware.
If a patient develops PML, administration of MabThera must be permanently discontinued.
Following immune system reconstitution in immunocompromised patients with PML, stabilization or improvement was noted. It is not known whether early detection of PML and discontinuation of MabThera therapy will lead to similar stabilization or improvement.
Non-Hodgkin's lymphoma and chronic lymphocytic leukemia
Infusion related reactions
MabThera is associated with infusion-related reactions, which are potentially associated with the release of cytokines and / or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions.
This set of reactions, which includes cytokine release syndrome, tumor lysis syndrome, and anaphylactic and hypersensitivity reactions, is described below. These reactions are not specifically related to the route of administration of MabThera and can be observed with both formulations.
Serious and fatal infusion-related reactions have been reported during post-marketing use of MabThera intravenous formulation, with onset occurring within 30 minutes to 2 hours after initiation of the first. IV infusion of MabThera. These reactions were characterized by pulmonary events and in some cases included rapid tumor lysis and symptoms of tumor lysis syndrome as well as fever, chills, shivering, hypotension, urticaria, angioedema and other symptoms (see section 4.8). .
Severe cytokine release syndrome is characterized by severe dyspnea, often accompanied by bronchospasm and hypoxia, as well as fever, chills, shivering, hives, and angioedema. This syndrome may be associated with some features of tumor lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcemia, hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) concentration and may be associated with acute respiratory failure and death. Acute respiratory failure may be accompanied by events such as pulmonary interstitial infiltration or pulmonary edema, visible on chest x-ray. The syndrome frequently occurs within one to two hours of starting the first infusion. Patients with a history of pulmonary insufficiency or lung tumor infiltration may be at increased risk of poor outcomes and should be treated with greater caution. Patients who develop severe cytokine release syndrome should have the infusion stopped immediately (see section 4.2) and should be given aggressive symptomatic treatment. Since initial improvement in clinical symptoms may be followed by worsening, these patients should be monitored carefully until the tumor lysis syndrome and pulmonary infiltration are resolved or excluded.
Further treatment of patients after complete resolution of symptoms and signs has rarely resulted in recurrence of severe cytokine release syndrome.
Patients with high tumor burden or with high numbers (≥ 25 x 109 / L) of circulating neoplastic cells such as CLL patients, who may be at increased risk of particularly severe cytokine release syndrome, should be treated with extreme caution. These patients should be monitored very closely throughout the course of the first infusion. In such patients, consideration should be given to using a reduced infusion rate for the first infusion or a split dose over two days during the first cycle and each subsequent cycle if the lymphocyte count is still> 25 x. 109 / l.
Infusion-related adverse reactions of all kinds (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) have been observed in 77% of patients treated with MabThera (see section 4.8). These symptoms are generally reversible. with the interruption of the MabThera infusion and with the administration of antipyretic drugs, antihistamines and, occasionally, oxygen, intravenous saline or bronchodilator drugs, and glucocorticoids if necessary. For severe reactions see cytokine release syndrome described above.
Anaphylactic and other hypersensitivity reactions have been reported in patients following intravenous administration of proteins. Unlike cytokine release syndrome, hypersensitivity reactions typically occur within minutes of starting the infusion. In case of an allergic reaction during the administration of MabThera, medicinal products for the treatment of hypersensitivity reactions, eg. epinephrine (adrenaline), antihistamines and glucocorticoids should be available for immediate use. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations of cytokine release syndrome (described above). Reactions attributed to hypersensitivity have been reported less frequently than those attributed to cytokine release.
Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia.Hypotension may occur during administration of MabThera, therefore discontinuation of antihypertensive medicinal products 12 hours prior to the MabThera infusion should be considered.
Cardiac disorders
Cases of angina pectoris, cardiac arrhythmia, such as atrial flutter and fibrillation, heart failure and / or myocardial infarction have occurred in patients treated with MabThera. Therefore patients with a history of heart disease and / or cardiotoxic chemotherapy should be carefully monitored.
Hematological toxicity
Although MabThera is not myelosuppressive on its own, special care should be taken when considering the treatment of patients with autologous bone marrow platelet neutrophils and other risk groups with presumably impaired bone marrow function without inducing myelotoxicity.
Complete blood counts, including neutrophil and platelet counts, should be performed regularly during MabThera therapy.
Infections
Serious infections, including fatalities, can occur during therapy with MabThera (see section 4.8).
MabThera must not be used in patients with severe active infections (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3).
Physicians should be cautious when considering the use of MabThera in patients with a history of recurrent or chronic infections or with underlying conditions that may further predispose patients to serious infections (see section 4.8).
Cases of hepatitis B reactivation have been reported in subjects receiving MabThera including reports of fulminant hepatitis with fatal outcome. Most of these subjects also received cytotoxic chemotherapy. Limited information from a study in patients with relapsed / refractory CLL suggests that treatment with MabThera may also worsen the outcome of primary hepatitis B infections. Hepatitis B virus (HBV) screening should be performed in all patients. before starting treatment with MabThera and should at least include HBsAg and HBcAb dosing. These tests can then be supplemented with other appropriate markers according to local guidelines. Patients with active hepatitis B infection should not be treated with MabThera. Patients with positive hepatitis B serology (both HBsAg and HBcAb) should be evaluated by a hepatologist clinician prior to initiation of treatment and should be monitored and followed up according to local clinical standards to prevent hepatitis B reactivation.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during post-marketing use of MabThera in NHL and CLL (see section 4.8). Most patients had received MabThera in combination with chemotherapy or as part of a hematopoietic stem cell transplant program.
Immunization
The safety of immunization with live viral vaccines following MabThera therapy has not been studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. Patients treated with MabThera may receive non-virus vaccinations. However, response rates to non-live virus vaccines may be reduced. In a non-randomized study, patients with relapsed low-grade NHL who received MabThera monotherapy when compared with untreated healthy volunteer controls had a lower rate of responses to vaccination with tetanus booster antigens (16% versus 81%) and Keyhole Limpet Haemocyanin (KLH) neoantigens (4% versus 76% when evaluated for> 2-fold increase in antibody titer). CLL are expected to have similar results considering the similarities between the two diseases, however this has not been evaluated by clinical studies. pre-therapeutic antibodies against an antigen panel (Streptococcus pneumoniae, influenza A, mumps, rubella, chicken pox) was maintained for at least 6 months after treatment with MabThera.
Skin reactions
Serious skin reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In the event of such events, if a relationship to MabThera is suspected, treatment should be permanently discontinued. Rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis.
Methotrexate (MTX) naïve populations with rheumatoid arthritis
The use of MabThera is not recommended in MTX naïve patients as a favorable benefit-risk ratio has not been established.
Infusion related reactions
MabThera is associated with infusion-related reactions (IRRs), which may be associated with the release of cytokines and / or other chemical mediators. Premedication with analgesic / antipyretic drugs and an antihistamine drug should always be administered prior to each infusion of MabThera In patients with rheumatoid arthritis, premedication with glucocorticoids should always be administered before each infusion of MabThera in order to reduce the frequency and severity of IRRs (see sections 4.2 and 4.8).
Serious cases of IRR with fatal outcome have been reported in patients with rheumatoid arthritis in the postmarketing setting.
In the treatment of rheumatoid arthritis, most infusion-related reactions in clinical trials were mild to moderate in intensity. The most common symptoms were allergic reactions such as headache, itching, throat irritation, redness, rash, hives, hypertension and pyrexia. In general, the proportion of patients experiencing some infusion reaction was higher after the first infusion than after the second in any treatment cycle. The incidence of IRR decreased in subsequent courses (see section 4.8). The reported reactions were generally reversible with either reducing the rate of the infusion or stopping the administration of MabThera and taking antipyretics, antihistamines and, occasionally, oxygen, intravenous saline or bronchodilators, and glucocorticoids, if necessary. Monitor patients closely. with pre-existing cardiac conditions and those who have experienced previous cardiopulmonary adverse reactions. Depending on the severity of the IRRs and the intervention required, temporarily or permanently discontinue the administration of MabThera. In most cases, the infusion can be resumed by reducing the rate to 50% (eg from 100 mg / h to 50 mg / h) when symptoms have completely resolved.
Medicines for the treatment of hypersensitivity reactions, eg. epinephrine (adrenaline), antihistamines and glucocorticoids, should be available for immediate use, in case of allergic reactions during the administration of MabThera.
There are no data on the safety of MabThera in patients with moderate heart failure (NYHA class III) or severe, uncontrolled heart disease. In patients treated with MabThera, pre-existing conditions of cardiac ischaemia, such as angina pectoris, have been observed to become symptomatic, as have atrial fibrillation and flutter. Therefore, in patients with a history of heart disease, and in those who have experienced previous reactions cardiopulmonary adverse events, the risk of cardiovascular complications resulting from infusion reactions should be considered prior to treatment with MabThera and patients should be closely monitored during administration. Hypotension may occur during MabThera infusion, therefore discontinuation of anti-hypertensive drugs 12 hours before the MabThera infusion.
The IRRs for patients with granulomatosis with polyangiitis and microscopic polyangiitis were similar to those observed in clinical studies in patients with rheumatoid arthritis (see section 4.8).
Cardiac disorders
Cases of angina pectoris, cardiac arrhythmia, such as atrial flutter and fibrillation, heart failure and / or myocardial infarction have occurred in patients treated with MabThera. Therefore, patients with a history of heart disease should be closely monitored (see "Infusion related reactions" above).
Infections
Based on the mechanism of action of MabThera and the knowledge that B cells play an important role in maintaining normal immune response, patients have an increased risk of infections following MabThera therapy (see section 5.1). Serious infections , including fatal events, may occur during therapy with MabThera (see section 4.8). MabThera must not be given to patients with severe active infection (e.g. tuberculosis, sepsis and opportunistic infections, see section 4.3) or to severely immunocompromised patients.
(e.g. where CD4 or CD8 values are very low). Physicians should exercise caution when considering the use of MabThera in patients with a history of recurrent or chronic infections or with underlying conditions that may further predispose patients to serious infections eg hypogammaglobulinaemia (see section 4.8). immunoglobulins are determined before starting treatment with MabThera.
Patients who experience signs and symptoms of infection following treatment with MabThera should be promptly evaluated and adequately treated. Before starting a subsequent course of treatment with MabThera, patients should be re-evaluated for any potential risk of infections.
Very rare cases of fatal progressive multifocal leukoencephalopathy (PML) have been reported following the use of MabThera for the treatment of rheumatoid arthritis and autoimmune diseases including Systemic Lupus Erythematosus (SLE) and vasculitis.
Hepatitis B infection
Cases of hepatitis B reactivation, including those with fatal outcome, have been reported in patients with rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis who received MabThera.
Screening for hepatitis B virus (HBV) should be performed in all patients prior to initiating treatment with MabThera and should at least include HBsAg and HBcAb testing. These tests can then be supplemented with other appropriate markers. according to local guidelines. Patients with active hepatitis B infection should not be treated with MabThera. Patients with positive hepatitis B serology (both HBsAg and HBcAb) should be evaluated by a hepatologist clinician and should be monitored and followed up according to local clinical standards to prevent hepatitis B reactivation.
Late onset neutropenia
Measure neutrophils before each course of MabThera and at regular intervals up to 6 months after stopping treatment and in case of signs or symptoms of infection (see section 4.8).
Skin reactions
Serious skin reactions such as toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported (see section 4.8). In the event of such events, if a relationship to MabThera is suspected, treatment should be permanently discontinued.
Immunization
Physicians should review the patient's vaccination status and follow current immunization guidelines prior to MabThera therapy. Vaccination should be completed at least 4 weeks prior to the first administration of MabThera.
The safety of immunization with live viral vaccines following MabThera therapy has not been studied. Therefore vaccination with live virus vaccines is not recommended during MabThera therapy or during the period of peripheral B cell depletion.
Patients treated with MabThera can receive non-live virus vaccinations. However, response rates to non-live virus vaccines can be reduced. In a randomized study, patients with rheumatoid arthritis treated with MabThera and methotrexate had similar response rates to those of patients who received only methotrexate to tetanus booster antigens (39% versus 42%), reduced rates to the polysaccharide vaccine. pneumococcus (43% versus 82% to at least 2 anti-pneumococcal antibody serotypes) and KLH neoantigens (47% versus 93%), when given 6 months after MabThera. If non-live virus vaccinations are required during MabThera therapy, these should be completed at least 4 weeks prior to the start of the next MabThera course.
In the "global experience of repeated treatments of MabThera in one year in the" setting of rheumatoid arthritis, the percentages of patients with positive antibody titers against S. pneumoniae, influenza, mumps, rubella, chicken pox, and tetanus toxin were generally similar to baseline rates.
Concomitant / sequential use of other DMARDs in the treatment of rheumatoid arthritis
The concomitant use of MabThera and antirheumatic therapies other than those specified in the indication and posology for rheumatoid arthritis is not recommended.
There are limited data from clinical trials to fully evaluate the safety of sequential use after MabThera of other DMARDs (including TNF inhibitors and other biologics) (see section 4.5). Available data indicate that the rate of clinically relevant infections is unchanged when these therapies are used in patients previously treated with MabThera; however, patients should be closely observed for signs of infection if biological agents and / or DMARDs are used after MabThera therapy.
Neoplasms
Immunomodulatory drugs can increase the risk of cancer. Based on the limited experience with MabThera in patients with rheumatoid arthritis (see section 4.8) the current data do not seem to suggest an increased risk of malignancy. However, the possible risk of developing solid tumors cannot currently be excluded.
04.5 Interactions with other medicinal products and other forms of interaction
There are currently limited data on possible drug interactions with MabThera.
In CLL patients, co-administration with MabThera does not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there is no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of MabThera.
Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera in patients with rheumatoid arthritis.
Patients who have developed anti-mouse or anti-chimeric antibodies (HAMA / HACA) may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies.
In patients with rheumatoid arthritis, 283 patients subsequently received biologic DMARD therapy after MabThera. In these patients, the rate of clinically relevant infections during MabThera therapy was 6.01 per 100 patient-years compared to 4.97 per 100 patient-years after biologic DMARD treatment.
04.6 Pregnancy and lactation
Contraception in men and women
Because rituximab has a long retention time in B-cell depleted patients, women of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months after completion of MabThera therapy.
Pregnancy
IgG immunoglobulins are known to cross the placental barrier.
B cell levels in human infants following maternal exposure to MabThera have not been evaluated in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to MabThera during pregnancy. Similar effects were observed in animal studies (see section 5.3). For this reason, MabThera should not be administered to pregnant women unless the possible benefit outweighs the potential risk.
Breastfeeding
It is unknown whether rituximab is excreted in human milk. However, because maternal IgG is excreted in human milk and rituximab was detected in the milk of lactating monkeys, women should not breastfeed during treatment with MabThera and for 12 months following treatment with MabThera.
Fertility
Animal studies revealed no deleterious effects of rituximab on the reproductive organs.
04.7 Effects on ability to drive and use machines
No studies on the effects of MabThera on the ability to drive and use machines have been performed, although the pharmacological activity and adverse reactions reported to date suggest that MabThera has no or negligible influence on the ability to drive or drive vehicles. to use machinery.
04.8 Undesirable effects
Experience in non-Hodgkin's lymphoma and chronic lymphocytic leukemia
Summary of the safety profile
The overall safety profile of MabThera in non-Hodgkin's lymphoma and chronic lymphocytic leukemia is based on data from patients in clinical trials and post-marketing surveillance. These patients were treated with MabThera as monotherapy (as induction treatment or as post-induction maintenance treatment) or in combination with chemotherapy.
The most frequently observed adverse drug reactions (ADRs) in patients who received MabThera were the IRRs that occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases significantly with subsequent infusions and is less than 1% after eight doses of MabThera.
Infectious events (mainly bacterial and viral) occurred in approximately 30-55% of NHL patients treated in clinical trials and approximately 30-50% of CLL patients treated in clinical trials. The most frequently reported or observed serious adverse drug reactions were:
• IRR (including cytokine release syndrome and tumor lysis syndrome), see section 4.4.
• Infections, see section 4.4.
• Cardiovascular events, see section 4.4.
Other serious ADRs reported include hepatitis B reactivation and PML (see section 4.4).
List of adverse reactions in the form of a table
The frequencies of ADRs reported with MabThera alone or in combination with chemotherapy are summarized in Table 1. Within each frequency class, undesirable effects are listed in order of decreasing severity. The frequency is defined as very common (≥ 1 / 10), common (≥ 1/100 to
ADRs identified only during post-marketing surveillance and for which a frequency cannot be estimated are listed under "not known".
Table 1 ADRs reported in clinical trials or during post-marketing surveillance in NHL and CLL patients treated with MabThera as monotherapy / maintenance or in combination with chemotherapy
The following terms have been reported as adverse events during clinical trials; however, haematological toxicity, neutropenic infection, urinary tract infection, sensory disturbance, pyrexia were reported with a similar or lower incidence in the MabThera arms compared to the control arms.
Characteristic signs and symptoms of an infusion-related reaction have been reported in more than 50% of patients in clinical studies and have been observed mainly during the first infusion, usually in the first two hours. These symptoms mainly include fever, chills and stiffness. Other symptoms include flushing, angioedema, bronchospasm, vomiting, nausea, urticaria / rash, fatigue, headache, throat irritation, rhinitis, pruritus, pain, tachycardia, hypertension, hypotension, dyspnoea, dyspepsia, asthenia and tumor lysis syndrome symptoms. Severe infusion-related reactions (such as bronchospasm, hypotension) occurred in up to 12% of cases. Additional reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary edema and acute reversible thrombocytopenia. Exacerbation of pre-existing heart conditions such as angina pectoris or congestive heart failure or severe heart disease (heart failure, myocardial infarction, atrial fibrillation), pulmonary edema, multi-organ failure, tumor lysis syndrome, cytokine release syndrome, renal failure and respiratory failure has been reported with a lower or unknown frequency. The incidence of infusion-related symptoms decreased substantially with subsequent infusions and is
Description of a selection of adverse reactions
Infections
MabThera induces B cell depletion in approximately 70-80% of patients, but this event has been associated with a decrease in serum immunoglobulin in only a minority of patients.
Localized candida infections such as herpes zoster have been reported at a higher incidence in the MabThera arm in randomized trials. Serious infections were reported in approximately 4% of patients treated with MabThera monotherapy. Higher rates of all infections, including grade 3 or 4 infections, were observed during the two-year maintenance treatment with MabThera when compared to observation. There was no cumulative toxicity in terms of infections reported in the two-year treatment period. In addition, other serious viral infections, either new, reactivated or exacerbated, have been reported during treatment with MabThera, some of which were fatal. Most patients received MabThera in combination to chemotherapy or as part of a hematopoietic stem cell transplant. Examples of these serious viral infections are infections caused by herpetic viruses (Cytomegalovirus, Varicella Zoster virus and Herpes Simplex), JC virus (progressive multifocal leukoencephalopathy (PML)) and virus. hepatitis C. Cases of fatal PML have also been reported during clinical trials to occur ti after disease progression and retreatment. Cases of hepatitis B reactivation have been reported, most of which occurred in patients who received MabThera in combination with cytotoxic chemotherapy. In patients with relapsed / refractory CLL, the incidence of grade 3/4 hepatitis B infection (reactivation and primary infection) was 2% in R-FC vs 0% in FC. Progression of Kaposi's sarcoma was observed. in MabThera-exposed patients with pre-existing Kaposi's sarcoma These cases occurred in unapproved indications and the majority of patients were HIV positive.
Haematological adverse reactions
In clinical trials using MabThera as monotherapy administered for 4 weeks, haematological abnormalities occurred in a minority of patients and were generally mild and reversible. Severe (grade 3/4) neutropenia was reported in 4.2% of patients, anemia in 1.1% and thrombocytopenia in 1.7% of patients. During the two-year maintenance treatment with MabThera, leukopenia (5% vs 2%, grade 3/4) and neutropenia (10% vs 4%, grade 3/4) were reported with a higher incidence when compared to observation. The incidence of thrombocytopenia was low (vs CHOP 79%, R-FC 23% vsHR 12%), neutropenia (R-CVP 24% vs CVP 14%; R-CHOP 97% vs CHOP 88%, R-FC 30% vs HR 19% in previously untreated CLL), pancytopenia (R-FC 3% vs CF 1% in previously untreated CLL), were generally reported with higher frequencies when compared with chemotherapy alone. However, the higher incidence of neutropenia in patients treated with MabThera and chemotherapy was not associated with a higher incidence of infections and infestations when compared to patients treated with chemotherapy alone. Previously untreated and relapsed / refractory CLL studies established that in 25% of patients treated with R-FC, neutropenia was prolonged (defined as neutrophil granulocyte count less than 1x109 / l between day 24 and day 42 after the last dose) or occurred with a late onset (defined as neutrophil granulocyte count less than 1x109 / l beyond day 42 after the last dose in patients who did not have previous prolonged neutropenia or who recovered before day 42) after treatment with MabThera and CF.
No differences in the incidence of anemia have been reported. A few cases of late neutropenia have been reported that occurred more than four weeks after the last infusion of MabThera. In the first-line CLL study, Binet stage C patients experienced more adverse events in the R-FC arm than in the FC arm (R-FC 83% vs HR 71%). In the relapsed / refractory CLL study, grade 3/4 thrombocytopenia was reported in 11% of patients in the RFC group versus 9% of patients in the CF group.
In studies with MabThera in patients with Waldestrom's macroglobulinemia, transient increases in serum IgM levels have been observed after initiation of treatment, which may be associated with hyperviscosity and related symptoms. Transient increases in IgM generally return to at least the level. baseline within 4 months.
Cardiovascular adverse reactions
In clinical trials with MabThera alone, cardiovascular reactions were reported in 18.8% of patients with hypotension and hypertension as the most frequently reported events. Cases of grade 3 or 4 arrhythmias (including ventricular and supraventricular tachycardia) and angina pectoris have been reported during infusion. During maintenance treatment, the incidence of grade 3/4 cardiac disorders was comparable among treated patients. with MabThera and observation. Cardiac events were reported as serious adverse events (including atrial fibrillation, myocardial infarction, left ventricular failure, myocardial ischaemia) in 3% of patients treated with MabThera compared to Grade 3 and 4 cardiac arrhythmias, especially supraventricular arrhythmias such as tachycardia and atrial flutter / fibrillation, was higher in the RCHOP group (14 patients, 6.9%) when compared to the CHOP group (3 patients, 1.5%) . All of these arrhythmias occurred in the context of the MabThera infusion or were associated with predisposing conditions such as fever, infection, acute myocardial infarction or pre-existing respiratory and cardiovascular disease. No difference was observed between the R-CHOP and CHOP group in terms of incidence of other Grade 3 and 4 cardiac events, including heart failure, myocardial disease, and manifestations of coronary artery disease. In CLL, the overall incidence of grade 3 or 4 cardiac disorders was low in both the first-line study (4% R-FC, 3% FC) and the relapse / refractory study (4% R-FC, 4 % FC).
Respiratory system
Cases of interstitial lung disease, some with fatal outcome, have been reported.
Neurological pathologies
During the treatment period (phase of induction therapy consisting of R-CHOP for up to eight cycles) four patients (2%) treated with R-CHOP, all with cardiovascular risk factors, experienced cerebrovascular thromboembolic accidents during the first cycle of treatment. There was no difference between the treatment groups in terms of the incidence of other thromboembolic events. In contrast, three patients (1.5%) had cerebrovascular events in the CHOP group, all of which occurred during the follow-up period. -up. In CLL, the overall incidence of grade 3 or 4 nervous system disorders was low in both the first-line study (4% R-FC, 4% FC) and the relapse / refractory study (3% R-FC, 3% FC).
Cases of posterior reversible encephalopathy syndrome (PRES) / posterior reversible leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbances, headache, seizures and changes in mental status, with or without associated hypertension. A diagnosis of PRES / RPLS requires confirmation with imaging cerebral. The reported cases have recognized risk factors for PRES / RPLS, including the patient's concomitant disease status, hypertension, immunosuppressive therapy, and / or chemotherapy.
Gastrointestinal disorders
Gastrointestinal perforation has been observed leading in some cases to death in patients receiving MabThera for the treatment of non-Hodgkin's lymphoma. In most of these cases, MabThera was administered with chemotherapy.
IgG levels
In the clinical study evaluating MabThera in maintenance treatment in relapsed / refractory follicular lymphoma, median IgG levels were below the lower limit of normal (LLN) (
A small number of spontaneous and literature cases related to hypogammaglobulinemia, in some cases severe and requiring long-term immunoglobulin replacement therapy, have been observed in pediatric patients treated with MabThera. The consequences of long-term B cell depletion in pediatric patients are unknown.
Skin and subcutaneous tissue disorders
Cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Patient subpopulations - MabThera monotherapy
Elderly patients (≥ 65 years old):
The incidence of all grade and grade 3/4 ADRs was similar in elderly versus younger patients (
Bulky disease
There was a "higher incidence of grade 3/4 ADRs in patients with bulky disease than in patients without bulky disease (25.6% vs 15.4%). The incidence of all grade ADRs was similar in these two groups.
Retreatment
The proportion of patients reporting ADRs during retreatment with further courses of MabThera was similar to the proportion of patients reporting ADRs during initial exposure (all grade and grade 3/4 ADRs).
Patient Subpopulations - Combination Therapy with MabThera
Elderly patients (≥ 65 years old)
The incidence of grade 3/4 adverse events in the blood and lymphatic system was higher in elderly patients compared to younger patients (
Experience in rheumatoid arthritis
Summary of the safety profile
The overall safety profile of MabThera in rheumatoid arthritis is based on data from patients treated in clinical trials and from post-marketing surveillance.
The safety profile of MabThera in patients with moderate to severe rheumatoid arthritis is summarized in the sections below. In clinical studies, more than 3,100 patients received at least one course of treatment and were followed for a period ranging from 6 months to more than 5 years; approximately 2400 patients received two or more courses of treatment with over 1000 patients undergoing 5 or more courses. The safety information gathered from post marketing experience reflects the expected adverse reaction profile already observed in clinical studies for MabThera (see section 4.4).
Patients received 2 1000 mg doses of MabThera separated by a two week interval, in combination with methotrexate (10-25 mg / week). MabThera infusions were administered following an intravenous infusion of 100 mg of methylprednisolone; patients also received oral prednisone treatment for 15 days.
List of adverse reactions in the form of a table
Adverse reactions are listed in table 2. Frequency is defined as very common (≥ 1/10), common (≥1 / 100 to
The most frequent adverse reactions believed to be due to taking MabThera were IRRs. The total incidence of IRRs in clinical trials was 23% with the first infusion and decreased with subsequent infusions. Serious IRRs were uncommon (0.5% of patients) and predominantly occurred during the initial cycle. In addition to the adverse reactions observed in rheumatoid arthritis clinical studies conducted with MabThera, progressive multifocal leukoencephalopathy (PML) and serum sickness-like reaction have been reported during post-marketing experience.
Table 2 Summary of adverse drug reactions reported in clinical trials or during post-marketing surveillance that occurred in patients with rheumatoid arthritis who received MabThera.
Repeated cycles
Repeated courses of treatment are associated with a similar adverse reaction profile to that observed following first exposure. The rate of all adverse reactions following the first exposure to MabThera was highest during the first 6 months and decreased thereafter. This was mainly the case for IRRs (most frequently during first treatment), exacerbation of rheumatoid arthritis and infections; all of these were more frequent in the first 6 months of treatment.
Infusion related reactions
In clinical trials, the most frequent adverse drug reactions (ADRs) after treatment with MabThera were IRRs (see Table 2). Among 3189 patients treated with MabThera, 1135 (36%) had at least one IRR with 733/3189 (23%) of patients experiencing an IRR following the first infusion of the first MabThera treatment. The incidence of IRRs decreases with subsequent infusions. Less than 1% (17/3189) of patients experienced a severe IRR in clinical trials. There were no Common Toxicity Criteria (CTC) grade 4 IRRs and no deaths due to IRRs in clinical trials. The proportion of CTC grade 3 events and IRRs leading to treatment discontinuation decreased over the course of treatments and were rare from cycle 3 onwards. Intravenous glucocorticoid premedication significantly reduced the incidence and severity of IRRs (see sections 4.2 and 4.4). Serious cases of IRR with fatal outcome have been reported in the post-marketing setting.
In a study designed to evaluate the safety of a "faster infusion of MabThera in patients with rheumatoid arthritis, patients with moderate to severe active rheumatoid arthritis who did not experience a severe IRR during or within 24 hours after the first infusion studied, was allowed to undergo a 2-hour intravenous infusion of MabThera. Patients with a history of severe infusion reaction to a biological therapy for rheumatoid arthritis were not admitted to the study. The incidence, types and severity of IRRs were consistent with historical data. No serious IRRs were observed.
Description of a selection of adverse reactions
Infections
The overall incidence of infections was approximately 94 per 100 patient-years in the MabThera group. Infections were predominantly mild to moderate and included mainly upper respiratory tract and urinary tract infections. they required IV antibiotics it was about 4 out of 100 patient-years. The incidence of serious infections showed no significant increase following repeated courses with MabThera. Lower respiratory tract infections (including pneumonia) were reported in clinical trials, with similar incidence in the MabThera groups compared to the MabThera groups. Control Cases of progressive multifocal leukoencephalopathy with fatal outcome have been reported following the use of MabThera for the treatment of autoimmune diseases. These include rheumatoid arthritis and out of indication autoimmune conditions such as systemic lupus erythematosus (SLE) and vasculitis. Reactivation of hepatitis B has been reported in patients with non-Hodgkin's lymphoma who received MabThera in combination with cytotoxic chemotherapy. (See non-Hodgkin's lymphoma.) Reactivations of hepatitis B infection have also been reported very rarely in RA patients who received MabThera (see section 4.4).
Cardiovascular adverse reactions
Serious cardiac reactions were observed at an "incidence of 1.3 per 100 patient-years among those treated with MabThera and 1.3 per 100 patient-years in patients treated with placebo. The proportion of patients with cardiac reactions (all or severe ) did not increase in the various cycles.
Neurological events
Cases of posterior reversible encephalopathic syndrome (PRES) / posterior reversible leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbances, headaches, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES / RPLS requires confirmation through brain imaging. The cases described had known risk factors for PRES / RPLS, including the patients' underlying disease, hypertension, immunosuppressive therapy, and / or chemotherapy.
Neutropenia
Cases of neutropenia have been observed following treatment with MabThera, most of which were transient and mild or moderate in intensity. Neutropenia can occur several months after administration of MabThera (see section 4.4).
In placebo-controlled clinical trials, 0.94% (13/382) of patients treated with MabThera and 0.27% (2/731) of patients treated with placebo developed severe neutropenia.
Neutropenic events, including severe and persistent late-onset neutropenia, some of which have been associated with fatal infections, have been reported rarely in post-marketing experience.
Skin and subcutaneous tissue disorders
Cases of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Laboratory anomalies
Hypogammaglobulinemia (IgG or IgM below the lower limit of normal) has been observed in patients with rheumatoid arthritis treated with MabThera. There was no increase in the rate of general or severe infections following low IgG or IgM levels (see section 4.4).
A small number of spontaneous and literature cases related to hypogammaglobulinemia, in some cases severe and requiring long-term immunoglobulin replacement therapy, have been observed in pediatric patients treated with MabThera. The consequences of long-term B cell depletion in pediatric patients are unknown.
Experience in granulomatosis with polyangiitis and microscopic polyangiitis
In a clinical study in granulomatosis with polyangiitis and microscopic polyangiitis, 99 patients were treated with MabThera (375 mg / m2, once weekly for 4 weeks) and glucocorticoids (see section 5.1).
List of adverse reactions in the form of a table
The ADRs listed in Table 3 represent all adverse events that occurred with an incidence ≥ 5% in the MabThera group.
Table 3. Adverse drug reactions occurring in ≥ 5% of patients who received MabThera and at a higher frequency than the comparator group in the 6-month pivotal clinical study.
Selection of adverse drug reactions
Infusion related reactions
IRRs in clinical studies referring to granulomatosis with polyangiitis and microscopic polyangiitis were defined as any adverse event occurring within 24 hours of infusion and considered infusion related by the investigator in the safety population. 99 patients were treated with MabThera and 12% experienced at least one IRR. All IRRs were grade 1 or 2 according to CTC. The most common IRR included cytokine release syndrome, hot flashes, throat irritation and tremor. MabThera was given in combination with intravenous glucocorticoids which may reduce the incidence and severity of these events.
Infections
In the 99 patients treated with MabThera, the overall rate of infections was approximately 237 per 100 patient-years (95% CI 197-285) at the 6-month primary endpoint. Infections were predominantly mild to moderate and consisted mainly of infections. respiratory tract, herpes zoster and urinary tract infections. The rate of serious infections was approximately 25 per 100 patient-years. The most frequently reported serious infection in the MabThera group was pneumonia with a frequency of 4%.
Neoplasms
The incidence of malignancies in patients treated with MabThera in clinical studies referring to granulomatosis with polyangiitis and microscopic polyangiitis was 2.00 per 100 patient-years at the joint study end date (when the last patient completed the follow-up period). -up). Based on the standardized incidence ratio, the incidence of malignancies appears to be similar to that previously reported in patients with ANCA associated vasculitis.
Cardiovascular adverse reactions
Cardiac events occurred with a rate of approximately 273 per 100 patient-years (95% CI 149-470) at the 6-month primary endpoint. The serious cardiac event rate was 2.2 per 100 patient-years (95 % CI 3-15) The most frequently reported adverse event was tachycardia (4%) and atrial fibrillation (3%) (see section 4.4).
Neurological events
Cases of posterior reversible encephalopathic syndrome (PRES) / posterior reversible leukoencephalopathy syndrome (RPLS) have been reported. Signs and symptoms included visual disturbances, headaches, seizures and altered mental status, with or without associated hypertension. A diagnosis of PRES / RPLS requires confirmation through brain imaging. The cases described had known risk factors for PRES / RPLS, including the patients' underlying disease, hypertension, immunosuppressive therapy, and / or chemotherapy.
Reactivation of hepatitis B
A small number of cases of hepatitis B reactivation, some with fatal outcome, have been reported in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with MabThera in the post-marketing setting.
Hypogammaglobulinemia
Hypogammaglobulinemia (IgA, IgG or IgM below the lower limit of normal) has been observed in patients with granulomatosis with polyangiitis and microscopic polyangiitis treated with MabThera. In the 6-month, multi-center, randomized, double-blind, active-controlled non-inferiority study in the MabThera group, 27%, 58%, and 51% of patients with normal baseline immunoglobulin levels had low levels of IgA, IgG and IgM, respectively, compared to 25%, 50% and 46% of the cyclophosphamide group. An increased rate of overall infections or serious infections was not observed in patients with low levels of IgA, IgG or IgM.
Neutropenia
In the multi-center, randomized, double-blind, active-controlled non-inferiority study of MabThera for granulomatosis with polyangiitis and microscopic polyangiitis, 24% of patients in the MabThera group (single cycle) and 23% of patients in the cyclophosphamide group have developed CTC grade 3 or higher neutropenia. Neutropenia was not associated with an observed increase in serious infections in patients treated with MabThera. The effect of multiple courses of MabThera in the development of neutropenia in patients with granulomatosis with polyangiitis and microscopic polyangiitis has not been studied in clinical studies.
Disorders of the skin and subcutaneous tissue:
Episodes of toxic epidermal necrolysis (Lyell's syndrome) and Stevens-Johnson syndrome, some with fatal outcome, have been reported very rarely.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
04.9 Overdose
There is limited experience from human clinical trials with doses higher than that approved for the intravenous formulation of MabThera. The highest intravenous dose of MabThera tested in humans to date is 5000 mg (2250 mg / m2), tested. in a dose escalation study in patients with chronic lymphocytic leukemia. No further safety signs were identified.
Patients who experience overdose should immediately stop the infusion and be closely monitored.
Five cases of MabThera overdose have been reported post marketing. Three of these cases reported no adverse events. The two adverse events that were reported were flu-like symptoms with a 1.8 g dose of rituximab and fatal respiratory failure with a 2 g dose of rituximab.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, monoclonal antibodies, ATC code: L01X C02.
Rituximab binds specifically to CD20 transmembrane antigen, a non-glycosylated phosphoprotein, found on pre-B lymphocytes and mature B lymphocytes. The antigen is expressed on more than 95% of all non-Hodgkin cell lymphomas B (NHLs).
CD20 is found in normal and neoplastic B cells, but not on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues. The antigen is not internalized after antibody binding and is not disseminated from the cell surface. CD20 does not circulate in the blood as a free antigen and therefore does not compete with antibody binding. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes. and the Fc domain can activate the effector functions of the immune system with the aim of causing lysis of B cells.Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) through C1q binding and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more Fcγ receptors on the surface of granulocytes, macrophages and NK cells. The binding of rituximab to the CD20 antigen on B lymphocytes has also been shown to induce cell death by apoptosis.
Peripheral B cell counts fell below normal following the administration of the first dose of MabThera. In patients treated for haematological cancers, B cell recovery is initiated within 6 months of treatment and generally returns to normal levels within 12 months after completion of therapy, although recovery may be longer in some patients (with a median of recovery of 23 months after induction therapy). In patients with rheumatoid arthritis, immediate depletion of peripheral blood B cells was observed following two infusions of 1000 mg each of MabThera, separated by an interval of 14 days. Peripheral B cell counts begin to increase from week 24 and signs of recovery are seen in most patients from week 40, both when MabThera is given as monotherapy and when given in combination with methotrexate. A small percentage of patients experienced prolonged peripheral B cell depletion for 2 years or more after the last dose of MabThera. In patients with granulomatosis with polyangiitis or microscopic polyangiitis, the number of peripheral blood B cells decreased to 2 , and remained at this level in most patients until time point 6 months. Most patients (81%) showed signs of B cell reconstitution with counts> 10 cells / μl within 12 months, reaching 87% of patients by month 18.
Clinical experience in non-Hodgkin's lymphoma and chronic lymphocytic leukemia
Follicular lymphoma
Monotherapy
Initial treatment, weekly for 4 doses
In the pivotal study, 166 patients with relapsed or chemoresistant low-grade or follicular B-cell NHL received 375 mg / m2 of MabThera as an intravenous infusion once weekly for four weeks. The percentage of overall responses (ORR) in the population assessed according to the "intent to treat analysis (ITT) was 48% (95% CI 41% - 56%) with 6% complete responses (CR) and 42% partial responses (PR). The median time to progression (TTP) projection for responding patients was 13.0 months. In a subgroup analysis, the ORR was higher in patients with IWF histological subtypes B, C and D compared to those with IWF histological subtype A (58% vs 12%), in patients with greater lesion diameter 7 cm (53% vs 38%) and in patients with chemosensitive relapse versus those with chemoresistant relapse (defined as duration of response
The ORR in patients previously treated with autologous bone marrow transplant (ABMT) was 78% versus 43% in patients not previously treated with ABMT. Age, gender, degree of lymphoma, initial diagnosis, presence or absence of bulky disease , Normal or elevated LDH, presence of extranodal disease did not have a statistically significant effect (Fisher's exact test) on response to MabThera. A statistically significant correlation was identified between response rate and bone marrow involvement. 40% of patients with bone marrow involvement responded versus 59% of patients without bone marrow involvement (p = 0.0186). This finding was not supported by the so-called "stepwise logistic regression" analysis in which the following factors were identified as prognostic factors: histological type, baseline bcl-2 positivity, resistance to last chemotherapy and bulky disease.
Initial treatment, weekly for 8 doses
In a multicenter, single-arm study, 37 patients with relapsed or chemoresistant, low-grade or follicular B-cell NHL received MabThera 375 mg / m2 as a weekly intravenous infusion for eight doses. The ORR was 57% (95% Confidence Interval (CI): 41% - 73%; CR 14%, PR 43%) with a median TTP projection for responders of 19.4 months ( range 5.3 to 38.9 months).
Initial treatment, bulky disease, weekly for 4 doses
In a data pool from 3 studies, 39 patients with relapsed or chemoresistant NHL, bulky disease (single lesion ≥ 10 cm in diameter), low grade or follicular B-cell disease, received MabThera 375 mg / m2 as a weekly intravenous infusion for four doses. The ORR was 36% (95% CI 21% - 51%; CR 3%, PR 33%) with a median TTP for responsive patients of 9.6 months (range 4.5 - 26.8 months) .
Retreatment, weekly for 4 doses
In a multicenter, single-arm study, 58 patients with relapsed or chemoresistant low-grade or follicular B-cell NHL who had achieved an objective clinical response to a previous course of treatment with MabThera were retreated with 375 mg / m2 of MabThera as a weekly intravenous infusion for four doses. Three of these patients had received two courses of MabThera prior to enrollment and thus received a third course in the study. Two patients were retreated twice in the study. For the 60 retreatments in the study, the ORR was 38% (95% CI 26% - 51%; 10% CR, 28% PR) with a median TTP projection for responsive patients of 17.8 months (range 5 , 4-26.6). This data is better than the TTP obtained after the first course of MabThera (12.4 months).
Initial treatment, in combination with chemotherapy
In a randomized open-label clinical trial, a total of 322 previously untreated patients with follicular lymphoma were randomized to either CVP chemotherapy (cyclophosphamide 750 mg / m2, vincristine 1.4 mg / m2 up to a maximum of 2 mg on day 1, and prednisolone 40 mg / m2 / day on days 1-5) every 3 weeks for 8 cycles or MabThera 375 mg / m2 in combination with CVP (R-CVP). MabThera was administered on the first day of each treatment cycle. Total 321 patients (162 R-CVP, 159 CVP) received therapy and were analyzed for efficacy. The median follow-up of the patients was 53 months. R-CVP resulted in a significant benefit over CVP for the primary endpoint, i.e. time to treatment failure (27 months versus 6.6 months, p
The difference between treatment groups in overall survival showed a significant clinical difference (p = 0.029, log-rank test stratified by center): the 53-month survival rate was 80.9% for patients in the R- group. CVP compared to 71.1% for patients in the CVP group.
Results from three other randomized trials using MabThera in combination with non-CVP chemotherapy regimens (CHOP, MCP, CHVP / Interferon-α) also demonstrated significant improvements in response rates, time-dependent parameters and overall survival. . The most important results from all four studies are summarized in Table 4.
Table 4 Summary of key findings from the four randomized phase III trials evaluating the benefit of MabThera with different chemotherapy regimens in follicular lymphoma.
EFS - Event Free Survival
TTP - Time to progression or death
PFS - Progression Free Survival
TTF - Time to treatment failure
OS percentages - survival rates at the time of the analysis
Maintenance therapy
Previously untreated follicular lymphoma
In a prospective, open-label, international, multicenter, phase III study 1193 patients with previously untreated advanced follicular lymphoma received induction therapy with R-CHOP (n = 881), R-CVP (n = 268) or R- FCM (n = 44), based on investigator choice. A total of 1078 patients responded to induction therapy, of which 1018 were randomized to MabThera maintenance (n = 505) or observation (n = 513). The two treatment groups were well balanced with respect to baseline characteristics and disease status. Maintenance treatment with MabThera consisted of a single infusion of MabThera administered at a dose of 375 mg / m2 body surface area every 2 months until disease progression or for up to 2 years.
After a median observation time of 25 months from randomization, maintenance therapy with MabThera produced a clinically relevant and statistically significant improvement in the investigator-assessed primary endpoint of progression-free survival (PFS) when compared to observation in patients. with previously untreated follicular lymphoma (table 5).
Significant benefit from MabThera maintenance treatment was also observed for the secondary endpoints event-free survival (EFS), time to next anti-lymphoma treatment (TNLT), time to next chemotherapy (TNCT) and overall response rate ( ORR) (table 5). The results of the primary analysis were confirmed with a longer follow-up (median observation time: 48 months and 73 months) and the updated results were added to Table 5 to illustrate the comparison between the follow-up period of 25, 48 and 73 months.
Table 5 Maintenance Phase: Summary of Efficacy Results of MabThera vs. observation after 73 months of median observation time (compared with the results of the primary analysis based on the median observation time of 25 months and the updated analysis based on the median observation time of 48 months)
* At the end of maintenance / observation; # p-values from chi-square test.
The main values correspond to the median observation time of 73 months, the values in italics in brackets correspond to 48 months of median observation time, and the values in brackets correspond to the median observation time of 25 months (primary analysis).
PFS: progression-free survival; EFS: event-free survival; OS: overall survival; TNLT: time to the next anti-lymphoma treatment; TNCT: time to next chemotherapy treatment; ORR: overall response rate: NR: not reachable at the time of cut-off clinical; OR: odds ratio.
Maintenance therapy with MabThera provided consistent benefit in all subgroups tested: gender (male, female), age (= 60 years), FLIPI score (= 3), induction therapy (R-CHOP, R-CVP or R-FCM) and regardless of the quality of response to induction therapy (CR, CRu or PR). Exploratory analyzes of the benefit of maintenance treatment showed a less pronounced effect in elderly patients (> 70 years of age), however the sample size was small.
Relapsed / refractory follicular lymphoma
In a prospective, open-label, international, multicenter, phase III study, 465 patients with relapsed / resistant follicular lymphoma were randomized in a first phase to induction therapy with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone; n = 231) o MabThera plus CHOP (R-CHOP, n = 234). The two treatment groups were well balanced with respect to baseline characteristics and disease status. A total of 334 patients who achieved complete or partial remission after induction therapy were randomized to a second phase to MabThera maintenance therapy (n = 167) or observation (n = 167). Maintenance treatment with MabThera consisted of a single infusion of MabThera at 375 mg / m2 body surface area administered every 3 months until disease progression or for up to two years.
The final efficacy analysis included all patients randomized in both parts of the study. After a median observation time of 31 months for patients randomized in the induction phase, R-CHOP significantly improved the prognosis of patients with lymphoma. follicular relapsed / resistant when compared with CHOP (see table 6).
Table 6 Induction phase: list of efficacy results of CHOP compared with R-CHOP (median observation time 31 months).
1) The estimate was calculated with the relative risk.
2) Latest tumor response as assessed by the investigator. The "primary" statistical test for "response" was the trend test of CR versus PR versus non-response (p
Abbreviations: NA, not available; ORR: percentage of global responses; CR: complete answer; PR: partial response.
For patients randomized to the maintenance phase of the study, the median observation time was 28 months from randomization to maintenance. Maintenance treatment with MabThera resulted in a clinically relevant and statistically significant improvement in the primary endpoint, PFS (time from randomization for maintenance to relapse, disease progression or death), when compared with observation alone ( p
Table 7 Maintenance phase: list of MabThera efficacy results with respect to observation (28 months of median observation time).
NR: not reached; a: Applicable only to patients who achieve CR.
The benefit of MabThera maintenance treatment was confirmed in all subgroups analyzed regardless of induction regimen (CHOP or R-CHOP) or quality of response to induction treatment (CR or PR) (table 7). Maintenance treatment with MabThera significantly prolonged the median of PFS in patients who responded to induction therapy with CHOP (median of PFS 37.5 months versus 11.6 months, p
Diffuse large B-cell non-Hodgkin's lymphoma
In a randomized, open-label study, a total of 399 previously untreated elderly patients (aged 60 to 80 years) with diffuse large B-cell lymphoma received standard courses of CHOP chemotherapy (cyclophosphamide 750 mg / m2, doxorubicin 50 mg / m2, vincristine 1.4 mg / m2 to a maximum of 2 mg given on day 1, and prednisolone 40 mg / m2 / day given on days 1-5) every 3 weeks for eight cycles, or MabThera 375 mg / m2 in association with CHOP (R-CHOP).
MabThera was administered on the first day of the treatment cycle.
The final analysis of the efficacy data included all randomized patients (197 CHOP, 202 R-CHOP) and presented a median follow-up duration of approximately 31 months. The two treatment groups were well balanced with respect to disease characteristics and status at baseline. The final analysis confirmed that R-CHOP treatment was associated with a clinically relevant and statistically significant improvement in the duration of event-free survival (the primary efficacy parameter; events were death, relapse or progression of lymphoma, or switch to a new anti-lymphoma treatment) (p = 0.0001). The Kaplan-Meier estimate of the median duration of event-free survival was 35 months in the R-CHOP arm versus 13 months in the CHOP arm, representing a risk reduction of 41%. At 24 months, the overall survival estimate was 68.2% in the R-CHOP arm versus 57.4% in the CHOP arm. A subsequent analysis of overall survival duration, performed at a median follow-up duration of 60 months, confirmed the benefit of R-CHOP treatment over CHOP (p = 0.0071), representing a 32% risk reduction. .
The analysis of all secondary parameters (rate of response, progression-free survival, disease-free survival, duration of response) verified the efficacy of the R-CHOP treatment compared to CHOP. The complete response rate after 8 cycles was 76.2% in the R-CHOP group and 62.4% in the CHOP group (p = 0.0028). The risk of disease progression was reduced by 46% and the risk of relapse by 51%.
In all patient subgroups (gender, age, age-adjusted IPI, Ann Arbor stage, ECOG, β2-microglobulin, LDH, albumin, B symptoms, bulky disease, extranodal sites, bone marrow involvement), the hazard ratios event-free survival and overall survival (RCHOP compared to CHOP) were less than 0.83 and 0.95 respectively. R-CHOP was associated with improved prognosis in both high- and low-risk patients according to age-adjusted IPI.
Clinical laboratory data
No responses were observed from the 67 patients who underwent the human antibody to mouse test (HAMA). Of the 356 patients who underwent the HACA test, 1.1% (4 patients) they tested positive.
Chronic lymphocytic leukemia
In two randomized open-label studies, a total of 817 patients with previously untreated CLL and 552 patients with relapsed / refractory CLL were randomized to receive CF chemotherapy (fludarabine 25 mg / m2, cyclophosphamide 250 mg / m2, days 1- 3) every 4 weeks for 6 cycles or MabThera in combination with FC (R-FC). MabThera was administered at a dose of 375 mg / m2 during the first cycle, one day before chemotherapy, and at a dose of 500 mg / m2 on day 1 of each subsequent treatment cycle. Patients were excluded from the relapsed / refractory CLL study if they had previously been treated with monoclonal antibodies or were refractory (defined as failure to achieve partial remission for at least 6 months) to fludarabine or any nucleoside analogue. A total of 810 patients (403 R-FC, 407 FC) for the first-line study (Table 8a and Table 8b) and 552 patients (276 R-FC, 276 FC) for the relapsed / refractory study (Table 9) , were analyzed for efficacy.
In the first-line study, after a median observation time of 48.1 months, the median of PFS was 55 months in the R-FC group and 33 months in the FC group (p
Overall survival analysis demonstrated a significant benefit of RFC treatment over CF chemotherapy alone (p = 0.0319, log-rank test) (table 8a). PFS benefit was consistently observed in most patient subgroups analyzed according to baseline disease risk (specifically Binet AC stages) (table 8b).
Table 8a First-line treatment of chronic lymphocytic leukemia Description of efficacy results of MabThera plus CF vs. HR alone - 48.1 months median observation time.
Percentage of responses and percent of CR analyzed according to the chi-square test. NR: not reached; n.a .: not
applicable.
*: Applicable only to patients who obtain a CR, nPR, PR.
**: Applicable only to patients who achieve CR.
Table 8b First-line treatment of chronic lymphocytic leukemia Hazard ratio of progression-free survival according to Binet stage (ITT) - 48.1 months median observation time
CI: Confidence Interval.
In the relapse / refractory study, the median progression-free survival (primary endpoint) was 30.6 months in the R-FC group and 20.6 months in the FC group (p = 0.0002, log-rank test).
The PFS benefit was observed in almost all patient subgroups analyzed by baseline disease risk. A slight but not significant improvement in overall survival was reported in the R-FC arm compared with the FC arm.
Table 9 Treatment of relapsed / refractory chronic lymphocytic leukemia - description of efficacy results of MabThera plus HR vs HR alone (median 25.3 months of observation time).
Percentage of responses and percent of CR analyzed according to the chi-square test.
*: applicable only to patients who obtain a CR, nPR, PR; NR = not reached; n.a. = not applicable.
**: Applicable only to patients who achieve CR.
Also the results of other supportive studies using MabThera in combination with other chemotherapy regimens (including CHOP, FCM, PC, PCM, bendamustine and cladribine) for the treatment of previously untreated and / or relapsed patients with CLL / refractory, showed a "high percentage of global responses with benefits in percentage terms of PFS, although with a slightly higher toxicity (especially myelotoxicity). These studies support the use of MabThera with any chemotherapy.
Data from approximately 180 patients pre-treated with MabThera demonstrated clinical benefit (including CR) and supports retreatment with MabThera.
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the pediatric population in follicular lymphoma and chronic lymphocytic leukemia. See section 4.2 for information on pediatric use.
Clinical experience in rheumatoid arthritis
The efficacy and safety of MabThera in relieving the symptoms and signs of rheumatoid arthritis in patients with inadequate response to TNF inhibitors were demonstrated in a pivotal, randomized, controlled, double-blind, multicenter study (Study 1).
Study 1 evaluated 517 patients with inadequate response or intolerance to one or more TNF inhibitor drugs. Eligible patients had "active rheumatoid arthritis, diagnosed according to American College of Rheumatology (ACR) criteria." MabThera was administered as 2 i.v. infusions. separated by an interval of 15 days. Patients received 2 x 1000 mg intravenous infusions of MabThera or placebo in combination with MTX. All patients received concomitantly 60 mg of prednisolone orally on days 2-7 and 30 mg on days 8 to 14 after the first infusion. The primary endpoint was the proportion of patients achieving an ACR20 response at week 24. Patients were followed up beyond 24 weeks for long-term goals, which included radiographic assessment at 56 weeks and 104 weeks. During this period, the "81% of patients from the original placebo group received MabThera between weeks 24 and 56, as part of an" open-label "protocol extension study.
Studies with MabThera in patients with stage arthritis early (patients not previously treated with methotrexate and patients with inadequate response to methotrexate but not yet treated with TNF-alpha inhibitors) met their primary endpoints. MabThera is not indicated for these patients as safety data on long-term treatment with MabThera are insufficient, particularly with regard to the risk of developing cancer or PML.
Results of disease activity
MabThera in combination with methotrexate significantly increased the proportion of patients achieving at least 20% improvement in ACR response compared to patients treated with methotrexate alone (table 10). In all pivotal studies, treatment benefit was similar in patients regardless of age, gender, body surface area, race, number of previous treatments or disease status.
Clinically and statistically significant improvements were also observed in all individual components of the ACR response (painful and swollen joint counts, overall patient and physician assessment, disability index (HAQ), pain assessment and C reactive protein (mg / dl)).
Table 10 Clinical response results at study 1 primary endpoint (ITT population).
† Result at 24 weeks.
Significant difference from placebo + MTX al time point primary: *** p ≤ 0.0001.
Patients treated with MabThera in combination with methotrexate had a significantly greater reduction in DAS28 (Disease Activity Score) compared to patients treated with methotrexate alone (table 9). Similarly, in all studies an EULAR response (European League Against Rheumatism) good to moderate was achieved by significantly more patients treated with MabThera and methotrexate than patients treated with methotrexate alone (Table 10).
Radiological response
Structural joint damage was radiologically ascertained and expressed as change in modified total sharp score (mTSS) and its components, erosion score and joint gap narrowing score.
In Study 1, performed in subjects with inadequate response or intolerance to therapies with one or more TNF antagonists who received MabThera in combination with methotrexate, patients had significantly less radiographic progression at week 56 than those who originally had received methotrexate alone. Of the patients originally treated with methotrexate alone, 81% received MabThera as rescue therapy between weeks 16 and 24, or as an extension of the study, before week 56. In addition, a higher proportion of patients who received the "original treatment with MabThera / MTX showed no progression of erosive lesions over 56 weeks (table 11).
Table 11 Radiological results after 1 year (mITT population)
150 patients originally randomized in Study 1 for placebo + MTX received at least one course of RTX + MTX
in a year.
* p
Inhibition of the rate of joint damage progression was also observed over the long term. 2-year radiographic analysis in Study 1 demonstrated a significant reduction in progression of structural joint damage in patients who received MabThera in combination with methotrexate compared to to those on methotrexate alone and a significantly higher percentage of patients with no progression of joint damage beyond 2 years.
Physical function and quality of life results
Significant reductions in disability index (HAQ-DI) and asthenia (FACIT-Fatigue) were observed in patients treated with MabThera compared to patients treated with methotrexate alone. The proportion of patients treated with MabThera who showed a clinically important minimal difference (MCID) in HAQ-DI (defined as a reduction in individual total score> 0.22) was also greater than that seen in patients who received methotrexate alone. (table 12).
A significant improvement in health in terms of quality of life has been demonstrated with a significant improvement in both the physical health score (PHS) and the mental health score (MHS) of the SF-36. In addition, a significantly higher percentage of patients achieved MCID for these scores (Table 12).
Table 12 Physical function and quality of life outcomes at week 24 in Study 1.
† Results at week 24.
Significant difference from placebo to time point primary: * p
MCID HAQ-DI ≥0.22, MCID SF-36 PHS> 5.42, MCID SF-36 MHS> 6.33.
Efficacy in seropositive patients with autoantibodies (RF and or anti-CCP)
Rheumatoid Factor (RF) and / or Cyclic Peptide Citrullinate (anti-CCP) seropositive patients who were treated with MabThera in combination with methotrexate showed a better response than patients negative to both.
Efficacy results in patients treated with MabThera were analyzed based on autoantibody status prior to initiation of treatment. At week 24, patients who were seropositive to RF and / or anti-CCPs at baseline had a significantly greater to achieve ACR20 and 50 responses than in seronegative patients (p = 0.0312 and p = 0.0096) (table 13). These results were replicated at week 48, where autoantibody seropositivity significantly increased the likelihood of achieving ACR70. At week 48, seropositive patients are 2-3 times more likely to achieve an ACR response than seronegative patients. seropositive also had a significantly greater reduction in DAS28-ESR than seronegative patients.
Table 13 Summary of efficacy based on autoantibody status at baseline.
Significant levels were defined as * p
Long-term efficacy with repeated courses of therapy
Treatment with MabThera in combination with methotrexate for multiple cycles resulted in dramatic improvements in clinical signs and symptoms of rheumatoid arthritis, as indicated by ACR, DAS28-VES, and EULAR responses that were evident in all populations studied. They were observed. Substantial improvements in physical function as indicated by the HAQ-DI score and the percentage of patients who achieved MCID for HAQ-DI.
Results from the clinical laboratory
In clinical studies, a total of 392 of 3095 (12.7%) patients with rheumatoid arthritis tested positive for HACA following treatment with MabThera. In most patients, the onset of HACA was not associated with clinical worsening or an increased risk of reactions to subsequent infusions. The presence of HACA may be associated with worsening of infusional or allergic reactions after the second infusion of subsequent courses. .
Pediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MabThera in all subsets of the pediatric population in autoimmune arthritis. See section 4.2 for information on pediatric use.
Clinical experience in granulomatosis with polyangiitis (Wegener's) and in microscopic polyangiitis A total of 197 patients aged 15 years and older with active and severe polyangiitis with polyangiitis (75%) and microscopic polyangiitis (24%) were enrolled. and treated in the multicentre, randomized, double-blind, active comparison non-inferiority study.
Patients were randomized in a 1: 1 ratio to receive either oral cyclophosphamide daily (2 mg / kg / day) for 3-6 months or MabThera (375 mg / m2) once weekly for 4 weeks. All patients in the cyclophosphamide arm received azathioprine maintenance therapy during follow-up. Patients in both arms received 1000 mg intravenous bolus methylprednisolone (or another equivalent dose glucocorticoid) per day for 1 to 3 days, followed by oral prednisone (1 mg / kg / day, not exceeding 80 mg / day). Prednisone reduction was completed within 6 months of initiation of study treatment. The primary endpoint measure was achievement of complete remission at 6 months defined as a Birmingham Vasculitis Activity for Wegener's granulomatosis (BVAS / WG) of 0, and absence of glucocorticoid therapy. The default non-inferiority margin for the difference between treatments was 20%. The study demonstrated non-inferiority of MabThera to cyclophosphamide for complete remission (CR) at 6 months (table 14). Efficacy was observed for both newly diagnosed patients and patients with relapsing disease (table 15).
Table 14 Percentage of patients who achieved complete remission at 6 months (Intent-to-Treat Population *).
Table 15 Complete remission at 6 months by disease status.
Worst case attribution is applied to patients with missing data.
Complete remission at 12 and 18 months
In the MabThera group, 48% of patients achieved CR at 12 months and 39% of patients achieved CR at 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of complete remission), 39% of patients achieved CR at 12 months and 33% of patients achieved CR at 18 months. From month 12 to month 18, 8 relapses were observed in the MabThera group compared with 4 in the cyclophosphamide group.
Retreatment with MabThera
Based on the investigator's judgment, 15 patients received a second course of MabThera therapy for the treatment of relapse of disease activity that occurred between 6 and 18 months after the first course of MabThera. Limited data from the current study preclude any conclusions concerning the efficacy of subsequent courses of MabThera in patients with granulomatosis with polyangiitis and microscopic polyangiitis.
Continuous immunosuppressive therapy may be particularly appropriate in patients at risk of relapse (e.g. with a history of previous relapses and granulomatosis with polyangiitis, or patients with B-cell reconstitution in addition to PR3-ANCA during monitoring). When remission with MabThera has been achieved, continuation of immunosuppressive therapy can be considered to prevent relapse. The efficacy and safety of MabThera in maintenance therapy has not been established.
Laboratory tests
A total of 23/99 (23%) of patients treated with MabThera in the study tested positive for HACA within 18 months. None of the 99 patients treated with MabThera were HACA positive at screening. The clinical significance of HACA development in patients treated with MabThera is unclear.
05.2 "Pharmacokinetic properties
Non-Hodgkin's lymphoma
Based on a "population pharmacokinetic analysis of 298 NHL patients who received a" single or multiple infusion of MabThera as a single agent or in combination with CHOP therapy (doses of MabThera used ranging from 100 to 500 mg / m2) , typical population estimates for nonspecific clearance (CL1), specific clearance (CL2) with probable contribution of B cells or tumor mass, and central compartment volume of distribution (V1) were 0.14 l / day, 0.59 L / day and 2.7 L, respectively. The median estimated terminal elimination half-life of MabThera was 22 days (range: 6.1 - 52 days). Baseline CD19-positive cell count and diameter of measurable tumor lesions contributed in part to the variability in CL2 of MabThera as seen from data from 161 patients who took 375 mg / m2 as an intravenous infusion for 4 weekly doses. Patients with higher CD19-positive cell counts or larger tumor lesions had a higher CL2. However, a large component of inter-individual variability remained for CL2 after correction for CD19-positive cell count and tumor lesion diameter. V1 varied based on body surface area (Body Surface Area, BSA) and CHOP therapy. This variability in V1 (27.1% and 19.0%) determined by the BSA range (1.53 to 2.32 m2) and concomitant CHOP therapy, respectively, was relatively small. Age, gender and performance WHO status had no effect on the pharmacokinetics of MabThera. This analysis suggests that adjustment of the dose of MabThera with any of the evaluated covariates is unlikely to result in a significant reduction in its pharmacokinetic variability.
MabThera, administered as an intravenous infusion at a dose of 375 mg / m2 at weekly intervals for 4 doses to 203 NHL patients naïve to MabThera, resulted in a mean Cmax after the fourth infusion of 486 mcg / ml (range: 77.5 - 996 , 6 mcg / ml). Rituximab was detectable in patient serum 3 - 6 months after completion of the last treatment.
After administration of MabThera at a dose of 375 mg / m2 as an i.v. at weekly intervals for 8 doses to 37 NHL patients, mean C increased with each subsequent infusion, ranging from a mean of 243 mcg / mL (range: 16 - 582 mcg / mL) after the first infusion to 550 mcg / mL ( range: 171 - 1177 mcg / ml) after the eighth infusion.
The pharmacokinetic profile of MabThera when administered as 6 infusions of 375 mg / m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with MabThera alone.
Chronic lymphocytic leukemia
MabThera was administered by intravenous infusion with the first cycle dose of 375 mg / m2 increased to 500 mg / m2 for each subsequent cycle, for 5 doses, in combination with fludarabine and cyclophosphamide in patients with CLL. The mean Cmax (N = 15) after the fifth infusion of 500 mg / m2 was 408 mcg / ml (range 97-764 mcg / ml) and the mean terminal half-life was 32 days (range 14-62 days).
Rheumatoid arthritis
Following two intravenous infusions of MabThera at a dose of 1000 mg, two weeks apart, the mean terminal half-life was 20.8 days (range 8.58 to 35.9 days), the mean systemic clearance was 0.23 L / day (range 0.091 to 0.67 L / day) and the mean steady-state volume of distribution was 4.6 L (range 1.7 to 7.51 L). Population of the same data gave similar mean values for systemic clearance and half-life, of 0.26 l / day and 20.4 days, respectively. Population pharmacokinetic analyzes revealed that BSA and gender were the most significant covariants to explain interindividual variability in pharmacokinetic parameters. After adjustment for BSA, male subjects had a higher volume of distribution and faster clearance than female subjects. Sex-related pharmacokinetic differences were not considered clinically relevant and no dosage adjustment was necessary. No pharmacokinetic data are available in patients with renal or hepatic insufficiency.
The pharmacokinetics of rituximab were evaluated after two intravenous (i.v.) doses of 500 mg and 1000 mg on days 1 and 15 in four studies. In all of these studies, the pharmacokinetics of rituximab were dose proportional over the limited dosing range studied. The mean serum Cmax of rituximab after the first infusion ranged from 157 to 171 mcg / mL for the 2 x 500 dose. mg and between 298 and 341 mcg / mL for the 2 x 1000 mg dose. After the second infusion, the mean Cmax value was between 183 and 198 mcg / mL for the 2 Ãù 500 mg dose and between 355 and 404 mcg / ml for the 2 dose is 1000 mg. The mean terminal elimination half-life was between 15 and 16 days for the 2 x 500 mg dose and between 17 and 21 days for the 2 dose is 1000 mg. Cmax was between 16 and 19%, higher after the second infusion compared to the first infusion for both dosages.
The pharmacokinetics of rituximab were evaluated following two i.v. 500 mg and 1000 mg after reprocessing in the second cycle. The mean serum Cmax of rituximab after the first infusion ranged from 170 to 175 mcg / mL for the 2 x 500 mg dose and between 317 to 370 mcg / mL for the 2 x 1000 mg dose. After the second infusion, the mean Cmax value was 207 mcg / mL for the 2 x 500 mg dose and between 377 and 386 mcg / mL for the 2 x 1000 mg dose. The mean terminal elimination half-life after the second infusion, after the second cycle, was 19 days for the 2 x 500 mg dose and between 21 and 22 days for the 2 x 1000 mg dose. The pharmacokinetic parameters for rituximab were comparable over the two treatment courses.
Pharmacokinetic parameters in the population of subjects with inadequate response to TNF antibodies, subjected to the same dosing regimen (2 x 1000 mg iv, 2 weeks apart), were similar with a mean maximum serum concentration of 369 mcg / ml and a "half-life" average terminal of 19.2 days.
Granulomatosis with polyangiitis and microscopic polyangiitis Based on population pharmacokinetic analyzes of data from 97 patients with granulomatosis with polyangiitis and microscopic polyangiitis who received 375 mg / m2 of MabThera once weekly for four weeks, the mean half-life of terminal elimination estimated was 23 days (range 9 to 49 days). The mean clearance and volume of distribution of rituximab were 0.313 L / day (range 0.116 to 0.726 L / day) and 4.50 L (range 2.25 to 7.39L), respectively. The pharmacokinetic parameters of rituximab in these patients appear similar to those seen in patients with rheumatoid arthritis.
05.3 Preclinical safety data
Rituximab was found to be highly specific for the CD20 antigen on B cells. Monkey toxicity studies cynomolgus they revealed no effects other than the expected pharmacological depletion of B cells in peripheral blood and lymph node tissue.
Evolutionary toxicity studies were conducted in monkeys cynomolgus with doses up to 100 mg / kg (treatment on gestation days 20-50) and have shown that there is no evidence of fetal toxicity due to rituximab. However, depletion has been observed in the lymphoid organs of the fetus dose-dependent B cell pharmacology, which was maintained until after birth and was associated with decreased IgG levels in affected newborn animals. B cell counts returned to normal in these animals within 6 months of birth and did not impair immunization reactions.
Standard tests to investigate mutagenicity have not been performed, as these tests are not relevant for this molecule. Long-term animal studies to determine the carcinogenic potential of rituximab have not been performed.
No specific studies have been performed to determine the effects of rituximab on fertility. Generally in monkey toxicity studiescynomolgus no deleterious effects on male or female reproductive organs were observed.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Sodium citrate
Polysorbate 80
Sodium chloride
Sodium hydroxide
Hydrochloric acid
Water for injections
06.2 Incompatibility
No incompatibilities were observed between MabThera and polyvinyl chloride or polyethylene bags, or infusion equipment.
06.3 Period of validity
30 months
The solution of MabThera prepared for the infusion is physically and chemically stable for 24 hours at a temperature between 2 ° C and 8 ° C and subsequently for 12 hours at room temperature.
From a microbiological point of view, the prepared solution for infusion should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be exceeded. 24 hours at a temperature between 2 ° C and 8 ° C, unless dilution has taken place in controlled and validated aseptic conditions.
06.4 Special precautions for storage
Store in a refrigerator (2 ° C - 8 ° C). Keep the container in the outer packaging to protect it from light.
For storage conditions after dilution of the medicinal product, see section 6.3.
06.5 Nature of the immediate packaging and contents of the package
Clear Type I glass vials with a butyl rubber stopper containing 100 mg of rituximab in 10 ml. Packs of 2 vials.
06.6 Instructions for use and handling
MabThera is supplied in sterile, preservative-free, non-pyrogenic, single use vials.
Aspirate, under sterile conditions, the required amount of MabThera and dilute to a calculated concentration of 1 to 4 mg / ml of rituximab into an infusion bag containing sterile, non-pyrogenic sodium chloride 9 mg / ml (0.9%) solution for injection. ), or 5% D-glucose in water. To mix the solution, slowly invert the bag to avoid foaming. Care must be taken to ensure the sterility of the prepared solutions. As the medicinal product does not contain antimicrobial preservatives or bacteriostatic agents, aseptic techniques should be observed. Parenteral medicinal products should be checked visually for particles or discolouration before being administered.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Roche Registration Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/98/067/001
033315019
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 2 June 1998
Date of last renewal: 2 June 2008
10.0 DATE OF REVISION OF THE TEXT
11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY
12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL
