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THERAPEUTIC ACTION:
Antineoplastic agent, monoclonal antibody
INDICATIONS:
Non-Hodgkin Lymphoma (NHL)
In patients with stage III/IV follicular non-Hodgkin lymphoma who have not previously been treated, rituximab is indicatedin combination with chemotherapy.
In patients with follicular lymphoma who have responded to induction treatment, rituximab is indicated for maintenance treatment.
In patients with stage III/IV follicular non-Hodgkin lymphoma who are chemoresistant or in their second or posterior relapse after chemotherapy, rituximab is indicated as monotherapy.
In patients with CD20-positive diffuse large B-cell non-Hodgkin lymphoma, rituximab is indicated in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine,
and prednisolone).
In patients with chronic lymphocytic leukemia (CLL) who have not been previously treated or who have relapsed or have been refractory to a previous treatment, rituximab is indicated in combination with chemotherapy.
Evidence is limited on the efficacy and safety of treatment with rituximab in patients previously treated with monoclonal antibodies, including rituximab (whether alone or in combination with chemotherapy).
Rheumatoid arthritis (RA) In adult patients with severe active rheumatoid arthritis who have presented inadequate response or intolerance to other disease-modifying antirheumatic drugs (DMARDs), including one or more treatments with tumor necrosis factor (TNF) inhibitors.
Rituximab in combination with methotrexate (MTX) is indicated for the treatment of rituximab has been shown to reduce the progression of joint damage measured by X-rays and to improve physical function when given in combination with methotrexate.
In adult patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA), rituximab is indicated in combination with glucocorticoids (MPA).
PRECAUTIONS AND WARNINGS:
Progressive Multifocal Leukoencephalopathy (PML):
All patients treated with rituximab must receive information to alert them to the potential risk of infections, including progressive multifocal leukoencephalopathy. This situation must be considered and evaluated and, if confirmed, rituximab treatment must be suspended.
The use of rituximab may be associated with a greater risk of PML. Patients must be monitored at regular intervals to detect any new neurological sign or symptom or any worsening that may suggest PML.
If the patient is suspected to have PML, rituximab administration must be suspended until this possibility has been ruled out. The physician must evaluate patients to determine whether the symptoms are indicative of neurological alteration and in such case, if these symptoms are indicative of PML, consider consultation with a neurologist.
In addition to evaluation, consider performing magnetic resonance imaging, preferably with contrast medium; CSF analysis to detect JC virus DNA; and repeat neurological evaluations.
The physician must be especially attentive to indicative symptoms of PML that the patient may not notice (e.g. cognitive, neurological or psychiatric symptoms). The patient must be advised to inform their partner or caregiver about their treatment, as these people may detect symptoms of which the patient is not aware. If the patient develops PML, treatment with rituximab must be permanently suspended and consider discontinuing any concurrent chemotherapy or immunosuppressant therapy.
Stabilization or improvement of the clinical outcome has been observed in immunocompromised patients with PML after immune system reconstitution. It is unknown whether early PML detection and discontinuation of rituximab treatment can lead to a similar stabilization or to an improvement in clinical outcome.
Infusion reactions:
Extreme precautions must be taken during treatment in patients who have a greater risk of developing severe cytokine-release syndrome. Infusion reactions caused by rituximab may be severe and even fatal. Severe reactions generally occur during the first infusion after 30 to 120 minutes; they include urticaria, hypotension, angioedema, bronchospasm, pulmonary infiltrates, respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactic events or death. The patients at risk are those with a large tumor mass or with a high number of circulating tumor cells (≥ 25,000/mm3), such as patients with chronic lymphocytic leukemia (CLL) and patients with pre-existing lung or heart conditions. Premedicate with paracetamol and antihistamines. RA with glucocorticoids.
These patients must be closely monitored during the first infusion, and consider reducing the rate of the first infusion or fractioning the dose over more than two days in the first cycle
and some subsequent cycles if the lymphocyte count is still high. If necessary, establish required medical treatment (e.g. glucocorticoids, epinephrine, bronchodilators or oxygen).
Severe cytokine release syndrome is characterized by severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, chills, stiffness, urticaria and angioedema.
This syndrome may be associated with some characteristics of tumor lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia, acute renal failure and lactate dehydrogenase (LDH) elevation, and it may be associated with acute respiratory failure and death.
Acute respiratory failure may be accompanied by interstitial infiltration or pulmonary edema, visible on a chest X-ray.
The syndrome frequently manifests within the first or second hour after starting the first infusion. Patients with a history of pulmonary failure or pulmonary tumor infiltration may have an
increased risk of poor prognosis and extra precautions must be taken during their treatment. In patients who develop severe cytokine release syndrome (see Posology and methods of administration) the infusion must be discontinued immediately and they must receive intensive symptomaticvtreatment. The following is suggested: suitably hydrate (IV), administer antipruriginous agents and closely monitor renal function.
Given that the initial improvement of clinical symptoms may follow a relapse, these patients must be closely monitored until tumor lysis syndrome and pulmonary infiltration have
been resolved or ruled out. Once the signs and symptoms have completely resolved, cytokine release syndrome rarely repeats in subsequent treatments.
Infusion-related adverse reactions have been observed in 77% of patients treated with rituximab (including cytokine release syndrome accompanied by hypotension and bronchospasm in 10% of patients) (see Adverse reactions).
These symptoms are generally reversible after discontinuation of the rituximab infusion and administration of an antipyretic, an antihistamine and, occasionally, oxygen, intravenous saline solution or bronchodilators and, if necessary, glucocorticoids. For severe reactions see “Cytokine release syndrome”.
Cases of hypersensitivity reactions have been reported, including anaphylactic relations, after intravenous protein administration. Unlike cytokine release syndrome, true hypersensitivity reactions typically present during the first few minutes of the infusion. It is best to have medicines used to fight hypersensitivity reactions, i.e. adrenaline, antihistamines and glucocorticoids, available for immediate use in case an allergic reaction occurs during rituximab administration. Clinical manifestations of anaphylaxis may be similar to those previously described for cytokine release syndrome. Reactions attributable to hypersensitivity have been reported less frequently than those attributable to cytokine release. In addition to the reactions reported in some patients, there have been cases of myocardial infarction, pulmonary edema and acute reversible thrombocytopenia. Given that hypotension may occur during rituximab infusion, discontinuation of antihypertensive treatments may be considered 12 hours before the infusion.
Severe mucocutaneous reactions:
Patients treated with rituximab may present mucocutaneous reactions, which in some cases may have a fatal outcome. These reactions include paraneoplastic pemphigus, Stevens-Johnson
syndrome, lichenoid dermatitis, vesiculobullous dermatitis and toxic epidermal necrolysis.
These reactions have had a variable onset that includes reports with onset on the first day of exposure to the drug.
This medicine should be discontinued in patients who experience severe mucocutaneous reactions. The safety of re-administration to patients who have experienced these types of events has not been determined.
Reactivation of hepatitis B virus:
In patients treated with drugs from the CD20-directed
cytolytic antibodies group, such as rituximab, hepatitis B virus
may sometimes be reactivated, resulting in fulminant
hepatitis, liver failure and death. Cases were reported in
patients with positive surface antigen (HBsAg+) and also in
patients with negative surface antigen (HBsAg-) but positive
for anti-core antibody (anti HBc+). Reactivation also occurred
in patients whose hepatitis B infection seemed not to have
been resolved (e.g. negative surface antigen, positive
anti-core and positive anti-HBs antibodies).
Reactivation is defined as a sudden increase in hepatitis B
virus replication manifested by a rapid increase in the level of
serum HBV DNA or HBsAg detection in a person with
previously negative HBsAg and positive anti-core
(anti-HBc+). Virus reactivation is often followed by hepatitis,
i.e. an increase in transaminase levels. In certain severe
cases an increase in bilirubin levels, impaired liver function
and death may occur.
Before starting treatment with rituximab, evaluate hepatitis B
infection in all patients, requesting HBsAg and anti-HBc. In
patients with evidence of prior infection (positive HBsAg,
beyond antibody level or negative HBsAg but with positive
anti-HBc) request consultation with an infectious disease
specialist, hepatologist or expert physician for case follow-up
and assessment of antiviral therapy before or during
treatment with rituximab. For patients with current or previous
evidence of hepatitis B infection, they must be monitored
clinically and with laboratory tests to detect virus reactivation
during rituximab treatment and for several months afterward.
Cases of reactivation have been reported up to 24 months
after completing treatment with rituximab.
In patients who develop virus reactivation while on treatment
with rituximab, immediately discontinue the treatment and
any concomitant chemotherapy and establish suitable
treatment. There is not enough data on the safety of
restarting treatment with rituximab in patients who had HBV
reactivation; this should be discussed among doctors with
experience in hepatitis B management once the reactivation
has been resolved.
Cardiac disorders:
Cases of angina pectoris, cardiac arrhythmias such as atrial
fibrillation and flutter, heart failure and/or myocardial infarction
have been reported in patients treated with rituximab.
Therefore, patients with a history of heart disease and/or
cardiotoxicity associated with chemotherapy must be
monitored closely.
Haematological toxicity:
Complete blood counts must be performed regularly before
each cycle during rituximab treatment, including neutrophils
and platelets. For combined treatment with chemotherapy,
obtain a complete blood count weekly to monthly, and more
often in patients who develop cytopenia. Although rituximab
with monotherapy does not have a myelosuppressive effect,
caution is advised before applying the treatment to patients
with a neutrophil count of < 1.5 x 10 9/l and/or platelets < 75 x
10 9/l, given that clinical experience in this population is
limited.
Rituximab has been used in patients undergoing autologous
bone marrow transplantation and in other risk groups with
presumably reduced bone marrow function without inducing
myelotoxicity.
Complete blood counts must be performed regularly during
rituximab treatment, including neutrophils and platelets.
Infections:
During rituximab treatment, or after it has been completed,
severe and even fatal bacterial or fungal infections may occur,
and viral infections may even appear or be reactivated; these
were reported in patients with hypogammaglobulinaemia. The
infections reported included cytomegalovirus, herpes simplex,
parvovirus B19, varicella zoster, West Nile virus and hepatitis
B. Discontinue the product in serious infections and establish
suitable anti-infectious treatment.
Rituximab must not be given to patients with severe active
infections (e.g. tuberculosis, sepsis and opportunistic
infections, see Contraindications). The physician must take
special care when considering the use of rituximab in patients
with a history of chronic or recurring infections, or in
underlying conditions that may cause a greater predisposition
to infections (see adverse reactions).
Rituximab treatment must not be initiated in patients with
severe active infections.
Cases of hepatitis B reactivation have been reported in
patients treated with rituximab, including cases of fulminant
hepatitis leading to death.
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported during the post-marketing use
of rituximab. Most of the patients had received this
monoclonal antibody in combination with chemotherapy or as
part of a stem cell transplant.
In patients with NHL and CLL the safety of immunization with
live virus vaccines has not been studied after receiving
treatment with rituximab; therefore, live virus vaccination is
not recommended.
Patients treated with rituximab may receive inactivated
vaccines; however, response percentages may be lower with
inactivated vaccines.
Immunizations: the vaccination status of patients must be
examined and current vaccination guidelines must be
followed before rituximab treatment. In patients with RA,
vaccination must have been completed at least 4 weeks
before starting treatment with rituximab.
The safety of immunization with live virus vaccines after
receiving rituximab treatment has not been studied.
Therefore, live virus vaccine vaccination is not recommended
during treatment with rituximab or while there is peripheral
B-cell depletion. Patients with RA treated with rituximab may
receive inactivated vaccines; however, response
percentages may be lower with inactivated vaccines.
Intestinal obstruction and perforation:
Abdominal pain, intestinal obstruction and perforation
sometimes leading to death may occur in patients on
rituximab treatment in combination with chemotherapy.
Perform a thorough evaluation of any patient who complains
of abdominal pain.
Renal toxicity:
Severe or even fatal renal toxicity may occur after the
administration of rituximab in patients with NHL; this was
seen in patients with tumor lysis syndrome and in patients
with NHL on combined treatment with cisplatin. This
combination is not recommended. Closely monitor for signs
of renal failure and discontinue rituximab therapy in the case
of increased creatinine or oliguria.
Rheumatoid arthritis, Wegener’s granulomatosis (WG)
and microscopic polyangiitis (MPA)
Rituximab is not recommended in populations with
rheumatoid arthritis who have not been previously treated
with methotrexate (MTX), as a favorable risk/benefit ratio has
not been established.
Concomitant/sequential use with other disease-modifying antirheumatic drugs (DMARDs):
Concomitant use of rituximab and other antirheumatic
treatments other than those included in the indication and
posology of rheumatoid arthritis is not recommended.
There is limited data in clinical trials to completely assess the
safety of sequential use of other DMARDs (including TNF
and other biological inhibitors) after rituximab therapy (see
Interactions). The available data suggest that the incidence of
clinically relevant infection does not change when these
therapies are used in patients previously treated with
rituximab; however, patients must be closely monitored for
signs of infection if biological agents or DMARDs are used
after rituximab treatment.
When there is peripheral B-cell depletion after rituximab
treatment, concomitant administration of immunosuppressants that are not corticosteroids has not yet been studied in
patients with Wegener’s granulomatosis (WG) or microscopic
polyangiitis (MPA).
Malignant neoplasms:
Immunomodulating drugs may increase the risk of malignant
neoplasms. Based on the limited experience with rituximab in
patients with rheumatoid arthritis (see Adverse reactions), the
existing data do not seem to suggest an increase in the risk of
malignant neoplasms. Nonetheless, a possible risk of
developing solid tumors cannot be excluded at this time.
In patients with Wegener’s granulomatosis (WG) or
microscopic polyangiitis (MPA), complete blood counts and
platelet counts must be performed at 2- to 4-month intervals
during rituximab treatment. Rituximab-induced cytopenia
may last for months beyond the treatment period.
Re-treatment of patients with Wegener’s Granulomatosis
(WG) and Microscopic Polyangiitis (MPA):
There are limited data on the safety and efficacy of rituximab in
subsequent cycles (see Posology and forms of administration).
Effects on the ability to drive and use machines:
Although studies on the ability to drive and use machines
have not been conducted for rituximab, the pharmacological
activity and adverse reactions reported to date do not
suggest that such effects would be probable.
Fertility pregnancy and breast-feeding:
Fertility / Pregnancy: It is known that immunoglobulin G (IgG)
crosses the placental barrier. Lymphocyte B levels have not
been determined in the newborns of mothers exposed to
rituximab in clinical trials. There is not sufficient controlled
data in pregnant women; however, temporary B-cell
depletion and lymphocytopenia have been reported in some
children born to mothers exposed to rituximab during
pregnancy. Therefore, rituximab should not be administered
to a pregnant woman unless the expected benefit outweighs
the potential risk.
During and for up to 12 months after treatment with rituximab,
females of childbearing potential must use effective
contraceptive methods due to the length of time that
rituximab stays in the body in patients with B-cell depletion.
Breast-feeding: It is unknown whether rituximab is excreted in
human milk. However, considering that IgG is excreted in
human milk and that rituximab has been detected in the milk
of lactating monkeys, women must not breast-feed their
children during rituximab treatment or during the following 12
months.
INTERACTIONS:
There is currently limited data on possible drug interactions with
rituximab. In patients with CLL, concomitant administration of
rituximab and fludarabine or cyclophosphamide does not seem
to have effects on the pharmacokinetics of these drugs.
Moreover, there is no apparent effect of fludarabine or
cyclophosphamide on the pharmacokinetics of rituximab.
Co-administration with methotrexate does not modify the
pharmacokinetics of rituximab in patients with rheumatoid
arthritis. Patients with titers of human antimurine antibody/human
antichimeric antibody (HAMA/HACA) may suffer from allergic
reactions or hypersensitivity when treated with other therapeutic
or diagnostic monoclonal antibodies. In patients with rheumatoid
arthritis, 283 patients received a sequential treatment with a
biological DMARD after rituximab. During rituximab treatment,
the incidence of clinically relevant infections in these patients
was 6.01 per 100 patient-years compared to 4.97 per 100
patient-years after treatment with the biological DMARD.
MODE OF ADMINISTRATION:
Rituxiver is a concentrated solution that must be diluted prior
to intravenous administration. It must not be administered as
pulse therapy or intravenous (IV) bolus.
Rituxiver infusions must be performed under the strict supervision
of an expert physician and in an environment that has immediate
access to complete resuscitation equipment.
Before every infusion, premedicate with an antipyretic and an
antihistamine such as paracetamol and diphenhydramine.
In patients with rheumatoid arthritis, administer methylprednisolone or an equivalent corticosteroid 30 minutes prior to the
infusion to reduce the frequency and severity of infusion-related reactions.
Premedication with glucocorticoids must be considered if
rituximab is not going to be given in combination with
chemotherapy that includes glucocorticoids for the treatment of
non-Hodgkin lymphoma and chronic lymphocytic leukemia.
In patients with granulomatosis (WG) and with microscopic
polyangiitis (MPA), administer glucocorticoids with rituximab.
In patients with chronic lymphocytic leukemia, consider
prophylaxis for pneumonia due to Pneumocystis jiroveci and
antiherpes drugs, and then after 12 months of treatment.
Also consider prophylaxis for pneumonia due to Pneumocystis jiroveci in patients with WG and MPA during rituximab
treatment and then 6 months after the last infusion.
First infusion:
The initial recommended infusion rate is 50 mg/hour; after the
first 30 minutes, in the absence of toxicity, this can be increased
by 50 mg/hour, every 30 minutes, up to a maximum of 400
mg/hour.
Subsequent infusions:
Start the infusion at an initial speed of 100 mg/hour; in the
absence of infusion toxicity this can be increased by 100
mg/hour every 30 minutes, up to a maximum of 400 mg/hour.
The prepared rituximab solutions must be administered as an
intravenous infusion, using a specific catheter. Prepared
solutions must not be administered in rapid infusion or IV
bolus.
Patients must be strictly monitored to detect the onset of
cytokine-release syndrome (see Precautions and warnings).
The infusion must be immediately discontinued in patients
who show evidence of severe reactions, especially severe
dyspnoea, bronchospasm or hypoxia. In patients with
non-Hodgkin lymphoma, evidence of tumor lysis syndrome
must be subsequently evaluated through suitable laboratory
tests, and evidence of pulmonary infiltration by chest X-ray.
The infusion should not be restarted in any patient until
complete remission of all symptoms and normalization of
laboratory values and chest X-ray results. At that point on, the
infusion may be restarted; initially the maximum rate is half
the rate of the previous infusion. If the same severe adverse
reactions were to occur a second time, the decision to
terminate treatment should be seriously considered on a
case-by-case basis. Mild or moderate reactions related to the
infusion (see adverse reactions) are generally resolved by
reducing the infusion rate. The infusion rate may be
increased when symptoms improve.
Ins tructions to prepare the dilution:
Rituxiver® is dispensed in single-dose, apyrogenic, sterile,
preservative-free vials.
Each milliliter of concentrated Rituxiver® solution contains 10
milligrams of rituximab.
Use aseptic techniques and disposable sterile materials
when preparing the dilution.
Calculate and extract the necessary quantity of Rituxiver®,
and dilute it in an infusion bag containing an aqueous solution
for injection of sodium chloride 9 mg/ml (0.9%) or an aqueous
solution for injection of 5% D-glucose up to a calculated
rituximab concentration of 1 to 4 mg/ml. To mix and
homogenize the diluted Rituxiver® solution, gently invert the
bag to prevent foam from forming; perform this mixing
process several times until the diluted rituximab solution is
visually homogenous.
The diluted solution prepared for intravenous infusion must
be used immediately.
ADVERSE CHEMICAL PROCESS:
Experience in Non-Hodgkin Lymphoma and Chronic
Lymphocytic Leukemia
Adverse reactions to the medicine observed with greater
frequency were those reactions related to the infusion that
occurred during the first infusion in most patients. The
incidence of infusion-related symptoms decreased
substantially with subsequent infusions and was less than 1%
after 8 doses of rituximab. During clinical trials in patients with
NHL, approximately 30-55% of patients experienced
infections reactions (mostly bacterial and viral); in studies
with CLL this figure was 30-50% of patients.
Serious adverse reactions to the medicine reported or
observed with the greatest frequency were:
– Infusion-related reactions (including cytokine release syndrome
and tumor lysis syndrome).
– Infections.
– Cardiovascular events.
– Other serious adverse reactions reported include hepatitis B
reactivation and PML.
The adverse reactions listed below are defined as: very
common (≥1/10); common (≥ 1/100 to < 1/10); uncommon (≥
1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very
rare (≤ 1/10,000). Adverse reactions to the medicine
identified only during post-marketing studies, the frequency of
which cannot be estimated, are defined as “not known”.
Infections:
Very common: bacterial and viral infections, bronchitis.
Common: sepsis, pneumonia, febrile infection, herpes zoster,
respiratory tract infection, fungal infection, infections of
unknown etiology, acute bronchitis, sinusitis, hepatitis B.
Rare: serious viral infections.
Hematopoietic disorders:
Very common: neutropenia, leukopenia, febrile neutropenia,
thrombocytopenia.
Common: anemia, pancytopenia, granulocytopenia.
Uncommon: clotting disorders, aplastic anemia, hemolytic
Very rare: temporary increase in IgM serum levels.
Not known: late-onset neutropenia.
Immune system disorders:
Very common: infusion-related reactions, angioedema.
Common: hypersensitivity.
Rare: anaphylaxis.
Very rare: tumor lysis syndrome, cytokine release syndrome.
Not known: severe infusion-related thrombocytopenia.
Metabolism and nutrition disorders:
Common: hyperglycemia, weight loss, peripheral edema,
facial edema, increase in LDH, hypocalcaemia.
Rare: anaphylaxis.
Psychiatric disorders:
Uncommon: depression, nervousness.
Neurological disorders:
Common: paresthesia, hypoesthesia, agitation, insomnia,
vasodilation, vertigo, anxiety.
Uncommon: dysgeusia.
Very rare: peripheral neuropathy with facial nerve paralysis.
Not known: cranial neuropathy, loss of other senses.
Eye and ear disorders:
Common: tearing, conjunctivitis, tinnitus, ear pain.
Very rare: serious vision loss.
Not known: hearing loss.
Cardiac disorders:
Common: myocardial infarction, arrhythmia, atrial fibrillation,
tachycardia, cardiac disorders.
Uncommon: left ventricular failure, supraventricular tachycardia,
ventricular tachycardia, angina, myocardial ischemia, and
bradycardia.
Rare: severe cardiac events.
Very rare: heart failure.
Vascular disorders:
Common: hypertension, orthostatic hypotension, hypotension.
Very rare: vasculitis (mainly cutaneous), leukocytoclastic
vasculitis.
Respiratory, thoracic and mediastinal disorders:
Common: bronchospasm, respiratory disease, chest pain,
dyspnea, increase in cough, rhinitis.
Uncommon: asthma, obliterative bronchitis, lung alteration,
hypoxia.
Rare: interstitial lung disease.
Very rare: respiratory failure.
Not known: pulmonary infiltration.
Gastrointestinal disorders:
Very common: nausea
Common: vomiting, diarrhea, abdominal pain, dysphagia,
stomatitis, constipation, dyspepsia, anorexia.
Uncommon: abdominal swelling.
Very rare: gastrointestinal perforation.
Skin and subcutaneous tissue disorders:
Very common: pruritus, rash, alopecia.
Common: urticaria, sweating, night sweats, skin disorders.
Very rare: severe bullous drug reactions, toxic epidermal
necrolysis.
Musculoskeletal and connective tissue disorders:
Common: hypertonia, myalgia, arthralgia, back pain, neck
pain, pain.
Renal and urinary disorders:
Very rare: kidney failure.
General disorders and administration site conditions:
Very common: fever, chills.
Common: tumor pain, flushing, malaise, cold syndrome, fatigue,
tremors, multiple organ failure.
Uncommon: pain at the infusion site.
Experience in Rheumatoid Arthritis
The adverse reactions listed below are defined as: very
common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥
1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very
rare (< 1/10,000).
The most common adverse reactions and those considered
to be attributable to rituximab administration were infusion
reactions. The total incidence of infusion-related reactions in
clinical trials was 23% in the first infusion and it decreased in
successive infusions. Rituximab consisted of infusion
reactions. The total incidence of infusion-related reactions in
clinical trials was 23% in the first infusion and it decreased in
successive infusions. Severe infusion-related reactions were
uncommon (0.5% of patients) and occurred mostly in the first
cycle. In addition to the adverse reactions observed in clinical
trials, during the marketing of rituximab Progressive
Multifocal Leukoencephalopathy (PML) (see precautions and
warnings) and serum sickness-like reactions have been
reported.
Infections:
Very common: upper respiratory tract infection, urinary tract
infection.
Common: bronchitis, sinusitis, tinea pedis.
Very uncommon: PML, reactivation of hepatitis B virus.
Hematopoietic disorders:
Very uncommon: serum sickness-like reactions.
Cardiac disorders:
Rare: angina pectoris, atrial fibrillation, heart failure, myocardial
infarction.
Very uncommon: atrial flutter.
Immune system disorders:
Very common: infusion-related reactions (hypertension,
nausea, rash, fever, pruritus, urticaria, throat irritation, sensation
of flushing, hypotension, rhinitis, stiffness, tachycardia, fatigue,
oropharyngeal pain, peripheral edema, and erythema.
Uncommon: infusion-related reactions such as generalized
edema, bronchospasm, wheezing, laryngeal edema,
angioneurotic edema, generalized pruritus, anaphylaxis,
anaphylactic reaction, hyperglycemia, weight loss, peripheral
edema, facial edema, increase in LDH, hypocalcaemia.
Metabolism and nutrition disorders:
Common: hypercholesterolemia.
Nervous system disorders:
Very common: headache.
Common: paresthesia, migraine, dizziness, sciatica.
Skin and subcutaneous tissue disorders:
Common: alopecia.
Psychiatric disorders:
Common: depression, anxiety.
Gastrointestinal disorders:
Common: dyspepsia, diarrhea, gastroesophageal reflux,
mouth ulcers, upper abdominal pain.
Musculoskeletal disorders:
Common: arthralgia/musculoskeletal pain, osteoarthritis,
bursitis.
Laboratory abnormalities
Hypogammaglobulinaemia (IgG or IgM below the lower limit
of normal) was observed in patients with rheumatoid arthritis
treated with rituximab. No increase in the general infection or
serious infection rate was observed after developing
hypogammaglobulinaemia.
Experience in Wegener’s Granulomatosis and Microscopic Polyangiitis (MPA)
The following adverse reactions were observed in ≥10% of
patients up to the 6th month in a clinical trial conducted in
patients with Wegener’s granulomatosis and microscopic
polyangiitis: infections, nausea, diarrhea, headache, muscle
spasms, arthralgia, anemia, leukocytopenia, peripheral edema,
fatigue, insomnia, increase in ALT, cough, epistaxis, dyspnea,
hypertension, infusion-related reactions, and skin rashes.
Laboratory abnormalities
Hypogammaglobulinaemia (IgA, IgG or IgM below the lower
limit of normal) was observed in these patients with WG and
MPA treated with rituximab in clinical trials.
Special precautions for storage, disposal and other handling:
Take care to ensure the sterility of the prepared solutions. The
medicine does not contain any antimicrobial preservatives or
bacteriostatic agents and, therefore, aseptic techniques must
be maintained. Before administration, parenteral medicines
must always be visually inspected to see if they contain
particles or present alterations in colour.
From a microbiological standpoint, the diluted solution
prepared for intravenous infusion must be used immediately.
If it is not used immediately, the storage time and preservation
until use and the conditions before use will be the responsibility
of the user and must not exceed 24 hours, refrigerating it
between 2°C and 8°C, and it must only be used if the dilution
was performed under controlled and validated aseptic
conditions.O
Once the amount of dilution to be used has been extracted,
the remaining concentrated Rituxiver solution must also be
discarded, from a microbiological standpoint. It is the user’s
responsibility to ensure that the extraction was performed
observing strict aseptic conditions to be able to preserve it
under the specified conditions (See Storage and preservation)
for the next use.
Any unused medicine or waste material in contact with it
should be disposed of in accordance with local requirements.
This medicine must not be used after the expiry date stated
on the container.
This medicine must be used exclusively under prescription
and medical supervision and cannot be repeated without a
new medical prescription.
CONDITIONS FOR PRESERVATION AND STORAGE:
Vials must be stored in a refrigerator between 2°C and 8°C.
Store vials in their original box and packaging to protect
contents from light. Do not freeze or shake.
Keep out of the reach and sight of children
FORMULA:
Each 100 mg vial of Rituxiver® contains: Rituximab 100 mg
(10 mg/ml). Excipients: polysorbate 80: sodium chloride,
sodium citrate dihydrate, water for injection q.s. 10 ml.
Each 500 mg vial of Rituxiver® contains: Rituximab 500 mg
(10 mg/ml). Excipients: polysorbate 80: sodium chloride,
sodium citrate dihydrate, water for injection q.s. 50 ml.
PRESENTATIONS:
Each box contains 1 vial of 100mg rituximab per 10 ml.
Each box contains 1 vial of 500mg rituximab per 50 ml.
Marketing Authorization Holder & Manufacturing site:
Actoverco Pharmaceutical Factory, Karaj – Iran
Drug Information Center Of Actoverco Company
Tel: 021- 41637100
