Rituximab

Registered South African indications:

• Non­-Hodgkin’s lymphoma
• Chronic lymphocytic leukaemia
• Rheumatoid arthritis
• Granulomatosis with polyangiitis
• Microscopic polyangiitis

Contraindications 

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to murine proteins
• Active, severe infections (such as tuberculosis, sepsis and opportunistic infections)
• Severely immunocompromised states
• Severe cardiac failure (New York Heart Association Class IV) or severe uncontrolled cardiac disease (when indicated for granulomatosis with polyangiitis and microscopic polyangiitis)

Cautions 

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• History of pulmonary insufficiency
• Pulmonary tumour infiltration 
• High tumour burden or a high number (≥25 x 10⁹/L) of circulating malignant cells
• Cardiovascular disease and/or cardiotoxic chemotherapy or history thereof
• Previous cardiopulmonary adverse reactions
• Haematological toxicities: patients with neutrophils <1.5 x 10⁹/L and/or platelet counts < 5 x 10⁹/L 
• History of recurring or chronic infections
• Underlying conditions which may predispose patients to serious infection
• Active hepatitis B infection or history thereof
• Positive hepatitis B (either HBsAg or HBcAb) serology
• Methotrexate naïve populations
• Immunisation (within 4 weeks prior to administration)
• Sodium controlled diet

Forms avail. in SA and covered in this monograph: inj

Rheumatoid arthritis

• IV: 1000mg; Initial rate: 50mg/hr; Titrate by 50mg/hr every 30min; Max rate: 400mg/hr, followed by 1000mg infusion 14 days later; Initial rate: 100mg/hr; Titrate by 100mg/hr every 30min; Max rate: 400mg/hr

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Pre-medication of an analgesic/anti-pyretic (e.g. paracetamol) and an antihistaminic (e.g. diphenhydramine) should always be administered 30-60 min before each infusion

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Patients should receive IV methylprednisolone to be completed 30 minutes prior to each infusion to reduce the frequency and severity of infusion-related reactions

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Re-evaluate 24 weeks after 1st course to see if course should be repeated. Min duration between courses: 16 weeks

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Should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available

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Granulomatosis with polyangiitis (Wegener’s) 
Microscopic polyangiitis

• IV: 375 mg/m² body surface area, once weekly for 4 weeks; Initial rate: 50mg/hr; Titrate by 50mg/hr every 30min; Max rate: 400mg/hr; Subsequent infusions initial rate: 100mg/hr; Titrate by 100mg/hr every 30min; Max rate: 400mg/hr

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Pre-medication of an analgesic/anti-pyretic (e.g. paracetamol) and an antihistaminic (e.g. diphenhydramine) should always be administered 30-60 min before each infusion

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Methylprednisolone IV for 1-3 days is recommended in combination with infusion, followed by oral prednisone during and after treatment

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Pneumocystis jiroveci pneumonia (PCP) prophylaxis is recommended

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Do not admin as IV injection or bolus; Admin through dedicated line; Admin. as IV infusion with saline or dextrose containing fluids

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Should be administered under the close supervision of an experienced healthcare professional, and in an environment where full resuscitation facilities are immediately available

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Follicular non-Hodgkin's lymphoma
Diffuse large B cell non-Hodgkin's lymphoma
Chronic lymphocytic leukaemia

• Consult specialist for dosages

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Rituximab 1400mg (SC) is indicated for the treatment of non-Hodgkin's lymphoma only

Not registered for use in South Africa for children below 18 years

Pregnancy 

• Caution; not recommended
• IgG immunoglobulins are known to cross the placental barrier
• B cell levels in human neonates following maternal exposure to rituximab have not been studied 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 some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies
• For these reasons, rituximab should not be administered to pregnant woman unless the possible benefit outweighs the potential risk

Breastfeeding 

• Caution; not recommended 
• Whether rituximab is excreted in human milk is not known. However, maternal IgG is excreted in human milk, and rituximab was detectable in milk from lactating monkeys
• Women should not breastfeed while treated with rituximab and for 12 months following rituximab treatment

Fertility

• Animal studies did not reveal the deleterious effects of rituximab on reproductive organs
• Due to the long retention time of rituximab in B cell-depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with rituximab

Renal Impairment 

• Caution; no information available

Hepatic Impairment 

• Caution; no information available 

Elderly 

• No dose adjustment recommended 

Porphyria Information

• Not porphyrinogenic (NP)

Drugs in Sport

• Permitted - No warnings

Central Nervous System Disorders  

• Depression
• Nervousness
• Paraesthesia
• Hypoaesthesia
• Agitation
• Insomnia
• Dizziness
• Anxiety
• Malaise
• Peripheral neuropathy
• Cranial neuropathy
• Facial nerve palsy
• Migraine
• Headache
• Sciatica
• Tremor

Cardiovascular Disorders

• Myocardial infarction
• Arrhythmia
• Atrial fibrillation
• Atrial flutter
• Tachycardia
• Cardiac disorder
• Left ventricular failure
• Angina
• Myocardial ischaemia
• Bradycardia
• Severe cardiac disorders
• Cardiac failure  
• Hypertension
• Orthostatic hypotension
• Hypotension
• Vasculitis
• Vasodilation
• Leukocytoclastic vasculitis

Respiratory Disorders

• Bronchitis
• Sinusitis  
• Bronchospasm
• Respiratory disease
• Chest pain
• Dyspnoea
• Increased cough
• Nasal congestion
• Wheezing
• Rhinitis
• Asthma
• Bronchiolitis obliterans
• Lung disorder
• Hypoxia
• Interstitial lung disease
• Respiratory failure
• Lung infiltration
• Pulmonary oedema
• Laryngeal oedema
• Oropharyngeal pain
• Epistaxis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Abdominal pain
• Dysphagia
• Stomatitis
• Constipation
• Dyspepsia
• Anorexia
• Throat irritation
• Abdominal enlargement
• Gastrointestinal perforation
• Gastro-oesophageal reflux
• Mouth ulceration
• Gastroenteritis

Genitourinary Disorders

• Renal failure
• Urinary tract infection

Endocrine and Metabolic Disorders

• Hyperglycaemia
• Decreased weight
• Increased lactate dehydrogenase
• Hypocalcaemia
• Hyperkalaemia
• Hypercholesterolaemia

Musculoskeletal Disorders

• Hypertonia
• Myalgia
• Arthralgia
• Back pain
• Neck pain
• Musculoskeletal pain
• Pain in extremities
• Osteoarthritis
• Bursitis
• Muscle weakness

Skin and Subcutaneous Tissue Disorders 

• Pruritus
• Rash
• Alopecia
• Urticaria
• Sweating
• Night sweats
• Skin disorder
• Severe bullous skin reactions
• Stevens-Johnson syndrome
• Toxic epidermal necrolysis (Lyell'ss Syndrome)
• Tinea pedis
• Acne

Immune, Blood and Lymphatic System Disorders

• Bacterial infections
• Viral infections
• Sepsis
• Febrile infection
• Herpes zoster
• Fungal infections
• Infections of unknown aetiology
• Neutropenia
• Leucopenia  
• Febrile neutropenia
• Thrombocytopenia  
• Anaemia
• Pancytopenia
• Granulocytopenia
• Coagulation disorders  
• Aplastic anaemia  
• Haemolytic anaemia
• Decreased haemoglobulin
• Haematotoxicity
• Neutropenic infection
• Lymphadenopathy
• Infusion-related reactions
• Angioedema
• Angioneurotic oedema
• Hypersensitivity
• Anaphylaxis
• Anaphylactoid reaction
• Tumour lysis syndrome
• Cytokine release syndrome
• Serum sickness  
• Acute reversible thrombocytopenia
• Decreased IgG level
• Decreased IgM level

Sensory Disorders

• Dysgeusia
• Lacrimation disorder
• Conjunctivitis
• Severe vision loss
• Tinnitus
• Ear pain  
• Hearing loss

Others

• Fever
• Chills
• Flushing
• Cold syndrome  
• Shivering
• Multi-organ failure  
• Face oedema
• Periperal oedema
• Influenza-like syndrome

• Vaccines
• Other diagnostic or therapeutic monoclonal antibodies
• Antihypertensives
• DMARDs (in rheumatoid arthritis)

• Full blood count

Clinical response and retreatment

• Available data suggest that clinical response is usually achieved within 16-24 weeks of an initial treatment course. The need for further courses should be evaluated 24 weeks following the previous course with retreatment given based on residual or disease activity returning to a level above a DAS28-ESR of 2,6 (treatment to remission). Patients may receive further courses no sooner than 16 weeks following the previous course

Infusion-related reactions

• Mild or moderate infusion-related reactions usually respond to a reduction in the rate of infusion. The infusion rate may be increased upon improvement of symptoms
• Patients who have clinically significant cardiovascular disease, including arrhythmias, or previous serious infusion reactions to any prior biologic therapy or to rituximab, should not be administered the more rapid infusion
• Patients should be closely monitored for the onset of cytokine release syndrome. Patients who develop evidence of severe reactions, especially severe dyspnoea, bronchospasm or hypoxia, should have the infusion interrupted immediately
• Patients with non-Hodgkin's lymphoma should then be evaluated for evidence of tumour lysis syndrome including appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, the infusion should not be restarted until complete resolution of all symptoms, and normalisation of laboratory values and chest X-ray findings. At this time, the infusion can be initially resumed at not more than one-half the previous rate. If the same severe adverse reactions occur for a second time, the decision to stop the treatment should be seriously considered on a case by case basis

Signs and symptoms of infection

• Patients reporting signs and symptoms of infection following rituximab therapy should be promptly evaluated and treated appropriately. Before giving a subsequent course of treatment, patients should be re-evaluated for any potential risk for infections

Immunisation

• The patient's vaccination status should be reviewed and, If possible, patients should be brought up-to-date with all immunisations in agreement with current immunisation guidelines prior to initiating therapy. Vaccination should be completed at least 4 weeks prior to first administration of rituximab

Chemical and Physical Stability

• From a microbiological point of view, the prepared infusion solution 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 longer than 24 hours at 2 °C–8 °C, unless dilution has taken place in controlled and validated aseptic conditions
• After aseptic dilution in 0.9% sodium chloride solution: stable for 30 days at 2-8 °C plus an additional 24 hours at < 30 °C
• After aseptic dilution in 5% D-glucose solution: stable for 24 hours at 2-8 °C plus an additional 12 hours at room temperature
• Parenteral medicinal products should be inspected visually for particulate matter and discolouration prior to administration

Rituximab is a monoclonal antibody which binds specifically to the transmembrane antigen, CD20, a non-glycosylated phosphoprotein, located on pre-B and mature B lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. The Fab domain of rituximab binds to the CD20 antigen on B lymphocytes and the Fc domain can recruit immune effector functions to mediate B cell lysis. Possible mechanisms of effector-mediated cell lysis include complement-dependent cytotoxicity (CDC) resulting from C1q binding, and antibody-dependent cellular cytotoxicity (ADCC) mediated by one or more of the Fcγ receptors on the surface of granulocytes, macrophages and NK cells. Rituximab binding to CD20 antigen on B lymphocytes has also been demonstrated to induce cell death via apoptosis.

Injection (per 10ml) 100mg

• Blitzima 100mg (Adcock Ingram Limited)
• Mabthera (Roche Products) originator
• Ristova 100 (Roche Products)
• Redditux 100 (Dr Reddy's Laboratories)

Injection (per 50ml) 500mg

• Blitzima 500mg (Adcock Ingram Limited)
• Mabthera (Roche Products) originator
• Ristova 500 (Roche Products)
• Redditux 500 (Dr Reddy's Laboratories)

Injection (per 11.7ml) 1400mg

• Mabthera SC (Roche Products) originator