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Gazyvaro is a brand name for Obinutuzumab. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: Chronic lymphocytic leukaemia (CLL) Gazyvaro in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine based therapy (see section 5.1). Follicular lymphoma (FL) Gazyvaro in combination with…
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Gazyvaro should be administered under the close supervision of an experienced physician and in an environment where full resuscitation facilities are immediately available. 3 Posology Prophylaxis and premedication for tumour lysis syndrome (TLS) Patients with a high tumour burden and/or a high circulating lymphocyte count (> 25 x 109/L) and/or renal impairment (CrCl < 70 mL/min) are considered at risk of TLS and should receive prophylaxis.
g. g. 4). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate. 4). Corticosteroid premedication is recommended for patients with FL and mandatory for CLL patients in the first cycle and for patients with LN (see Table 1).
Premedication for subsequent infusions and other premedication should be administered as described below. Hypotension, as a symptom of IRRs, may occur during Gazyvaro intravenous infusions. 4). 4) Indication/Day of treatment/ Cycle Patients requiring premedication Premedication Administration Cycle 1: Day 1 for CLL and FL All patients Intravenous corticosteroid1,4 (mandatory for CLL, recommended for FL) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusionAnti-histaminic medicine3 Cycle 1: Day 2 for CLL only All patients Intravenous corticosteroid1 (mandatory) Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusionAnti-histaminic medicine3 All subsequent infusions for CLL and FL Patients with no IRR during the previous infusion Oral analgesic/anti-pyretic2 At least 30 minutes before Gazyvaro infusion 4 Indication/Day of treatment/ Cycle Patients requiring premedication Premedication Administration Patients with an IRR (Grade 1 or 2) with the previous infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 Patients with a Grade 3 IRR with the previous infusion OR Patients with lymphocyte counts >25 x 109/L prior to next treatment Intravenous corticosteroid1,4 Completed at least 1 hour prior to Gazyvaro infusion Oral analgesic/anti-pyretic2 Anti-histaminic medicine3 At least 30 minutes before Gazyvaro infusion LN All patients Intravenous corticosteroid5 Completed between 30 and 60 minutes prior to Gazyvaro infusion Starting from Dose 6, intravenous corticosteroid should only be administered to patients who have experienced an IRR in the prior infusion Oral analgesic/anti-pyretic6 Anti-histaminic medicine3 1100 mg prednisone/prednisolone or 20 mg dexamethasone or 80 mg methylprednisolone.
Undesirable effects are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications. 19 Chronic lymphocytic leukaemia (CLL) and follicular lymphoma (FL) Summary of the safety profile The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies: • BO21004/CLL11 (N=781): Patients with previously untreated CLL • BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL) • GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.
These trials investigated Gazyvaro in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyvaro maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL.
e. iNHL). Table 10 summarises all ADRs including those of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in: • Patients with CLL receiving Gazyvaro plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11) • Patients with previously untreated iNHL receiving Gazyvaro plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyvaro maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM) • Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyvaro plus bendamustine, followed by Gazyvaro maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN) The incidences presented in Table 10 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.
Traceability In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded. Special warnings and precautions are presented separately for the Oncology (Chronic lymphocytic leukaemia and Follicular lymphoma), and for the Lupus nephritis indications.
1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyvaro plus chemotherapy and the patient-specific situation. Infusion related reactions The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyvaro were IRRs, which occurred predominantly during infusion of the first 1 000 mg.
IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. 2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which were based on a relatively small number of patients) were similar before and after mitigation measures were implemented.
2). 8). In the majority of patients, irrespective of indication, IRRs were mild to moderate and could be managed by the slowing or temporary halting of the first infusion, but severe and life-threatening IRRs requiring symptomatic treatment have also been reported.
g. anaphylaxis). Patients with a high tumour burden and/or high circulating lymphocyte count in CLL [> 25 x 109/L] may be at increased risk of severe IRRs. 8). 2 Posology and method of administration. e. life threatening) IRR or, • a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion).
13 Patients who have pre-existing cardiac or pulmonary conditions should be monitored carefully throughout the infusion and the post-infusion period. Hypotension may occur during Gazyvaro intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each Gazyvaro infusion and for the first hour after administration.
1.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Hydrocortisone should not be used as it has not been effective in reducing rates of IRR. g. g. If a corticosteroid-containing chemotherapy regimen is administered on the same day as Gazyvaro, the corticosteroid can be administered as an oral medicinal product if given at least 60 minutes prior to Gazyvaro, in which case additional IV corticosteroid as premedication is not required.
5 80 mg IV methylprednisolone 6 650-1 000 mg acetaminophen/paracetamol Dose Chronic lymphocytic leukaemia (CLL, in combination with chlorambucil1) For patients with CLL the recommended dose of Gazyvaro in combination with chlorambucil is shown in Table 2.
Cycle 1 The recommended dose of Gazyvaro in combination with chlorambucil is 1 000 mg administered over Day 1 and Day 2, (or Day 1 continued), and on Day 8 and Day 15 of the first 28 day treatment cycle. Two infusion bags should be prepared for the infusion on Days 1 and 2 (100 mg for Day 1 and 900 mg for Day 2).
If the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on the same day (no dose delay necessary, no repetition of premedication), provided that appropriate time, conditions and medical supervision are available throughout the infusion.
If there are any modifications of the infusion rate or interruptions during the first 100 mg the second bag must be administered the following day. Cycles 2 – 6 The recommended dose of Gazyvaro in combination with chlorambucil is 1 000 mg administered on Day 1 of each cycle.
1 for information on chlorambucil dose Duration of treatment Six treatment cycles, each of 28 day duration. Delayed or missed doses If a planned dose of Gazyvaro is missed, it should be administered as soon as possible; do not wait until the next planned dose.
The planned treatment interval for Gazyvaro should be maintained between doses. Follicular lymphoma For patients with FL, the recommended dose of Gazyvaro in combination with chemotherapy is shown in Table 3. Patients with previously untreated follicular lymphoma Induction (in combination with chemotherapy2) Gazyvaro should be administered with chemotherapy as follows: • Six 28-day cycles in combination with bendamustine2 or, • Six 21-day cycles in combination with cyclophosphamide, doxorubicin, vincristine, prednisolone […]
Frequencies 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), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
20 Tabulated list of adverse reactions Table 10 Summary of ADRs reported in patients# receiving Gazyvaro + chemotherapy* System organ class Frequency All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Infections and infestations Very common Upper respiratory tract infection, sinusitis§, urinary tract infection, pneumonia§, herpes zoster§, nasopharyngitis Common Oral herpes, rhinitis, pharyngitis, lung infection, influenza Urinary tract infection, pneumonia, lung infection, upper respiratory tract infection, sinusitis, herpes zoster Uncommon Hepatitis B reactivation Nasopharyngitis, rhinitis, influenza, oral herpes Neoplasms benign, malignant and unspecified (incl cysts and polyps) Common Squamous cell carcinoma of skin, Basal cell carcinoma Squamous cell carcinoma of skin, Basal cell carcinoma Blood and lymphatic system disorders Very common Neutropenia§, thrombocytopenia, anaemia, leukopenia Neutropenia, thrombocytopenia Common Febrile neutropenia Anaemia, leukopenia, febrile neutropenia Uncommon Disseminated intravascular coagulation## Metabolism and nutrition disorders Common Tumour lysis syndrome, hyperuricaemia, hypokalaemia Tumour lysis syndrome, hypokalaemia Uncommon Hyperuricaemia Psychiatric disorders Very common Insomnia Common Depression, anxiety Uncommon Insomnia, depression, anxiety Nervous system disorders Very common Headache Uncommon Headache Not known Progressive multifocal leukoencephalopathy Cardiac disorders Common Atrial fibrillation Atrial fibrillation Vascular disorders Common Hypertension Hypertension Respiratory, thoracic and mediastinal disorders Very common Cough§ Common Nasal congestion, rhinorrhoea, oropharyngeal pain Uncommon Cough, oropharyngeal pain Gastrointestinal disorders Very common Diarrhoea, constipation§ Common Dyspepsia, haemorrhoids gastrointestinal perforation Diarrhoea Uncommon Constipation, haemorrhoids Skin and subcutaneous tissue disorders Very common Alopecia, pruritus Common Eczema 21 System organ class Frequency All Grades Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Grades 3-5† Gazyvaro + chemotherapy* (CLL, iNHL) followed by Gazyvaro maintenance (iNHL) Uncommon Pruritus Musculoskeletal and connective tissue disorders Very common Arthralgia§, back pain, pain in extremity Common Musculoskeletal chest pain, bone pain Pain in extremity Uncommon Arthralgia, back pain, musculoskeletal chest pain, bone pain Renal and Urinary Disorders Common Dysuria, urinary incontinence Uncommon Dysuria, urinary incontinence General disorders and administration site conditions Very common Pyrexia, Asthenia, fatigue Common Chest pain Pyrexia, asthenia, fatigue Uncommon Chest pain Immune system disorders Rare Cytokine release syndrome** Investigations Common White blood cell count decreased, neutrophil count decreased, weight increased White blood cell count decreased, neutrophil count decreased Uncommon Hypogammaglobulinemia Injury, poisoning and procedural complications Very common IRRs IRRs # Only the highest frequency observed in the trials is reported (based on studies BO21004/previously […]
Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medicine. g. g. serum sickness) have been reported in patients treated with Gazyvaro. Hypersensitivity may be difficult to clinically distinguish from IRRs.
Hypersensitivity symptoms can occur after previous exposure and very rarely with the first infusion. If a hypersensitivity reaction is suspected during or after an infusion, the infusion must be stopped and treatment permanently discontinued.
3). Tumour lysis syndrome (TLS) TLS has been reported with Gazyvaro. g. patients with a high tumour burden and/or a high circulating lymphocyte count [> 25 x 109/L] and/or renal impairment [CrCl < 70 mL/min]) should receive prophylaxis.
g. g. 2). All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Any additional guidelines according to standard practice should be followed.
For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. Neutropenia Severe and life-threatening neutropenia including febrile neutropenia has been reported during treatment with Gazyvaro.
Patients who experience neutropenia should be closely monitored with regular laboratory tests until resolution. If treatment is necessary it should be administered in accordance with local guidelines and the administration of granulocyte-colony stimulating factors (G-CSF) should be considered.
Any signs of concomitant infection should be treated as appropriate. Dose delays should be considered in case of severe or life-threatening neutropenia. It is strongly recommended that patients with severe neutropenia lasting more than 1 week receive antimicrobial prophylaxis throughout the treatment period until resolution to Grade 1 or 2.
2). Late onset neutropenia (occurring >28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been […]