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General: Infusion Related Reactions (IRRs): The most frequently observed adverse drug reactions (ADRs) in patients receiving GAZYVA were infusion related reactions (IRRs) which occurred predominantly during infusion of the first 1000 mg.
In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti-histamine, omission of antihypertensive medication) 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. Mitigation measures to reduce IRRs (see Dosage & Administration) should be followed. The incidence and severity of infusion-related symptoms decreased substantially after the first 1000 mg was infused, with most patients having no IRRs during subsequent administrations of GAZYVA (see Adverse Reactions).
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. IRRs may be clinically indistinguishable from IgE mediated allergic reactions (e.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 IRR. See Dosage & Administration for information on prophylaxis and Table 7 Infusion Rate Modification Guidelines for Infusion Related Reactions on how to manage IRRs based on grade of reaction.
Patients should not receive further GAZYVA infusions if they experience: acute life-threatening respiratory symptoms, a Grade 4 (i.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).
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 GAZYVA intravenous infusions. Therefore, withholding of antihypertensive treatments should be considered for 12 hours prior to and throughout each GAZYVA infusion and for the first hour after administration. Patients at acute risk of hypertensive crisis should be evaluated for the benefits and risks of withholding their anti-hypertensive medication.
Hypersensitivity Reactions: Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness), have been reported in patients treated with GAZYVA. If a hypersensitivity reaction is suspected during or after an infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion should be stopped and treatment permanently discontinued. Patients with known hypersensitivity to GAZYVA must not be treated (see Contraindications). Hypersensitivity may be clinically difficult to distinguish from infusion related reactions.
Tumour Lysis Syndrome (TLS): Tumour lysis syndrome (TLS) has been reported with GAZYVA. Patients who are considered to be at risk of TLS [e.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. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol), or a suitable alternative such as a urate oxidate (e.g. rasburicase), prior to the infusion of GAZYVA as described in Dosage & Administration. 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 GAZYVA. 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 administration of granulocyte colony-stimulating factors (G-CSF) should be considered. Any signs of concomitant infection should be treated as appropriate. Late onset neutropenia (occurring 28 days after the end of treatment) or prolonged neutropenia (lasting more than 28 days after treatment has been completed/stopped) may occur.
Thrombocytopenia: Severe and life threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with GAZYVA. Fatal haemorrhagic events have also been reported in Cycle 1 in patients treated with GAZYVA. A clear relationship between thrombocytopenia and haemorrhagic events has not been established.
Patients should be closely monitored for thrombocytopenia, especially during the first cycle; regular laboratory tests should be performed until the event resolves, and dose delays should be considered in case of severe or life-threatening thrombocytopenia. Transfusion of blood products (i.e. platelet transfusion) according to institutional practice is at the discretion of the treating physician. Use of any concomitant therapies, which could possibly worsen thrombocytopenia-related events, such as platelet inhibitors and anticoagulants, should also be taken into consideration, especially during the first cycle.
Worsening of Pre-existing Cardiac Conditions: In patients with underlying cardiac disease, arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with GAZYVA (see Adverse Reactions). These events may occur as part of an IRR and can be fatal. Therefore, patients with a history of cardiac disease should be monitored closely. In addition, these patients should be hydrated with caution in order to prevent a potential fluid overload.
Infections: GAZYVA should not be administered in the presence of an active infection and caution should be exercised when considering the use of GAZYVA in patients with a history of recurring or chronic infections. Serious, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of GAZYVA therapy. Fatal infections have been reported.
In the FL studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in maintenance. During the follow-up phase, grade 3-5 infections are observed more in patients who received GAZYVA plus bendamustine in the induction phase.
Hepatitis B reactivation: Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including GAZYVA (see Clinical Trials under Adverse Reactions).
Hepatitis B virus (HBV) screening should be performed in all patients before initiation of treatment with GAZYVA. At minimum this should include HBsAg-status and HBcAb-status. These can be complemented with other appropriate markers as per local guidelines. Patients with active Hepatitis B disease should not be treated with GAZYVA. Patients with positive hepatitis B serology should consult liver disease experts before start of treatment and should be monitored and managed following local medical standards to prevent hepatitis reactivation.
Progressive multifocal leukoencephalopathy (PML): PML has been reported in patients treated with GAZYVA (see Adverse Reactions). The diagnosis of PML should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. The symptoms of PML are nonspecific and can vary depending on the affected region of the brain. Motor symptoms with corticospinal tract findings (e.g. muscular weakness, paralysis, and sensory disturbances), sensory abnormalities, cerebellar symptoms, and visual field defects are common. Some signs/symptoms regarded as "cortical" (e.g. aphasia or visual-spatial disorientation) may occur. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain magnetic resonance imaging (MRI), and lumbar puncture (CSF testing for JC viral DNA). Therapy with GAZYVA should be withheld during the investigation of potential PML and permanently discontinued in case of confirmed PML. Discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy should also be considered. The patient should be referred to a neurologist for the evaluation and treatment of PML.
Immunization: The safety of immunization with live or attenuated viral vaccines, following GAZYVA therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery.
Exposure in utero to GAZYVA and vaccination of infants with live virus vaccines: Due to the potential depletion of B cells in infants of mothers who have been exposed to GAZYVA during pregnancy, the safety and timing of vaccinations with live virus vaccines should be discussed with the child's healthcare provider. Postponing vaccination with live vaccines should be considered for infants born to mothers who have been exposed to GAZYVA during pregnancy until the infants' B cell levels are within normal ranges (see Pregnancy under Use in Pregnancy & Lactation).
Drug Abuse and Dependence: No data to report.
Renal Impairment: Chronic Lymphocytic Leukaemia: In the pivotal study in CLL, 27% (90 out of 336) of patients treated with GAZYVA plus chlorambucil had moderate renal impairment (creatinine clearance (CrCl) <50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than those associated with CrCl ≥50 mL/min (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). No significant differences in efficacy were observed between patients with CrCl <50mL/min and those with CrCl ≥50 mL/min. Patients with CrCl <30 mL/min were excluded from the study (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Non-Hodgkin Lymphoma: In the pivotal studies in iNHL, 7.7% patients (GAO4753g: 14 out 204) and 5% patients (BO21223: 35 out of 698) had moderate renal impairment (CrCl <50 mL/min). These patients experienced more serious adverse events, grade 3 to 5 adverse events and adverse events leading to treatment withdrawal (patients in Study BO21223 only) than those associated with CrCl ≥50 mL/min (see Special Dosage Instructions under Dosage & Administration and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions). Patients with CrCl <40 mL/min were excluded from the studies (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Hepatic Impairment: The safety and efficacy of GAZYVA in patients with hepatic impairment have not been established.
Ability to Drive and Use Machines: No studies on the effects of GAZYVA on the ability to drive and to use machines have been performed. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.
Use in Children: The safety and efficacy of GAZYVA in children below 18 years of age have not been established.
Use in Elderly: Chronic Lymphocytic Leukaemia: In the pivotal study in CLL, 46% (156 out of 336) of patients treated with GAZYVA plus chlorambucil were 75 years old or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than patients < 75 years of age. No significant differences in efficacy were observed between patients ≥75 years of age and those < 75 years of age (see Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions).
Non-Hodgkin Lymphoma: In the pivotal studies in iNHL, patients 65 years old or older experienced more serious adverse events, and adverse events leading to withdrawal or death than patients < 65 years of age. No clinically meaningful differences in efficacy were observed.
