Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Traceability
In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Based on a subgroup analysis in previously untreated follicular lymphoma, the efficacy in FLIPI low risk (0-1) patients is currently inconclusive (see section 5.1). A therapy choice for these patients should carefully consider the overall safety profile of Gazyva plus chemotherapy and the patient- specific situation.
Infusion related reactions

The most frequently observed adverse drug reactions (ADRs) in patients receiving Gazyva 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 Gazyva treated patients. In CLL patients who received the combined measures for prevention of IRRs (adequate corticosteroid, oral analgesic/anti- histamine, omission of antihypertensive medicine in the morning of the first infusion, and the Cycle 1 Day 1 dose administered over 2 days) as described in section 4.2, 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. Mitigation measures to reduce IRRs should be followed (see section 4.2). The incidence and severity of infusion related symptoms decreased substantially after the first 1,000 mg was infused, with most patients having no IRRs during subsequent administrations of Gazyva (see section 4.8).

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. IRRs may be clinically indistinguishable from immunoglobulin E (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 IRRs. Patients with renal impairment (CrCl < 50 mL/min) and patients with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs (see section 4.8). For management of IRRs see section 4.2 Posology and method of administration.

Patients must 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 medicine.

Hypersensitivity reactions

Hypersensitivity reactions with immediate (e.g. anaphylaxis) and delayed onset (e.g. serum sickness) have been reported in patients treated with Gazyva. 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. Patients with known hypersensitivity to obinutuzumab must not be treated (see section 4.3).

Tumour lysis syndrome (TLS)

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) starting 12-24 hours prior to the infusion of Gazyva as per standard practice (see section 4.2). 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 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 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. Antiviral and antifungal prophylaxis should also be considered (see section 4.2). 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. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of neutropenia (see section 4.8).

Thrombocytopenia

Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after the infusion) has been observed during treatment with Gazyva. Patients with renal impairment (CrCl < 50 mL/min) are more at risk of thrombocytopenia (see section 4.8). 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.

Coagulation abnormalities including disseminated intravascular coagulation (DIC) 
DIC including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyva. The majority of cases involved non-overt DIC, with subclinical (asymptomatic) changes in platelets and laboratory coagulation parameters occurring within 1-2 days after the first infusion with spontaneous resolution usually occurring within one to two weeks, not requiring drug discontinuation or specific intervention. In some cases, the events were associated with IRRs and/or TLS. No specific baseline risk factors for DIC were identified. Patients suspected to have non-overt DIC should be monitored closely with coagulation parameters including platelets and clinical observation for signs or symptoms of overt DIC. Gazyva should be discontinued at first onset of suspected overt DIC and appropriate treatment initiated.


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 section 4.8). 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.

Patients (CLL) with both CIRS > 6 and CrCl < 70 mL/min are more at risk of infections, including severe infections (see section 4.8). In the follicular lymphoma studies, a high incidence of infections was observed in all phases of the studies, including follow-up, with the highest incidence seen in the maintenance phase. 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 section 4.8).
HBV screening should be performed in all patients before initiation of treatment with Gazyva. At a minimum this should include hepatitis B surface antigen (HBsAg) status and hepatitis B core antibody (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)

Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with Gazyva (see section 4.8). 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 (cerebrospinal fluid testing for John Cunningham 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.

Immunisation

The safety of immunisation 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 obinutuzumab 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, infants should be monitored for B-cell depletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell count has recovered. The safety and timing of vaccination should be discussed with the infant’s physician (see section 4.6).





Effects on Driving

4.7    Effects on ability to drive and use machines

Gazyva has no or negligible influence on the ability to drive and use machines. IRRs are very common during the first infusion of Gazyva, and patients experiencing infusion related symptoms should be advised not to drive or use machines until symptoms abate.