Gazyva

Gazyva

obinutuzumab

Manufacturer:

Roche

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Obinutuzumab.
Description
Active ingredient: Obinutuzumab.
Gazyva is a clear, colourless to slightly brownish liquid supplied as a single 1000 mg dose in a sterile, preservative-free, non-pyrogenic 50 ml glass vial containing 40 ml of liquid concentrate (25 mg/ml).
Excipients/Inactive Ingredients: L-histidine/L-histidine hydrochloride, trehalose, poloxamer 188, and water for injection.
Action
Pharmacotherapeutic Group: Antineoplastic agent, monoclonal antibody. ATC code: L01XC15 obinutuzumab.
Pharmacology: Pharmacodynamics: Mechanism of Action: Gazyva is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20 antibody of the IgG1 isotype. It specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre-B- and mature B-lymphocytes, but not on hematopoietic stem cells, pro-B-cells, normal plasma cells or other normal tissue. Glycoengineering of the Fc part of Gazyva results in higher affinity for FcɣRIII receptors on immune effector cells such as natural killer (NK) cells, and macrophages and monocytes as compared to non-glycoengineered antibodies.
In non-clinical studies, Gazyva induces direct cell death and mediates antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) through recruitment of FcɣRIII-positive immune effector cells. In addition, Gazyva mediates low degree of complement-dependent cytotoxicity (CDC). In animal models, Gazyva mediates potent B-cell depletion and antitumour efficacy. Compared to Type I CD20 antibodies, Gazyva, a Type II antibody, is characterised by an enhanced direct cell death induction with a concomitant reduction in CDC. Compared to non-glycoengineered CD20 antibodies, Gazyva is characterised by enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) as a consequence of the glycoengineering. This translates in superior B-cell depletion and antitumour efficacy in animal models.
Pharmacodynamic Effects: In the pivotal clinical trial BO21004/CLL11, 91% (40 out of 44) of evaluable patients treated with Gazyva were B-cell-depleted (defined as CD19+ B-cell counts <0.07x 109/l) at the end of treatment period and remained depleted during the first 6 months of follow-up. Recovery of B-cells was observed within 12 to 18 months of follow-up in 35% (14 out of 40) of patients without progressive disease and 13% (5 out of 40) with progressive disease.
Clinical/Efficacy Studies: Chronic Lymphocytic Leukemia: A Phase III, international, multicentre, open-label, randomised, two-stage, three-arm study (BO21004/CLL11) investigating the safety and efficacy profile of Gazyva plus chlorambucil compared to rituximab plus chlorambucil or chlorambucil alone was conducted in patients with previously untreated chronic lymphocytic leukemia with comorbidities.
Prior to enrolment, patients had to have documented CD20+ CLL, and one or both of the following measures of coexisting medical conditions: comorbidity score [total cumulative illness rating scale (CIRS)] of greater than 6 or reduced renal function as measured by CrCl <70 ml/min. Patients with inadequate liver function (NCICTC Grade 3 liver function tests [AST, ALT >5 x ULN for >2 weeks; Bilirubin >3 x ULN]) and renal function (CrCl <30 ml/min) were excluded.
A total of 781 patients were randomised 2:2:1 to receive Gazyva plus chlorambucil, rituximab plus chlorambucil or chlorambucil alone. Stage 1 compared Gazyva plus chlorambucil to chlorambucil alone in 356 patients and Stage 2 compared Gazyva plus chlorambucil to rituximab plus chlorambucil in 663 patients. Efficacy results are summarised in Table 1 and in Figures 1-3.
In the majority of patients, Gazyva was given intravenously as a 1000 mg initial dose administered on day 1, day 8 and day 15 of the first treatment cycle. In order to reduce the rate of infusion related reactions in patients, an amendment was implemented and 140 patients received the first Gazyva dose administered over 2 days (day 1 [100 mg] and day 2 [900 mg]) (see Dosage & Administration). For each subsequent treatment cycle (cycles 2 to 6), patients received Gazyva 1000 mg on day 1 only. Chlorambucil was given orally at 0.5 mg/kg body weight on day 1 and day 15 of all treatment cycles (1 to 6).
The demographics data and baseline characteristics were well balanced between the treatment groups. The majority of patients enrolled were Caucasian (95%) and male (61%). The median age was 73 years, with 44% being 75 years or older. At baseline, 22% patients had Binet Stage A, 42% had Binet Stage B and 36% had Binet Stage C. The median comorbidity score was 8 and 76% of the patients enrolled had a comorbidity score above 6. The median estimated CrCl was 62 ml/min and 66% of all patients had a CrCl <70 ml/min. Forty-two percent of patients enrolled had both a CrCl <70 ml/min and a comorbidity score of >6. Thirty-four percent of patients were enrolled on comorbidity score alone, and 23% of patients were enrolled with only impaired renal function.
The most frequently reported coexisting medical conditions (using a cutoff of 30% or higher) in the MedDRA body systems are: vascular disorders 73%; cardiac disorders 46%; GI disorders 38%; metabolism and nutrition disorders 40%; renal and urinary disorders 38%, and musculoskeletal and connective tissue disorders 33%.
The primary endpoint of the study was investigator assessed progression-free survival (PFS-INV). In addition, an independent review committee (IRC) assessed all patients for progression and IRC assessed PFS (PFS-IRC) was evaluated.
Key secondary efficacy endpoints were end-of-treatment response rate, molecular remission at end of treatment (minimal residual disease status) and time-to-event endpoints (event-free survival, new antileukemic therapy). Overall survival for stage 1 is presented in Figure 2. Overall survival for stage 2 will continue to be followed and is not yet mature. (See Table 1.)

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Results of the PFS subgroup analysis (i.e. sex, age, Binet stages, CrCl, CIRS score, beta2-microglobulin, IGVH status, chromosomal abnormalities, lymphocyte count at baseline) were consistent with the results seen in the overall Intent-to-treat population. The risk of disease progression or death was reduced in the Gazyva plus chlorambucil arm (GClb) compared to the rituximab plus chlorambucil arm (RClb) and chlorambucil-alone arm (Clb) in all subgroups. The hazard ratios ranged from 0.08 to 0.42 for GClb vs Clb and 0.28 to 0.71 for GClb vs RClb. (See Figure 1, Figure 2 and Figure 3.)

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Patient-Reported Outcomes: In the QLQC30 and QLQ-CLL-16 questionnaires conducted during the treatment period, no substantial difference in any of the subscales was observed. Data during follow-up, especially for the chlorambucil-alone arm, is limited. However, no notable differences in quality of life during follow-up have been identified to date.
Health-related quality of life assessments, specific to fatigue through treatment period, show no statistically significant difference suggesting that the addition of Gazyva to chlorambucil regimen does not increase the experience of fatigue for patients.
Non-Hodgkin Lymphoma (Follicular Lymphoma): Previously Untreated Follicular Lymphoma: In a multicentre phase III, open-label, randomized study (BO21223/GALLIUM), 1202 previously untreated patients with stage II (bulky)/III/IV follicular lymphoma (FL) were evaluated. Patients were randomized 1:1 to receive either Gazyva or rituximab in combination with chemotherapy (CHOP, CVP, or bendamustine) followed by Gazyva or rituximab maintenance in patients who achieved a complete or partial response.
The demographic data and baseline characteristics of the FL population were well balanced [median age was 59 years, the majority of patients were Caucasian (81%), and female (53%)]. Seventy-nine percent had a FLIPI score of ≥2 and 7% had Stage II (bulky), 35% had Stage III and 57% had Stage IV disease. Fifty-seven percent received bendamustine, 33% received CHOP, and 10% received CVP chemotherapy. Forty-four percent had bulky disease (>7 cm), 34% had at least one B-symptom at baseline and 97% had an ECOG performance status of 0-1 at baseline.
Gazyva (1000 mg) was administered intravenously (as in Dosage & Administration) prior to chemotherapy. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyva. Standard dosing of CHOP and CVP was given. Following Cycles 6-8, when Gazyva was given in combination with chemotherapy, Gazyva maintenance therapy was given every 2 months for 2 years for responding patients or until disease progression.
Efficacy results are summarized in Table 2. Kaplan-Meier curves for PFS are shown in Figure 4. (See Table 2.)

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Response rates at the end of induction assessed by positron emission tomography (PET) were available for 297/601 patients in the Gazyva plus chemotherapy arm and 298/601 patients in the rituximab plus chemotherapy arm of the study. Complete response rates at end of induction as assessed by PET were 62.3% in the Gazyva plus chemotherapy arm and 56.7% in the rituximab plus chemotherapy arm. Overall response rates were similar in the two arms, with a difference of 4.3% in favour of the Gazyva plus chemotherapy arm (85.9% for G-chemo vs 81.5% for R-chemo). (See Figure 4.)

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Results of subroup analyses: Results of subgroup were, in general, consistent with the results seen in the FL population, supporting the robustness of the overall result. The subgroups evaluated included IPL, FLIPI, Chemo Regimen, Bulky Disease, B Symptoms at Baseline, Ann Arbor Stage and ECOG at Baseline.
Relapsed/Refractory Follicular Lymphoma: In a phase III, open-label, multicenter, randomized study (GAO4753g/GADOLIN), 396 patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximub or a rituximab-containing regimen were evaluated. Patients were randomized 1:1 to receive either bendamustine (B) alone (n = 202) or Gazyva in combination with bendamustine (G+B) (n = 194) for 6 cycles, each of 28 days duration. Patients in the G+B arm who did not have disease progression [i.e. patients with a complete response (CR), partial response (PR) or stable disease (SD)] at the end of induction continued receiving Gazyva maintenance until disease progression or for up to two years (whichever occurred first).
The demographic data and baseline characteristics were well balanced [median age was 63 years; the majority of patients were Caucasian (88%) and male (58%)]. The median time from initial diagnosis was 3 years and the median number of prior therapies was 2 (range 1 to 10); 44% of patients had received 1 prior therapy and 34% of patients had received 2 prior therapies.
Gazyva was given intravenously as a 1000 mg dose on Days 1, 8 and 15 of Cycle 1, on Day 1 of Cycles 2-6, and in patients who did not have disease progression, every 2 months for up to 2 years or until disease progression. Bendamustine was given intravenously on Days 1 and 2 for all treatment cycles (Cycles 1-6) at 90 mg/m2/day when given in combination with Gazyva or 120 mg/m2/day when given alone.
The primary analysis demonstrated a statistically significant and clinically meaningful 45% reduction in the risk of disease progression (PD) or death, based on IRC assessment, in patients with iNHL receiving G+B followed by G maintenance vs B alone stratified log-rank test p value = 0.0001). IRC-assessed response rates at the end of induction treatment and IRC-assessed best overall response within 12 months of start of treatment were similar in the two treatment arms.
The majority of the patients had follicular lymphoma (FL) (81.1%). Efficacy results from the primary analysis in the FL population are shown in Table 3 and Figure 5 and 6. Of the non-follicular patients, 11.6% had marginal zone lymphoma (MZL) and 7.1% had small lymphocytic lymphoma (SLL). No conclusions could be drawn on efficacy in the MZL and SLL.
At final analysis, the median observation time was 45.9 months (range: 0-100.9 months) for FL patients in the B arm and 57.3 months (range: 0.4-97.6 months) for patients in the G+B arm, representing an additional 25.6 months and 35.2 months of median follow-up in B and G+B arms, respectively, since the primary analysis. Only Investigator (INV) assessed endpoints were reported at final analysis since IRC assessments did not continue. Overall, the efficacy results were consistent with what was observed in the primary analysis. The overall survival (OS) in patients with FL was stable with longer follow-up (see Figure 7); the HR for risk of death was 0.71 (95%CI: 0.51, 0.98). (See Table 3 and Figure 5.)

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Results of subgroup analyses: Results of subgroup analyses were in general consistent with the results seen in the overall the FL population, supporting the robustness of the overall result. (See Figure 6 and Figure 7.)

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Patient Reported Outcomes: Previously Untreated Follicular Lymphoma: Based on the FACT-Lym questionnaire collected during treatment and follow-up periods, both arms experienced clinically meaningful improvements in lymphoma-related symptoms as defined by a ≥ 3 point increase from baseline in the Lymphoma subscale, a ≥ 6 point increase from baseline in the FACT Lym TOI and a ≥ 7 point increase from baseline in the FACT Lym Total score. EQ-5D utility scores were similar at baseline, during treatment and follow-up. No meaningful differences were seen between the arms in HRQOL or health status measures.
Relapsed/Refractory Follicular Lymphoma: Based on the FACT-Lym questionnaire and EQ-5D index scale collected during the treatment and follow-up periods, health-related quality of life was generally maintained in the pivotal study with no meaningful difference between the arms. However, the addition of Gazyva to bendamustine delayed the time to worsening of quality of life as measured by the FACT-Lym TOI score (HR = 0.83; 95% CI: 0.60, 1.13).
Immunogenicity: Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, assay robustness to quantities of Gazyva /antibody in circulation, sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of incidence of antibodies to Gazyva with the incidence of antibodies to other products may be misleading. Patients in the CLL pivotal trial, BO21004/CLL11, were tested at multiple time points for antitherapeutic antibodies (ATA) to Gazyva. In Gazyva treated patients, 8 out of 140 in the randomised phase and 2 out of 6 in the run-in phase tested positive for ATA at 12 months of follow-up. Of these patients, none experienced either anaphylactic or hypersensitivity reactions that were considered related to ATA, nor was clinical response affected.
No post-baseline HAHA (Human Anti-Human Antibody) were observed in patients with iNHL treated in study GAO4753g/GADOLIN. In study BO21223/GALLIUM, 1/565 patient (0.2% of patients with a post-baseline assessment) developed HAHA at induction completion. While the clinical significance of HAHA is not known, a potential correlation between HAHA and clinical course cannot be ruled out.
Pharmacokinetics: A population pharmacokinetic model was developed to analyse the PK data in 469 iNHL, 342 CLL, and 130 DLBCL patients from Phase 1, Phase II and Phase III studies who received Gazyva.
Absorption: Gazyva is administered intravenously, there have been no clinical studies performed with other routes of administration.
From the population PK model, after the cycle 6 day 1 infusion in CLL patients, the estimated median Cmax value was 465.7 μg/ml and AUC(τ) value was 8.961 μg·d/ml and in iNHL patients the estimated median Cmax value was 539.3 μg/ml and AUC(τ) value was 10,956 μg*d/ml.
Distribution: Following intravenous administration, the volume of distribution of the central compartment (2.72 l), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid.
Metabolism: The metabolism of Gazyva has not been directly studied. Antibodies are mostly cleared by catabolism.
Elimination: The clearance of Gazyva was approximately 0.11 l/day in CLL patients and 0.08 l/day in iNHL patients with a median elimination t½ of 26.4 days in CLL patients and 36.8 days in iNHL patients.
Gazyva elimination comprises two parallel pathways which describe clearance, a linear clearance pathway and a non-linear clearance pathway which changes as a function of time. During the initial treatment, the non-linear time-varying clearance pathway is dominant and is consequently the major clearance pathway. As treatment continues, the impact of this pathway diminishes and the linear clearance pathway predominates. This is indicative of target-mediated drug disposition (TMDD), where the initial abundance of CD20 cells causes a rapid removal of Gazyva from the circulation. However, once the majority of CD20 cells are bound with Gazyva, the impact of TMDD on PK is minimized.
Pharmacokinetics in Special Populations: In the population pharmacokinetic analysis, gender was found to be a covariate which explains some of the inter-patient variability, with an 18% greater steady-state clearance (Clss) and an 19% greater volume of distribution (V) in males. However, results from the population analysis have shown that the differences in exposure are not significant (with an estimated median AUC and Cmax in CLL patients of 11282 μg*·d/ml and 578.9 μg/ml in females and 8451 μg·d/ml and 432.5 μg/ml in males, respectively, at Cycle 6, and AUC and Cmax in iNHL patients of 13172 μg·d/mL and 635.7 μg/mL in females and 9769 μg*d/mL and 481.3 μg/mL in males, respectively), indicating that there is no need to dose adjust based on gender.
Geriatric Population: The population pharmacokinetic analysis of Gazyva showed that age did not affect the pharmacokinetics of Gazyva. No significant difference was observed in the pharmacokinetics of Gazyva among patients <65 years (n=454), patients between 65-75 years (n=317) and patients >75 years (n=190).
Pediatric Population: No studies have been conducted to investigate the pharmacokinetics of Gazyva in children.
Renal Impairment: The population pharmacokinetic analysis of Gazyva showed that creatinine clearance does not affect pharmacokinetics of Gazyva. Pharmacokinetics of Gazyva in patients with mild creatinine clearance (CrCl 50-89 ml/min, n=464) or moderate (CrCl 30 to 49 ml/min, n=106) renal impairment were similar to those in patients with normal renal function (CrCl ≥ 90 ml/min, n=383). Pharmacokinetic data in patients with severe renal impairment (CrCl 15-29 ml/min) is limited (n=8), therefore no dosage recommendations can be made.
Hepatic Impairment: No formal pharmacokinetic study has been conducted and no population PK data was collected in patients with hepatic impairment.
Toxicity: Nonclinical Safety: Carcinogenicity: No carcinogenicity studies have been performed to established the carcinogenic potential of Gazyva.
Genotoxicity: No studies have been performed to establish the genotoxic potential of Gazyva.
Impairment of Fertility: No specific studies in animals have been performed to evaluate the effect of Gazyva on fertility. No adverse effects on male and female reproductive organs were observed in repeat-dose toxicity studies in cynomolgus monkey.
Reproductive Toxicity: An enhanced pre- and postnatal development (ePPND) toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received weekly intravenous Gazyva doses [mean AUC0-168 h at steady state (on day 139 p.c.) was 125,000 and 250,000 (μg·h)/ml at 25 and 50 mg/kg, respectively; mean Cmax was 1,220 and 2,470 μg/ml at 25 and 50 mg/kg, respectively] during gestation (organogenesis period; postcoitum days 20 through delivery). Exposed offspring did not exhibit any teratogenic effects but B-cells were completely depleted on day 28 postpartum. Offspring exposures on day 28 postpartum suggest that Gazyva can cross the blood-placenta barrier. Concentrations in infant serum on day 28 postpartum were in the range of concentrations in maternal serum, whereas concentrations in milk on the same day were very low (less than 0.5% of the corresponding maternal serum levels) suggesting that exposure of infants must have occurred in utero. B-cell counts returned to normal levels, and immunologic function was restored within 6 months postpartum.
Other: In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanized antibody in cynomolgus monkeys [Cmax and AUC0-168 h at steady state (day 176) after weekly administration of 5, 25, and 50 mg/kg were 377, 1,530, and 2,920 μg/ml and 39,800, 183,000, and 344,000 (μg·h)/ml, respectively]. Findings included acute anaphylactic or anaphylactoid reactions and an increased prevalence of systemic inflammation and infiltrates consistent with immune-complex mediated hypersensitivity reactions, such as arteritis/periarteritis, glomerulonephritis, and serosal/adventitial inflammation. These reactions led to unscheduled termination of 6/36 animals treated with Gazyva during dosing and recovery phases; these changes were partially reversible. No renal toxicity with a causal relationship to Gazyva has been observed in humans.
Indications/Uses
Chronic Lymphocytic Leukemia (CLL): Gazyva in combination with chlorambucil is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia with comorbidities.
Follicular Lymphoma: Gazyva in combination with chemotherapy, followed by Gazyva maintenance therapy in patients achieving a response, is indicated for the treatment of patients with previously untreated advanced follicular lymphoma.
Gazyva in combination with bendamustine followed by Gazyva maintenance is indicated for the treatment of patients with follicular lymphoma (FL) who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.
Dosage/Direction for Use
General: Substitution of Gazyva with any other biological medicinal product requires the consent of the prescribing physician. Gazyva should be administered as an intravenous infusion through a dedicated line in an environment where full resuscitation facilities are immediately available and under the close supervision of an experienced physician. Gazyva infusions should not be administered as an intravenous push or bolus. Isotonic 0.9% sodium chloride solution should be used as the infusion vehicle (see Special Instructions for Use, Handling and Disposal under Cautions for Usage).
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. Prophylaxis should consist of adequate hydration and administration of uricostatics (e.g. allopurinol) or suitable alternative such as a urate oxidase (e.g. rasburicase) prior to start of Gazyva infusion as per standard practice (see Precautions). Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate.
Prophylaxis and Premedication for Infusion-Related Reactions (IRR): Premedication to reduce the risk of infusion related reactions (see Precautions) is outlined in Table 4. Corticosteroid premedication is recommended for FL patients and mandatory for CLL patients for the first infusion. Premedication for subsequent infusions and other premedication should be administered as described as follows.
Hypotension, as a symptom of IRR, 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 (see Precautions). (See Table 4.)

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Standard Dosage: Chronic Lymphocytic Leukemia (in combination with chlorambucil1): Cycle 1: The recommended dosage of Gazyva is 1000 mg administered over Day 1 and Day 2 and on Day 8 and Day 15 of the first 28-day treatment cycle as shown in Table 5.
Two infusion bags should be prepared for the first dose 100 mg for the first infusion and 900 mg for the second infusion. If the 100 mg dose is completed without modifications of the infusion rate or interruptions, the 900 mg dose can be administered on the same day (without dose delay) 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 900 mg infusion must be administered the following day (see Table 5).
Cycle 2-6: The recommended dosage of Gazyva is 1000 mg administered on Day 1 for each 28 day treatment cycle as shown in Table 5. (See Table 5.)

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Delayed or Missed Doses (CLL): If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not wait until the next planned dose. The planned treatment interval for Gazyva should be maintained between doses.
Follicular Lymphoma: The recommended dosage of Gazyva is 1000 mg administered intravenously according to Table 6.
Previously Untreated Follicular Lymphoma: For patients with previously untreated follicular lymphoma, Gazyva should be administered with chemotherapy as follows: Six 28 day cycles in combination with bendamustine2 or, Six 21 day cycles in combination with CHOP, followed by 2 additional cycles of Gazyva alone or, Eight 21 day cycles in combination with CVP.
Previously untreated patients who achieve a complete or partial response to Gazyva plus chemotherapy should continue to receive Gazyva (1000 mg) alone as maintenance therapy once every 2 months until disease progression or for up to 2 years.
Relapsed/Refractory Follicular Lymphoma: For patients with follicular lymphoma who have relapsed after or who are refractory to rituximab or a rituximab-containing regimen, Gazyva should be administered in six 28 day cycles in combination with bendamustine2.
Relapsed/Refractory patients who achieve complete or partial response or have stable disease should continue to receive Gazyva 1000 mg alone as maintenance therapy once every 2 months until disease progression or for up to 2 years. (See Table 6.)

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Delayed or missed doses (FL): If a planned dose of Gazyva is missed, it should be administered as soon as possible; do not omit it or wait until the next planned dose. If toxicity occurs before Cycle 1 Day 8 or Cycle 1 Day 15, requiring delay of treatment, these doses should be given after resolution of toxicity. In such instances, all subsequent visits and the start of Cycle 2 will be shifted to accommodate for the delay in Cycle 1. During maintenance, maintain the original dosing schedule for subsequent doses.
Dosage Modifications During Treatment (all indications): No dose reductions of Gazyva are recommended.
For management of symptomatic adverse events (including IRRs), see Table 7 as follows and Precautions. (See Table 7.)

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Special Dosage Instructions: Pediatric Use: The safety and efficacy of Gazyva in children below 18 years of age have not been established.
Geriatric Use: No dose adjustment is required in patients ≥65 years of age (see Use in Elderly under Precautions).
Renal Impairment: No dose adjustment is required in patients with mild or moderate renal impairment. Gazyva has not been studied in patients with a CrCl ≤30 ml/min (see Renal Impairment under Precautions and Pharmacology: Pharmacokinetics: Pharmacokinetics in Special Populations under Actions).
Hepatic Impairment: The safety and efficacy of Gazyva in patients with hepatic impairment have not been established.
Overdosage
No experience with overdosage is available from human clinical trials. In clinical trials with Gazyva, doses ranging from 50 mg up to and including 2000 mg per infusion have been administered. The incidence and intensity of adverse reactions reported in these studies did not appear to be dose-dependent.
Patients who experience overdose should have immediate interruption or reduction of their infusion and should be closely supervised. Consideration should be given to the need for regular monitoring of blood cell count and for increased risk of infections while patients are B-cell-depleted.
Contraindications
Gazyva is contraindicated in patients with a known hypersensitivity to obinutuzumab or to any of the excipients.
Special Precautions
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.
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 antihypertensive 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 hemorrhagic events have also been reported in cycle 1 in patients treated with Gazyva. A clear relationship between thrombocytopenia and hemorrhagic 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 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.
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 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.
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.
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% 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 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: Pharmacodyamics: Efficacy/Clinical studies under Actions).
Hepatic Impairment: The safety and efficacy of Gazyva in patients with hepatic impairment have not been established.
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.
Use In Pregnancy & Lactation
Pregnancy: Gazyva should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Women of child-bearing potential should use effective contraception while receiving Gazyva and for 18 months following treatment with Gazyva (see Pharmacology: Pharmacokinetics: Elimination under Actions). 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.
No studies in pregnant women have been performed. A reproduction study in cynomolgus monkeys showed no evidence of embryofoetal toxicity or teratogenic effects but resulted in a complete depletion of B lymphocytes in offspring. B-cell counts returned to normal levels in the offspring, and immunologic function was restored within 6 months of birth. Furthermore, the serum concentrations of Gazyva in offspring were similar to those in the mothers on day 28 post-partum, whereas concentrations in milk on the same day were very low, suggesting that Gazyva crosses the placenta.
Labor and Delivery: No data to report.
Lactation: Since human IgG is secreted in human milk, and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue nursing during Gazyva therapy and for 18 months after the last dose of Gazyva (see Pharmacology: Pharmacokinetics: Elimination under Actions). Animal studies have shown excretion of Gazyva in breast milk (see Pharmacology: Toxicology: Nonclinical Safety: Reproductive toxicity under Actions).
Adverse Reactions
Clinical Trials: Clinical trials were conducted in patients with various hematologic malignancies (e.g. CLL and iNHL) who were treated with Gazyva, predominantly in combination with chemotherapy (CHOP, CVP, Chlorambucil or Bendamustine). The safety profile from the clinical trial population of approximately 4900 patients is presented in this section. See Post-marketing Experience as follows and Pharmacology: Pharmacodynamics: Clinical/Efficacy Studies under Actions.
The most serious adverse drug reactions were: Infusion related reactions which is more common in CLL patients (see General under Precautions).
Tumor Lysis Syndrome which is more common in patients with a high tumour burden and/or a high circulating lymphocyte count patients and/or renal impairment (see General under Precautions).
Thrombocytopenia, which can be fatal in Cycle 1 (see General under Precautions).
The most frequently observed adverse drug reactions across clinical trials in patients receiving Gazyva were IRR, neutropenia, diarrhea, constipation, and cough.
Table 8 lists adverse drug reactions associated with the use of Gazyva in combination with different chemotherapy regimens in multiple indications.
The adverse drug reactions listed in this table fall into the following categories (Very Common (≥ 10%), Common (≥ 1% - < 10%) and Uncommon (≥ 0.1% - < 1%)). Adverse drug reactions are added to the appropriate category in the table as follows according to the highest incidence (difference of ≥ 2% compared to the relevant comparator arm) seen in any of the major clinical trials. Within each frequency grouping adverse drug reactions are presented in order by system organ class. (See Table 8.)

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Further Information on Selected Adverse Drug reactions: Infusion-related reactions: Most frequently reported (≥5%) symptoms associated with an IRR were nausea, vomiting, diarrhoea, headache, dizziness, fatigue, chills, pyrexia, hypotension, flushing, hypertension, tachycardia, dyspnoea, and chest discomfort. Respiratory symptoms such as, bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and cardiac symptoms such as atrial fibrillation have also been reported (see Precautions).
Chronic Lymphocytic Leukaemia: The incidence of IRRs was 65% with the infusion of the first 1000 mg of Gazyva (20% of patients experiencing a Grade 3-4 IRR). Overall, 7% of patients experienced an IRR leading to discontinuation of Gazyva. The incidence of IRR with subsequent infusions was 3% with the second 1000 mg dose and 1% thereafter. No Grade 3-5 IRR were reported beyond the first 1000 mg infusions of cycle 1.
In patients who received the recommended measures for prevention of IRRs as described in Dosage & Administration, a decreased incidence of all grades IRRs was observed. The rates of Grade 3-4 IRRs (which are based on a relatively low number of patients) were similar before and after mitigation measures were implemented.
Non-Hodgkin Lymphoma: In Cycle 1, the overall incidence of IRRs was higher in patients receiving Gazyva plus chemotherapy compared to patients in the comparator arm. In patients receiving Gazyva plus chemotherapy, the incidence of IRR was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyva.
Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyva.
Neutropenia and infections: Chronic Lymphocytic Leukaemia: The incidence of neutropenia was higher in the Gazyva plus chlorambucil arm compared to the rituximab plus chlorambucil arm with the neutropenia resolving spontaneously or with use of granulocyte colony-stimulating factors. The incidence of infection was 38% in the Gazyva plus chlorambucil arm and 37% in the rituximab plus chlorambucil arm (with Grade 3-5 events reported in 12% and 14%, respectively, and fatal events reported in <1% in both treatment arms)]. Cases of prolonged neutropenia (2% in the Gazyva and chlorambucil arm and 4% in rituximab plus chlorambucil arm) and late onset neutropenia (16% in the Gazyva plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see Precautions).
Non-Hodgkin Lymphoma: In the Gazyva plus chemotherapy arm, the incidence of neutropenia was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia in the Gazyva plus chemotherapy arm were 3% and 7%, respectively. The incidence of infection was 78% in the Gazyva plus chemotherapy arm (with Grade 3-5 events reported in 22% and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections. (see Precautions).
Thrombocytopenia and haemorrhagic events: Chronic Lymphocytic Leukaemia: The incidence of thrombocytopenia was higher in the Gazyva plus chlorambucil arm compared to the rituximab plus chlorambucil arm especially during the first cycle. Four percent of patients treated with Gazyva arm plus chlorambucil experienced acute thrombocytopenia (occurring within 24 hours after the Gazyva infusion) (see Precautions). The overall incidence of haemorrhagic events was similar in the Gazyva treated arm and in the rituximab treated arm. The number of fatal hemorrhagic events was balanced between the treatment arms; however all of the events in patients treated with Gazyva were reported in cycle 1. A clear relationship between thrombocytopenia and hemorrhagic events has not been established.
Non-Hodgkin Lymphoma: Thrombocytopenia occurred more frequently during Cycle 1 in the Gazyva plus chemotherapy arm. Thrombocytopenia occurring during or 24 hours from end of infusion (acute thrombocytopenia) was more frequently observed in patients treated with Gazyva plus chemotherapy than in the relevant comparator arm. The incidence of haemorrhagic AEs was similar across all treatment arms. Haemorrhagic events and Grade 3-5 haemorrhagic events occurred in 12% and 4% of patients, respectively. While fatal haemorrhagic events occurred in less than 1% of patients, none of these fatal AEs occurred in Cycle 1.
Progressive multifocal leukoencephalopathy (PML): PML has been reported in patients treated with Gazyva (see Precautions).
Hepatitis B Reactivation: Cases of hepatitis B reactivation have been reported in patients treated with Gazyva (see Precautions).
Worsening of pre-existing cardiac conditions: Cases of fatal cardiac events have been reported in patients treated with Gazyva (see Precautions).
Gastro-Intestinal Perforation: Cases of gastro-intestinal perforation have been reported in patients receiving Gazyva, mainly in NHL.
Maintenance treatment in iNHL patients: In GAO4753g, patients in the B arm received 6 months of induction treatment only, whereas after the induction period, patients in the G+B arm continued on with Gazyva maintenance treatment. During the maintenance period with Gazyva, the most common adverse reactions were cough (20.3%), neutropenia (12.7%), upper respiratory tract infections (12.0%), diarrhoea (10.1%), bronchitis (9.5%), sinusitis (9.5%), nausea (8.9%), fatigue (8.9%), infusion related reactions (8.2%), urinary tract infections (7.0%), nasopharyngitis (7.0%), pyrexia (7.0%), arthralgia (6.3%), vomiting (5.7%), rash (5.7%), pneumonia (5.1%), dyspnea (5.1%) and pain in extremity (5.1%). The most common grade 3-5 adverse reactions were neutropenia (10.8%), febrile neutropenia (1.9%) and anaemia, thrombocytopenia, pneumonia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1.3%).
Laboratory Abnormalities: Transient elevation in liver enzymes (AST, ALT, ALP) has been observed shortly after the first infusion of Gazyva.
For additional information, see previously mentioned, Further Information on Selected Adverse Drug Reactions, Neutropenia and infections, and Thrombocytopenia.
Post-marketing Experience: No data to report.
Drug Interactions
No formal drug-drug interaction studies have been performed, although limited drug interaction sub-studies have been undertaken for Gazyva with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC (fludarabine, cyclophosphamide) and chlorambucil. Co-administration with Gazyva had no effect on the pharmacokinetics of bendamustine, FC or the individual components of CHOP; in addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyva. A risk for interactions with concomitantly used medicinal products cannot be excluded.
Caution For Usage
Special Instructions for Use, Handling and Disposal: Instructions for Dilution: Gazyva should be prepared by a healthcare professional using aseptic technique.
For CLL cycles 2-6 and all FL cycles: Withdraw 40 mL of Gazyva liquid concentrate from the vial and dilute in PVC or non-PVC polyolefin infusion bags containing sterile, non-pyrogenic 0.9% aqueous sodium chloride solution.
For preparation of infusion bags for CLL only Cycle 1, Day 1 dose administered over 2 days: To ensure differentiation of the two infusion bags for the initial 1000 mg dose, the recommendation is to utilise bags of different sizes to distinguish between the 100 mg dose for cycle 1 day 1 and the 900 mg dose for cycle 1 day 1 (continued) or day 2. To prepare the infusion bags, withdraw 40 ml of Gazyva liquid concentrate from vial and dilute 4 ml into a 100 ml infusion bag and the remaining 36 ml in a 250 ml PVC or non-PVC polyolefin infusion bags containing sterile, non-pyrogenic 0.9% aqueous sodium chloride solution. Clearly label each infusion bag. (See Table 9.)

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Do not use other diluents such as dextrose (0.5%) solution (see Incompatibilities as follows).
The bag should be gently inverted to mix the solution in order to avoid excessive foaming.
Parenteral drug products should be inspected visually for particulates and discoloration prior to administration.
Incompatibilities: No incompatibilities between Gazyva and polyvinyl chloride or polyethylene or polypropylene or polyolefine bags or polyvinyl chloride (PVC) or polyurethane (PUR) or polyethylene (PE) infusion sets as well as optional inline filters with product contact surfaces of polyethersulfon (PES), a 3-way stopcock infusion aid made from polycarbonate (PC), and catheters made from polyetherurethane (PEU) have been observed in concentration ranges from 0.4 mg/ml to 20.0 mg/ml after dilution of Gazyva with 0.9% sodium chloride. Diluted product should be shaken or frozen.
Do not use other diluents such as dextrose (5%) solution to dilute Gazyva since its use has not been tested.
Disposal of Unused/Expired Medicines: The release of pharmaceuticals in the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Use established "collection system", if available in the location.
Storage
Store vials in a refrigerator at 2°C-8°C.
Keep vial in the outer carton in order to protect from light.
Do not freeze. Do not shake.
Shelf-life of the Solution for Infusion Containing the Product: Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C-8°C followed by 24 hours at ambient temperature (≤30°C) followed by an infusion taking no longer than 24 hours.
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.
Gazyva does not contain antimicrobial preservatives. Therefore care must be taken to ensure that the solution for infusion is not microbiologically compromised during preparation.
ATC Classification
L01XC15 - obinutuzumab ; Belongs to the class of monoclonal antibodies, other antineoplastic agents. Used in the treatment of cancer.
Presentation/Packing
Infusion conc (clear, colourless to slightly brownish liquid in vial) 1,000 mg/40 mL.
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