Gazyva: Indications, Dosage, Precautions, Adverse Effects
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Gazyva - Product Information

Manufacture: Roche
Country: Australia
Condition: Chronic Lymphocytic Leukemia, Follicular Lymphoma
Class: Antineoplastics, CD20 monoclonal antibodies
Form: Liquid solution, Intravenous (IV)
Ingredients: obinutuzumab, histidine, histidine hydrochloride monohydrate, trehalose dehydrate, poloxamer 188

obinutuzumab

CAS: 949142-50-1

Warning

Progressive Multifocal Leucoencephalopathy

Progressive Multifocal Leukoencephalopathy (PML) including fatal PML can occur in patients receiving GAZYVA. Patients must be monitored for any new or worsening neurological symptoms or signs suggestive of PML. If such symptoms occur, further administration of GAZYVA should be immediately suspended until a diagnosis of PML has been excluded. If a diagnosis of PML is confirmed GAZYVA must be permanently discontinued (see PRECAUTIONS).

GAZYVA (obinutuzumab) is a recombinant monoclonal humanised and glycoengineered Type II anti-CD20 antibody of the IgG1 isotype.

Description

GAZYVA is supplied in a single-dose vial containing 40 mL of preservative-free concentrate solution for infusion. Each vial contains 1000 mg of obinutuzumab (25 mg/mL) with the following excipients: histidine, histidine hydrochloride monohydrate, trehalose dehydrate and poloxamer 188.

Pharmacology

Pharmacodynamics

Obinutuzumab specifically targets the extracellular loop of the CD20 transmembrane antigen on the surface of non-malignant and malignant pre B and mature B lymphocytes. CD20 is not expressed on haemopoietic stem cells, pro B cells, or normal plasma cells. Glycoengineering of the Fc part of obinutuzumab 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 nonclinical studies, obinutuzumab 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, obinutuzumab mediates a low degree of complement dependent cytotoxicity (CDC). In animal models, obinutuzumab mediates potent B cell depletion and anti-tumour efficacy. Compared to Type I CD20 antibodies, obinutuzumab, a Type II antibody, is characterised by a direct cell death induction with a concomitant reduction in CDC. Compared to non-glycoengineered CD20 antibodies, obinutuzumab is characterised by greater ADCC as a consequence of the glycoengineering, but in vivo studies in xenograft tumour models in SCID mice showed no difference in tumour growth inhibition between obinutuzumab and non-glycoengineered wild type obinutuzumab.

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.

Pharmacokinetics

A population pharmacokinetic (PK) model was developed to analyse the PK data in 590 no-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) patients from phase I, phase II and phase III studies who received GAZYVA. This population PK model was used to describe the PK characteristics of obinutuzumab in patients with CLL. From the population model, after the Cycle 6 Day 1 infusion in CLL patients, the Cmax value was 510.6 μg/mL and AUC(T) value was 10,113 μg.d/mL.

Absorption

Obinutuzumab is administered intravenously therefore absorption is not applicable. There have been no clinical studies performed with other routes of administration.

Distribution

Following intravenous administration, the volume of distribution of the central compartment (2.77 L), approximates serum volume, which indicates distribution is largely restricted to plasma and interstitial fluid.

Metabolism

The metabolism of obinutuzumab has not been directly studied. Antibodies are mostly cleared by catabolism.

Excretion

The clearance of obinutuzumab on Cycle 6 in CLL patients is approximately 0.085 L/day with an elimination t½ of approximately 30.4 days. Obinutuzumab elimination comprises a time varying clearance model with 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 initiation of treatment, the non-linear time-varying clearance pathway is dominant and accounts for the major clearance pathway. As treatment progresses, 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 depletion of obinutuzumab. However, once the majority of CD20 cells are bound to obinutuzumab, there is reduced impact of TMDD on PK.

Pharmacokinetics in special populations

In the population PK analysis, gender was found to be statistically significant in explaining the inter-patient variability, with a 23% greater steady state clearance (CLss) and an 18% 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 of 11256 μg*d/mL and 578.8 μg/mL in females and 8064 μg*h/mL and 431.3 μg/mL in males, respectively at Cycle 6), indicating that there is no need to dose adjust based on gender.

Elderly Patients: The population pharmacokinetic analysis of obinutuzumab showed that age did not affect the pharmacokinetics of obinutuzumab. No significant difference was observed in the pharmacokinetics of obinutuzumab among patients < 65 years (n=265), patients between 65-75 years (n=197) and patients > 75 years (n=128).

Paediatric Patients: No studies have been conducted to investigate the pharmacokinetics of obinutuzumab in children.

Renal impairment: The population pharmacokinetic analysis of obinutuzumab showed that creatinine clearance does not affect the pharmacokinetics of obinutuzumab. Pharmacokinetics of obinutuzumab in patients with mild creatinine clearance (CrCl 50 to 89 mL/min, n=306) or moderate (CrCl 30 to 49 mL/min, n=72) renal impairment were similar to those in patients with normal renal function (CrCl ≥ 90 mL/min, n=207). PK data in patients with severe renal impairment (CrCl 15-29 mL/min) is limited (n=5), therefore no dosage recommendations can be made.

Hepatic impairment: No formal PK study has been conducted and no population PK data was collected in patients with hepatic impairment.

Clinical trials

Chronic Lymphocytic Leukaemia (CLL)

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 CLL 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 1-5.

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 reactions in patients, an amendment was implemented and 140 patients received the first GAZYVA dose administered over 2 days (Day 1 (100mg) and Day 2 (900mg), see DOSAGE AND 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% of 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 cut off of 30% or higher) in the MedDRA body systems are: Vascular disorders 73%, Cardiac disorders 46%, Gastrointestinal disorders 38%, Metabolism and Nutrition disorders 40%, Renal and Urinary disorders 38%, 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, molecular remission at end of treatment (minimal residual disease status) and time to event endpoints (event-free survival, new anti-leukemic therapy). Overall survival for Stage 1 is presented in Figure 3. Overall survival for Stage 2 will continue to be followed and is not yet mature.

Table 1 Summary of efficacy from BO21004 (CLL11) study
Stage 1 Stage 2
Chlorambucil
n = 118
GAZYVA +
Chlorambucil
n =238
Rituximab +
Chlorambucil
n = 330
GAZYVA +
Chlorambucil
n =333
22.8 months median
observation time
18.7 months median
observation time
Investigator-assessed PFS
(PFS-INV)*
Number (%) of patients with
event
96 (81.4%) 93 (39.1%) 199 (60.3%) 104 (31.2%)
Median duration of PFS
(months)
11.1 26.7 15.2 26.7
HR (95% Cl) 0.18 [0.13; 0.24] 0.39 [0.31; 0.49]
p-value (Log-Rank test,
stratified)
< 0.0001 < 0.0001
IRC-assessed PFS (PFS-IRC)*
Number (%) of patients with
event
90 (76.3%) 89 (37.4%) 183 (55.5%) 103 (30.9%)
Median duration of PFS
(months)
11.2 27.2 14.9 26.7
HR (95% Cl) 0.19 [0.14; 0.27] 0.42 [0.33; 0.54]
p-value (Log-Rank test,
stratified)
< 0.0001 < 0.0001
End of Treatment Response
No. of patients included in the
analysis
118 238 329 333
Responders (%) 37 (31.4 %) 184 (77.3%) 214 (65.0%) 261 (78.4%)
Non-responders (%) 81 (68.6%) 54 (22.7%) 115 (35.0%) 72 (21.6%)
Difference in response (95% Cl) 45.95 [35.6; 56.3] 13.33 [6.4; 20.3]
p-value (Chi-squared Test) < 0.0001 < 0.0001
No. of complete responders
(%)
0 (0.0%) 53 (22.3%) 23 (7.0%) 69 (20.7%)
Molecular Remission at end of
treatment§
No. of patients included in the
analysis
90 168 244 239
MRD negative (%) 0 (0%) 45 (26.8%) 6 (2.5%) 61 (25.5%)
MRD positive\\ (%) 90 (100%) 123 (73.2%) 238 (97.5%) 178 (74.5%)
Difference in MRD (95% Cl) 26.79 [19.5; 34.1] 23.06 [17.0; 29.1]
Event Free Survival
No. (%) of patients with event 103 (87.3%) 104 (43.7%) 208 (63.0%) 118 (35.4%)
Median time to event (months) 10.8 26.1 14.3 26.1
(95% Cl) 0.19 [0.14; 0.25] 0.43 [0.34; 0.54]
p-value (Log-Rank test,
stratified)
< 0.0001 < 0.0001
Time to new anti-leukaemic
therapy
No. (%) of patients with event 65 (55.1%) 51 (21.4%) 86 (26.1%) 55 (16.5%)
Median duration of event
(months)
14.8 - 30.8 -
HR (95% Cl) 0.24 [0.16; 0.35] 0.59 [0.42; 0.82]
p-value (Log-Rank test,
stratified)
< 0.0001 < 0.0018
Overall Survival
No. (%) of patients with event 24 (20.3%) 22 (9.2%) 41 (12.4%) 28 (8.4%)
Median time to event (months) NR NR NR** NR**
HR (95% Cl) 0.41 [0.23; 0.74] 0.66 [0.41; 1.06]**
p-value (Log-Rank test,
stratified)
0.0022 0.0849**

PFS: progression-free survival; HR: hazard ratio; CI: confidence intervals; MRD: minimal residual disease; NR: not reached

* Defined as the time from randomisation to the first occurrence of progression, relapse or death from any cause as assessed by the investigator

** Data not yet mature

† stratified by Binet stage at baseline

‡ includes 11 patients in the GClb arm with a complete response with incomplete marrow recovery

§ blood and bone marrow combined

¶ Minimal Residual Disease (MRD) negativity is defined as <1 CLL cell in 10,000 leucocytes

\\ includes MRD positive patients and patients who progressed or died before the end of treatment

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 ITT population. The risk of disease progression or death was reduced in the GAZYVA plus chlorambucil (GClb) arm compared to the rituximab plus chlorambucil (RClb) arm and the chlorambucil (Clb) alone arm 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.

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.

Figure 1 Kaplan-Meier curve of Investigator-assessed PFS from Stage 1



Figure 2 Kaplan-Meier curve of IRC-assessed PFS from Stage 1



Figure 3 Kaplan-Meier curve of Overall Survival from Stage 1



Figure 4 Kaplan-Meier curve of Investigator-assessed PFS from Stage 2



Figure 5 Kaplan-Meier curve of IRC-assessed PFS from Stage 2



Immunogenicity

Patients in the pivotal trial, BO21004/CLL11, were tested at multiple time-points for anti therapeutic antibodies (ATA) to GAZYVA. In GAZYVA treated patients, 8 out of 140 in the randomised phase and 2 out 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.

Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, assay robustness to quantities of GAZYVA 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.

Indications

GAZYVA in combination with chlorambucil is indicated for the treatment of patients with previously untreated chronic lymphocytic leukaemia (CLL).

Contraindications

GAZYVA is contraindicated in patients with a known hypersensitivity (IgE mediated) to obinutuzumab, murine proteins or to any of the excipients.

Precautions

In order to improve traceability of biological medicinal products, the trade name of the administered product should be clearly recorded in the patient medical record.

Infusion Related Reactions (IRR)

The most frequently observed adverse drug reactions (ADRs) in patients receiving GAZYVA were infusion related reactions (IRR) which occurred predominantly during infusion of the first 1000 mg. In patients who received the combined measures for prevention of IRRs (glucocorticoid; oral analgesic/anti-histamine (H1 histamine receptor blockade); omission of antihypertensive medication in the morning of the first infusion; Cycle 1 Day 1 dose administered over 1 or 2 days; see DOSAGE AND ADMINISTRATION) decreased incidence of all Grades IRRs was observed. The incidence of IRRs was independent of the corticosteroid pre-medication given (prednisone/prednisolone or methylprednisolone/ dexamethasone). The incidence 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 DOSAGE AND ADMINISTRATION). 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 EFFECTS).

In the majority of patients, 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 (i.e. high peripheral lymphocyte count in CLL (> 25 x 109/L)) may be at increased risk of severe IRR. See DOSAGE AND ADMINISTRATION for information on prophylaxis.

If the patient experiences an IRR, the infusion should be managed according to the grade of the reaction. For Grade 4 IRR, the infusion must be stopped and permanently discontinued. For Grade 3 IRR, the infusion should be temporarily interrupted and appropriate medication administered to treat the symptoms. For Grade 1-2 IRR, the infusion should be slowed down and symptoms treated as appropriate. Upon resolution of symptoms, infusion can be restarted, except following Grade 4 IRR, at no more than half the previous rate and, if the patient does not experience the same adverse event with the same severity, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose. If the previous infusion rate was not well tolerated, instructions for the Cycle 1, Day 1 and Day 2 infusion rate should be used (see Table 6 DOSAGE AND ADMINISTRATION).

Patients should not receive further GAZYVA infusions if they experience:

  • acute life-threatening respiratory symptoms,
  • other life-threatening anaphylactoid 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 including anaphylaxis

Hypersensitivity may be difficult to distinguish from IRRs; however, anaphylaxis has been reported in patients treated with GAZYVA. If a hypersensitivity reaction is suspected during infusion (e.g. symptoms typically occurring after previous exposure and very rarely with the first infusion), the infusion should be stopped, appropriate treatment of the hypersensitivity reaction should be commenced, and GAZYVA treatment permanently discontinued. Patients with known IgE mediated hypersensitivity to GAZYVA should not be treated (see CONTRAINDICATIONS).

In a 26-week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised 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.

Tumour Lysis Syndrome

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 oxidase (e.g. rasburicase), prior to the infusion of GAZYVA as described under DOSAGE AND 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 should also be followed, according to standard practice. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated (see PRECAUTIONS, Worsening of Pre-existing Cardiac Conditions).

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. Concomitant infection should be treated as appropriate. If treatment is necessary, it should be administered in accordance with local guidelines, and administration of granulocyte colony-stimulating factors should be considered. Cases of 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) have also been reported.

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 all 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 EFFECTS). 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.

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 EFFECTS). HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e. HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti HBs] positive).

Screen all patients for HBV infection by measuring HBsAg and anti-HBc. The results of HBsAg and anti-HBc testing should be known in all patients before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy.

Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for at least 12 months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy.

In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment and refer the patient to a gastroenterologist. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who developed HBV reactivation.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) has been reported in patients treated with GAZYVA (see BOXED WARNING, ADVERSE EFFECTS). 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 unspecific 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, during or following GAZYVA therapy has not been studied. Vaccination with live virus vaccines is not recommended during treatment and until B-cell recovery. Treatment with GAZYVA following vaccination should only commence once protective antibody titres have been reached.

Use in renal impairment

In the pivotal study, 27% (90 out of 336) of patients with CLL treated with GAZYVA plus chlorambucil had moderate renal impairment (CrCl < 50 mL/min). These patients experienced more serious adverse events and adverse events leading to death than those with CrCl ≥ 50 mL/min (see DOSAGE AND ADMINISTRATION and PHARMACOLOGY Pharmacokinetics in special populations). No significant differences in efficacy were observed between patients with CrCl < 50 mL/min and those with CrCl ≥ 50 mL/min (see CLINICAL TRIALS).

Use in hepatic impairment

The safety and efficacy of GAZYVA in patients with hepatic impairment have not been established.

Effects on 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 monkeys at up to 100 mg/kg/day for 3 months (8 times the clinical exposure based on AUC at the clinical dose of 1000 mg/kg, 3 doses per 28 day cycle) and 50 mg/kg/day for 6 months (6 times the clinical exposure based on AUC).

Use in pregnancy – Category C

GAZYVA should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the foetus. Women of child bearing potential should use effective contraception while receiving GAZYVA and for 18 months following treatment with GAZYVA (see PHARMACOLOGY, Excretion). Newborns to mothers who have been exposed to GAZYVA during pregnancy should not receive live vaccines until their B-cell levels are within normal ranges.

No studies in pregnant women have been performed. A reproduction study in pregnant cynomolgus monkeys showed no evidence of teratogenic effects. However, weekly obinutuzumab dosing from post-coitum day 20 to delivery resulted in complete depletion of B-lymphocytes, opportunistic infections and immune-complex mediated hypersensitivity reactions in infants at weekly intravenous obinutuzumab doses of 25 and 50 mg/kg (2-5 times the clinical exposure based on Cmax and AUC). Offspring exposures on day 28 postpartum (mean Cmax 80-240 μg/mL, in the range of concentrations in maternal serum) and very low concentrations in milk (less than 0.5% of the corresponding maternal serum levels) suggest in utero exposure. B-cell counts returned to normal levels in the infants, 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.

Use in lactation

As human IgG is excreted in human milk and the potential for absorption and harm to the infant is unknown, women should be advised to discontinue breast-feeding during GAZYVA therapy and for 18 months after the last dose of GAZYVA (see PHARMACOLOGY, Excretion). Animal studies have shown excretion of GAZYVA in breast milk (see PRECAUTIONS Use in pregnancy).

Paediatric use

The safety and efficacy of GAZYVA in children below 18 years of age have not been established.

Use in the elderly

In the pivotal study, 46% (156 out of 336) of patients with CLL 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 those of 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 CLINICAL TRIALS).

Genotoxicity

No studies have been performed to establish the mutagenic potential of GAZYVA.

Carcinogenicity

No carcinogenicity studies have been performed to establish the carcinogenic potential of GAZYVA.

Effect on laboratory tests

See PRECAUTIONS.

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.

Interactions with other medicines

No formal drug-drug interaction studies have been performed. A risk for interactions with concomitantly used medicinal products cannot be excluded.

Adverse effects

The adverse drug reactions (ADRs) described in this section were identified during treatment and follow-up from the pivotal clinical trial, BO21004/CLL11, in which GAZYVA was given in combination with chlorambucil compared to chlorambucil alone (Stage 1) or rituximab plus chlormabucil (Stage 2). In patients treated with GAZYVA in combination with chlorambucil, 81% received all 6 treatment cycles compared to 89% of patients in the rituximab plus chlorambucil arm and 67% of patients in the chlorambucil alone arm.

Tables 2 and 3 summarise the ADRs that occurred at a higher incidence (difference of ≥2%) in patients receiving GAZYVA plus chlorambucil as compared to chlorambucil alone or rituximab plus chlorambucil, respectively.

Table 2 Summary of ADRs reported with a higher incidence (difference of ≥ 2%) in patients receiving GAZYVA plus chlorambucil vs chlorambucil alone (Stage 1)*
ADR (MedDRA)
System Organ Class
All Grades % Grades 3-5 %
chlorambucil
n = 116
GAZYVA +
chlorambucil
n = 241
chlorambucil
n = 116
GAZYVA +
chlorambucil
n = 241
Injury, Poisoning and Procedural
Complications
Infusion related reactions N/A 68.9 N/A 21.2
Blood and lymphatic system
disorders
Neutropenia 18.1 40.7 15.5 34.9
Thrombocytopenia 7.8 15.4 4.3 11.2
Anaemia 10.3 12.4 4.3 4.6
Leucopenia 0 7.1 0 5.4
Infections and Infestations
Urinary tract infection 2.6 6.2 < 1 1.7
Oral herpes < 1 3.7 0 0
Rhinitis‡ < 1 2.1 0 0
Pharyngitis 0 2.1 0 0
General disorders and
administration site conditions
Pyrexia 6.9 10.4 0 < 1
Respiratory, thoracic and
mediastinal disorders
Cough 6.9 9.5 < 1 0
Metabolism and nutrition disorders
Tumour lysis syndrome < 1 4.1 0 1.7
Hyperuricaemia 0 3.3 0 < 1
Musculoskeletal and connective
tissue disorders
Arthralgia 2.6 4.6 < 1 < 1
Back pain 1.7 5.0 0 < 1
Musculoskeletal chest pain 0 2.5 0 < 1
Vascular disorders
Hypertension 1.7 3.7 1.7 1.7
Investigations
White blood cell count decreased‡ < 1 2.1 0 2.1
Neutrophil count decreased 0 2.1 0 2.1
Weight increased 0 2.1 0 0
Cardiac disorders
Atrial fibrillation 0 2.1 0 < 1
Neoplasms benign, malignant and
unspecified (incl cysts and polyps)
Squamous cell carcinoma of skin 0 2.1 0 1.2
Gastrointestinal disorders
Diarrhoea‡ 11.2 10.4 < 1 2.5
Skin and subcutaneous tissue
disorders
Alopecia 0 2.1 0 0

* In all Grades or Grade 3-5

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms

With Stage 1 update and Stage 2 data, this event was no longer reported with a difference of ≥ 2% between the treatment arms

Table 3 Summary of ADRs reported with a higher incidence (difference of ≥ 2%) in patients receiving GAZYVA plus chlorambucil vs rituximab plus chlorambucil (Stage 2)*
ADR (MedDRA)
System Organ Class
All Grades % Grades 3-5 %
rituximab +
chlorambucil
n = 321
GAZYVA +
chlorambucil
n = 336
rituximab +
chlorambucil
n = 321
GAZYVA +
chlorambucil
n = 336
Injury, Poisoning and Procedural
Complications
Infusion related reactions 37.7 65.8 3.7 19.9
Blood and lymphatic system
disorders
Neutropenia 32.1 38.1 28.3 33.0
Thrombocytopenia 6.5 14.3 3.1 10.4
Leucopenia 1.9 6.3 < 1 4.5
Gastrointestinal disorders
Diarrhoea 7.5 10.1 0 2.1
Constipation 5.0 8.3 0 0
Infections and Infestations
Nasopharyngitis 3.1 5.7 0 < 1
Urinary tract infection 1.6 5.4 < 1 1.5
Musculoskeletal and connective
tissue disorders
Back pain 2.8 4.8 < 1 < 1
Arthralgia 2.5 4.8 0 < 1
Metabolism and nutrition disorders
Tumour lysis syndrome 0 4.2 0 1.8

* In all Grades or Grade 3-5

No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms

Further information on selected adverse reactions

Infusion related reactions

The incidence of IRRs was 65% with the infusion of the first 1000 mg of GAZYVA (20% of patients experiencing a Grade 3-5 IRR, with no fatal events reported). 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 combined measures for prevention of IRRs (glucocorticoid; oral analgesic/anti-histamine (H1 histamine receptor blockade); omission of antihypertensive medication in the morning of the first infusion; Cycle 1 Day 1 dose administered over 2 days) as described under DOSAGE AND ADMINISTRATION, decreased incidence of all Grades IRRs was observed. The incidence of Grade 3-4 IRRs (which are based on a relatively low number of patients) were similar before and after mitigation measures were implemented.

Most frequently reported symptoms associated with an IRR were nausea, chills, hypotension, pyrexia, vomiting, dyspnoea, flushing, hypertension, headache, tachycardia, and diarrhoea. Respiratory and cardiac symptoms such as bronchospasm, larynx and throat irritation, wheezing, laryngeal oedema and atrial fibrillation have also been reported (see PRECAUTIONS).

Neutropenia and infections

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 plus chlorambucil arm and 4% in the rituximab plus chlorambucil arm) and late onset neutropenia (16% in GAZYVA treated arm and 12% in chlorambucil alone arm) were also reported (see PRECAUTIONS).

Thrombocytopenia

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 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 haemorrhagic 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 haemorrhagic events has not been established.

Additional Safety Information from clinical trial experience

Progressive multifocal leukoencephalopathy (PML)

PML has been reported in patients treated with GAZYVA (see BOXED WARNING, 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).

Malignancies

There is an increased incidence of second malignancies in patients with CLL. Data from the pivotal study in CLL does not demonstrate an increased risk of second malignancies following GAZYVA therapy

Laboratory Abnormalities

Transient elevation in liver enzymes (AST, ALT, ALP) has been observed shortly after the first infusion of GAZYVA.

For additional information see Further information on selected adverse reactions, Neutropenia and infections; Thrombocytopenia.

Dosage and administration

Substitution by any other biological medicinal product requires the consent of the prescribing physician.

General

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 Disposal of unused/expired medicines).

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 a 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)

Hypotension as a symptom of IRR may occur during GAZYVA intravenous infusions. Consider withholding antihypertensive treatments for 12 hours prior to and throughout each infusion, and for the first hour after administration (see PRECAUTIONS).

Table 4 Premedication to be administered before GAZYVA infusion to reduce the risk of infusion-related reactions
Day of Treatment
Cycle
Patients requiring
premedication
Premedication Administration
Cycle 1: Day 1* All patients Intravenous corticosteroid1 Completed at least 1
hour prior to
GAZYVA infusion
Oral analgesic/anti-pyretic2 At least 30 minutes
before GAZYVA
infusion
Anti-histaminic drug3
Cycle 1: Day 2 All patients Intravenous corticosteroid1 Completed at least 1
hour prior to
GAZYVA infusion
Oral analgesic/anti-pyretic2 At least 30 minutes
before GAZYVA
infusion
Anti-histaminic drug3
Cycle 1: Day 8 &
Day 15
Cycles 2-6: Day 1
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 Completed at least 1
hour prior to
GAZYVA infusion
All patients Oral analgesic/anti-pyretic2 At least 30 minutes
before GAZYVA
infusion
Patients with an IRR
(Grade 1 or more) with
the previous infusion
Anti-histaminic drug3

*If the 100 mg dose of GAZYVA is administered without interruption or modification of the infusion rate the subsequent 900 mg dose may also be administered on the same day (see Table 5). In the event the 900 mg dose is given on the same day no additional premedication is required prior to commencement of the 900 mg dose.

1 20 mg dexamethasone or 80 mg methylprednisolone. Hydrocortisone is not recommended as it has not been effective in reducing the rate of infusion reactions

2 e.g. 1000 mg paracetamol

3 H1 histamine receptor blockade

Dosage of GAZYVA in combination with chlorambucil*

The recommended dosage of GAZYVA is 1000 mg administered on Day 1-2, Day 8 and Day 15 of the first 28 day treatment cycle followed by 1000 mg administered on Day 1 only for each subsequent treatment cycle (Cycles 2 to 6) as shown in Table 5.

Two infusion bags should be prepared for the Day 1 and 2 infusions (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 can be administered on the same day (no dose delay necessary) 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 (see Table 5).

Table 5 Dose of GAZYVA to be administered during 6 treatment cycles each of 28 days duration
Day of Treatment Cycle Dose of
GAZYVA
Rate of infusion (in the absence of
infusion reactions/hypersensitivity
during previous infusions)
Cycle 1 Day 1 100 mg Administer at 25 mg/hr over 4 hours.
Do not increase the infusion rate.
Day 2
or Day 1
(continued)
900 mg Administer at 50 mg/hr.
The rate of the infusion can be escalated
in increments of 50 mg/hr every 30
minutes to a maximum rate of 400
mg/hr.
Day 8 1000 mg Infusions can be started at a rate of
100 mg/hr and increased by 100 mg/hr
increments every 30 minutes to a maximum
of 400 mg/hr.
Day 15 1000 mg
Cycles 2 – 6 Day 1 1000 mg

* see CLINICAL TRIALS for information on chlorambucil dose.

If an infusion reaction occurs, adjust infusion as outlined in Table 6 and PRECAUTIONS, Infusion Related Reactions

Table 6 Infusion Rate Modification Guidelines for Infusion Related Reactions (see PRECAUTIONS, Infusion Related Reactions)
Grade 4 (life-threatening) Stop infusion and permanently discontinue therapy.
Grade 3 (severe)

Temporarily interrupt infusion and treat symptoms.

Upon resolution of symptoms, restart infusion at no more than half the previous rate (the rate being used at the time that the IRR occurred) and, if patient does not experience any IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose (see Table 5). The Day 1 infusion rate may be increased back to 25 mg/hr after 60 minutes, but not increased further. Stop infusion and permanently discontinue therapy if patients experience a second occurrence of a Grade 3 IRR.

Grade 1-2 (mild and moderate)

Reduce infusion rate and treat symptoms.

Upon resolution of symptoms, continue infusion and, if patient does not experience any IRR symptoms, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment dose (see Table 5). The Day 1 infusion rate may be increased back up to 25 mg/hr after 1 hour, but not increased further.

Duration of treatment

Six treatment cycles, each of 28 day duration.

Delayed or missed doses

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 thereafter.

Dosage modifications during treatment

No dose reductions of GAZYVA are recommended.

For management of symptomatic adverse events (including IRRs), see Table 6 and PRECAUTIONS.

Dosage modifications in Special Populations

Children: The safety and efficacy of GAZYVA in children below 18 years of age have not been established.

Elderly: No dose adjustment is required in elderly patients (see PRECAUTIONS, Use in the elderly).

Renal Impairment: No dose adjustment is required in renally impaired patients (creatinine clearance (CrCl) > 30mL/min). GAZYVA has not been studied in patients with a CrCl ≤ 30mL/min (see PRECAUTIONS, Use in renal impairment).

Hepatic Impairment: The safety and efficacy of GAZYVA in patients with hepatic impairment have not been established.

Instructions for dilution

GAZYVA should be prepared by a healthcare professional using aseptic technique.

The table below provides guidance on the volume of GAZYVA liquid concentrate to be diluted and the volume of sterile 0.9% sodium chloride solution it is to be diluted in. Withdraw the required amount of GAZYVA liquid concentrate from the vial and dilute in a PVC or non-PVC polyolefin infusion bag containing the appropriate volume of sterile, non-pyrogenic 0.9% aqueous sodium chloride solution. Do not use dextrose-containing solutions or other diluents (see Incompatibilities).

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 2 infusion bags, withdraw 40 mL of GAZYVA liquid concentrate from the vial and dilute 4 mL into a 100 mL infusion bag and the remaining 36 mL into a 250 mL PVC or non-PVC polyolefin infusion bag containing sterile, non pyrogenic 0.9% aqueous sodium chloride solution. Clearly label each infusion bag.

Each bag should be gently inverted to mix the solution in order to avoid foaming.

Dose of GAZYVA to be
administered
Required amount of GAZYVA
liquid concentrate
Volume of PVC or non-PVC
polyolefin infusion bag
100 mg 4 mL 100 mL
900 mg 36 mL 250 mL
1000 mg 40 mL 250 mL

Parenteral drug products should be inspected visually for particulates and discolouration prior to administration.

GAZYVA is for single use in one patient only. Once the infusion is prepared it should be administered immediately (see PRESENTATION AND STORAGE CONDITIONS).

Incompatibilities

No incompatibilities between GAZYVA and polyvinyl chloride, polyethylene, polypropylene or polyolefine bags, polyvinyl chloride, polyurethane, or polyethylene infusion sets, as well as optional inline filters with product contact surfaces of polyethersulfon, a 3-way stopcock infusion aid made from polycarbonate, and catheters made from polyetherurethane 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 not be shaken or frozen. Do not use other diluents such as dextrose (5%) solution to dilute GAZYVA since their use has not been tested.

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. Patients should be closely monitored with regular blood cell counts, and for increased risk of infections, while B cell-depleted.

Treatment of overdose should consist of general supportive measures.

Contact the Poison Information Centre for advice on management of overdosage.

Presentation and storage conditions

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 concentrate solution for infusion (25mg/mL).

Storage conditions

Store vial 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. Do not use after the expiry date (EXP) shown on the pack.

Shelf-life of reconstituted solution

GAZYVA does not contain any anti-microbial preservative; therefore, care must be taken to ensure the sterility of the prepared solution. Product is for single use in one patient only. Discard any residue.

Physical and chemical stability of the prepared infusion solution of GAZYVA 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. To reduce microbiological hazard, the prepared infusion solution should be used immediately. If storage is necessary, hold at 2°C - 8°C for not more than 24 hours.

Disposal of unused/expired medicines

The release of medicines into the environment should be minimised. Medicines should not be disposed of via wastewater and disposal through household waste should be avoided. Unused or expired medicine should be returned to a pharmacy for disposal.

Name and address of the sponsor

Roche Products Pty Limited

ABN 70 000 132 865

4–10 Inman Road

Dee Why NSW 2099

AUSTRALIA


Customer enquiries: 1800 233 950

Poison schedule of the medicine

Schedule 4. Prescription Only Medicine.

Date of first inclusion in the australian register of therapeutic goods (the artg)

15 May 2014

Date of most recent amendment

28 April 2015