Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The adverse drug reactions (ADRs) from clinical trials were identified during induction, maintenance and follow up for indolent Non-Hodgkin lymphoma (iNHL) including FL; treatment and follow up for CLL in the three pivotal clinical studies:
•     BO21004/CLL11 (N=781): Patients with previously untreated CLL
•     BO21223/GALLIUM (N=1390): Patients with previously untreated iNHL (86% of the patients had FL)
•     GAO4753g/GADOLIN (N=409): Patients with iNHL (81% of the patients had FL) who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen.

These trials investigated Gazyva in combination with chlorambucil for CLL and with bendamustine, CHOP or CVP followed by Gazyva maintenance therapy for iNHL. The studies BO21223/GALLIUM and GAO4753g/GADOLIN enrolled patients with iNHL including FL. Therefore, in order to provide the most comprehensive safety information, the analysis of ADRs presented in the following has been performed on the entire study population (i.e. iNHL).

Table 7 summarises all ADRs including those of the pivotal studies (BO21004/CLL11, BO21223/GALLIUM GAO4753g/GADOLIN) that occurred at a higher incidence (difference of ≥ 2%) compared to the relevant comparator arm in at least one pivotal study in:
•     Patients with CLL receiving Gazyva plus chlorambucil compared with chlorambucil alone or rituximab plus chlorambucil (study BO21004/CLL11)
•     Patients with previously untreated iNHL receiving Gazyva plus chemotherapy (bendamustine, CHOP, CVP) followed by Gazyva maintenance in patients achieving a response, compared to rituximab plus chemotherapy followed by rituximab maintenance in patients achieving a response (study BO21223/GALLIUM)
•     Patients with iNHL who had no response to or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen receiving Gazyva plus bendamustine, followed by Gazyva maintenance in some patients, compared to bendamustine alone (study GAO4753g/GADOLIN)
The incidences presented in Table 7 (all grades and Grades 3-5) are the highest incidence of that ADR reported from any of the three studies.

Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) and very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Tabulated list of adverse reactions

Table 7     Summary of ADRs reported in patients# receiving Gazyva + chemotherapy* 
System organ class                             All Grades                            Grades 3-5† Frequency                            Gazyva + chemotherapy* (CLL,           Gazyva + chemotherapy* (CLL, iNHL) followed by Gazyva               iNHL) followed by Gazyva maintenance (iNHL)                     maintenance (iNHL)
Infections and infestations
Very common                          Upper respiratory tract infection, sinusitis§, urinary tract infection,
pneumonia§ ,herpes zoster§,
nasopharyngitis
Common                               Oral herpes, rhinitis, pharyngitis,    Urinary tract infection, lung infection, influenza              pneumonia, lung infection, upper respiratory tract infection,
sinusitis, herpes zoster
Uncommon                             Hepatitis B reactivation               Nasopharyngitis, rhinitis, influenza, oral herpes
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Common                           Squamous cell carcinoma of skin            Squamous cell carcinoma of skin Basal cell carcinoma                       Basal cell carcinoma
Blood and lymphatic system disorders
Very common                      Neutropenia§, thrombocytopenia,            Neutropenia, thrombocytopenia anaemia, leukopenia
Common                           Febrile neutropenia                        Anaemia, leukopenia, febrile neutropenia
Uncommon                          Disseminated intravascular coagulation##
Metabolism and nutrition disorders
Common                            Tumour lysis syndrome,                    Tumour lysis syndrome, hyperuricaemia, hypokalaemia              hypokalaemia
Uncommon                                                                    Hyperuricaemia Psychiatric disorders
Very common                       Insomnia
Common                            Depression, anxiety
Uncommon                                                                    Insomnia, depression, anxiety Nervous system disorders
Very common                       Headache
Uncommon                                                                    Headache Not known                         Progressive multifocal leukoencephalopathy
Cardiac disorders
Common                            Atrial fibrillation                       Atrial fibrillation Vascular disorders
Common                            Hypertension                              Hypertension Respiratory, thoracic and mediastinal disorders
Very common                          Cough§
Common                               Nasal congestion, rhinorrhoea,
oropharyngeal pain
Uncommon                                                                    Cough, oropharyngeal pain Gastrointestinal disorders
Very common                          Diarrhoea, constipation§
Common                               Dyspepsia, haemorrhoids                Diarrhoea gastrointestinal perforation
Uncommon                                                                    Constipation, haemorrhoids Skin and subcutaneous tissue disorders
Very common                       Alopecia, pruritus
System organ class                               All Grades                             Grades 3-5† Frequency                              Gazyva + chemotherapy* (CLL,            Gazyva + chemotherapy* (CLL, iNHL) followed by Gazyva               iNHL) followed by Gazyva maintenance (iNHL)                      maintenance (iNHL)
Common                                 Eczema
Uncommon                                                                       Pruritus Musculoskeletal and connective tissue disorders
Very common                        Arthralgia§, back pain , pain in extremity
Common                             Musculoskeletal chest pain, bone            Pain in extremity pain
Uncommon                                                                       Arthralgia, back pain, musculoskeletal chest pain, bone pain
Renal and Urinary Disorders
Common                            Dysuria, urinary incontinence
Uncommon                                                                       Dysuria, urinary incontinence General disorders and administration site conditions
Very common                       Pyrexia, Asthenia, fatigue
Common                            Chest pain                                   Pyrexia, asthenia, fatigue Uncommon                                                                       Chest pain Immune system disorders
Rare                              Cytokine release syndrome**
Investigations
Common                            White blood cell count decreased,            White blood cell count decreased, neutrophil count decreased, weight           neutrophil count decreased increased
Uncommon                          Hypogammaglobulinemia
Injury, poisoning and procedural complications
Very common                       IRRs                                         IRRs #
Only the highest frequency observed in the trials is reported (based on studies BO21004/previously untreated CLL, BO21223/previously untreated advanced iNHL and GAO4753g/rituximab refractory iNHL) ##
Disseminated intravascular coagulation (DIC) including fatal events, has been reported in clinical studies and in postmarketing surveillance in patients receiving Gazyva (see section 4.4) †
No Grade 5 adverse reactions have been observed with a difference of ≥ 2% between the treatment arms * Chemotherapy: Chlorambucil in CLL; bendamustine, CHOP, CVP in iNHL including FL § observed also during maintenance treatment with at least 2% higher incidence in Gazyva arm (BO21223) **Based on clinical trial exposures in FL and CLL


The profile of adverse reactions in patients with FL was consistent with the overall iNHL population in both studies.

Description of selected adverse reactions

The incidences presented in the following sections if referring to iNHL are the highest incidence of that ADR reported from either pivotal study (BO21223/GALLIUM, GAO4753g/GADOLIN).

The study MO40597 was designed to characterize the safety profile of short duration infusions (approximately 90 minutes) from Cycle 2, in patients with previously untreated FL (see section 5.1 Pharmacodynamic properties).

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 section 4.4).
Chronic Lymphocytic Leukaemia

The incidence of IRRs was higher in the Gazyva plus chlorambucil arm compared to the rituximab plus chlorambucil arm. The incidence of IRRs was 66% with the infusion of the first 1,000 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 IRRs with subsequent infusions was 3% with the second 1,000 mg dose and 1% thereafter. No Grade 3-5 IRRs were reported beyond the first 1,000 mg infusions of Cycle 1.

In patients who received the recommended measures for prevention of IRRs as described in section 4.2, a decreased incidence of IRRs of all Grades was observed. The rates of Grade 3-4 IRRs (which occurred in relatively few patients) were similar before and after mitigation measures were implemented.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

Grade 3-4 IRRs occurred in 12% of patients. 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 IRRs was highest on Day 1 and gradually decreased with subsequent infusions. This decreasing trend continued during maintenance therapy with Gazyva alone. Beyond Cycle 1 the incidence of IRRs in subsequent infusions was comparable between the Gazyva and the relevant comparator arms. Overall, 4% of patients experienced an infusion related reaction leading to discontinuation of Gazyva.

Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597 assessing the safety of SDI, a greater proportion of patients experienced any grade IRRs at Cycle 2 compared to the proportion who experienced IRRs after standard infusion at Cycle 2 in study BO21223 (10/99 [10.1%] vs. 23/529 [4.3%] respectively; IRRs attributed by the investigator to any component of study therapy). No patients experienced Grade 3 IRRs after SDI at Cycle 2 in MO40597; 3/529 (0.6%) experienced Grade 3 IRRs at Cycle 2 in study BO21223. IRR symptoms and signs were similar in both studies.
Infusion related reactions observed in Study MO40597/GAZELLE are summarized in Table 8.

Table 8     Study MO40597/GAZELLE Short-Duration Infusion: Infusion Related Reactionsa by Cycle (Safety-Evaluable Population)

CTCAE C1                C1b by day                              C2C      C3       C4        C5       C6       C7          Over all Grade Overall                                                                                                             induction (standard                                                                                                           cycles infusion)         Day 1 Day 2d Day 8 Day 15
All   65/113            57/113 4/51    6/112 5/111 13/110 9/108 7/108 6/107 5/105 2/55          71/113 Grade (57.5%)           (50.4%) (7.8%) (5.4%) (4.5%) (11.8%) (8.3%) (6.5%) (5.6%) (4.8%) (3.6%) (62.8%) 

Grade      6/113        5/113     1/51   0           0          0        0        0         1/107 0           0           7/113 3         (5.3%)       (4.4%)    (2.0%)                                                    (0.9%)                        (6.2%) 

Ccycle; CTCAE = Common Terminology Criteria for Adverse Events; IRRinfusion related reaction a
Infusion related reaction defined as any event that occurred during or within 24 hours from the end of study treatment infusion that were judged by the investigator to be related to any components of therapy.
b
C1 comprised three infusions at the standard infusion rate, administered at weekly intervals c
Patients received short-duration infusion from C2 onward. The denominator at C2 and subsequent cycles represents the number of patients who received SDI at that cycle.
d
Patients treated with bendamustine on Cycle 1 Day 2.


Neutropenia and infections
Chronic Lymphocytic Leukaemia

The incidence of neutropenia was higher in the Gazyva plus chlorambucil arm (41%) 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 the Gazyva plus chlorambucil arm and 12% in the rituximab plus chlorambucil arm) were also reported (see section 4.4).

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

In the Gazyva plus chemotherapy arm, the incidence of Grade 1-4 neutropenia (50%) was higher relative to the comparator arm with an increased risk during the induction period. The incidence of prolonged neutropenia and late onset neutropenia was 3% and 8%, respectively. The incidence of infection was 81% in the Gazyva plus chemotherapy arm (with Grade 3-5 events reported in 22% of patients and fatal events reported in 3% of patients). Patients who received G-CSF prophylaxis had a lower rate of Grade 3-5 infections (see section 4.4).

Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597, assessing the safety of SDI, neutropenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients receiving standard duration infusion 69/113 [61.1%] vs 247/595 [41.5%], respectively, throughout induction). The median and range of neutrophil count values were similar in both studies at each time point. Febrile neutropenia was reported in a similar proportion of patients in MO40597 and BO21223 (6/113 [5.3%] vs 31/595 [5.2%], respectively). Infection was reported less frequently in MO40597 than in BO21223 (45/113 [39.8%] vs 284/595 [47.7%], respectively).


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 (16% vs. 7%) 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 section 4.4). 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. No Grade 5 events of thrombocytopenia were reported.
A clear relationship between thrombocytopenia and haemorrhagic events has not been established.

Indolent Non-Hodgkin Lymphoma including Follicular Lymphoma

The incidence of thrombocytopenia was 15%. Thrombocytopenia occurred more frequently in 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 in the Gazyva plus chemotherapy arm than in the comparator arm. The incidence of haemorrhagic events 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 the fatal adverse events occurred in Cycle 1.
Short Duration Infusion in patients with Follicular Lymphoma

In study MO40597, assessing the safety of SDI, thrombocytopenia was reported as an adverse event in a higher proportion of patients compared to study BO21223 in which patients received standard duration infusion (21/113 [28.6%] vs 63/595 [10.6%], respectively, throughout induction). The median and range of platelet count values were similar in both studies at each time point. No thrombocytopenia events reported in MO40597 were associated with bleeding.


Special populations
Elderly

Chronic Lymphocytic Leukaemia

In the pivotal BO21004/CLL11 study, 46% (156 out of 336) of patients with CLL treated with Gazyva plus chlorambucil were 75 years or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than those patients < 75 years of age.

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, patients 65 years or older experienced more serious adverse events and adverse events leading to withdrawal or death than patients < 65 years of age.

Renal impairment

Chronic Lymphocytic Leukaemia
In the pivotal BO21004/CLL11 study, 27% (90 out of 336) of patients 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 patients with a CrCl ≥ 50 mL/min (see section 4.2, 4.4 and 5.2). Patients with a CrCl < 30 mL/min were excluded from the study (see section 5.1).

Indolent Non Hodgkin Lymphoma including Follicular Lymphoma

In the pivotal studies (BO21223/GALLIUM, GAO4753g/GADOLIN) in iNHL, 5% (35 out of 698) and 7% (14 out of 204) of patients treated with Gazyva, respectively, 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 patients with a CrCl ≥ 50 mL/min (see section 4.2 and 5.2). Patients with a CrCl < 40 mL/min were excluded from the studies (see section 5.1).

Additional safety information from clinical studies experience

Worsening of pre-existing cardiac conditions
Cases of arrhythmias (such as atrial fibrillation and tachyarrhythmia), angina pectoris, acute coronary syndrome, myocardial infarction and heart failure have occurred when treated with Gazyva (see section 4.4). These events may occur as part of an IRR and can be fatal.

Laboratory abnormalities
Transient elevation in liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase) has been observed shortly after the first infusion of Gazyva.
Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: http://sideeffects.health.gov.il