Adverse reactions : תופעות לוואי

8. ADVERSE REACTIONS

The following clinically significant adverse reactions are also discussed in other sections of the labeling:
• Peripheral Neuropathy (see Warnings and Precautions (7.1);
• Hypotension (see Warnings and Precautions (7.2))
• Cardiac Toxicity (see Warnings and Precautions (7.3))
• Pulmonary Toxicity (see Warnings and Precautions (7.4))
• Posterior Reversible Encephalopathy Syndrome (PRES) (see Warnings and Precautions (7.5))
• Gastrointestinal Toxicity (see Warnings and Precautions (7.6))
• Thrombocytopenia/Neutropenia (see Warnings and Precautions (7.7)) • Hepatic impairment [see Warnings and Precautions (7.8)]
• Tumor Lysis Syndrome (see Warnings and Precautions (7.9))
• Hepatic Toxicity (see Warnings and Precautions (7.10))
• Thrombotic Microangiopathy [see Warnings and Precautions (7.11)]

8.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Summary of Clinical Trial in Patients with Previously Untreated Multiple Myeloma: Table 8 describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.

The safety profile of bortezomib in combination with melphalan/prednisone is consistent with the known safety profiles of both bortezomib and melphalan/prednisone.


Table 8: Most Commonly Reported Adverse Reactions (≥10% in Bortezomib, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the previously untreated Multiple Myeloma Study
Bortezomib, Melphalan and                    Melphalan and
Prednisone                             Prednisone
(n=340)                                (n=337)
Body System                  Total      Toxicity Grade, n (%)   Total        Toxicity Grade, n (%) Adverse reaction             n (%)           3       ≥4         n (%)             3       ≥4 Blood and Lymphatic System Disorders
Thrombocytopenia            164 (48)     60 (18)     57 (17)    140 (42)      48 (14)     39 (12) Neutropenia                 160 (47)    101(30)      33 (10)    143 (42)      77 (23)     42 (12) Anaemia                     109 (32)     41 (12)      4 (1)     156 (46)      61 (18)     18 (5) Leukopenia                  108 (32)     64 (19)      8 (2)      93 (28)      53 (16)     11 (3) Lymphopenia                  78 (23)     46 (14)     17 (5)      51 (15)       26 (8)      7 (2) Gastrointestinal Disorders
Nausea                      134 (39)      10 (3)        0       70 (21)       1 ( <1)        0 Diarrhea                    119 (35)      19 (6)      2 (1)     20 ( 6)       1 ( <1)        0 Vomiting                     87 (26)      13 (4)        0       41 (12)        2 (1)         0 Constipation                 77 (23)       2 (1)        0        14 (4)          0           0 Abdominal Pain Upper         34 (10)     1 ( <1)        0        20 (6)          0           0 Nervous System Disorders
Peripheral Neuropathy*      156 (46)    42 ( 12)      2 (1)      4 ( 1)         0            0 Neuralgia                   117 (34)      27 (8)      2 (1)      1 (<1)         0            0 Paraesthesia                 42 (12)       6 (2)        0        4 ( 1)         0            0 General Disorders and Administration Site Conditions
Fatigue                      85 (25)      19 (6)      2 (1)     48 (14)        4 (1)         0 Asthenia                     54 (16)      18 (5)        0        23 (7)        3 ( 1)        0 Pyrexia                      53 (16)       4 (1)        0        19 (6)       1 ( <1)     1 (<1) Infections and Infestations
Herpes Zoster                39 (11)      11 (3)        0        9 (3)         4 (1)         0 Metabolism and Nutrition Disorders
Anorexia                     64 (19)       6 (2)        0        19 (6)         0            0 Skin and Subcutaneous Tissue Disorders
Rash                         38 (11)      2 ( 1)        0        7 (2)          0            0 Psychiatric Disorders
Insomnia                     35 (10)     1 ( <1)        0       21 (6)          0            0 *
Represents High Level Term Peripheral Neuropathies NEC

Relapsed Multiple Myeloma Randomized Study of Bortezomib vs. Dexamethasone The safety data described below and in Table 10 reflect exposure to either Bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma.
Bortezomib was administered intravenously at doses of 1.3 mg/m2 twice weekly for two out of three weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian [see Clinical Studies (15.1)].

Among the 331 Bortezomib-treated patients, the most commonly reported (>20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the bortezomib-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.

Serious Adverse Reactions and Adverse reactions Leading to Treatment
Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib vs.
Dexamethasone
Serious adverse reactions are defined as any reaction that results in death, is life- threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event.

A total of 80 (24%) patients from the bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).

A total of 145 patients, including 84 (25%) of 331 patients in the bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions.

Among the 331 bortezomib-treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the 
dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).

Four deaths were considered to be bortezomib-related in this relapsed multiple myeloma study: one case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: two cases of sepsis, one case of bacterial meningitis, and 1 case of sudden death at home.

Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib vs. Dexamethasone
The most common adverse reactions from the relapsed multiple myeloma study are shown in Table 9. All adverse reactions with incidence ≥10% in the bortezomib arm are included.

Table 9: Most Commonly Reported Adverse Reactions
(≥10% in Bortezomib arm), with Grades 3 and 4 Intensity in Relapsed Multiple Myeloma Study of Bortezomib vs. Dexamethasone (N=663)
Bortezomib                  Dexamethasone
(n=331)                        (n=332)
Adverse Reactions      All    Grade 3 Grade 4       All     Grade 3 Grade 4 Any Adverse
324 (98) 193(58)    28 (8)   297 (89) 110(33)      29 (9)
Reactions
Nausea              172 (52)    8 (2)      0      31 (9)         0       0 Diarrhea NOS         171(52)   22 (7)      0      36 (11)     2 (< 1)    0 Fatigue             130 (39)   15 (5)      0      82 (25)      8 (2)     0 Peripheral
115 (35)   23 (7)   2 (< 1)   14 (4)         0    1 (< 1) neuropathies*
Thrombocytopenia 109 (33) 80 (24)       12 (4)    11 (3)       5 (2)  1 (< 1) Constipation         99 (30)    6 (2)      0      27 (8)      1 (<1)     0 Vomiting NOS         96 (29)    8 (2)      0      10 (3)      1 (<1)     0 Anorexia             68 (21)     8(2)      0       8 (2)      1 (<1)     0 Pyrexia              66 (20)   2(<1)       0      21 (6)      3 (<1)  1 (<1) Paresthesia          64 (19)     5(2)      0      24 (7)         0       0 Anemia NOS           63 (19)    20(6)   1 (<1)    21 (6)       8(2)      0 Headache NOS         62 (19)   3(<1)       0      23 (7)      1 (<1)     0 Neutropenia          58 (18)   37(11)    8 (2)    1 (<1)      1 (<1)     0 Rash NOS             43 (13)   3(<1)       0       7 (2)         0       0 Appetite decreased
36 (11)       0           0       12 (4)        0            0
NOS
Dyspnea NOS           35 (11)     11(3)      1 (<1)     37 (11)     7 (2)       1 (<1) 
                     Table 9: Most Commonly Reported Adverse Reactions
(≥10% in Bortezomib arm), with Grades 3 and 4 Intensity in Relapsed Multiple Myeloma Study of Bortezomib vs. Dexamethasone (N=663)
Bortezomib                      Dexamethasone
(n=331)                          (n=332)
Abdominal pain
35 (11)      5(2)       0         7 (2)        0      0
NOS
Weakness             34 (10)     10(3)       0        28 (8)      8 (2)    0 * Represents High Level Term Peripheral Neuropathies NEC


Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma
In the phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study [see Clinical Studies (15.1)].

Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous vs. Intravenous in Relapsed Multiple Myeloma
The safety and efficacy of bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m2. This was a randomized, comparative study of bortezomib subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 10 reflect exposure to either bortezomib subcutaneous (n=147) or bortezomib intravenous (n=74) (see Clinical Studies (15.1)).


Table 10: Most Commonly Reported Adverse reactions (≥ 10%),
with Grade 3 and ≥ 4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of Bortezomib Subcutaneous vs Intravenous
Subcutaneous                            Intravenous
(n=147)                                 (n= 74)
Body System                       Total Toxicity grade, n (%)         Total      Toxicity grade, n (%) Adverse Reaction                  n (%)      3         ≥4             n (%)          3          ≥4 Blood and lymphatic system disorders
Anemia                         28(19)          8 (5)         0        17 (23)      3 (4)         0 Leukopenia                     26 (18)         8 (5)         0        15 (20)      4 (5)       1 (1) Neutropenia                    34 (23)        15 (10)      4 (3)      20 (27)     10 (14)      3 (4) Thrombocytopenia               44 (30)         7 (5)       5 (3)      25 (34)      7 (9)       5 (7) Gastrointestinal disorders
Diarrhea                          28 (19)      1 (1)         0       21 (28)     3 (4)          0 Nausea                            24 (16)        0           0       10 (14)       0            0 Vomiting                           13 (9)      3 (2)         0        8 (11)       0            0 General disorders and administration site conditions
Asthenia                           10 (7)      1 (1)         0       12 (16 )    4 (5)          0 Fatigue                            11 (7)      3 (2)         0       11 (15)     3 (4)          0 Pyrexia                           18(12)         0           0        6 (8)        0            0 Nervous system disorders
Neuralgia                         34 (23)      5 (3)         0       17 (23)     7 (9)          0 *
Peripheral neuropathies NEC       55 (37)      8 (5)       1 (1)     37 (50)    10 (14)       1 (1) Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least 1 dose of study medication.
* Represents High Level Term Peripheral Neuropathies NEC.


In general, safety data were similar for the subcutaneous and intravenous treatment groups.
Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies NEC (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).

A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness.
Only two (1%) patients were reported as having severe reactions, one case of pruritus and one case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.

Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).

Serious Adverse Reactions and Adverse Reactions Leading to Treatment
Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib Subcutaneous versus Intravenous
The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group.
Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

Two patients (1%) in the subcutaneous treatment group and one (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.

Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma
Table 11 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received Bortezomib (1.3 mg/m2) administered intravenously in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and prednisone (100 mg/m2) (VcR-CAP) in a prospective randomized study.

Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% versus R-CHOP 5%).

Table 11: Most Commonly Reported Adverse Reactions (≥5%) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study
VcR-CAP                           R-CHOP
(n=240)                           (n=242)
Body System             All        Toxicity    Toxicity        All        Toxicity      Toxicity Adverse Reactions      n (%)       Grade 3,    Grade ≥4       n (%)       Grade 3,      Grade ≥4, n (%)       n (%)                      n (%)         n (%)
Blood and lymphatic system disorders
Neutropenia          209 (87)    32 (13)        168 (70)     172 (71)       31 (13)      125 (52) Leukopenia           116 (48)    34 (14)         69 (29)      87 (36)       39 (16)       27 (11) Anemia               106 (44)    27 (11)          4 (2)       71 (29)       23 (10)        4 (2) 
Thrombocytopenia       172 (72)    59 (25)    76 (32)     42 (17)        9 (4)       3 (1) Febrile neutropenia     41 (17)    24 (10)     12 (5)     33 (14)       17 (7)       15 (6) Lymphopenia             68 (28)    25 (10)    36 (15)     28 (12)       15 (6)       2 (1) Nervous system disorders
Peripheral             71 (30)     17 (7)      1 (< 1)   65 (27)       10 (4)          0 neuropathy *

Hypoesthesia            14 (6)      3 (1)         0       13 (5)          0            0 Paresthesia             14 (6)      2 (1)         0       11 (5)          0            0 Neuralgia              25 (10)      9 (4)         0      1 (< 1)          0            0 General disorders and administration site conditions
Fatigue                43 (18)     11 (5)      1 (< 1)   38 (16)        5 (2)          0 Pyrexia                48 (20)      7 (3)         0      23 (10)        5 (2)          0 Asthenia               29 (12)      4 (2)      1 (< 1)    18 (7)       1 (< 1)         0 Edema peripheral        16 (7)     1 (< 1)        0       13 (5)          0            0 Gastrointestinal disorders
Nausea                 54 (23)     1 (< 1)        0      28 (12)          0             0 Constipation           42 (18)     1 (< 1)        0       22 (9)        2 (1)           0 Stomatitis              20 (8)      2 (1)         0       19 (8)          0          1 (< 1) Diarrhea               59 (25)     11 (5)         0       11 (5)        3 (1)        1 (< 1) Vomiting               24 (10)     1 (< 1)        0       8 (3)           0             0 Abdominal               13 (5)        0           0       4 (2)           0             0 distension
Infections and infestations
Pneumonia               20 (8)      8 (3)       5 (2)     11 (5)        5 (2)         3 (1) Skin and subcutaneous tissue disorders
Alopecia               31 (13)     1 (< 1)     1 (< 1)   33 (14)        4 (2)          0 Metabolism and nutrition disorders
Hyperglycemia           10 (4)     1 (< 1)        0       17 (7)       10 (4)          0 Decreased appetite     36 (15)      2 (1)         0       15 (6)       1 (< 1)         0 Vascular disorders
Hypertension            15 (6)     1 (< 1)        0       3 (1)           0            0 Psychiatric disorders
Insomnia                16 (7)     1 (< 1)        0       8 (3)           0            0 Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP=Bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
*
Represents High Level Term Peripheral Neuropathies NEC

The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R- CHOP arm. Antiviral prophylaxis was mandated by protocol amendment.


The incidences of Grade ≥3 bleeding events were similar between the two arms (four patients in the VcR-CAP arm and three patients in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the VcR-CAP arm.

Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; three patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (< 1%; two patients).

Mantle Cell Lymphoma (MCL)
The safety profile of bortezomib in 240 MCL patients treated with bortezomib at 1.3 mg/m2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR CAP) versus 242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described below. Additional adverse drug reactions identified associated with the use of the combination therapy (VcR CAP) were hepatitis B infection (< 1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to bortezomib alone. Notable differences in the MCL patient population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.

Adverse drug reactions identified as those with a ≥ 1% incidence, similar or higher incidence in the VcR CAP arm and with at least a possible or probable causal relationship to the components of the VcR CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in the VcR CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib based on historical data in the multiple myeloma studies.

Adverse reactions are listed below by system organ class and frequency grouping.
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); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 12 has been generated using Version 16 of the MedDRA.


Table 12: Adverse reactions in patients with Mantle Cell Lymphoma treated with VcR CAP in a clinical trial

System Organ
Incidence                       Adverse reaction
Class
Infections and      Very         Pneumonia* infestations        Common
Common       Sepsis (inc septic shock)*, Herpes zoster (inc disseminated & ophthalmic), Herpes virus infection*, Bacterial infections*, Upper/lower respiratory tract infection*,
Fungal infection*, Herpes simplex*
Uncommon        Hepatitis B, Infection*, Bronchopneumonia
Blood and        Very            Thrombocytopenia*, Febrile neutropenia, Neutropenia*, lymphatic system Common          Leukopenia*, Anaemia*, Lymphopenia* disorders        Uncommon        Pancytopenia*
Immune system Common             Hypersensitivity* disorders        Uncommon        Anaphylactic reaction
Metabolism and Very              Decreased appetite nutrition        Common disorders        Common          Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*, Diabetes mellitus*, Fluid retention
Uncommon     Tumour lysis syndrome
Psychiatric         Common       Sleep disorders and disturbances* disorders
Nervous system      Very         Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia* disorders           Common
Common       Neuropathies*, Motor neuropathy*, Loss of consciousness
(inc syncope), Encephalopathy*, Peripheral sensorimotor neuropathy, Dizziness*, Dysgeusia*, Autonomic neuropathy
Uncommon     Autonomic nervous system imbalance
Eye disorders       Common       Vision abnormal*
Ear and labyrinth   Common       Dysacusis (inc tinnitus)* disorders           Uncommon     Vertigo*, Hearing impaired (up to and inc deafness) Cardiac disorders   Common       Cardiac fibrillation (inc atrial), Arrhythmia*, Cardiac failure (inc left and right ventricular)*, Myocardial ischaemia, Ventricular dysfunction*
Uncommon     Cardiovascular disorder (inc cardiogenic shock)
Vascular            Common       Hypertension*, Hypotension*, Orthostatic hypotension disorders
Respiratory,        Common        Dyspnoea*, Cough*, Hiccups thoracic and        Uncommon      Acute respiratory distress syndrome, Pulmonary mediastinal                       embolism, Pneumonitis, Pulmonary hypertension, disorders                         Pulmonary oedema (inc acute)
Gastrointestinal    Very          Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*, disorders           Common        Constipation
Common        Gastrointestinal haemorrhage (inc mucosal)*, Abdominal distension, Dyspepsia, Oropharyngeal pain*, Gastritis*,
Oral ulceration*, Abdominal discomfort, Dysphagia,
Gastrointestinal inflammation*, Abdominal pain (inc gastrointestinal and splenic pain)*, Oral disorder*
Uncommon      Colitis (inc clostridium difficile)*
Hepatobiliary       Common        Hepatotoxicity (inc liver disorder) disorders           Uncommon      Hepatic failure
Skin and            Very          Hair disorder* subcutaneous        Common tissue disorders    Common        Pruritus*, Dermatitis*, Rash*
Musculoskeletal     Common        Muscle spasms*, Musculoskeletal pain*, Pain in extremity and connective tissue disorders
Renal and           Common        Urinary tract infection* urinary disorders
General disorders   Very          Pyrexia*, Fatigue, Asthenia and                 Common administration      Common    Oedema (inc peripheral), Chills, Injection site reaction*, site conditions               Malaise*
Investigations  Common        Hyperbilirubinaemia*, Protein analyses abnormal*, Weight decreased, Weight increased
* Grouping of more than one MedDRA preferred term.

Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma)
Safety data from phase 2 and 3 studies of single agent Bortezomib 1.3 mg/m2/dose twice weekly for two weeks followed by a ten-day rest period in 1163 patients with previously treated multiple myeloma (N=1008) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the phase 3 open- label study of Bortezomib subcutaneous vs. intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma [see Clinical Studies (15)].


In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least one episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).

In the Phase 2 relapsed multiple myeloma clinical trials of Bortezomib administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Bortezomib was not associated with tissue damage.

Serious Adverse Reactions and Adverse Reactions Leading to Treatment
Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each).

Adverse reactions leading to discontinuation occurred in 22% of patients. The reasons for discontinuation included peripheral neuropathy (8%), and fatigue, thrombocytopenia, and diarrhea (2% each).

In total, 2% of the patients died and the cause of death was considered by the investigator to be possibly related to study drug: including reports of cardiac arrest, congestive heart failure, respiratory failure, renal failure, pneumonia and sepsis.

Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety. The most common adverse reactions are shown in Table 13. All adverse reactions occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse reactions that are drug-caused and those that reflect the patient’s underlying disease. Please see the discussion of specific adverse reactions that follows.


         Table 13: Most Commonly Reported (≥10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies using the 1.3 mg/m2 Dose (n=1163)
Mantle Cell
All Patients         Multiple Myeloma
Lymphoma
(n=1163)                (n=1008)
(n=155)
Adverse Reactions      All       ≥Grade 3       All       ≥Grade 3       All      ≥Grade 3 Nausea               567 (49)     36 (3)      511 (51)     32 (3)      56 (36)       4 (3) Diarrhea NOS         530 (46)     83 (7)      470 (47)     72 (7)      60 (39)      11 (7) Fatigue              477 (41)     86 (7)      396 (39)     71 (7)      81 (52)     15 (10) Peripheral
443 (38)    129 (11)    359 (36)   110 (11)       84 (54)      19 (12) neuropathies*
Thrombocytopenia 369 (32)        295 (25)    344 (34)   283 (28)       25 (16)      12 (8) Vomiting NOS         321 (28)     44 (4)     286 (28)    40 (4)        35 (23)       4 (3) Constipation         296 (25)     17 (1)     244 (24)    14 (1)        52 (34)       3 (2) Pyrexia              249 (21)     16 (1)     233 (23)    15 (1)        16 (10)      1 (< 1) Anorexia             227 (20)     19 (2)     205 (20)    16 (2)        22 (14)       3 (2) Anemia NOS           209 (18)     65 (6)     190 (19)    63 (6)        19 (12)       2 (1) Headache NOS         175 (15)     8 (< 1)    160 (16)    8 (< 1)       15 (10)         0 Neutropenia          172 (15)    121 (10)    164 (16)   117 (12)        8 (5)        4 (3) Rash NOS             156 (13)     8 (< 1)    120 (12)    4 (< 1)       36 (23)       4 (3) Paresthesia          147 (13)     9 (< 1)    136 (13)    8 (< 1)       11 (7)       1 (< 1) Dizziness (excl
129 (11)     13 (1)     101 (10)    9 (< 1)       28 (18)       4 (3) vertigo)
Weakness             124 (11)     31 (3)     106 (11)    28 (3)        18 (12)       3 (2) * Represents High Level Term Peripheral Neuropathies NEC


Description of Selected Adverse Reactions from the Integrated Phase 2 and 3 Relapsed Multiple Myeloma and Phase 2 Relapsed Mantle Cell Lymphoma Studies

Gastrointestinal Toxicity
A total of 75% of patients experienced at least one gastrointestinal disorder. The most common gastrointestinal disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other gastrointestinal disorders included dyspepsia and dysgeusia.
Grade 3 adverse reactions occurred in 14% of patients; ≥Grade 4 adverse reactions were ≤1%. Gastrointestinal adverse reactions were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a gastrointestinal adverse reaction. Nausea was reported more often in patients with multiple myeloma (51%) compared to patients with mantle cell lymphoma (36%).


Thrombocytopenia
Across the studies, bortezomib-associated thrombocytopenia was characterized by a decrease in platelet count during the dosing period (days 1 to 11) and a return toward baseline during the ten day rest period during each treatment cycle. Overall, thrombocytopenia was reported in 32% of patients. Thrombocytopenia was Grade 3 in 22%, ≥Grade 4 in 4%, and serious in 2% of patients, and the reaction resulted in
Bortezomib discontinuation in 2% of patients [see Warnings and Precautions (7.7)].

Thrombocytopenia was reported more often in patients with multiple myeloma (34%) compared to patients with mantle cell lymphoma (16%). The incidence of ≥Grade 3 thrombocytopenia also was higher in patients with multiple myeloma (28%) compared to patients with mantle cell lymphoma (8%).

Peripheral Neuropathy
Overall, peripheral neuropathy occurred in 38% of patients. Peripheral neuropathy was Grade 3 for 11% of patients and ≥ Grade 4 for <1% of patients. Eight percent (8%) of patients discontinued Bortezomib due to peripheral neuropathy. The incidence of peripheral neuropathy was higher among patients with mantle cell lymphoma (54%) compared to patients with multiple myeloma (36%).

In the bortezomib versus dexamethasone phase 3 relapsed multiple myeloma study, among the 62 bortezomib-treated patients who experienced ≥ Grade 2 peripheral neuropathy and had dose adjustments, 48% had improved or resolved with a median of 3.8 months from first onset.

In the phase 2 relapsed multiple myeloma studies, among the 30 patients who experienced Grade 2 peripheral neuropathy resulting in discontinuation or who experienced ≥ Grade 3 peripheral neuropathy, 73% reported improvement or resolution with a median time of 47 days to improvement of one grade or more from the last dose of bortezomib.

Hypotension
The incidence of hypotension (postural, orthostatic and hypotension NOS) was 8% in patients treated with bortezomib. Hypotension was Grade 1 or 2 in the majority of patients and Grade 3 in 2% and ≥ Grade 4 in <1%. Two percent (2%) of patients had hypotension reported as a serious adverse reaction, and 1% discontinued due to hypotension. The incidence of hypotension was similar in patients with multiple myeloma (8%) and those with mantle cell lymphoma (9%). In addition, <1% of patients experienced hypotension associated with a syncopal reaction.


Neutropenia
Neutrophil counts decreased during the bortezomib dosing period (days 1 to 11) and returned toward baseline during the ten day rest period during each treatment cycle.
Overall, neutropenia occurred in 15% of patients and was Grade 3 in 8% of patients and ≥ Grade 4 in 2%. Neutropenia was reported as a serious adverse reaction in <1% of patients and <1% of patients discontinued due to neutropenia. The incidence of neutropenia was higher in patients with multiple myeloma (16%) compared to patients with mantle cell lymphoma (5%). The incidence of ≥Grade 3 neutropenia also was higher in patients with multiple myeloma (12%) compared to patients with mantle cell lymphoma (3%).

Asthenic Conditions (Fatigue, Malaise, Weakness, Asthenia)
Asthenic conditions were reported in 54% of patients.
Fatigue was reported as Grade 3 in 7% and ≥ Grade 4 in < 1% of patients. Asthenia was reported as Grade 3 in 2% and ≥ Grade 4 in < 1% of patients. Two percent (2%) of patients discontinued treatment due to fatigue and < 1% due to weakness and asthenia. Asthenic conditions were reported in 53% of patients with multiple myeloma and 59% of patients with mantle cell lymphoma.

Pyrexia
Pyrexia (>38°C) was reported as an adverse reaction for 21% of patients. The reaction was Grade 3 in 1% and ≥ Grade 4 in <1%. Pyrexia was reported as a serious adverse reaction in 3% of patients and led to Bortezomib discontinuation in <1% of patients. The incidence of pyrexia was higher among patients with multiple myeloma (23%) compared to patients with mantle cell lymphoma (10%). The incidence of ≥ Grade 3 pyrexia was 1% in patients with multiple myeloma and <1% in patients with mantle cell lymphoma.

Herpes Virus Infection
Consider using antiviral prophylaxis in subjects being treated with bortezomib. In the randomized studies in previously untreated and relapsed multiple myeloma, herpes zoster reactivation was more common in subjects treated with bortezomib (ranging between 6 to 11%) than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with bortezomib and 1 to 3% in the control groups. In the previously untreated multiple myeloma study, herpes zoster virus reactivation in the bortezomib, melphalan and prednisone arm was less common in subjects receiving prophylactic antiviral therapy (3%) than in subjects who did not receive prophylactic antiviral therapy (17%).

Retreatment in Relapsed Multiple Myeloma
A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib - 
treated patients with relapsed multiple myeloma as demonstrated in Tables 10, 11, and 13; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥Grade 3 peripheral neuropathy reported at 6%.

The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).

Adverse reactions leading to discontinuation occurred in 13% of patients. The reasons for discontinuation included peripheral neuropathy (5%) and diarrhea (3%).

Two deaths considered to be bortezomib -related occurred within 30 days of the last bortezomib dose; one in a patient with cerebrovascular accident and one in a patient with sepsis.

Additional Adverse Reactions from Clinical Studies
The following clinically important serious adverse reactions that are not described above have been reported in clinical trials in patients treated with bortezomib administered as monotherapy or in combination with other chemotherapeutics. These studies were conducted in patients with hematological malignancies and in solid tumors.

Blood and Lymphatic System Disorders: Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia.

Cardiac Disorders: Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion, Torsades de pointes, ventricular tachycardia.

Ear and Labyrinth Disorders: Hearing impaired, vertigo.

Eye Disorders: Diplopia and blurred vision, conjunctival infection, irritation.
Gastrointestinal Disorders: Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux.


General Disorders and Administration Site Conditions: Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis.

Hepatobiliary disorders: Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure.

Immune System Disorders: Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema.

Infections and infestations: Aspergillosis, bacteremia, bronchitis, urinary tract infection, herpes viral infection, listeriosis, nasopharyngitis, pneumonia, respiratory tract infection, septic shock, toxoplasmosis, oral candidiasis, sinusitis, catheter-related infection.

Injury, poisoning and procedural complications: Catheter-related complication, skeletal fracture, subdural hematoma.

Investigations: Weight decreased.

Metabolism and Nutrition Disorders: Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia.

Musculoskeletal and connective tissue disorders: Arthralgia, back pain, bone pain, myalgia, pain in extremity.

Nervous System Disorders: Ataxia, coma, dizziness, dysarthria, dysesthesia, dysautonomia, encephalopathy, cranial palsy, grand mal convulsion, headache, hemorrhagic stroke, motor dysfunction, neuralgia, spinal cord compression, paralysis, postherpetic neuralgia, transient ischemic attack.

Psychiatric Disorders: Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation.

Renal and urinary Disorders: Calculus renal, bilateral hydronephrosis, bladder spasm, hematuria, hemorrhagic cystitis, urinary incontinence, urinary retention, renal failure (acute and chronic), glomerular nephritis proliferative.

Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, 
dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension.

Skin and Subcutaneous Tissue Disorders: Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus.

Vascular Disorders: Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension.

Mantle cell lymphoma
Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR CAP arm.
The incidence of herpes zoster among patients in the VcR CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis (see section 7.13).

Hepatitis B Virus (HBV) reactivation and infection
Mantle cell lymphoma
HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R CHOP ) and 0.4% (n=1) of patients receiving bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR CAP or with R CHOP (0.8% vs 1.2% respectively).

Mantle cell lymphoma
In study LYM 3002 in which bortezomib was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R CAP), the incidence of peripheral neuropathy in the combination regimens is presented in the table below: 

Table 14: Incidence of peripheral neuropathy in study LYM 3002 by toxicity and treatment discontinuation due to peripheral neuropathy
VcR-CAP                    R-CHOP
(N=240)                    (N=242)
Incidence of PN (%)
All Grade PN                                     30                         29  Grade 2 PN                                     18                          9  Grade 3 PN                                      8                          4 Discontinuation due to PN (%)                     2                         <1 VcR-CAP= bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; PN=peripheral neuropathy
Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

Elderly MCL patients
42.9% and 10.4% of patients in the VcR CAP arm were in the range 65-74 years and ≥ 75 years of age, respectively. Although in patients aged ≥ 75 years, both VcR-CAP and R- CHOP were less tolerated, the serious adverse event rate in the VcR-CAP groups was 68%, compared to 42% in the R-CHOP group.

8.2 Post-marketing Experience
The following adverse drug reactions have been identified from the worldwide post- marketing experience with Bortezomib. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure:

Cardiac Disorders: cardiac tamponade

Ear and Labyrinth Disorders: deafness bilateral
Eye Disorders: optic neuropathy, blindness, chalazion/blepharitis

Gastrointestinal Disorders: ischemic colitis

Infections and Infestations: progressive multifocal leukoencephalopathy (PML), ophthalmic herpes, herpes meningoencephalitis

Nervous System Disorders: Posterior reversible encephalopathy syndrome (PRES 
formerly RPLS), Guillain-Barre Syndrome, Demyelinating polyneuropathy 
Respiratory, Thoracic and Mediastinal Disorders: acute diffuse infiltrative pulmonary disease

Skin and Subcutaneous Tissue Disorders: Stevens-Johnson Syndrome/ toxic epidermal necrolysis (SJS/TEN), acute febrile neutrophilic dermatosis (Sweet’s syndrome) 
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: https://sideeffects.health.gov.il