Special Warning : אזהרת שימוש

5 WARNINGS AND PRECAUTIONS
BORTEZOMIB S.K. should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with BORTEZOMIB S.K..

There have been fatal cases of inadvertent itrathecal administration of BORTEZOMIB S.K.. BORTEZOMIB S.K. is authorized for IV and subcutaneous use only. DO NOT ADMINISTER BORTEZOMIB S.K.
INTRATHECALLY.

5.1 Peripheral Neuropathy
BORTEZOMIB S.K. treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with preexisting symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with BORTEZOMIB S.K.. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the phase 3 relapsed multiple myeloma trial comparing BORTEZOMIB S.K. subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting BORTEZOMIB S.K. subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during BORTEZOMIB S.K. therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2)].
In the BORTEZOMIB S.K. versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see Adverse Events (6)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

5.2 Hypotension
The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8 %. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. [see Adverse Events (6)] 
5.3 Cardiac Toxicity
Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during BORTEZOMIB S.K. therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for, or existing heart disease should be closely monitored.
In the relapsed multiple myeloma study of BORTEZOMIB S.K. vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the BORTEZOMIB S.K. and dexamethasone groups, respectively. The incidence of adverse events suggestive of heart failure (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was ≤ 1% for each individual event in the BORTEZOMIB S.K. group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported events of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

5.4 Pulmonary Toxicity
There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration, lung and Acute Respiratory Distress Syndrome (ARDS) in patients receiving BORTEZOMIB S.K.. Some of these events have been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential post-treatment pulmonary changes.

In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and BORTEZOMIB S.K. for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours is not recommended.

There have been reports of pulmonary hypertension associated with BORTEZOMIB S.K. administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, consider interrupting BORTEZOMIB S.K. until a prompt and comprehensive diagnostic evaluation is conducted.

5.5 Posterior Reversible encephalopathy Syndrome (PRES)
Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving BORTEZOMIB S.K.. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue BORTEZOMIB S.K.. The safety of reinitiating BORTEZOMIB S.K. therapy in patients previously experiencing PRES is not known.

5.6 Gastrointestinal Toxicity
BORTEZOMIB S.K. treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Events (6)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.
Interrupt BORTEZOMIB S.K. for severe symptoms.

5.7 Thrombocytopenia/Neutropenia
BORTEZOMIB S.K. is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.

Monitor complete blood counts (CBC) frequently during treatment with BORTEZOMIB S.K.. Measure platelet counts prior to each dose of BORTEZOMIB S.K.. Adjust dose/schedule for thrombocytopenia [see Tables 2 and 3 and Dosage and Administration (2.5)]. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with BORTEZOMIB S.K.. Support with transfusions and supportive care, according to published guidelines.

In the single-agent, relapsed multiple myeloma study of BORTEZOMIB S.K. versus dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 7. The incidence of bleeding (≥ Grade 3) was 2% on the BORTEZOMIB S.K. arm and was < 1% in the dexamethasone arm.

Table 7 Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Bortezomib vs dexamethasone

Number (%) of                  Number (%) of             Number (%) of Pretreatment          Patients (N=331)**            Patients with Platelet    Patients with Platelet Platelet Count*                                           Count <10,000/μL        Count 10,000-25,000/μL 
≥75,000/μL                      309                           8 (3%)                  36 (12%) 
≥50,000/μL-                        14                         2 (14%)                  11 (79%) 
<75,000/μL
≥10,000/μL-                         7                         1 (14%)                   5 (71%) 
<50,000/μL

* A baseline platelet count of 50,000/μL was required for study eligibility.
** Data were missing at baseline for 1 patient.


In the combination study of BORTEZOMIB with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥ Grade 4) was 32% versus 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R- CHOP) arm as shown in Table 11. The incidence of bleeding events (≥ Grade 3) was 1% in the VcR-CAP arm (3 patients) and was < 1% in the R- CHOP arm (1 patient).
Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R- CHOP arm.
The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the R- CHOP arm.
The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R- CHOP arm.

5.8 Tumor Lysis Syndrome
Because BORTEZOMIB S.K. is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, the complications of tumor lysis syndrome may occur. Tumor lysis syndrome has been reported with BORTEZOMIB S.K. therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.
Monitor patients closely and take appropriate precautions.

5.9 Hepatic Toxicity
Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Interrupt BORTEZOMIB S.K. therapy to assess reversibility.
There is limited re-challenge information in these patients


5.10 Hepatic Impairment:
Bortezomib is metabolized by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with BORTEZOMIB S.K. at reduced starting doses and closely monitored for toxicities. [see Dosage and Administration (2.7), Use in Specific Populations(8.6) and Clinical Pharmacology (11.3)]


5.11 Embryo-fetal Risk
Women of reproductive potential should avoid becoming pregnant while being treated with BORTEZOMIB S.K.. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses [see Use in Specific Populations (8.1)].

5.12 Herpes zoster virus reactivation
Antiviral prophylaxis should be considered in patients being treated with BORTEZOMIB S.K..
In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with BORTEZOMIB S.K.+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the VcR-CAP arm and 1.2% in the R-CHOP arm.

5.13 Progressive multifocal leukoencephalopathy (PML)
Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with BORTEZOMIB S.K.. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of BORTEZOMIB S.K.. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated.
Discontinue BORTEZOMIB S.K. if PML is diagnosed.

5.14 Seizures
Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

5.15 Renal impairment
Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely.

5.16 Concomitant medicinal products
Patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors.
Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates.
Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics.

5.17 Potentially immunocomplex-mediated reactions
Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.

5.18 Hepatitis B Virus (HBV) reactivation and infection
When rituximab is used in combination with BORTEZOMIB S.K., HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with BORTEZOMIB S.K.. Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics of rituximab for more information.


6. ADVERSE EVENTS

The following adverse events are also discussed in other sections of the labeling:
• Peripheral Neuropathy [see Warnings and Precautions (5.1) ; Dosage and Administration(2.6) (Table 4)]
• Hypotension [see Warnings and Precautions (5.2) ]
• Cardiac Toxicity [see Warnings and Precautions (5.3) ]
• Pulmonary Toxicity [see Warnings and Precautions (5.4) ]
• Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.5) ]
• Gastrointestinal Toxicity [see Warnings and Precautions (5.6)]
• Thrombocytopenia/Neutropenia [see Warnings and Precautions (5.7)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.8)] • Hepatic Toxicity [see Warnings and Precautions (5.9)]

6.1 Clinical Trials Safety Experience
Because clinical trials are conducted under widely varying conditions, adverse events 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 Events (≥10% in BORTEZOMIB S.K. IV, 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)
System Organ Class                           Total     Toxicity Grade, n (%)     Total          Toxicity Grade, n (%) Preferred Term                               n (%)        3         ≥4           n (%)           3            ≥4 Blood and Lymphatic System
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 Diarrhoea                                   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
a                     156 ( 46)   42 ( 12)    2 ( 1)       4 ( 1)      0              0 Peripheral Neuropathy
Neuralgia                                   117 ( 34)   27 ( 8)     2 ( 1)        1(         0              0 <1)
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 



a
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 multiple myeloma. BORTEZOMIB was administered intravenously at doses of 1.3 mg/m2 twice weekly for 2 out of 3 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 (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 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 events was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian. [see Clinical Studies (13.1)]

Among the 331 BORTEZOMIB treated patients, the most commonly reported (>20%) adverse events overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies NEC (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse event 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 event; the most common events were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasonetreated patients experienced a Grade 4 adverse event. All individual dexamethasone-related Grade 4 adverse events were less than 1%.

Serious Adverse Events (SAEs) and Events Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of BORTEZOMIB vs. Dexamethasone
Serious adverse events are defined as any event 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 event during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse events 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 events 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 events.
Among the 331 BORTEZOMIB treated patients, the most commonly reported adverse event leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse events 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: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.

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

Table 9: Most Commonly Reported Adverse Events (≥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
Preferred Term                    All          Grade 3             Grade 4      All       Grade 3          Grade 4 Adverse events                  324 (98)       193 (58)             28 (8)   297 (89)     110 (33)          29 (9) 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 neuropathies         115 (35)         23 (7)            2 (< 1)     14 (4)         0            1 (< 1) NECa
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) Abdominal pain NOS               35 (11)           5(2)                0       7 (2)          0               0 Weakness                         34 (10)          10(3)                0      28 (8)        8 (2)             0 
a
Based on High Level Term
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 (13)] 
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 (13.1)].


Table 10: Most Commonly Reported Adverse Events (≥ 10%), with Grade 3 and ≥ 4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of BORTEZOMIB Subcutaneous versus Intravenous 
Subcutaneous                          Intravenous

(N=147)                             (N=74)

System Organ Class                                    Total      Toxicity Grade, n (%)     Total      Toxicity Grade, n (%) Preferred Term                                        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 NECa                         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
a
Represents MedDRA High Level Term.

In general, safety data were similar for the subcutaneous and intravenous treatment groups.
Differences were observed in the rates of some Grade ≥ 3 adverse events. 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 event was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe events, 1 case of pruritus and 1 case of redness. Local events led to reduction in injection concentration in one patient and drug discontinuation in one patient.
Local events resolved in a median of 6 days.
Dose reductions occurred due to adverse events in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse events 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 Events and Adverse Events Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of BORTEZOMIB Subcutaneous versus Intravenous

The incidence of serious adverse events was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse events in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse events were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).

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

Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse event 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

Toxicity       Toxicity                    Toxicity   Toxicity
System Organ Class                          All           Grade 3        Grade ≥4        All         Grade 3    Grade ≥4 Preferred Term                             n (%)           n (%)          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 neuropathya                 71 (30)         17 (7)          1 (< 1)     65 (27)        10 (4)          0 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 distension                    13 (5)            0                 0       4 (2)           0           0 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.
a
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 2 arms (3 patients in the VcR-CAP arm and 1 patient 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%; 3 patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (< 1%; 2 patients).


Integrated Summary of Safety (Multiple Myeloma and Mantle Cell Lymphoma) Safety data from phase 2 and 3 studies of single agent BORTEZOMIB 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-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 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 (13)]

In the integrated analysis, the most commonly reported (> 20%) adverse events were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 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 Events (SAEs) and Events Leading to Treatment Discontinuation in the Integrated Summary of Safety
A total of 26% of patients experienced a serious adverse event during the studies. The most commonly reported serious adverse events included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

Adverse events 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 Events in the Integrated Summary of Safety The most common adverse events are shown in Table 12. All adverse events occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient’s underlying disease. Please see the discussion of specific adverse events that follows.


Table 12: Most Commonly Reported (≥10% Overall) Adverse Events
in Integrated Analyses of Relapsed Multiple Myeloma and Mantle Cell Lymphoma Studies using the 1.3 mg/m2 Dose (N=1163)

All Patients                    Multiple Myeloma      Mantle Cell Lymphoma N=1163                      N=1008                          N=155

All         ≥Grade 3            All         ≥Grade 3      All         ≥Grade 3 
Preferred Term
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) a
neuropathies NEC
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 vertigo)      129 (11)          13 (1)           101 (10)        9 (< 1)     28 (18)         4 (3) Weakness                      124 (11)          31 (3)           106 (11)        28 (3)      18 (12)         3 (2) a
Based on High Level Term

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

Gastrointestinal Events
A total of 75% of patients experienced at least one GI disorder. The most common GI disorders included nausea, diarrhea, constipation, vomiting, and appetite decreased. Other GI disorders included dyspepsia and dysgeusia. Grade 3 GI events occurred in 14% of patients; ≥Grade 4 events were rare (≤1%). GI events were considered serious in 7% of patients. Four percent (4%) of patients discontinued due to a GI event. 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 10-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 event resulted in BORTEZOMIB S.K. discontinuation in 2% of patients [see Warnings and Precautions (5. 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 NEC 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 S.K..


Hypotension
The incidence of hypotension (postural hypotension, orthostatic hypotension 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 an SAE, 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 event.
Neutropenia
Neutrophil counts decreased during the BORTEZOMIB dosing period (days 1 to 11) and returned toward baseline during the 10-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 event 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 (>38ºC) was reported as an adverse event for 21% of patients. The event was Grade 3 in 1% and ≥Grade 4 in <1%. Pyrexia was reported as a serious adverse event 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 6-11%) than in the control groups (3-4%). Herpes simplex was seen in 1-3% in subjects treated with BORTEZOMIB and 1-3% 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%).

Additional Serious Adverse Events from Clinical Studies
The following clinically important SAEs 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 

6.2 Postmarketing Experience
The following adverse drug events have been identified from the worldwide post-marketing experience with BORTEZOMIB. Because these events 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: atrioventricular block complete, cardiac tamponade, ischemic colitis, encephalopathy, dysautonomia, deafness bilateral, disseminated intravascular coagulation, hepatitis, acute pancreatitis, progressive multifocal leukoencephalopathy (PML), acute diffuse infiltrative pulmonary disease, PRES (formerly RPLS), toxic epidermal necrolysis, acute febrile neutrophilic dermatosis (Sweet’s syndrome), herpes meningoencephalitis, optic neuropathy, blindness and ophthalmic herpes, Stevens- Johnson Syndrome, septic shock, Angioedema, Anaphylactic reaction, autonomic neuropathy, Decubitus ulcer, Intestinal obstruction

Reporting suspected adverse reactions after authorisation 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/

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