Bortezomib for Injection Instructions

Approval date: 01/15/2007
Revision date: March 26, 2008
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 Instructions for bortezomib for injection
Please read the instructions carefully and use under the guidance of a physician.
    
【Drug name】.
Generic name: bortezomib for injection
Trade name: Vanco®
English name: Bortezomib for Injection
Hanyu Pinyin：Zhusheyong Pengtizuomi
Ingredients
Active ingredient: Bortezomib
Chemical name: [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinecarboxy)amino]propyl]amino]butyl]boronic acid
Chemical structure formula.
Molecular formula: C19H25BN4O4
Molecular weight: 384.24
Excipients: mannitol, nitrogen
Properties
This product is white or off-white lump or powder.
Indications
Multiple myeloma
This product can be used in combination with melphalan and prednisone (MP regimen) for the treatment of previously untreated multiple myeloma patients who are not suitable for high-dose chemotherapy and bone marrow transplantation; or used alone for the treatment of multiple myeloma patients who have relapsed after receiving at least one or more treatments.
Stromal cell lymphoma
This product may be used in combination with rituximab, cyclophosphamide, doxorubicin and prednisone in adult patients with previously untreated and unsuitable for hematopoietic stem cell transplantation for the treatment of patients with relapsed or refractory sarcoid lymphoma who have received at least one therapy prior to the use of this product.
Specification
3.5mg
Dosage]
This product may be administered by the following methods.
– Intravenous push (concentration 1 mg/mL) for 3-5 seconds, or
– Subcutaneously (concentration 2.5 mg/mL)
Care must be taken when calculating the volume to be administered, as each route of administration has a different concentration of re-dissolution.
Intrathecal injection can result in death.
Patients with untreated multiple myeloma
This product is administered in combination with oral melphalan and oral prednisone for 6 weeks per course (as shown in Table 1) for a total of 9 courses of therapy. During courses 1 to 4, this product was given twice a week (days 1, 4, 8, 11, 22, 25, 29, and 32). During courses 5 to 9, this product was given once a week (days 1, 8, 22 and 29). The two doses were given at least 72 hours apart.
Table 1: Dosing regimen for patients with untreated multiple myeloma
Give this product twice weekly (1st to 4th course) Week 123456 This product
(1.3 mg/m2) Day 1 —- Day 4 Day 8 Day 11 rest period Day 22 Day 25 Day 29 Day 32 rest period melphalan
(9mg/m2)
Prednisone
(60mg/m2) Day 1 Day 2 Day 3 Day 4 —- rest period ——– rest period Give this product once a week (5th to 9th course) week 123456 this product
(1.3 mg/m2) day 1 —— day 8 rest period day 22 day 29 rest period melphalan
(9mg/m2)
Prednisone
(60mg/m2) Day 1 Day 2 Day 3 Day 4 – rest period —- rest period Dose adjustment of this product in combination with melphalan and prednisone
Prior to the start of any course of treatment with this product in combination with melphalan and prednisone, the patient should meet the following conditions.
Platelet count should be ≥ 70 x 109/L , ANC should be ≥ 1.0 x 109/L
Non-hematologic toxicity should be reduced to grade 1 or baseline level
Table 2: Dose adjustment of this product in combination therapy with melphalan and prednisone
Toxicity Dose adjustment or hematologic toxicity within a delayed dosing regimen.
If persistent grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed during the previous course consider reducing the melphalan dose by 25% during the latter course.
Discontinue if platelet count ≤ 30 x 109/L or ANC ≤ 0.75 x 109/L on the day of administration (other than day 1). If this product is discontinued several times during a course of therapy (≥3 times during 2 weekly dosing regimens or ≥2 times during 1 weekly dosing regimens) it should be reduced by one dose level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2) in the subsequent course of therapy. non-hematologic toxicity of grade 3 and higher discontinue this product until symptoms of toxicity are reduced to grade 1 or baseline levels. grade or baseline level. Then, discontinue at a reduced dose level (from 1.3 mg/m2 to 1 mg/m2
or from 1 mg/m2 to 0.7 mg/m2) to restart treatment with this drug. For neuropathic pain and/or peripheral neuropathy associated with this product, the dose of this product may be suspended or adjusted as indicated in Table 3. For information on melphalan and prednisone, please refer to their instructions.
Patients with relapsed multiple myeloma and relapsed set of cell lymphoma
Single agent
Recommended Dose for Treatment
The recommended dose of this product is a single injection of 1.3 mg/m2 twice weekly for 2 weeks (i.e., injections on days 1, 4, 8, and 11) followed by 10 days of discontinuation (i.e., from day 12 to day 21).
Three weeks is a course of treatment, with a minimum of 72 hours between doses.
For continuation therapy beyond 8 courses, the drug may be administered according to the standard regimen. For patients with relapsed multiple myeloma, a maintenance regimen of 1 weekly dose administered for 4 consecutive weeks (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35) is also available.
Dose adjustment and restart of therapy
Treatment with this product should be suspended when any grade 3 non-hematologic toxicity or any grade 4 hematologic toxicity (excluding neuropathy as discussed below) occurs. Once symptoms of toxicity have resolved, treatment with this product may be restarted with a 25% dose reduction (e.g., 1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If a patient develops neuropathic pain or peripheral sensory neuropathy related to this treatment, the recommended dose adjustment according to the table below is recommended, and the treating physician should choose an appropriate dose adjustment regimen based on the patient’s actual condition. There have been reports of interruption or discontinuation of treatment due to severe autonomic neuropathy. If the patient has severe neuropathy himself, this product should be used only after weighing the pros and cons.
Table 3: Recommended dose adjustments when neuropathic pain or peripheral sensory or motor neuron disease occurs in association with treatment with this product
Severity of signs and symptoms of peripheral neuropathy* Dosage adjustment Grade 1 (no symptoms; abnormal sensation or loss of deep tendon reflexes) without pain or loss of function No change Grade 1 with pain or Grade 2 (moderate symptoms; instrumental activities of daily living (ADL) limitation**) Dose reduced to 1.0 mg/m2 or change the regimen to 1.3 mg/m2 once weekly Grade 2 with pain or Grade 3 (moderate symptoms; instrumental activities of daily living (ADL) limitation**) With pain or Grade 3 (severe symptoms; ADL limitation ***) withhold treatment until toxicity resolves and resume treatment at a dose of 0.7 mg/m2 once weekly. Grade 4 (life-threatening; indication for urgent intervention) discontinue treatment. * Graded according to NCI Common Toxicity Criteria CTCAE v 4.0.
** Instrumental ADL: refers to cooking, shopping for sundries or clothing, making phone calls, managing money, etc.
*** Autonomic ADL: refers to bathing, dressing and undressing, eating on their own, toileting, taking medications and not requiring bed rest.
 Patients with untreated condylomatous lymphoma
Recommended dose of this product in combination with rituximab, cyclophosphamide, doxorubicin and prednisone
See the monotherapy section for the dose of this product. 6 courses of treatment are required and 2 additional courses of treatment are recommended for patients who first document remission on the 6th course of treatment.
Prednisone 100 mg/m2 is administered orally on days 1, 2, 3, 4, and 5 of each course.
 Dose adjustment during treatment in patients with untreated laparoscopic lymphoma
By day 1 of each course (except course 1).
Platelet count should be ≥100×109 /L and absolute neutrophil count (ANC) should be ≥1.5×109 /L
Hemoglobin should be ≥8g /dL (≥4.96
mmol /L)
Non-hematologic toxicity should have returned to grade 1 or baseline levels
If any Grade 3 non-hematologic toxicity or Grade 3 hematologic toxicity (excluding neuropathy) occurs, treatment with this product must be suspended.
Table 4: Dose adjustment during treatment in untreated patients with set cell lymphoma
Toxicity Dose adjustment or delayed dosing Hematologic toxicity
≥ grade 3 neutropenia with fever, grade 4 neutropenia lasting more than 7 days, platelet count <10´109/L
 
 
 
 If platelet count < 25 ´ 109/L or ANC < 0.75 ´ 109/L on the day of administration (other than day 1) this drug should be suspended for up to 2 weeks until the patient’s ANC ≥ 0.75 ´ 109/L and platelet count ≥ 25 ´ 109/L.
If the toxicity does not subside to these levels after suspension of therapy, the drug should be discontinued.
If the toxicity subsides, i.e., the patient’s ANC ≥ 0.75 ´ 109/L and platelet count ≥ 25 ´ 109/L, the dose of this product should be reduced by one dose level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2)
 Treatment with this product should be suspended. ≥ Grade 3 non-hematologic toxicity should be suspended until symptoms of toxicity subside to Grade 2 or lower levels. Treatment may then be restarted at a lower dose level (from 1.3 mg/m2 to 1 mg/m2 or from 1 mg/m2 to 0.7 mg/m2).
 If neuropathic pain and/or peripheral neuropathy associated with this product occurs, the administration of this product should be suspended and/or adjusted as described in Table 3.
 See the instructions for rituximab, cyclophosphamide, doxorubicin, or prednisone for information about them.
 Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require adjustment of the starting dose and should be treated at the recommended dose. The starting dose should be reduced to 0.7 mg/m2 in patients with moderate to severe hepatic impairment and subsequently increased to 1.0 mg/m2 or further reduced to 0.5 mg/m2 depending on the patient’s tolerability during the first cycle.
Table 5: Recommended starting dose adjustment table for patients with hepatic impairment
 Bilirubin level SGOT (AST) level starting dose adjustment (single dose 1.3mg/m2 twice weekly) Mild£ 1.0x ULN> ULN unchanged> 1.0x to 1.5x ULN any value unchanged Moderate> 1.5x to 3x ULN any value First treatment cycle dose reduced to 0.7mg/m2. depending on patient tolerability, subsequent treatment doses Severe> 3x ULN any value Abbreviations: SGOT = serum glutamic oxaloacetic transaminase
AST = aspartate aminotransferase
ULN = upper limit of normal value in patients with renal impairment
The pharmacokinetics of this product are not affected by the degree of renal impairment in the patient, so no dose adjustment is required in patients with renal impairment. Since dialysis decreases the concentration of this product, it should be given after the end of dialysis.
Method of administration
This product is administered intravenously or subcutaneously. For intravenous administration, the product should be administered by intravenous push for 3-5 seconds through a peripheral or central intravenous catheter, followed by flushing with 0.9% sodium chloride injection. For subcutaneous administration, the redissolved solution should be injected into the thigh (right or left side) or abdomen (right or left side). Rotate different injection sites for multiple subcutaneous injections.
If local injection site reactions occur after subcutaneous injection of this product, a lower concentration (1 mg/mL instead of 2.5 mg/mL) of this product solution can be administered subcutaneously or transferred to intravenous injection.
Adverse reactions]
Summary of adverse reactions in clinical trials of intravenous administration in patients with relapsed or refractory multiple myeloma
The efficacy and safety of bortezomib at the recommended dose of 1.3 mg/m2 was evaluated in three clinical studies, including a randomized dexamethasone controlled phase III trial (M34101-039) in 669 patients with relapsed or refractory multiple myeloma after 1 to 3 lines of therapy and a single-arm, open, multicenter phase II trial in 202 patients who had received at least 2 patients who had received at least 2 treatments and had recently been found to have disease progression (M34100-025); and a phase II clinical trial evaluating the dose-effect of bortezomib in patients with relapsed multiple myeloma treated with bortezomib 1.0 mg/m2 or 1.3 mg/m2 (M34100-024) who had disease progression or relapse during or after first-line therapy.
Table 6: Adverse reactions to bortezomib in phase II and III clinical trials for relapsed or refractory multiple myeloma
MedDRA Systematic Organ Classification
Preferred Terminology Trial Number M34100-039
(N=331)M34100-024/025
(N=228a)Blood and lymphatic system disordersThrombocytopenia115 (35%)97 (43%)Anemia87 (26%)74 (32%)Neutropenia62 (19%)55 (24%)Leukopenia24 (7%)15 (7%)Lymphocytopenia15 (5%)11 (5%)Holocytopenia2 (<1%)6 (3%)febrile neutropenia1 (<1%)1 (<1%)cardiac organ disease arrhythmias4 (1%)2 (<1%)tachycardia9 (3%)17 (7%)atrial fibrillation6 (2%)2 (<1%)palpitations5 (2%)4 (2%)acute onset or worsening of heart failure, including congestive heart failure7 (2%)8 (4% )Pulmonary edema6 (2%)3 (1%)Cardiogenic shockb1 (<1%)-Newly developed decreased left ventricular ejection fraction1 (<1%)-Atrial flutter1 (<1%)-Bradycardia3 (<1%)1 (<1%)Ear and vagus-like disordersImpaired hearing1 (<1%)1 (<1%)Eye organ disordersBlurred vision9 ( 3%)25 (11%)Conjunctival infection and irritation14 (4%)7 (3%)Gastrointestinal system disordersConstipation140 (42%)97 (43%)Diarrhea190 (57%)116 (51%)Nausea190 (57%)145 (64%)Vomiting117 (35%)82 (36%)Gastrointestinal and abdominal pain, except oropharyngeal pain80 (24%)48 ( 21%)dyspepsia32 (10%)30 (13%)sore throat25 (8%)19 (8%)gastroesophageal reflux10 (3%)1 (<1%)belching2 (<1%)4 (2%)bloating14 (4%)13 (6%)oral mucositis and mouth ulcers24 (7%)10 (4%)dysphagia4 (1%)5 (2%)gastrointestinal bleeding ( upper and lower gastrointestinal tract)b7 (2%)3 (1%)rectal bleeding (including hemorrhagic diarrhea)7 (2%)3 (1%)tongue ulcers2 (<1%)1 (<1%)dry vomiting3 (<1%)2 (<1%)upper gastrointestinal bleeding1 (<1%)-vomiting blood1 (<1%)-oral mucosal stasis3 (<1%)-paralytic intestinal obstruction1 (<1%)2 (<1%)Systemic diseases and various reactions at the administration site Weakness201 (61%)149 (65%) -Lack of energy40 (12%)44 (19%) -Fatigue140 (42%)118 (52%) -Sleepiness12 (4%)9 (4%) -Discomfort13 (4%)22 (10%)Fever116 (35% ) 82 (36%) chills37 (11%)27 (12%) lower extremity swelling35 (11%)27 (12%) neuropathic pain21 (6%)5 (2%) chest pain26 (8%)16 (7%) injection site pain and irritation1 (<1%)1 (<1%)injection site phlebitis1 (<1%)1 (<1%)hepatobiliary system disorders Hyperbilirubinemia1 (<1%)-Abnormal liver function tests3 (<1%)2 (<1%)Hepatitis2 (<1%) In the M34101-040 testc-Immune system disordersDrug hypersensitivity reactions1 (<1%)1 (<1%)Infections and infestationsUpper respiratory tract infections26 (8%)41 (18%)Nasopharyngitis45 ( 14%)17 (7%)Lower respiratory and pulmonary infections48 (15%)29 (13%)Infectious pneumoniab21 (6%)23 (10%)Herpes zoster (including multidermatomal or diffuse)42 (13%)26 (11%)Herpes simplex25 (8%)13 (6%)Bronchiectasis26 (8%)6 (3%)Postherpetic neuropathic pain4 (1%)1 (<1%)Sinusitis14 (4%)15 (7%)Pharyngitis6 (2%)2 (<1%)Oral candidiasis6 (2%)3 (1%)Urinary tract infections13 (4%)14 (6%)Catheter-related infections10 (3%)6 (3%)Sepsis and bacteraemiab9 (3%)9 (4%)Gastroenteritis7 (2%)-All types of injuries, poisonings and surgical complicationsCatheter Associated complications7 (2%)8 (4%)Various tests ALT elevation3 (<1%)10 (4%)AST elevation5 (2%)12 (5%)Alkaline phosphatase elevation6 (2%)8 (4%)GGT elevation1 (<1%)4 (2%)Metabolic and nutritional disorders Loss of appetite and anorexia112 (34%)99 (43%)Dehydration24 (7%) 42 (18%)Hyperglycemia5 (2%)16 (7%)Hypoglycemia7 (2%)4 (2%)Hyponatremia8 (2%)18 (8%)Musculoskeletal and connective tissue disordersLimb pain50 (15%)59 (26%)Myalgia39 (12%)32 (14%)Arthralgia45 (14%)60 (26%)Benign, malignant and unspecified tumors (including cysts and polyps)Tumor lysis syndrome2 (<1%) In the M34101-040 trialc- Neurological disordersPeripheral neuropathyd
120 (36%)84 (37%)Sensory abnormalities and dullness91 (27%)53 (23%)Dizziness, excluding vertigo45 (14%)48 (21%)Headache85 (26%)63 (28%)Taste disturbances17 (5%)29 (13%)Polyneuropathy9 (3%)1 (<1%)Syncope8 (2%)17 (7%)Convulsions4 ( 1%)-Loss of consciousness2 (<1%)-Loss of taste2 (<1%)-Mental illness disordersAnxiety31 (9%)32 (14%)Renal and urological disordersRenal injury and failure21 (6%)21 (9%)Difficulty in urination2 (1%)3 (1%)Hematuria5 (2%)4 (2%)Respiratory, thoracic and mediastinal disordersEpistaxis21 (6%)23 ( 10%)Cough70 (21%)39 (17%)Dyspnea65 (20%)50 (22%)Dyspnea with activity21 (6%)18 (8%)Pleural effusion4 (1%)9 (4%)Rhinorrhea4 (1%)14 (6%)Hemoptysis3 (<1%)2 (<1%)Skin and subcutaneous tissue disordersRash, which may be pruritic, erythematous, or with leukocyte rupture vasculitis manifestations61 (18%)47 (21%)Urticaria7 (2%)5 (2%)Vascular and lymphovascular-like disordersLow blood pressure 20 (6%)27 (12%)Postural/erectile hypotension14 (4%)8 (4%)Petechiae6 (2%)7 (3%)Cerebral hemorrhageb1 (<1%)-a All 228 patients received bortezomib at a dose of 1.3 mg/m2
b Including lethal outcomes
c One study of bortezomib at the recommended dose of 1.3 mg/m2 for multiple myeloma in patients who had received at least 4 therapies or who had worsened after receiving high-dose dexamethasone in regimen M34101-039
d Includes all preferred terms under the MedDRA HLT “peripheral neuropathy (not otherwise classified)”
 Summary of Adverse Reactions in Clinical Trials of Intravenous Versus Subcutaneous Administration in Patients With Relapsed Multiple Myeloma
The safety and efficacy of subcutaneous administration of bortezomib at the recommended dose of 1.3 mg/m2 was evaluated in a phase III clinical trial. This was a randomized, controlled trial of subcutaneous versus intravenous administration in 222 patients with relapsed multiple myeloma.
Table 7: Adverse drug reactions to bortezomib reported in ≥ 10% of patients in a phase III clinical trial of intravenous versus subcutaneous administration for relapsed multiple myeloma
 Intravenous administration Subcutaneous administration (N=74) (N=147) MedDRA Systematic organ classification Total toxicity classification, n (%) Total toxicity classification, n (%) Preferred term n (%) 3 ≥ 4 n (%) 3 ≥ 4 Hematologic and lymphatic system disorders Anemia 26 (35) 6 (8) 053 (36) 14 (10) 4 (3) Leukopenia 16 (22) 4 (5 ) 1 (1)29 (20)9 (6)0 neutropenia 20 (27)10 (14)3 (4)42 (29)22 (15)4 (3) thrombocytopenia 27 (36)8 (11)6 (8)52 (35)12 (8)7 (5) gastrointestinal disorders abdominal pain 8 (11)005 (3)1 (1)0 epigastric pain 8 (11)003 (2) 00Constipation11 (15)1 (1)021 (14)1 (1)0Diarrhea27 (36)3 (4)1 (1)35 (24)2 (1)1 (1)Nausea14 (19)0027 (18)00Vomiting12 (16)01 (1)17 (12)3 (2)0Systemic diseases and various reactions at the site of administrationLack of energy14 (19)4 (5)023 (16 )3 (2)0 Fatigue15 (20)3 (4)017 (12)3 (2)0 Fever12 (16)0028 (19)00Infections and InfectionsHerpes zoster7 (9)1 (1)016 (11)2 (1)0Metabolic and nutritional disordersDecreased appetite7 (9)0014 (10)00Musculoskeletal and connective tissue disordersLimb pain8 (11)2 (3)08 ( 5)1 (1)0 Neurological disorders headache8 (11)005 (3)00 Neuropathic pain17 (23)7 (9)035 (24)5 (3)0 Peripheral sensory neuropathy36 (49)10 (14)1 (1)51 (35)7 (5)0 Mental disorders insomnia8 (11)0018 (12)00 Respiratory, thoracic and mediastinal disorders dyspnea9 ( 12)2 (3)011(7)2(1)0 Note: The number of subjects in each group was used as the denominator to calculate the percentages under “Total” for each group.
The number of subjects in each group was used as the denominator to calculate the percentages under toxicity classification subgroups. Although the overall safety data were similar for the intravenous and subcutaneous treatment groups, the table below highlights the adverse drug reactions that differed by more than 10% in overall incidence between the two treatment groups.
Table 8: Adverse drug reactions with an overall incidence difference of >10% between the intravenous and subcutaneous treatment groups in the phase III trial for relapsed multiple myeloma, by toxicity class and whether they led to discontinuation
 Intravenous administration Subcutaneous administration (N=74) (N=147) MedDRA Systemic organ classification Classification, n (%) Classification, n (%) MedDRA High term TEAEG ≥ 3DiscTEAEG ≥ 3Disc All subjects with TEAE 73 (99) 52 (70) 20 (27) 140 (95) 84 (57) 33 (22 ) Gastrointestinal system diseases Diarrhea (except infectious diarrhea)27(36)4(5)1(1)35 (24)3(2)1(1) Gastrointestinal and abdominal pain (except oropharyngeal pain)14(19)009(6)1(1)0 Systemic diseases and various reactions at the administration site Weakness29(39)7 (9)1 (1)40 (27)6 (4)2 (1) Infections and infestations Upper respiratory tract infections19 (26)2 (3)020 (14)00 Neurological disorders Peripheral neuropathy a39 (53)12 (16)10 (14)56 (38)9 (6)9 (6)a Represents high level terms.
TEAE indicates treatment-emergent adverse events.
G ≥ 3 indicates toxicity rating ≥ 3; Disc indicates discontinuation of any study drug. The overall incidence of on-treatment adverse drug reactions with grade 3 or higher toxicity was 13% lower in patients receiving subcutaneous administration than in the intravenous group (57% versus 70%, respectively) and resulted in discontinuation of bortezomib at a rate 5% lower than in the intravenous group (22% versus 27%). Regarding the overall incidence of diarrhea (24% in the subcutaneous group vs. 36% in the sedation group), gastrointestinal and abdominal pain (6% in the subcutaneous group vs. 19% in the sedation group), weakness (27% in the subcutaneous group vs. 39% in the sedation group), upper respiratory tract infections (14% in the subcutaneous group vs. 26% in the sedation group), and peripheral neuropathy (not otherwise classified) (38% in the subcutaneous group vs. 53% in the sedation group), the subcutaneous group was 12% to 15% lower than that of the sedated group. In addition, the incidence of peripheral neuropathy with grade 3 or higher toxicity was 10% lower in the subcutaneous group than in the sedation group (6% in the subcutaneous group versus 16% in the sedation group), and the rate of discontinuation due to peripheral sensory neuropathy was 8% lower in the subcutaneous group than in the sedation group.
Local adverse reactions, mostly erythema, were reported in 6% of patients after subcutaneous administration. Only 2 (1%) subjects reported severe reactions. These severe local reactions included one case of pruritus and one case of erythema. These reactions rarely resulted in dose adjustments and all resolved after 6 days (median).
Retreatment of patients with relapsed multiple myeloma
The following table summarizes the adverse drug reactions to bortezomib reported by at least 10% of patients with relapsed multiple myeloma retreated with intravenous bortezomib (MMY-2036 study).
Table 9: Incidence of bortezomib adverse drug reactions reported in ≥ 10% of patients (MMY-2036 study)
 Bortezomib retreatment (MMY-2036) Toxicity class total 3 ≥4 Analysis set: safety population, number 130 Number of subjects with adverse drug reactions, n (%) 126 (97) MedDRA system organ classification Preferred term Blood and lymphatic system disorders Thrombocytopenia 71 (55) 19 (15) 14 (11) Anemia 48 (37) 5 (4) 1 ( 1)Neutropenia23 (18)9 (7)0Leukopenia20 (15)5 (4)0Gastrointestinal system disordersDiarrhea45 (35)9 (7)0Constipation36 (28)00Nausea14 (11)00Systemic disorders and various reactions at the site of administrationFever31 (24)2 (2)0Lethargy29 (22)6 (5)0Fatigue21 (16)00Peripheral Edema15 (12)00 Infection and invasive respiratory tract infection17 (13)3 (2)1 (1)Bronchitis13 (10)1 (1)0 Neurological disorders Peripheral sensory neuropathy22 (17)4 (3)0 Peripheral neuropathy13 (10)3 (2)0 Respiratory, thoracic and mediastinal disorders Cough15 (12)1 (1)0 Dyspnea14 (11)1 (1)0 Note : Percentages were calculated using the number of subjects in each group as the denominator.
Adverse events were reported according to MedDRA version 14.1.
In study MMY-2036, for adverse events where only the severity level was reported, the severity level was remapped according to the NCI CTCAE toxicity level.
Adverse events with missing toxicity levels were counted according to level 3.
 Summary of clinical trials of bortezomib co-administration in patients with relapsed multiple myeloma
The following table summarizes the adverse drug reactions reported by at least 10% of patients receiving bortezomib in combination with dexamethasone (MNY-2045 study) or bortezomib in combination with polyethylene glycol doxorubicin liposomes (DOXIL-MMY-3001 study) for the treatment of relapsed multiple myeloma.
Table 10: Most common (reported by at least 10% of patients in either treatment group) adverse drug reactions occurring during treatment according to toxicity class, system organ classification, preferred term classification, safety analysis set (DOXIL-MMY-3001 study and MMY-2045 study)
  Combination therapy bortezomib monotherapy
Bortezomib + polyethylene glycol doxorubicin liposomes
Bortezomib + dexamethasone combined
n (%) level ≥3 n (%) total
n (%) Level ≥3 n (%) Total
n (%) Level ≥3 n (%) Analysis set: safety population 318 318 163 Subjects who experienced adverse drug reactions 301 (95) 314 (99) 154 (94) MedDRA Systemic Organ Classification
Preferred term Gastrointestinal system disorders Diarrhea 124 (39)16 (5)145 (46)23 (7)51 (31)7 (4) Nausea 126 (40)3 (1)154 (48)8 (3)20 (12)1 (1) Constipation 98 (31)2 (1)99 (31)3 (1)50 (31)9 (6) Vomiting 69 (22)3 (1)101 (32 ) 13 (4)11 (7)2 (1)Oral mucositis 11 (3)1 (< 1)56 (18)7 (2)1 (1)0 Abdominal pain 24 (8)4 (1)34 (11)2 (1)11 (7)1 (1)Peripheral neuropathy in neurological disorders a143 (45)35 (11)133 (42)22 (7)79 (48)23 (14) Neuropathic pain63 (20)14 (4)54 (17)9 (3)26 (16)4 (2)Headache56 (18)059 (19)3 (1)9 (6)0 Sensory abnormalities31 (10)041 (13)1 (< 1)22 (13)2 (1)Dizziness26 (8)4 (1)32 (10)4 (1)14 (9)0 Systemic diseases and drug administration Department various reactions fatigue 88 (28)8 (3)115 (36)22 (7)37 (23)2 (1)fever 71 (22)4 (1)100 (31)4 (1)21 (13)4 (2)malaise 56 (18)12 (4)71 (22)19 (6)33 (20)2 (1)peripheral edema 27 (8)1 (< 1)32 (10) 1 (< 1)43 (26)3 (2)Blood and lymphatic system disorders thrombocytopenia 89 (28)53 (17)106 (33)76 (24)61 (37)28 (17)Neutropenia 71 (22)51 (16)114 (36)102 (32)12 (7)6 (4)Anemia 68 (21)30 (9)80 ( 25)29 (9)35 (21)16 (10)Infections and Infections Herpes zoster29 (9)6 (2)34 (11)6 (2)16 (10)1 (1)Bronchitis21 (7)3 (1)31 (10)1 (< 1)18 (11)1 (1)Upper respiratory tract infections33 (10)3 (1)33 (10)2 (1)15 (9)3 (2) Musculoskeletal and connective tissue disorders Back pain39 (12)6 (2)39 (12)4 (1)25 (15)2 (1)Limb pain48 (15)8 (3)34 (11)1 (< 1)16 (10)2 (1)Arthralgia27 (8)5 (2)34 (11)1 (< 1)14 (9)1 (1)Respiratory, thoracic and mediastinal disorders Cough 38 (12)058 (18)026 (16)1 (1)Dyspnea28 (9)10 (3)34 (11)3 (1)13 (8)3 (2)Metabolic and nutritional diseases Decreased appetite50 (16)1 (< 1)83 (26)8 (3)9 (6)0 Skin and subcutaneous tissue diseases Rash29 (9)3 (1)48 (15)2 (1)8 ( 5)0All types of screening weight loss12 (4)037 (12)03 (2)0Psychiatric disorders insomnia43 (14)2 (1)35 (11)018 (11)1 (1)
a Includes the following preferred terms: peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuron disease, peripheral sensorimotor neuropathy, polyneuropathy. Note: Percentages were calculated using the number of subjects in each group as the denominator.
Adverse events are reported according to MedDRA version 14.1.
In study MMY-2045, for adverse events where only the severity level was reported, the severity level was remapped according to the NCI CTCAE toxicity level.
 Summary of adverse reactions in clinical trials in patients with untreated multiple myeloma
The following table presents safety data for bortezomib IV (1.3 mg/m2) in combination with MP combination therapy [melphalan (9 mg/m2) and prednisone (60 mg/m2)] in 340 untreated patients with multiple myeloma in a prospective phase III study.
Table 11: Drug-related adverse events in treatment reported by ≥10% of patients in trials of bortezomib in combination with MP combination therapy
 Bortezomib in combination with MP group
(n=340)MP group
(n=337) MedDRA System Organ Classification Total Toxicity Class, n (%) Total Toxicity Class, n (%) Preferred Term n (%) 3 ≥ 4 n (%) 3 ≥ 4 Hematologic 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)Anemia 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)Lymphocytopenia 78 (23)46 (14)17 (5) 51 (15)26 (8)7 (2)Gastrointestinal system disorders Nausea 134 (39)10 (3)070 (21)1 (<1)0 Diarrhea 119 (35)19 (6)2 (1)20 (6)1 (<1)0 Vomiting 87 (26)13 (4)041 (12)2 (1)0 Constipation 77 (23)2 (1)014 (4)00 Upper Abdominal pain 34 (10)1 (<1)020 (6)00 Neurological disorders Peripheral neuropathy 156 (46)42 (12)2 (1)4 (1)00 Neuropathic pain 117 (34)27 (8)2 (1)1 (<1)00 Sensory abnormalities 42 (12)6 (2)04 (1)00 Systemic disorders and various reactions at the site of administration Fatigue 85 ( 25)19 (6)2 (1)48 (14)4 (1)0 Fatigue54 (16)18 (5)023 (7)3 (1)0 Fever53 (16)4 (1)019 (6)1 (<1)1 (<1)Infections and infestations Herpes zoster39 (11)11 (3)09 (3)4 (1)0 Metabolic and nutritional disorders Loss of appetite64 (19)6 (2)019 (6)00 Skin and subcutaneous tissue disorders Rash38 (11)2 (1)07 (2)00 Mental disorders Insomnia35 (10)1 (<1)021 (6)00
Herpes zoster virus reactivation
Physicians should consider giving antiviral prophylaxis to patients using bortezomib. In untreated multiple myeloma patients enrolled in phase III studies, reactivation of herpes zoster was more common in patients in the bortezomib combined with MP group compared with the MP treatment group (4% and 14%, respectively). In the bortezomib-combined MP treatment group, 26% of patients received antiviral prophylaxis, and the incidence of herpes zoster was 17% in patients who did not receive prophylactic antiviral therapy compared with 3% in patients who received prophylactic antiviral therapy.
Adverse reactions that may be causally associated with bortezomib in untreated patients with multiple myeloma who are candidates for bone marrow transplantation receiving bortezomib intravenously (1.3 mg/m2) are listed in the table below. In the MMY-3003 study, 410 patients treated with bortezomib in combination with doxorubicin and dexamethasone were compared with 411 patients treated with vincristine, doxorubicin, and dexamethasone; in the IFM2005-01 study, 239 patients treated with bortezomib in combination with dexamethasone only were compared with 239 patients treated with vincristine, doxorubicin, and dexamethasone in the MMY-3010 study, 130 patients treated with bortezomib in combination with thalidomide and dexamethasone were compared with 126 patients treated with thalidomide and dexamethasone. For the three studies mentioned above (MMY3003, IFM2005-01 and MMY3010) that were performed in the transplant setting, the adverse reactions listed in the table below were limited to the induction phase.
Table 12: Incidence of adverse drug reactions in treatments with an incidence of ≥10% during the induction period
 Combined Bortezomib Not Combined Bortezomib (N=779) (N=776) MedDRA System Organ Classification Total Toxicity Class, n (%) Total Toxicity Class, n (%) Preferred Term n (%) 2 ≥ 3n (%) 2 ≥ 3 All subjects with adverse reactions 715 (92) 679 (88) Gastrointestinal Disorders Constipation 242 (31) 89 (11) 10 (1 ) 214 (28)67 (9)8 (1) Nausea215 (28)71 (9)22 (3)206 (27)77 (10)9 (1) Diarrhea133 (17)29 (4)23 (3)110 (14)26 (3)6 (1) Vomiting95 (12)30 (4)18 (2)87 (11)35 (5)6 (1) Neurological disorders Peripheral neuropathy147 (19)53 (7)20 (3)54 (7)11 (1)4 (1) Sensory abnormalities101 (13)24 (3)11 (1)80 (10)15 (2)2 (<1) Peripheral sensory neuropathy101 (13)41 (5)19 (2)55 (7)13 (2)1 (<1) Headache64 (8)23 (3 ) 4 (1)76 (10)23 (3)1 (<1) Systemic diseases and various reactions at the administration site Fatigue 158 (20)50 (6)21 (3)161 (21)68 (9)21 (3) Fever 153 (20)56 (7)25 (3)159 (20)40 (5)36 (5) Lethargy 110 (14)33 (4)16 (2) 91 (12)33 (4)10 (1) Blood and lymphatic system disorders Thrombocytopenia 239 (31)54 (7)63 (8)171 (22)27 (3)27 (3) Anemia 211 (27)95 (12)55 (7)222 (29)108 (14)77 (10) Leukopenia 196 (25)51 (7)109 (14) 206 (27)53 (7)120 (15) Infections and infestations Herpes zoster 86 (11)50 (6)24 (3)18 (2)9 (1)5 (1) Metabolic and nutritional disorders Hyperglycemia 122 (16)46 (6)26 (3)138 (18)46 (6)31 (4) Hyponatremia 100 (13)2 (<1)29 (4)82 ( 11)6 (1)12 (2) Psychiatric disorders Insomnia 96 (12)32 (4)6 (1)82 (11)30 (4)6 (1) Note: The number of subjects in each group was used as the denominator to calculate the percentages for each group. Incidence calculated as the number of subjects who experienced at least one adverse reaction, not the number of events.
Adverse events were reported according to MedDRA version 13.1.
 Adverse reactions in Chinese patients
This study of untreated patients with multiple myeloma enrolled 41 Chinese patients, 20 of whom were randomized to the bortezomib combined with MP treatment arm and 21 to the MP treatment arm. The following table lists the drug-related adverse events that occurred in Chinese patients during treatment.
Table 13: Drug-related adverse events in Chinese patients on treatment
 MP group Bortezomib in combination with MP group MedDRA system organ classification Chinese patients
n=21 Overall
n=337 Chinese patients
n=20 overall
n=340 Total number of subjects with adverse events on treatment n (%) 21 (100) 326 (97) 20 (100) 338 (99) Blood and lymphatic system disorders 18 (86) 259 (77) 20 (100) 279 (82) Heart organ disorders 3 (14) 48 (14) 3 (15) 59 (17) Various congenital, familial genetic disorders 0001(<1)Ear and vagus type diseases018(5)038(11)Endocrine system diseases02(1)1(5)10(3)Eye organ diseases028(8)1(5)73(21)Gastrointestinal system diseases9(43)185(55)18(90)262(77)Systemic diseases and various reactions at the administration site8(38)199(59) 16(80)239(70)Hepatobiliary system diseases2(10)27(8)5(25)31(9)Immune system diseases1(5)6(2)05(1)Infectious and invasive diseases10(48)182(54)13(65)234(69)Various types of injuries, poisonings and surgical complications040(12)040(12)Various types of examinations2(10)21 (6)1(5)32(9)Metabolic and nutritional diseases6(29)124(37)10(50)159(47)All kinds of musculoskeletal and connective tissue diseases5(24)151(45)7(35)172(51)Benign, malignant and tumors of unknown nature (including cystic and polypoid)04(1)07(2)All kinds of neurological diseases4(19) 122(36)13(65)253(74)Psychiatric diseases4(19)76(23)0112(33)Diseases of the kidney and urinary system4(19)62(18)2(10)54(16)Diseases of the reproductive system and breast1(5)15(4)1(5)21(6)Diseases of the respiratory system, chest and mediastinum5(24)123(36)8(40) 133(39)Skin and subcutaneous tissue diseases1(5)80(24)8(40)140(41)Various surgical and medical operations03(1)07(2)Vascular and lymphatic vessel diseases1(5)69(20)6(30)112(33)
 Summary of Adverse Reactions in Clinical Trials in Patients with Relapsed Sarcomatoid Lymphoma
The safety of bortezomib at the recommended dose of 1.3 mg/m2 was evaluated in 155 patients with relapsed sarcoid lymphoma in a phase II clinical study (M34103-053). The overall safety of bortezomib in patients with condylomatous lymphoma was similar to that observed in patients with multiple myeloma. Notable differences between these two patient groups were that patients with multiple myeloma reported higher levels of thrombocytopenia, neutropenia, anemia, nausea, vomiting, and fever than patients with condylomatous lymphoma, while patients with condylomatous lymphoma reported higher levels of peripheral neuropathy, rash, and pruritus than patients with multiple myeloma.
Summary of Clinical Trials in Untreated Patients with Follicular Lymphoma
Table 14 describes the safety data from a prospective randomized study in which 240 untreated patients with setocytic lymphoma received bortezomib intravenously (1.3 mg/m2) in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and prednisone (100 mg/m2) (VcR-CAP ) combination therapy.
The incidence of grade ≥3 bleeding events was similar in both groups (4 cases in the VcR-CAP group and 3 cases in the R-CHOP group). all grade ≥3 bleeding events in the VcR-CAP group resolved without sequelae.
Infections were reported in 31% of patients in the VcR-CAP group and 23% of patients in the R-CHOP group. Respiratory and pulmonary infectious events were reported in both groups, with the main preferred term being infectious pneumonia (8% in the VcR-CAP group and 5% in the R-CHOP group).
The incidence of herpes zoster reactivation was 4.6% and 0.8% in the VcR-CAP and R-CHOP groups, respectively. The use of prophylactic antiviral therapy was mandatory in the revised version of the study protocol.
 Table 14: Most frequently reported (≥5%) grade 3 and ≥4 adverse reactions in the condyloma study comparing VcR-CAP and R-CHOP (study LYM-3002, N=482)
 VcR-CAP
n=240R-CHOP
n=242Systematic organ classification
Total Preferred Terms
n(%) Grade 3 toxicity
n(%) ≥ grade 4 toxicity
n(%) Total
n(%) Grade 3 toxicity
n(%) ≥ grade 4 toxicity
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)Lymphocytopenia 68 (28)25 (10)36 (15)28 (12)15 (6)2 (1)Various neurological diseases Peripheral sensory neuropathy53 (22)11 (5)1 (< 1)45 (19)6 (3)0 Peripheral neuropathy18 (8)4 (2)018 (7)2 (1)0 Hyperalgesia14 (6)3 (1)013 (5)00 Sensory confusion14 (6)2 (1)011 (5)00 Neuralgia25 (10)9 (4) 01 (< 1)00 Systemic disease and various reactions at the site of administration Fatigue43 (18)11 (5)1 (< 1)38 (16)5 (2)0 Fever48 (20)7 (3)023 (10)5 (2)0 Lethargy29 (12)4 (2)1 (< 1)18 (7)1 (< 1)0 Peripheral edema16 (7)1 (< 1)013 (5)00 Gastrointestinal disorders Nausea54 (23)1 (< 1)028 (12)00 Constipation42 (18)1 (< 1)022 (9)2 (1)0 Oral mucositis20 (8)2 (1)019 (8)01 (< 1)Diarrhea59 (25)11 (5)011 (5)3 (1)1 (< 1)Vomiting 24 (10)1 (< 1)08 (3)00 Abdominal distension13 (5)004 (2)00 Infectious and invasive diseases Infectious pneumonia20 (8)8 (3)5 (2)11 (5)5 (2)3 (1)Skin and subcutaneous tissue diseases Alopecia31 (13)1 (< 1)1 (< 1)33 (14)4 (2)0 Metabolic and nutritional diseases      Hyperglycemia10 (4)1 (< 1)017 (7)10 (4)0 Decreased appetite36 (15)2 (1)015 (6)1 (< 1)0 Hypokalemia11 (5)3 (1)1 (< 1)6 (2)1 (< 1)0 Vascular and lymphatic disorders Hypertension15 (6)1 (< 1)03 (1)00 Psychiatric disorders Insomnia 16 (7)1 (< 1)08 (3)00 Note: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; VcR-CAP = vanco, rituximab, cyclophosphamide, doxorubicin and prednisone.
 Post-marketing experience
Adverse drug reactions that were not reported in the above clinical trials but were clinically significant are listed in Table 15.
The incidence of the following adverse reactions is based on the global post-marketing experience with bortezomib. Adverse reactions were classified according to frequency of occurrence as: very common (≥1/10); common (≥1/100 and <1/10); occasional (≥1/1000 and <1/100); rare (≥1/10,000 and <1/1000); and very rare (<1/10,000, including isolated cases).
The following spontaneously reported adverse reaction data do not accurately evaluate the incidence rates derived in clinical trials and epidemiologic studies. It does not represent the true incidence rates shown in clinical trials or epidemiological studies.
Table 15: Post-marketing Adverse Reaction Reports
Hematologic and lymphatic disorders Rare diffuse intravascular coagulation Very rare thrombotic microangiopathy Cardiac disorders Rare complete atrioventricular block, pericardial tamponade Ear and vagus disorders Rare bilateral deafness Ocular disorders Rare ocular herpes, optic neuropathy, blindness Rare blepharocyst/eyeliditis Gastrointestinal disorders Rare ischemic colitis, acute pancreatitis Occasional intestinal obstruction Infection and infestation Rare herpes meningoencephalitis, septic shock very rare progressive multifocal leukoencephalopathy* immune system disorders rare angioedema very rare tachyphylaxis neurological disorders rare encephalopathy, autonomic neuropathy, reversible posterior encephalopathy syndrome respiratory system, thoracic and mediastinal disorders rare acute diffuse infiltrative lung disease, pulmonary hypertension skin and subcutaneous tissue disorders very rare Stevens-Johnson syndrome and toxic epidermal necrolysis rare acute febrile neutrophilic leukocytosis dermatosis (Sweet’s syndrome)* very rare case of reported patient infected with John Cunningham (JC) virus during treatment with bortezomib resulting in progressive multifocal cerebral leukomalacia and death, the causality of which is unclear. [Contraindicated].
Contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
Precautions]
It should be used under the supervision of a physician experienced in the use of antineoplastic drugs, and the complete blood count (CBC) should be monitored frequently during the use of this product. This product is an antineoplastic drug and should be prepared with care and gloves to prevent skin contact.
There have been reported cases of death due to inadvertent intrathecal injection of bortezomib. Therefore, it is intended for intravenous and subcutaneous administration only, and intrathecal injection is strictly prohibited.
Overall, the safety profile of bortezomib monotherapy is similar to that observed with regimens combining melphalan and prednisone.
Peripheral neuropathy
Treatment with this product may result in peripheral neuropathy (PN), which primarily affects sensory nerves, but severe motor neuropathy with or without peripheral sensory neuropathy has also been reported.
Patients who have had symptoms of peripheral neuropathy (numbness, pain, or burning sensation in the feet or hands) or signs of peripheral neuropathy may have worsened symptoms of neuropathy (including grade ≥3) during treatment with this product. Monitoring for symptoms of neuropathy such as burning sensation, sensory hypersensitivity, hyperalgesia, abnormal sensation, discomfort, neuropathic pain, or weakness is recommended in such patients. In a phase III trial comparing intravenous versus subcutaneous bortezomib, the incidence of grade 2 and higher peripheral neuropathy events was 24% in the subcutaneous group and 41% in the intravenous group (p=0.0124). The incidence of grade 3 and higher peripheral neuropathy was 6% in the subcutaneous group compared with 16% in the intravenous group (p=0.0264) (Table 8). Therefore, on the basis of comparable response rates to treatment in both the intravenous and subcutaneous groups, starting treatment with subcutaneous administration may benefit patients with existing peripheral neuropathy or at high risk for peripheral neuropathy.
If patients develop new peripheral neuropathy or their symptoms worsen, it may be necessary to adjust the dose of this product, the treatment regimen, or to adjust to the subcutaneous route of administration. In a phase III trial of bortezomib versus dexamethasone monotherapy for multiple myeloma, 51% of patients with grade 2 and higher peripheral neuropathy reported improvement or disappearance of peripheral neuropathy with dose adjustment. In a phase II trial in multiple myeloma, 73% of patients who withdrew due to grade 2 neuropathy or had grade 3 or greater peripheral neuropathy reported improvement or disappearance of peripheral neuropathy. Long-term regression of peripheral neuropathy has not been studied in set cell lymphoma.
Hypotension
The incidence of hypotension (upright or postural and not otherwise specified) was 11% to 12% in phase II and phase III trials of monotherapy for multiple myeloma. This phenomenon was observed throughout the course of treatment. Caution is recommended in patients with a history of syncope, who are taking medications that can cause hypotension, or who are dehydrated. Upright or postural hypotension can be treated by adjustment of antihypertensive medications, rehydration, or the use of salt corticosteroids and/or sympathomimetic drugs.
Heart disease
Reports of acute congestive heart failure or worsening, and/or reduced left ventricular ejection fraction have been reported, including in patients without risk of reduced left ventricular ejection fraction or with very low risk factors. Patients at risk or with cardiac disease should be monitored closely. In a phase III trial of monotherapy for multiple myeloma, the incidence of sudden cardiac disease was 15% in the bortezomib group and 13% in the dexamethasone group. The incidence of heart failure (acute pulmonary edema, heart failure, congestive heart failure, cardiogenic shock, and pulmonary edema) was similar in both groups, at 5% and 4%, respectively. Individual cases of QT interval prolongation have occurred, but no causal relationship has been established.
Adverse events in the liver
Rare reports of acute hepatic failure have been reported in patients who are on multiple other concomitant medications and in those with severe underlying disease. Other hepatic adverse events include elevated liver enzymes, hyperbilirubinemia, and hepatitis. These changes may be reversible with discontinuation of this product. There is limited information on re-administration to these patients.
Pulmonary Disease
Acute diffuse infiltrative lung disease of unknown etiology, such as non-infectious pneumonia, interstitial pneumonia, pulmonary infiltrates and acute respiratory distress syndrome (ARDS), have been reported in patients. Some of the above events were fatal. Japan has a high rate of reporting for the above events. Patients with new symptoms of pulmonary disease or worsening symptoms should be diagnosed rapidly and treated promptly.
In a clinical trial, 2 patients with relapsed acute myeloid leukemia died from ARDS that occurred during the initial phase of treatment with high-dose (2 g/m2 per day) continuous infusion of cytarabine combined with ruxolithromycin and bortezomib.
Pulmonary hypertension associated with bortezomib has been reported in patients with no concomitant left heart failure or severe pulmonary disease. The development of new or exacerbated cardiopulmonary disease should prompt a full diagnostic evaluation.
Reversible posterior encephalopathy syndrome (PRES)
PRES has been reported in patients treated with bortezomib. PRES is a rare, reversible neurological disorder that can manifest as seizures, hypertension, headache, drowsiness, confusion, blindness, and other visual and neurological deficits. Brain imaging, preferably MRI (magnetic resonance imaging), can be used to confirm the diagnosis. The product should be discontinued in patients who present with PRES. The safety of restarting treatment with this product in patients with a history of PRES is unknown.
Laboratory Tests
Complete blood counts should be monitored closely during treatment with this product.
Thrombocytopenia/neutropenia
This product can cause thrombocytopenia and neutropenia, with platelets usually falling to a minimum on day 11 of each course of therapy and returning to baseline levels at the start of the next course of therapy. This cyclical pattern of platelet count reduction and recovery has been consistent in studies of multiple myeloma and set cell lymphoma, and cumulative thrombocytopenia and neutropenia have not been observed in either dosing regimen. Platelet counts should be monitored prior to each dose. Treatment should be discontinued when platelet counts <25,000/µL. Gastrointestinal or intracerebral hemorrhage associated with bortezomib has been reported and blood transfusions and supportive therapy should be considered in such patients. In a study of bortezomib versus dexamethasone as monotherapy for multiple myeloma, the mean platelet count was at a minimum of approximately 40% of baseline. The severity of thrombocytopenia in relation to pretreatment platelet counts is listed in Table 16. The incidence of important bleeding events (≥ grade 3) was similar in the dexamethasone and bortezomib groups, at 5% and 4%, respectively.
Table 16: Severity of thrombocytopenia in relation to pretreatment platelet count in a phase III trial of bortezomib versus dexamethasone
Pretreatment platelet count* Number of patients (N=331)** Number of patients with platelet count <10,000/µL (%) Number of patients with platelet count 10,000/µL to 25,000/µL (%) ≥75,000/µL3098 (3%)36 (12%)≥50,000/µL ~<75,000/µL142 (14% )11 (79%)≥10,000/µL ~<50,000/µL71 (14%)5 (71%)*A platelet count of 50,000/µL is a requirement for eligibility for this test
**1 patient with missing baseline data A combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) in previously untreated patients with set cell lymphoma showed a 32% incidence of grade ≥4 thrombocytopenia adverse events in the VcR-CAP group compared with rituximab, cyclophosphamide, doxorubicin, vincristine The incidence of grade ≥3 bleeding adverse events in the VcR-CAP and R-CHOP groups was 1.7% (4 patients) and 1.2% (3 patients), respectively.
No patients died due to bleeding events in either group. there were no central nervous system (CNS) bleeding events in the VcR-CAP group, while there was one CNS bleeding event in the R-CHOP group. platelet transfusion was performed in 23% and 3% of patients in the VcR-CAP and R-CHOP groups, respectively.
The incidence of grade ≥4 neutropenia was 70% and 52% in the VcR-CAP and R-CHOP groups, respectively, and the incidence of grade ≥4 febrile neutropenia was 5% and 6% in the VcR-CAP and R-CHOP groups, respectively. Seventy-eight percent and 61% of patients in the two groups received supportive colony-stimulating factor therapy, respectively.
Gastrointestinal Adverse Events
Treatment with this product may cause nausea, diarrhea, constipation and vomiting, sometimes requiring treatment with antiemetics and antidiarrheal drugs. If the patient is dehydrated, fluids and electrolytes should be replaced. Because vomiting and/or diarrhea may result from treatment with this product, patients should be advised to take appropriate measures to avoid dehydration. Patients should be advised to consult their physician if they experience vertigo, mild headache or coma.
Tumor lysis syndrome
Because this product is cytotoxic and kills malignant cells rapidly, it may cause complications of tumor lysis syndrome. Patients with high tumor load prior to treatment are at risk for tumor lysis syndrome and should be monitored closely and appropriate precautions should be taken.
Patients with hepatic impairment
This product is metabolized by hepatic enzymes and exposure is increased in patients with moderate to severe hepatic impairment. Such patients should be treated with a lower starting dose of this product and should be closely monitored for toxicity.
Effects on driving and ability to operate machinery
This product may cause fatigue, dizziness, lightheadedness or blurred vision. Therefore, driving and operating machinery are not recommended for patients who experience these symptoms.
Keep out of the reach of children.
Pregnant women and nursing mothers
For pregnant women
Women of childbearing age should avoid conception during treatment with this product.
Preclinical toxicological studies have shown that the highest test dose of bortezomib administered to rats at 0.075 mg/kg (0.5 mg/m2) and rabbits at 0.05 mg/kg (0.6 mg/m2) during organogenesis did not produce malformations. The above doses were approximately half of the clinical dose of 1.3 mg/m2 (based on body surface area).
Pregnant rabbits injected with 0.05 mg/kg (0.6 mg/m2) during organogenesis exhibited significant abortions and decreased fetal viability. The body weight of viable fetuses was significantly lower. The above dose is approximately half of the clinical dose of 1.3 mg/m2 (based on body surface area).
Studies have not been conducted to determine whether bortezomib crosses the placental barrier. Adequate formal studies have not been performed in pregnant women. If this product is used during pregnancy or if conception occurs during treatment, pregnant women should be informed of the possible hazards to the fetus.
During treatment with this product, patients are advised to use effective contraception and to avoid breastfeeding.
Use in nursing women
It is not known whether bortezomib is secreted through human milk. In view of the fact that many drugs are secreted through human milk and that feeding an infant with milk containing bortezomib may cause potentially serious adverse reactions, nursing women should be advised not to breastfeed during treatment with this drug.
Pediatric Use]
The safety and efficacy of this product in pediatric patients have not been established in the treatment of multiple myeloma and set cell lymphoma.
Geriatric use]
Of the 669 patients in the relapsed multiple myeloma study, 245 (37%) were ≥65 years of age: 125 (38%) in the bortezomib group and 120 (36%) in the dexamethasone group. Median time to disease progression and median duration of remission were longer in patients ≥65 years of age in the bortezomib group than in the dexamethasone group (median time to disease progression: 5.5 versus 4.3 months, median duration of remission: 8.0 versus 4.9 months). Remission (CR+PR) occurred in 40% (n=46) of evaluable patients aged ≥65 years in the bortezomib group compared to 18% (n=21) in the dexamethasone group. The incidence of grade 3 and 4 adverse events in the bortezomib group was 64%, 78%, and 75% in patients ≤50, 51-64, and ≥65 years of age, respectively.
Among patients treated with bortezomib, there was no overall difference in safety and efficacy between patients ≥65 years of age and younger patients; however, it cannot be ruled out that some older patients with multiple myeloma and sarcoid lymphoma are more sensitive to bortezomib.
[Drug Interactions].
In vitro and animal ex vivo studies have shown that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) enzymes 1A2, 2C9, 2C19, 2D6 and 3A4. Since CYP2D6 has a limited effect on bortezomib metabolism (7%), it can be expected that the slow metabolizing phenotype CYP2D6 will not affect the overall distribution of bortezomib.
In a drug interaction study evaluating the effect of ketoconazole (a potent inhibitor of CYP3A4) on the pharmacokinetics of bortezomib, data from 12 patients resulted in a mean 35% increase in bortezomib AUC. Therefore, patients should be closely monitored when bortezomib is combined with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir).
In a drug interaction study evaluating the effect of omeprazole (a potent inhibitor of CYP2C19) on the pharmacokinetics of bortezomib, the results of data from 17 patients showed no significant effect on the pharmacokinetics of bortezomib.
In a drug interaction trial evaluating the effect of rifampicin (a strong inducer of CYP3A4) on the pharmacokinetics of bortezomib, data from 6 patients showed a mean 45% reduction in the AUC of bortezomib. CYP3A4 inducers such as rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s wort are not recommended for combination with CYP3A4 strong inducers as their effectiveness may be reduced. The effect of the CYP3A4 weak inducer dexamethasone was also evaluated in this drug interaction trial, and data from seven patients showed no significant effect on the pharmacokinetics of bortezomib.
In a drug interaction study evaluating the effect of melphalan and prednisone combination therapy on bortezomib, data from 21 patients resulted in a mean 17% increase in bortezomib AUC . This result was not considered to be clinically relevant.
In clinical trials, hypoglycemia and hyperglycemia have been reported in diabetic patients following oral hypoglycemic agents. When treating with this product, the blood glucose levels of patients taking oral antidiabetic agents should be closely monitored and care should be taken to regulate the dose of the antidiabetic agent.
Advise patients that they should be cautious about combining drugs that may cause peripheral neuropathy (e.g., amiodarone, antivirals, isoniazid, furantoin, or statins) and drugs that cause a decrease in blood pressure.
[Drug overdose].
Pharmacological studies of cardiovascular safety in monkeys and dogs have shown that intravenous doses (approximately 2 to 3 times the clinically recommended dose in mg/m2) are associated with increased heart rate, decreased contractility, hypotension, and death. Decreased cardiac contractility and hypotension can be treated with positive inotropic or antihypertensive agents. A slight increase in QT interval has been observed after administration of lethal doses to dogs. Monkeys given 3.0 mg/m2 and higher (approximately twice the clinically recommended dose) developed hypotension 1 hour after dosing and then died 12 to 14 hours after dosing.
Acute episodes of associated symptomatic hypotension or thrombocytopenia with lethal regression have been reported in patients who were dosed at doses higher than two times the recommended dose.
There is no specific antidote for an overdose of this product. In the event of an overdose, patients should be monitored for vital signs and supportive therapy should be administered to maintain blood pressure (e.g., rehydration, antihypertensive agents and/or positive inotropic agents) and body temperature.
[Clinical trials].
Clinical studies of relapsed or refractory multiple myeloma after receiving at least two treatments
An open, single-arm, multicenter clinical study (M34100-025) was conducted to evaluate the safety and efficacy of this product in 202 patients who had received at least two treatments and had recently been found to have progressive disease. The median number of previous treatments was 6. Table 17 summarizes the basic conditions and disease characteristics of the patients at enrollment.
The product was given intravenously at a dose of 1.3 mg/m2 twice weekly, with 10 days of discontinuation after 2 weeks of continuous injections (i.e., 21 days as a course of treatment) for a maximum of 8 courses of treatment. The dose was adjusted in the study to account for toxicity. Those patients who showed therapeutic benefit to this product were allowed to continue in the continuation trial.
Table 17: Summary of patient population and disease characteristics*
 Number of cases = 202 Median age of patient characteristics (range) 59 (34, 84) Gender: male / female 60% / 40% Ethnicity: Caucasian / black / other 81% / 10% / 8% Carlson physical status score ≤ 7020% Hemoglobin <100 g/L 44% Platelet count <75 × 109/L 21% Disease characteristics Myeloma type (%) : IgG / IgA / light chain60%/24%/14% Median β2-microglobulin (mg/L)3.5 Median creatinine clearance (ml/min)73.9 Abnormal cytogenetics35% Chromosome 13 deletion15% Median duration since diagnosis of multiple myeloma (years)4.0 Previous treatmentAny steroid, e.g., dexamethasone, VAD99% Any alkylating agent such as mercaptopurine, VBMCP92% Any anthracycline such as VAD, mitoxantrone81% Any treatment with thalidomide83% Received at least two of the above 98% Received at least three of the above 92% Received all four of the above 66% Any stem cell transplant/other high-dose treatment 64% Participated in a trial or other type of treatment 44% *Based on the availability of underlying Number of patients with underlying condition data. The efficacy of monotherapy with this product is shown in Table 18. The remission rate for this product was determined by an independent review committee based on the criteria published by Bladé et al. Complete remission required less than 5% plasma cells in the bone marrow, a 100% reduction in M-protein, and a negative immunofixation electrophoresis test (IF-). The remission rates determined using the SWOG criteria are also presented in Table 18. SWOG remission required a ≥75% reduction in serum M-protein and/or a ≥90% reduction in urinary M-protein. Efficacy was evaluated in 188 patients. 9 patients could not be evaluated for efficacy because of non-measurable disease. 5 patients were excluded from efficacy evaluation because of a low number of prior treatments.
Ninety-eight percent of patients received the initial dose of 1.3 mg/m2 administered intravenously. Of these patients, 28% maintained this dose throughout the trial, with 33% decreasing the dose over the course of the trial. 63% of patients maintained at least one dose over the course of the study. Typically, after complete remission was confirmed, patients continued to receive 2 additional courses of this product. The mean of the dosing regimens was 6.
The median time to onset of action was 38 days (range 30 to 127 days).
The median survival time for all patients was 16 months (range 1 to 18 months).
Table 18: Summary of disease outcomes
Efficacy analysis (monotherapy with this product) N=188N (%) (95% CI) Overall remission rate (Bladé) (CR+PR) 52 (27.7%) (21, 35) Complete remission (CR) 15 (2.7%) (1, 6) Partial remission (PR) 247 (25%) (19, 32) Clinical remission (SWOG) 333 (17.6%) (12 24) Kaplan-Meier estimated median duration of remission (95% CI) 365 days (224, NE) 1 Complete remission: less than 5% plasma cells in bone marrow, 100% reduction in M-protein and negative immunofixation electrophoresis test (IF-) were required.
2 Partial remission: requires ≥50% reduction in serum M-protein and/or ≥90% reduction in urinary M-protein measured twice at a minimum of 6 weeks; stable calcium and bone disease.
3 Clinical remission (SWOG): ≥75% reduction in serum M-protein and/or ≥90% reduction in urinary M-protein, measured at least twice in 6 weeks; stable calcium and bone disease.
 In this study, the rate of remission to this product was independent of the number and type of treatment ever received. The potential for reduced remission rates exists in patients with >50% plasma cells in the bone marrow or with cytogenetic abnormalities. This product was observed to be effective in patients with chromosome 13 abnormalities in the trial.
In a dose-effect relationship study (M34100-24) in 54 patients with multiple myeloma, the product was injected at 1.0 mg/m2 or 1.3 mg/m2 per injection twice weekly for 2 weeks with 1 week off. Complete remission was observed at both doses, with overall remission rates (CR+PR) of 30% (8/27) and 38% (10/26), respectively.
Randomized, Open Clinical Study of Relapsed Multiple Myeloma After Receiving at Least One or More Treatments
The improvement in time to disease progression (TTP) was compared with high-dose dexamethasone in an international, prospective, randomized (1:1), stratified, open phase III clinical trial [M34101-039 (APEX)] enrolling 669 patients with progressive multiple myeloma who had received one to three previous treatments. Patients refractory to high doses of dexamethasone and those with peripheral neuropathy of grade 2 and above or platelet counts <50,000/µL at baseline were not eligible for the trial. A total of 627 patients were evaluated for efficacy.
Stratification factors included the type of treatment received (1 versus more than 1), the time from more prior treatment to disease progression (disease progression during or within 6 months after cessation of the last treatment versus relapse after 6 months of the last treatment), and screening β2-microglobulin levels (≤2.5 mg/L versus >2.5 mg/L).
The baseline values and disease characteristics of the patients at baseline are shown in Table 19.
Table 19: Baseline Values and Disease Characteristics of Patients at Baseline in Phase III Trials
Patient Characteristics
This product
N=333 Dexamethasone
N=336 Median age (range) 62.0 (33, 84) 61.0 (27, 86) Gender: male / female 56% / 44% 60% / 40% Race: Caucasian / black / other 90% / 6% / 4% 88% / 7% / 5% Carlson physical status score ≤ 7013% 17% Hemoglobin & lt;100g/L 32% 28% Platelet count & lt;75×109/L6%4%Disease characteristicsMyeloma type (%): IgG / IgA / light chain60% / 23% / 12%59% / 24% / 13%Median β2-microglobulin (mg/L)3.73.6Median albumin (g/L)39.039.0Creatinine clearance£30ml/min [n (%)]17 (5%)11 ( 3%) Median duration after diagnosis of multiple myeloma (years) 3.53.1 Median number of treatments ever received22 one treatment 40% 35% more than one treatment 60% 65% all patients (N=333) (N=336) ever received any steroid e.g. dexamethasone, VAD 98% 99% ever received any anthracycline e.g. VAD, mitoxantrone 77% 76% had received any alkylating agent such as mercaptopurine, VBMCP91%92% had received any thalidomide48%50% had received vincristine74%72% had received stem cell transplantation/other high-dose therapies67%68% had received experimental or other kinds of therapy3%2%
 Patients in this group received 3 courses of treatment (5 weeks each) after 8 courses of treatment (3 weeks each). In the 3-week treatment, 1.3 mg/m2 of this product was given intravenously alone, twice weekly, for 2 weeks (i.e., injections on days 1, 4, 8, and 11) followed by 10 days of discontinuation (i.e., from days 12 to 21). In the 5-week treatment, the product was given intravenously alone at 1.3 mg/m2 once a week for 4 weeks (i.e., injections on days 1, 8, 15, and 22) followed by 13 days of discontinuation (i.e., from days 23 to 35).
Patients in the dexamethasone group received 5 courses of treatment (4 weeks each) after 4 courses of treatment (5 weeks each). In the 5-week treatment, dexamethasone 40 mg/day was administered orally from day 1 to day 4, day 9 to day 12, and day 17 to day 20, after which it was discontinued for 15 days (i.e., from day 21 to day 35). In the 4-week treatment, oral dexamethasone 40 mg/day was administered from day 1 to day 4, followed by a 24-day discontinuation (i.e., from day 5 to day 28). Patients who developed disease progression on oral dexamethasone were included in relevant additional trials administered this product at standard doses and methods.
After an interim analysis of the time to disease progression was performed as planned, dexamethasone administration was discontinued in the dexamethasone group. All patients randomized to the dexamethasone group were switched to treatment with this product regardless of disease. Final statistical analyses were performed at the time of trial discontinuation. The median follow-up for surviving patients (n=534) was set at 8.3 months because the trial ended early.
During all 8 courses of treatment (3 weeks per course) in the product group, 34% of patients received at least 1 dose of this product and 13% of patients received at least 1 dose of this product during all 11 courses of treatment. The mean number of doses administered in this trial was 22, ranging from 1 to 44. 40% of patients received at least 1 dose of dexamethasone during 4 courses of dexamethasone (5 weeks per course) and 6% of patients received at least 1 dose of dexamethasone during all 9 courses.
Time-to-event analysis and remission rates for the phase III trials described above are shown in Table 20. The European Bone Marrow Transplantation Collaborative Group (EBMT) criteria were applied to evaluate remission and progression. Complete remission (CR): requires less than 5% plasma cells in the bone marrow, 100% reduction in serum M-protein, and negative immunofixation electrophoresis test (IF-). Partial remission (PR): requires a minimum of no less than two tests every 6 weeks, ≥ 50% reduction in serum M-protein and/or ≥ 90% reduction in urinary M-protein; normal calcium and stable bone disease. Near complete remission (nCR) was defined as meeting all criteria for complete remission including a 100% reduction in M-protein on protein electrophoresis results, but M-protein (IF+) was still measurable on immunofixation electrophoresis assays.
Table 20: Effectiveness analysis of phase III randomized clinical trials
 All patients had received one treatment had received more than one treatment Benzo dexamethasone Benzo dexamethasone Benzo dexamethasone Efficacy endpoint n=333n=336n=132n=119n=200n=217 to time to disease progression –
Events n (%)
 147(44)
 196(58)
 55(42)
 64(54)
 92(46)
 132(61)
 Median a (95% CI) 6.2 months
(4.9, 6.9)3.5 months
(2.9, 4.2)7.0 months
(6.2, 8.8)5.6 months
(3.4, 6.3)4.9 months
(4.2, 6.3)2.9 months
(2.8, 3.5)Risk ratiob
(95% CI) 0.55
(0.44, 0.69)0.55
(0.38, 0.81)0.54
(0.41, 0.72) p-value c< 0.00010.0019< 0.0001 Overall survival
Event (death) n (%)
 51(15)
 84(25)
 12(9)
 24(20)
 39(20)
 60(28) Risk ratio b
(95% CI) 0.57
(0.40, 0.81)0.39
(0.19, 0.81)0.65
(0.43, 0.97) p-value c,d<0.05<0.05<0.05 remission rate
Number of cases e n = 627
 n=315
 n=312
 n=128
 n=110
 n=187
 n=202CRf n (%)20(6)2(<1)8(6)2(2)12(6)0(0)PRf n (%)101(32)54(17)49(38)27(25)52(28)27(13)nCRf,g n (%)21(7)3(<1)8(6)2(2)13(7)1(<1) CR + PRf n (%) 121 (38)56 (18)57(45)29(26)64(34)27(13) p-value h<0.0001 0.0035<0.0001 Median duration of remission n CRf9.9 month NEi9.9 month NE6.3 month NAjnCRf11.5 month 9.2 month NENE11.5 month 9.2 month CR + PRf8.0 month 5.6 month 8.1 month 6.2 month 7.8 month 4.1 month a Kaplan-Meier assessment.
b Risk ratios were obtained by COX proportional-risk model using treatment as an independent variable. A risk ratio less than 1 indicates an advantage for this product.
c p-values were obtained by a stratified log-rank test including random stratification factors.
d Exact p-values could not be obtained.
e Number of cases evaluated for remission, including patients with evaluable disease at baseline and who have received at least one treatment in this trial.
f EBMT criteria; nCR met all EBMT criteria for CR but tested positive for IF. In EBMT criteria, nCR is included in PR.
g In 2 patients, IF results were unknown.
h The p-value for the remission rate (CR + PR) was obtained from the Cochran-Mantel-Haenszel chi-square test corrected for stratification factors.
i Not assessed.
j Not applicable, no patients in this classification.
 Randomized, open clinical study of untreated multiple myeloma
An international multicenter, prospective, randomized (1:1), open phase III clinical trial [MMY-3002 (VISTA)] in 682 patients was conducted to investigate whether this product (1.3 mg/m2) in combination with MP combination therapy improves time to disease progression (TTP) compared to MP combination therapy in patients with untreated multiple myeloma. The maximum duration of treatment is 9 courses (approximately 54 weeks), with early termination in the event of disease progression or intolerable toxicity. Baseline values and disease characteristics of patients at baseline are shown in Table 21.
Table 21: Baseline values and baseline disease characteristics of patients in the VISTA trial
Patient characteristics MP group in combination with this product
N=344 MP group
N=338 Median age (range) 71.0 (57, 90) 71.0 (48, 91) Gender: male / female 51% / 49% 49% / 51% Race: Caucasian / Asian / Black / Other 88% / 10% / 1% / 1% 87% / 11% / 2% / 0% Carlson physical status score ≤7035%33% Hemoglobin <100 g/ L37%36% platelet count <75 × 109/L<1%1% disease characteristics myeloma type (%): IgG/IgA/light chain 64% / 24% / 8%62% / 26% / 8% b2-microglobulin median (mg/L)4.24.3 albumin median (g/L)33.033.0 creatinine clearance £30 ml/min [n (%)]20 (6%)16 (5%)
 Pre-set interim analysis with a median follow-up of 16.3 months, the primary study endpoint – to the time of disease progression had been reached and patients in the MP group crossed over to receive treatment in the MP group in combination with this product. A final update of survival data was performed at a median follow-up of 60.1 months. A statistically significant survival benefit was observed in the MP group (HR=0.695; p=0.00043) despite the use of a drug-based chemotherapy regimen in follow-up. median survival was predicted to be 43.1 months in the MP group and 56.4 months in the MP group, with efficacy results shown in Table 22.
Table 22: Summary of the efficacy analysis of the VISTA trial
Efficacy endpoint Benzedrine in combination with MP group
n=344 MP group
n=338 Time to disease progression
Events n (%)
 101 (29)
 152 (45) Mediana (95% CI) 20.7 months
(17.6, 24.7) 15.0 months
(14.1, 17.9) Risk ratiob
(95% CI) 0.54
(0.42, 0.70) p-valuec0.000002 Progression-free survival
Events n (%)
 135 (39)
 190 (56) Mediana (95% CI) 18.3 months
(16.6, 21.7) 14.0 months
(11.1, 15.0) Risk ratiob
(95%CI)0.61
(0.49, 0.76) p-valuec0.00001 Overall survival h
Events (deaths) n (%) 176 (51.2) 211 (62.4) Mediana (95% CI) 56.4 months
(52.8, 60.9) 43.1 months
(35.3, 48.3) Risk ratiob
(95% CI) 0.695
(0.567, 0.852) p-valuec 0.00043 Remission rate
Number of casese n = 668n=337n=331CRf n (%)102 (30)12 (4)PRf n (%)136 (40)103 (31) nCR n (%)5 (1) 0CR + PRf n (%)238 (71)115 (35)p-valued
<10-10 Serum-M protein decreased
Number of casesg n=667n=336n=331>=90% n (%)151 (45)34 (10)Time to first remission in CR and PR cases Median 1.4 months 4.2 months Median duration of remissiona CRf24.0 months 12.8 months CR + PRf19.9 months 13.1 months to next treatment
Events n (%) 224 (65.1) 260 (76.9) Mediana (95% CI) 27.0 months
(24.7, 31.1) 19.2 months
(17.0, 21.0) Risk ratiob
(95% CI) 0.557
(0.462, 0.671) p-valuec(< 0.000001) Note: All results are based on a median follow-up analysis of 16.3 months, except for the analysis used for overall survival which is based on a median follow-up of 60.1 months.
a Kaplan-Meier assessment.
bRisk ratios were obtained based on a COX proportional-risk model corrected for stratification factors (β2-microglobulin, albumin, and region). Risk ratios less than 1 indicate an advantage in the MP group for this product combination.
c p values were obtained based on stratified log-rank tests corrected for stratified factors (β2-microglobulin, albumin, and region).
d
The p-value for remission rate (CR + PR) was obtained from a Cochran-Mantel-Haenszel chi-square test corrected for stratified factors.
e
Remission cases, including patients with evaluable lesions at baseline.
f EBMT criteria.
g
All randomized patients with secretory disease.
hUpdated for survival based on a median follow-up period of 60.1 months.
NE: Not evaluated
 Summary of effectiveness data in Chinese patients
The untreated multiple myeloma study described above enrolled 41 Chinese patients, 20 of whom were randomized to this product in combination with the MP treatment arm and 21 to the MP treatment arm. The results of the effectiveness analysis for the Chinese patient subgroup are presented in Table 23.
Table 23: Effectiveness analysis results for Chinese patient subgroups in the VISTA trial
Efficacy endpoint MP group
n=21 MP group in combination with this product
n=20 Time to disease progression
Events n (%)14(67)9(45)Median (95% CI)11.1 months
(8.4, 15.7) 14.8 months
(7.2, NE)Risk ratio
(95% CI) 0.468
(0.183; 1.199) p-value 0.10676 Progression-free survival
Events n (%) 19 (90) 12 (60) Median (95% CI) 9.7 months
(7.3, 12.6)9.6 months
(6.2, NE)Risk ratio
(95% CI) 0.604
(0.279; 1.309) p-value 0.1975 Overall survival
Events n (%) 9 (43) 4 (20) Risk ratio
(95% CI) 0.385
(0.117; 1.259) p-value 0.10135 Remission rate CR n (%)0 (0)8(40)PR n (%)5(24)5(25)CR + PR
n (%) 5 (24) 13 (65) Dominance ratio 6.1 (1.4, 27.2) p-value 0.01112NE: not evaluated
Note: All results in the table are based on a median follow-up analysis of 16.3 months.
 Phase II, single-arm clinical study of relapsed condylomatous lymphoma
The safety and efficacy of this product was evaluated in an open, single-arm, multicenter trial [M34103-053 (PINNACLE)] for the treatment of patients with relapsed or refractory setback lymphoma in 155 patients who had received at least one prior treatment and had progressive disease. The median age of the patients was 65 years (42-89 years), 81% of whom were male and 92% were white. 75% of the patients had one or more extranodal lesions, and 77% had stage IV lymphoma. 91% of the patients were treated with a prior anthracycline antibiotic or mitoxantrone, cyclophosphamide, and rituximab. 37% of the patients were resistant to the last line of prior therapy. Resistant. The recommended dose of this product is 1.3 mg/m2 twice weekly for 2 weeks (administered on days 1, 4, 8 and 11, followed by a 10-day break). The median number of treatment cycles for all patients treated with this drug was 4 (range: 1-17), and the median number of cycles for patients with a significant response to this drug was 8. The remission rates following treatment with this drug in the trial are shown in Table 24. [International Workshop Response Criteria (IWRC) and based on CT scan The remission rates after treatment with this drug, as determined by the International Workshop Response Criteria (IWRC) and based on independent imaging evaluation of CT scans.
The median follow-up for surviving patients was more than 13 months, median survival was not yet available, Kaplan Meier assessment of 1-year survival was 69%, Kaplan Meier assessment of 1- year survival was 94% in patients who achieved remission, and Kaplan Meier assessment of 1- year survival was 100% in patients who achieved CR or CRu .
Table 24: Summary of efficacy results of phase II trials in laparoscopic lymphoma
a Efficacy analysis (N = 141) N (%) 95% CI overall remission rate (IWRC) (CR + CRu + PR) 47 (33) (26, 42) complete remission rate (CR + CRu)
11 (8)(4, 14) CR9 (6)(3, 12) CRu2 (1)(0, 5) Partial remission (PR)36 (26)(19, 34) Median time to event analysis 95% CI Kaplan-Merier assessed duration of remission CR + CRu + PR (N = 47)9.2 months (4.9, 13.5)CR + CRu ( N = 11)13.5 months (13.5, NE) Kaplan-Meier-assessed time to progression (N = 155)6.2 months (4.0, 6.9) ** Kaplan-Merier-assessed discontinuation interval CR + CRu (N = 11)13.8 months (13.4, NE) Median time to next treatment CR + CRu + PR ( N = 47) 12.7 months (9.33, NE) CR + CRu (N = 11) 19.4 months (17.8, NE)a Based on International Workshop Remission Criteria (IWRC). Patients used for efficacy analysis were those with measurable lesions at the time of screening and who had at least 1 post-baseline tumor evaluation (including measurable or evaluable lesions) (N=141).
CRu=complete remission without confirmation
NE=not evaluable
**Additional analysis
 Clinical studies of untreated condylomatous lymphoma
A randomized, open, phase 3 study (LYM-3002) was conducted in 487 adult patients with previously untreated sarcoid lymphoma (stage II, III, or IV) to determine whether the combination of this product, rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) compared with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone ( R-CHOP) compared to whether it improves progression-free survival (PFS). This clinical study used an independent pathological confirmatory method and an independent imaging remission assessment method.
Patients in the VcR-CAP group received this product intravenously (1.3 mg/m2) on days 1, 4, 8 and 11 and discontinued it on days 12-21; patients received rituximab (375 mg/m2), cyclophosphamide (750 mg/m2) and doxorubicin (50 mg/m2) on day 1 of the 21-day treatment cycle and prednisone on days 1-5 (100 mg/m2 ). Patients who first documented remission in cycle 6 received an additional 2 cycles of treatment.
The median age of patients was 66 years, 74% were male, 66% were white, and 32% were of Asian descent. Sixty-nine percent of patients had positive bone marrow aspiration and/or bone marrow biopsy results for MCL, 54% had an International Prognostic Index (IPI) score of 3 (intermediate to high risk) and above, and 76% had stage IV disease. the median number of treatment cycles in the R-CHOP and VcR-CAP groups was 6, and 17% and 14% of patients in the two treatment groups, respectively, received an additional 2 cycles of treatment. the R -The majority of patients in the CHOP group (83%) and the VcR-CAP group (84%) received ≥6 cycles of treatment.
The primary efficacy endpoint was progression-free survival as assessed by an independent review committee (IRC). Secondary endpoints included time to disease progression (TTP), time to next anti-lymphoma treatment (TNT), treatment-free interval (TFI), overall remission rate (ORR) and complete remission rate (CR/CRu), overall survival (OS), and duration of remission. The remission criteria used for efficacy assessment were developed based on the International Workshop on Standardization of Efficacy Criteria for Non-Hodgkin’s Lymphoma (IWRC).
Statistically significant benefits were observed in the VcR-CAP treatment group in terms of PFS, TTP, TNT, TFI, overall complete remission rate, and overall survival. At a median follow-up of 40 months, the median value of the primary endpoint PFS was 59% longer in the VcR-CAP group (24.7 months) compared with the median value in the R-CHOP group (14.4 months) (hazard ratio [HR] = 0.63; p <0.001). the median duration of complete remission in the VcR-CAP group (42.1 months) was greater than that in the R-CHOP group (18 months), and the median overall duration of remission was 21.4 months longer than that of the R-CHOP group. At a median follow-up of 40 months, the median OS (56.3 months in the R-CHOP group and not reached in the VcR-CAP group) was favorable for the VcR-CAP group (estimated HR=0.80; p=0.173). There was also a trend in favor of the VcR-CAP group in terms of overall survival prolongation; the 4-year survival estimates were 53.9% and 64.4% in the R-CHOP and VcR-CAP groups, respectively. The efficacy results other than OS at a median follow-up time of 40 months are presented in Table 25.
After a median follow-up time of 82 months, a final OS analysis was performed. the median OS in the VcR-CAP group was 90.7 months, which was approximately three years longer than the median OS in the R-CHOP group (55.7 months) (HR=0.66; p=0.001).
The efficacy results are summarized in Table 25
 Table 25: Summary of efficacy results of the phase 3 study (LYM-3002) in patients with primary treatment of sarcoid lymphoma
Efficacy endpoint VcR-CAP
R-CHOP
 n: ITT patients 243244 Progression-free survival (IRC)a
Events n (%) 133 (54.7)165 (67.6) HRd (95% CI)=0.63 (0.50;0.79)
p-value e
< 0.001 median valuec (95% CI) (months) 24.7 (19.8; 31.8) 14.4 (12; 16.9) Progression-free survival (investigator)b events n (%) 128 (52.7) 179 (73.4) HRd (95% CI) = 0.51 (0.41; 0.65)
p-value e < 0.001 median valuec (95% CI) (months) 30.7 (25.1; 37.3) 16.1 (14.0; 18.4) time to disease progressiona event n (%) 114 (46.9) 148 (60.7) HRd (95% CI) = 0.58 (0.45; 0.74)
p-value e < 0.001 median c (95% CI) (months) 30.5 (22.9; 40.9) 16.1 (13.7; 18.1) to next anti-lymphoma treatment time event n (%) 94 (38.7) 145 (59.4) HRd (95% CI) = 0.50 (0.38; 0.65)
p-value e < 0.001 median c (95% CI) (months) 44.5 (38.8; NE) 24.8 (22.1; 27.5) no treatment interval n: all treated patients 240242 events n (%) 93 (38.8) 145 ( 59.9) HRd (95% CI)=0.50 (0.38; 0.65)
p-value e < 0.001 Median valuec (95% CI) (months) 40.6 (33.6; NE) 20.5 (17.8; 22.8) Overall survival at a median follow-up time of 82 months n: ITT patients 243244 events n (%) 103 (42.4) 138 (56.6) HRd (95% CI)=0.66 (0.51; 0.85)
p-value e = 0.001 Median value c (95% CI) (months) 90.7 (71.4; NE) 55.7 (47.2; 68.9) Remission rate n: remission evaluable patients 229228 Overall complete remission (CR+CRu)h n (%) 122 (53.3) 95 (41.7) ORf (95% CI) = 1.688 (1.148; 2.481)
p-value g =0.007 Overall radiological remission (CR+CRu+PR)i n (%) 211 (92.1)204 (89.5) ORf (95% CI)=1.428 (0.749; 2.722)
p-value g = 0.275 duration of remission duration of complete remission (CR+CRu) jn = remission evaluable patients 12295 median value c (95% CI) (months) 42.1 (30.7; 49.1) 18.0 (14.0; 23.4) duration of remission (CR+CRu+PR) kn: remission evaluable patients 211204 median value c ( 95% CI) (months) 36.5 (26.7; 46.7) 15.1 (12.5; 17.0) Note: All results in the table above are based on analyses conducted at a median follow-up of 40 months, except for the results of the overall survival analysis.
Based on IRC assessment (using radiological data only).
Based on investigator assessment.
Based on Kaplan-Meier product limit estimates.
Risk ratio estimates were calculated using a Cox model stratified by IPI risk and disease stage. A risk ratio less than 1 indicates favorable treatment for VcR-CAP.
Log-rank test based on stratification by IPI risk and disease stage.
Mantel-Haenszel estimates of common ratio were used in the stratification table, and IPI and disease stage were used as stratification factors for estimation. A ratio (OR) >1 indicates favorable treatment for VcR-CAP.
The p-values are from the Cochran Mantel-Haenszel chi-square test with IPI and disease stage used as stratification factors at the time of testing.
Includes all IRC-determined CR+CRu (with bone marrow and LDH).
Includes all IRC-determined radiological CR+CRu+PR (whether confirmed by bone marrow or LDH).
Calculated as the time between first complete remission (IRC-determined CR+CRu with bone marrow and LDH) and PD or death due to PD.
Calculated as the time between first remission (including all IRC-determined radiological CR+CRu+PR) and PD or death due to PD.
IRC = independent review committee; IPI = international prognostic index; LDH = lactate dehydrogenase; CR = complete remission; CRu = complete remission without confirmation; PR = partial remission; CI = confidence interval; HR = risk ratio; OR = ratio ratio; ITT = intention-to-treat; PD = disease progression
 Randomized, Open Clinical Study Comparing Intravenous and Subcutaneous Administration of This Product in Patients With Recurrent Multiple Myeloma
An open, randomized, phase 3, non-inferiority study (MMY-3021) compared the efficacy and safety of subcutaneous versus intravenous administration of this product. This study enrolled 222 patients with relapsed multiple myeloma who were randomly assigned in a 2:1 ratio to receive 8 cycles of 1.3 mg/m2 of dexamethasone subcutaneously or intravenously. patients who did not achieve optimal remission (complete remission (CR) or less) on dexamethasone monotherapy after 4 cycles were allowed to receive daily dexamethasone 20 mg on the day of dexamethasone administration or the next day. Patients with grade 2 peripheral neuropathy or a platelet count <50,000/µL at baseline were excluded. A total of 218 patients were available for treatment response evaluation.
Stratification factors were based on the number of previous lines of therapy the patient had received (previous line of therapy and beyond) and the stage in the International Staging System (ISS) (containing β2 microglobulin and albumin levels; stage I, II, or III). Baseline patient and disease characteristics are summarized in Table 26.
Table 26: Summary of Baseline Patient and Disease Characteristics in the Phase 3 Intravenous and Subcutaneous Administration Trial of This Product (MMY-3021)
Patient Characteristics Intravenous Administration
N=74 Subcutaneous administration
N=148 Median age, years (range) 64.5 (38,86) 64.5 (42,88) Gender: male / female 64% / 36% 50% / 50% Race: Caucasian / Asian 96% / 4% 97% / 3% Karnofsky physical status score ≤ 7016% 22% Disease characteristics Myeloma type (%): IgG/IgA/light chain 72% / 19% / 8%65% / 26% / 8%ISS stagea I/II/III (%)27/41/3227/41/32Median β2-microglobulin (mg/L) 4.254.20Median albumin (g/L) 3.603.55Creatinine clearance ≤30 mL/min [n (%)]2 (3%)5 (3%)From diagnosis Median duration of disease in multiple myeloma (years) 2.932.68 Number of lines previously treated Previously received 1 line 65% 62% Previously received >1 line 35% 38%a ISS staging was based on baseline central laboratory data.
 This study met its primary objective of non-inferiority of subcutaneous administration compared to intravenous administration in terms of remission rates (CR+PR) after 4 cycles of monotherapy with the subcutaneous and intravenous routes of administration of this product, 42% in both groups. In addition, remission-related and time-to-event-related secondary efficacy endpoints showed consistent results between subcutaneous and intravenous administration (Table 27).
Table 27: Summary of efficacy analysis for subcutaneous and intravenous administration of this product (MMY-3021)
 Intravenous administration Subcutaneous administration Treatment response evaluable population an=73n=1454 Remission rate after cycle ORR (CR+PR)31 (42)61 (42) p-value b0.00201CR n (%)6(8)9(6)PR n (%)25(34)52(36)nCR n (%)4(5)9(6)8 Remission rate after cycle ORR ( CR+PR)38(52)76(52)p-value b0.0001CR n (%)9 (12)15 (10)PR n (%)29(40)61(42)nCR n (%)7(10)14(10)Intent-to-treat population cn=74n=148Median time to disease progression, months 9.410.4 (95% CI)(7.6,10.6 )(8.5,11.7) Risk ratio (95% CI) d
p-value e0.839 (0.564,1.249)
0.38657 Progression-free survival, months 8.010.2 (95% CI)(6.7,9.8)(8.1,10.8) Risk ratio (95% CI) d
p-value e0.824 (0.574,1.183)
0.295 1-year survival (%)f76.772.6 (95% CI)(64.1,85.4)(63.1,80.0)a All randomized subgroup subjects who received at least one non-zero dose of study drug had measurable disease at study entry
b The p-value addresses the following non-inferiority assumption: remission rates in the subcutaneous group were at least 60% of those in the intravenous group.
c 222 subjects were enrolled in the study; 221 subjects were treated with this product
d Risk ratio estimates were based on a Cox model corrected for the following stratification factors: ISS stage and number of prior lines of treatment received.
e Log-rank test corrected for the following stratification factors: ISS stage and number of previously treated lines.
f The median follow-up time was 11.8 months.
Pharmacology and Toxicology
Pharmacological effects
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome, a large protein complex that degrades ubiquitinated proteins, in mammalian cells. The ubiquitin-proteasome channel plays an important role in regulating the intracellular concentration of specific proteins to maintain intracellular homeostasis. Protein hydrolysis affects multiple intracellular signaling cascade responses, and this disruption of normal homeostatic mechanisms can lead to cell death. Inhibition of the 26S proteasome prevents this targeted protein hydrolysis. In vitro tests have shown that bortezomib is cytotoxic to several types of cancer cells. In vivo trials in preclinical tumor models have demonstrated that bortezomib can retard the growth of tumors including multiple myeloma.
In vitro, ex vivo and animal model data indicate that bortezomib promotes osteoblast differentiation and increases their activity and inhibits osteoclast function. These effects were observed in patients with multiple myeloma suffering from advanced osteolytic lesions treated with this product.
The maximum inhibition of 20S proteasome activity in whole blood (relative to baseline) occurred 5 minutes after administration of 1 mg/m2 and 1.3 mg/m2 doses twice weekly (n=12 per dose level). The maximum inhibition ranges from 70% to 84% and 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 doses, respectively.
Toxicological studies
Toxicity observed in animal studies using doses similar to those recommended for patients and dosing frequency (i.e., 2 doses per week for 2 weeks followed by a one-week break) included severe anemia and thrombocytopenia as well as gastrointestinal, neurologic, and lymphoid-like systemic toxicity. Neurotoxicity of bortezomib in animal studies included axonal swelling and degenerative changes in peripheral nerves, spinal nerve roots, and spinal cord tracts. In addition, multifocal hemorrhages and necrosis were observed in the brain, eyes, and heart.
Cardiovascular toxicity.
Administration of approximately two times the clinically recommended dose of bortezomib to monkeys resulted in an elevated heart rate followed by severe progressive hypotension, bradycardia and death 12 to 14 hours after administration. Doses greater than or equal to 1.2 mg/m2 induce dose-proportional changes in various cardiac parameters. Studies have shown that bortezomib is distributed to most tissues in the body, including the myocardium. Myocardial hemorrhage, inflammation and necrosis were observed in repeated administration toxicity tests in monkeys.
Genotoxicity.
An in vitro chromosomal aberration assay in Chinese hamster ovary cells showed that bortezomib has fission-inducing activity (structural aberrations of chromosomes.) Results from the Ames test and in vivo micronucleus test in mice did not indicate that bortezomib is genotoxic.
Reproductive toxicity.
Reproductive effects have not been studied, but reproductive tissues were evaluated in general toxicology tests. 6-month rat toxicology tests showed that bortezomib degenerated the ovaries at doses ≥0.3 mg/m2 (1/4 of the clinically recommended dose), and degenerative changes were observed in the ovaries at a dose of 1.2 mg/m2. This product may have potential effects on fertility in men or women.
Carcinogenicity.
No carcinogenicity studies have been conducted with bortezomib.
[Pharmacokinetics].
After intravenous administration of bortezomib at 1.0 mg/m2 and 1.3 mg/m2 to 11 patients with multiple myeloma, the mean maximum blood concentrations at the first dose (day 1) were 57 and 112 ng/mL, respectively. 120ng/mL (1.3mg/m2 dose group). The mean elimination half-life of bortezomib after multiple dosing was 40 to 193 hours. Clearance after the first administration of bortezomib was more rapid compared to subsequent doses. The mean overall clearance after the first administration of 1.0 mg/m2 and 1.3 mg/m2 was 102 and 112 L/h, respectively, while the mean overall clearance for subsequent doses in the 1.0 mg/m2 and 1.3 mg/m2 groups ranged from 15 to 32 L/h.
In the PK/PD study of the phase III trial, total systemic exposure (AUClast) after multiple dosing was comparable in both groups after multiple dosing in patients with multiple myeloma who received a single 1.3 mg/m2 dose administered intravenously or subcutaneously (n = 14 in the sedation group and n = 17 in the subcutaneous dosing group). The maximum blood concentration after subcutaneous administration (20.4 ng/mL) was lower than that after sedative (223 ng/mL) administration. the ratio of geometric means of AUClast was 0.99 with a 90% confidence interval of 80.18% ~ 122.80%.
Distribution
The range of mean volume of distribution in patients with multiple myeloma following single or multiple doses of 1.0 mg/m2 or 1.3 mg/m2 bortezomib was 489 to 1884 L/m2, indicating that bortezomib is widely distributed to peripheral tissues. The average binding rate of bortezomib to human plasma proteins was 83% at concentrations of 100~1000ng/mL.
Metabolism
In vitro studies using human liver microsomes and complementary deoxyribonucleic acid (cDNA)-expressing cytochrome P450 isozymes have shown that bortezomib is metabolized primarily by oxidation of the cytochrome P450 enzymes 3A4, 2C19 and 1A2, and to a lesser extent by 2D6 and 2C9. The main metabolic pathway is de-borylation, forming 2 de-borylated metabolites, followed by hydroxylation to form several metabolites. The de-borated bortezomib metabolites did not inhibit the activity of the 26S proteasome. plasma data from 8 patients at 10 and 30 minutes after intravenous administration showed lower concentrations of metabolites in plasma than the prototype drug.
Elimination
The elimination pathway of bortezomib in humans has not been studied.
Age, sex and ethnicity
Data from 104 pediatric patients (2 to 16 years of age) following twice-weekly intravenous infusions of 1.3 mg/m2 bortezomib were also used to analyze the pharmacokinetic profile of bortezomib. Population pharmacokinetic analysis showed that bortezomib clearance increased with increasing body surface area. The geometric mean (%CV) of clearance was 7.79 (25%) L/hr/m2, the steady-state volume of distribution was 834 (39%) L/m2, and the elimination half-life was 100 (44%) hours. After correction for body surface area, other demographic data, such as age, weight and sex, did not have a clinically meaningful effect on bortezomib clearance. Bortezomib clearance after body surface correction was observed to be similar to that of adults in pediatric patients.
The effect of gender and ethnicity on the pharmacokinetics of bortezomib has not been evaluated.
Patients with hepatic impairment
The effect on the pharmacokinetics of bortezomib was evaluated in 60 patients with cancer and hepatic impairment in trials ranging from 0.5 to 1.3 mg/m2. mild hepatic impairment did not alter the dose normalized AUC of bortezomib compared to patients with normal hepatic function. The AUC of bortezomib normalized to a dose of moderate or severe hepatic impairment is increased by approximately 60%. A lower starting dose is recommended for patients with moderate or severe hepatic impairment and should be monitored closely.
Patients with renal impairment
In a pharmacokinetic study, patients with varying degrees of renal impairment were grouped by creatinine clearance (CrCL): normal (CrCL ≥60 mL/min/1.73 m2, n=12), mild (CrCL=40-59 mL/min/1.73 m2, n=10), moderate (CrCL=20-39 mL/min/1.73 m2, n=9) and severe (CrCL < 20 mL/min/1.73 m2, n=3). This study included 8 patients who required dialysis and were given bortezomib again at the end of dialysis. Bortezomib was administered intravenously at a dose of 0.7 to 1.3 mg/m2 twice weekly. The exposure (dose normalized AUC and maximal blood concentration) of bortezomib was comparable in all the above groups.
Storage
Keep away from light, not more than 30 ºC.
Package
Packed in glass vials; 1 vial/box.
Expiration date
24 months
Execution standard
JX20180195
Imported drug registration number
3.5mg: H20171086
Approval number for distribution
3.5mg: State Drug Certificate J20171067
Manufacturer
Company Name: BSP Pharmaceuticals S.p.A.
Production Address: Via Appia Km 65, 561, 04013 Latina, Italy
[Dispense Company
Company name: Xi’an Janssen Pharmaceuticals Co.
Address: No. 34 Wanshou North Road, Xincheng District, Xi’an City, Shaanxi Province
Postal Code: 710043
Telephone number: 400 888 9988
Website: http://www.xian-janssen.com.cn
Introduction to use]
This product does not contain antibacterial preservatives. The prepared solution should be stored at 25ºC and used within 8 hours after preparation. The prepared solution should not be left in the original container or syringe for more than 8 hours and should not be exposed to indoor light for more than 8 hours.
Unopened product should be stored at 30ºC or below, do not open the original light-proof packaging.
Handling Precautions
This product is an antineoplastic drug, so care should be taken when handling and preparing it, and appropriate aseptic practices should be adopted. It is recommended to wear gloves and protective clothing to avoid skin contact during preparation. Local skin irritation has been reported in 5% of patients in clinical trials, but no tissue damage has occurred.
There have been reported cases of death due to inadvertent intrathecal injection of bortezomib. Therefore, this product is intended for intravenous and subcutaneous administration only and intrathecal injection is strictly prohibited.
Redissolution/Configuration for Intravenous and Subcutaneous Administration
Dissolve the product using 0.9% sodium chloride solution according to the table below. The prepared solution should be clear and transparent. Visual observation of the color of the solution and particulate matter is required prior to use of this drug, as far as the solution and container allow. If a change in the color of the solution or particulate matter is observed, the product should not be used.
 Intravenous administration Subcutaneous administration 1mg of this product 3.5mg of this product 3.5mg of this product Dissolve this product (each bottle) of the solution (0.9% sodium chloride solution) volume 1.0mL 3.5mL 1.4 mL After preparation final concentration (mg/mL) 1.0mg/mL 1.0mg/mL 2.5mg/mL