There is no known specific antidote for Борамилан ФС overdosage. In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given.
Studies in monkeys and dogs showed that intravenous bortezomib doses as low as 2 times the recommended clinical dose on a mg/m2 basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m2 and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at 1 hour post-administration, with progression to death in 12 to 14 hours following drug administration.
Борамилан ФС is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions.
Борамилан ФС is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Борамилан ФС.
The following adverse reactions are also discussed in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Summary Of Clinical Trial In Patients With Previously Untreated Multiple MyelomaTable 9 describes safety data from 340 patients with previously untreated multiple myeloma who received Борамилан ФС (1.3 mg/m2) administered intravenously in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) in a prospective randomized study.
The safety profile of Борамилан ФС in combination with melphalan/prednisone is consistent with the known safety profiles of both Борамилан ФС and melphalan/prednisone.
Table 9: Most Commonly Reported Adverse Reactions (≥ 10% in the Борамилан ФС, Melphalan and Prednisone arm) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Multiple Myeloma Study
| Борамилан ФС, Melphalan and Prednisone (n=340) | Melphalan and Prednisone (n=337) | |||||
| System Organ Class | Total | Toxicity Grade, n (%) | Total | Toxicity Grade, n (%) | ||
| Preferred Term | n (%) | 3 | ≥ 4 | n (%) | 3 | ≥ 4 |
| Blood and lymphatic system 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 | 108 (32) | 64 (19) | 8 (2) | 93 (28) | 53 (16) | 11 (3) |
| Lymphopenia | 78 (23) | 46 (14) | 17 (5) | 51 (15) | 26 (8) | 7 (2) |
| Gastrointestinal disorders | ||||||
| Nausea | 134 (39) | 10 (3) | 0 | 70 (21) | 1 (< 1) | 0 |
| Diarrhea | 119 (35) | 19 (6) | 2 (1) | 20 (6) | 1 (< 1) | 0 |
| Vomiting | 87 (26) | 13 (4) | 0 | 41 (12) | 2 (1) | 0 |
| Constipation | 77 (23) | 2 (1) | 0 | 14 (4) | 0 | 0 |
| Abdominal Pain Upper | 34 (10) | 1 (< 1) | 0 | 20 (6) | 0 | 0 |
| Nervous system disorders | ||||||
| Peripheral Neuropathya | 156 (46) | 42 (12) | 2 (1) | 4 (1) | 0 | 0 |
| Neuralgia | 117 (34) | 27 (8) | 2 (1) | 1 (< 1) | 0 | 0 |
| Paresthesia | 42 (12) | 6 (2) | 0 | 4 (1) | 0 | 0 |
| General disorders and administration site conditions | ||||||
| Fatigue | 85 (25) | 19 (6) | 2 (1) | 48 (14) | 4 (1) | 0 |
| Asthenia | 54 (16) | 18 (5) | 0 | 23 (7) | 3 (1) | 0 |
| Pyrexia | 53 (16) | 4 (1) | 0 | 19 (6) | 1 (< 1) | 1 (< 1) |
| Infections and infestations | ||||||
| Herpes Zoster | 39 (11) | 11 (3) | 0 | 9 (3) | 4 (1) | 0 |
| Metabolism and nutrition disorders | ||||||
| Anorexia | 64 (19) | 6 (2) | 0 | 19 (6) | 0 | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| Rash | 38 (11) | 2 (1) | 0 | 7 (2) | 0 | 0 |
| Psychiatric disorders | ||||||
| Insomnia | 35 (10) | 1 (< 1) | 0 | 21 (6) | 0 | 0 |
| a Represents High Level Term Peripheral Neuropathies NEC | ||||||
The safety data described below and in Table 10 reflect exposure to either Борамилан ФС (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Борамилан ФС was administered intravenously at doses of 1.3 mg/m2 twice weekly for 2 out of 3 weeks (21-day cycle). After eight 21-day cycles patients continued therapy for three 35-day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (9 months) with a median duration of 6 cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and 1 to 3 prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients < 65 and ≥ 65 years of age. Most patients were Caucasian.
Among the 331 Борамилан ФС-treated patients, the most commonly reported (> 20%) adverse reactions overall were nausea (52%), diarrhea (52%), fatigue (39%), peripheral neuropathies (35%), thrombocytopenia (33%), constipation (30%), vomiting (29%), and anorexia (21%). The most commonly reported (> 20%) adverse reaction reported among the 332 patients in the dexamethasone group was fatigue (25%). Eight percent (8%) of patients in the Борамилан ФС-treated arm experienced a Grade 4 adverse reaction; the most common reactions were thrombocytopenia (4%) and neutropenia (2%). Nine percent (9%) of dexamethasone-treated patients experienced a Grade 4 adverse reaction. All individual dexamethasone-related Grade 4 adverse reactions were less than 1%.
Serious Adverse Reactions And Adverse Reactions Leading To Treatment Discontinuation In The Relapsed Multiple Myeloma Study Of Борамилан ФС Versus DexamethasoneSerious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the Борамилан ФС treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the Борамилан ФС treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).
A total of 145 patients, including 84 (25%) of 331 patients in the Борамилан ФС treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 Борамилан ФС treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).
Four deaths were considered to be Борамилан ФС-related in this relapsed multiple myeloma study: 1 case each of cardiogenic shock, respiratory insufficiency, congestive heart failure and cardiac arrest. Four deaths were considered dexamethasone-related: 2 cases of sepsis, 1 case of bacterial meningitis, and 1 case of sudden death at home.
Most Commonly Reported Adverse Reactions In The Relapsed Multiple Myeloma Study Of Борамилан ФС Versus DexamethasoneThe most common adverse reactions from the relapsed multiple myeloma study are shown in Table 10. All adverse reactions with incidence ≥ 10% in the Борамилан ФС arm are included.
Table 10: Most Commonly Reported Adverse Reactions (≥ 10% in Борамилан ФС arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Борамилан ФС versus Dexamethasone (N=663)
| Борамилан ФС N=331 | Dexamethasone N=332 | |||||
| Preferred Term | All | Grade 3 | Grade 4 | All | Grade 3 | Grade 4 |
| Adverse Reactions | 324 (98) | 193 (58) | 28 (8) | 297 (89) | 110 (33) | 29 (9) |
| Nausea | 172 (52) | 8 (2) | 0 | 31 (9) | 0 | 0 |
| Diarrhea NOS | 171 (52) | 22 (7) | 0 | 36 (11) | 2 (< 1) | 0 |
| Fatigue | 130 (39) | 15 (5) | 0 | 82 (25) | 8 (2) | 0 |
| Peripheral neuropathiesa | 115 (35) | 23 (7) | 2 (< 1) | 14 (4) | 0 | 1 (< 1) |
| Thrombocytopenia | 109 (33) | 80 (24) | 12 (4) | 11 (3) | 5 (2) | 1 (< 1) |
| Constipation | 99 (30) | 6 (2) | 0 | 27 (8) | 1 (< 1) | 0 |
| Vomiting NOS | 96 (29) | 8 (2) | 0 | 10 (3) | 1 (< 1) | 0 |
| Anorexia | 68 (21) | 8 (2) | 0 | 8 (2) | 1 (< 1) | 0 |
| Pyrexia | 66 (20) | 2 (< 1) | 0 | 21 (6) | 3 (< 1) | 1 (< 1) |
| Paresthesia | 64 (19) | 5 (2) | 0 | 24 (7) | 0 | 0 |
| Anemia NOS | 63 (19) | 20 (6) | 1 (< 1) | 21 (6) | 8 (2) | 0 |
| Headache NOS | 62 (19) | 3 (< 1) | 0 | 23 (7) | 1 (< 1) | 0 |
| Neutropenia | 58 (18) | 37 (11) | 8 (2) | 1 (< 1) | 1 (< 1) | 0 |
| Rash NOS | 43 (13) | 3 (< 1) | 0 | 7 (2) | 0 | 0 |
| Appetite decreased NOS | 36 (11) | 0 | 0 | 12 (4) | 0 | 0 |
| Dyspnea NOS | 35 (11) | 11 (3) | 1 (< 1) | 37 (11) | 7 (2) | 1 (< 1) |
| Abdominal pain NOS | 35 (11) | 5 (2) | 0 | 7 (2) | 0 | 0 |
| Weakness | 34 (10) | 10 (3) | 0 | 28 (8) | 8 (2) | 0 |
| a Represents High Level Term Peripheral Neuropathies NEC |
In the phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged Борамилан ФС treatment. These patients were treated for a total of 5.3 to 23 months, including time on Борамилан ФС in the prior Борамилан ФС study.
Safety Experience From The Phase 3 Open-Label Study Of Борамилан ФС Subcutaneous Versus Intravenous In Relapsed Multiple MyelomaThe safety and efficacy of Борамилан ФС administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m2. This was a randomized, comparative study of Борамилан ФС subcutaneous versus intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in Table 11 reflect exposure to either Борамилан ФС subcutaneous (n=147) or Борамилан ФС intravenous (n=74).
Table 11: Most Commonly Reported Adverse Reactions (≥ 10%), with Grade 3 and ≥ 4 Intensity in theRelapsed Multiple Myeloma Study (N=221) of Борамилан ФС Subcutaneous versus Intravenous
| Subcutaneous (N=147) | Intravenous (N=74) | |||||
| System Organ Class | Total | Toxicity Grade, n (%) | Total | Toxicity Grade, n (%) | ||
| Preferred Term | n (%) | 3 | ≥ 4 | n (%) | 3 | ≥ 4 |
| Blood and lymphatic system disorders | ||||||
| Anemia | 28 (19) | 8 (5) | 0 | 17 (23) | 3 (4) | 0 |
| Leukopenia | 26 (18) | 8 (5) | 0 | 15 (20) | 4 (5) | 1 (1) |
| Neutropenia | 34 (23) | 15 (10) | 4 (3) | 20 (27) | 10 (14) | 3 (4) |
| Thrombocytopenia | 44 (30) | 7 (5) | 5 (3) | 25 (34) | 7 (9) | 5 (7) |
| Gastrointestinal disorders | ||||||
| Diarrhea | 28 (19) | 1 (1) | 0 | 21 (28) | 3 (4) | 0 |
| Nausea | 24 (16) | 0 | 0 | 10 (14) | 0 | 0 |
| Vomiting | 13 (9) | 3 (2) | 0 | 8 (11) | 0 | 0 |
| General disorders and administration site conditions | ||||||
| Asthenia | 10 (7) | 1 (1) | 0 | 12 (16) | 4 (5) | 0 |
| Fatigue | 11 (7) | 3 (2) | 0 | 11 (15) | 3 (4) | 0 | Pyrexia | 18 (12) | 0 | 0 | 6 (8) | 0 | 0 |
| Nervous system disorders | ||||||
| Neuralgia | 34 (23) | 5 (3) | 0 | 17 (23) | 7 (9) | 0 |
| Peripheral neuropathiesa | 55 (37) | 8 (5) | 1 (1) | 37 (50) | 10 (14) | 1 (1) |
| Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least 1 dose of study medication a Represents High Level Term Peripheral Neuropathies NEC | ||||||
In general, safety data were similar for the subcutaneous and intravenous treatment groups. Differences were observed in the rates of some Grade ≥ 3 adverse reactions. Differences of ≥ 5% were reported in neuralgia (3% subcutaneous versus 9% intravenous), peripheral neuropathies (6% subcutaneous versus 15% intravenous), neutropenia (13% subcutaneous versus 18% intravenous), and thrombocytopenia (8% subcutaneous versus 16% intravenous).
A local reaction was reported in 6% of patients in the subcutaneous group, mostly redness. Only 2 (1%) patients were reported as having severe reactions, 1 case of pruritus and 1 case of redness. Local reactions led to reduction in injection concentration in one patient and drug discontinuation in one patient. Local reactions resolved in a median of 6 days.
Dose reductions occurred due to adverse reactions in 31% of patients in the subcutaneous treatment group compared with 43% of the intravenously-treated patients. The most common adverse reactions leading to a dose reduction included peripheral sensory neuropathy (17% in the subcutaneous treatment group compared with 31% in the intravenous treatment group); and neuralgia (11% in the subcutaneous treatment group compared with 19% in the intravenous treatment group).
Serious Adverse Reactions And Adverse Reactions Leading To Treatment Discontinuation In The Relapsed Multiple Myeloma Study Of Борамилан ФС Subcutaneous Versus IntravenousThe incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported serious adverse reactions in the subcutaneous treatment arm were pneumonia and pyrexia (2% each). In the intravenous treatment group, the most commonly reported serious adverse reactions were pneumonia, diarrhea, and peripheral sensory neuropathy (3% each).
In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group. Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).
Two patients (1%) in the subcutaneous treatment group and 1 (1%) patient in the intravenous treatment group died due to an adverse reaction during treatment. In the subcutaneous group the causes of death were one case of pneumonia and one case of sudden death. In the intravenous group the cause of death was coronary artery insufficiency.
Safety Experience From The Clinical Trial In Patients With Previously Untreated Mantle Cell LymphomaTable 12 describes safety data from 240 patients with previously untreated mantle cell lymphoma who received Борамилан ФС (1.3 mg/m2) administered intravenously in combination with rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and prednisone (100 mg/m2) (VcR-CAP) in a prospective randomized study.
Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% versus R-CHOP 5%).
Table 12: Most Commonly Reported Adverse Reactions (≥ 5%) with Grades 3 and ≥ 4 Intensity in the Previously Untreated Mantle Cell Lymphoma Study
| VcR-CAP n=240 | R-CHOP n=242 | |||||
| System Organ Class | All | Toxicity Grade 3 | Toxicity Grade ≥4 | All | Toxicity Grade 3 | Toxicity Grade ≥4 |
| Preferred Term | n (%) | n (%) | n (%)n (%) | n (%) | n (%) | n (%)n (%) |
| Blood and lymphatic system disorders | ||||||
| Neutropenia | 209 (87) | 32 (13) | 168 (70) | 172 (71) | 31 (13) | 125 (52) |
| Leukopenia | 116 (48) | 34 (14) | 69 (29) | 87 (36) | 39 (16) | 27 (11) |
| Anemia | 106 (44) | 27 (11) | 4 (2) | 71 (29) | 23 (10) | 4 (2) |
| Thrombocytopenia | 172 (72) | 59 (25) | 76 (32) | 42 (17) | 9 (4) | 3 (1) |
| Febrile neutropenia | 41 (17) | 24 (10) | 12 (5) | 33 (14) | 17 (7) | 15 (6) |
| Lymphopenia | 68 (28) | 25 (10) | 36 (15) | 28 (12) | 15 (6) | 2 (1) |
| Nervous system disorders | ||||||
| Peripheral neuropathya | 71 (30) | 17 (7) | 1 (< 1) | 65 (27) | 10 (4) | 0 |
| Hypoesthesia | 14 (6) | 3 (1) | 0 | 13 (5) | 0 | 0 |
| Paresthesia | 14 (6) | 2 (1) | 0 | 11 (5) | 0 | 0 |
| Neuralgia | 25 (10) | 9 (4) | 0 | 1 (< 1) | 0 | 0 |
| General disorders and administration site conditions | ||||||
| Fatigue | 43 (18) | 11 (5) | 1 (< 1) | 38 (16) | 5 (2) | 0 |
| Pyrexia | 48 (20) | 7 (3) | 0 | 23 (10) | 5 (2) | 0 | Asthenia | 29 (12) | 4 (2) | 1 (< 1) | 18 (7) | 1 (< 1) | 0 | Edema peripheral | 16 (7) | 1 (< 1) | 0 | 13 (5) | 0 | 0 |
| Gastrointestinal disorders | ||||||
| Nausea | 54 (23) | 1 (< 1) | 0 | 28 (12) | 0 | 0 |
| Constipation | 42 (18) | 1 (< 1) | 0 | 22 (9) | 2 (1) | 0 |
| Stomatitis | 20 (8) | 2 (1) | 0 | 19 (8) | 0 | 1 (< 1) |
| Diarrhea | 59 (25) | 11 (5) | 0 | 11 (5) | 3 (1) | 1 (< 1) | Vomiting | 24 (10) | 1 (< 1) | 0 | 8 (3) | 0 | 0 | Abdominal distension | 13 (5) | 0 | 0 | 4 (2) | 0 | 0 |
| Infections and infestations | ||||||
| Pneumonia | 20 (8) | 8 (3) | 5 (2) | 11 (5) | 5 (2) | 3 (1) |
| Skin and subcutaneous tissue disorders | ||||||
| Alopecia | 31 (13) | 1 (< 1) | 1 (< 1) | 33 (14) | 4 (2) | 0 |
| Metabolism and nutrition disorders | ||||||
| Hyperglycemia | 10 (4) | 1 (< 1) | 0 | 17 (7) | 10 (4) | 0 |
| Decreased appetite | 36 (15) | 2 (1) | 0 | 15 (6) | 1 (< 1) | 0 |
| Vascular disorders | ||||||
| Hypertension | 15 (6) | 1 (< 1) | 0 | 3 (1) | 0 | 0 |
| Psychiatric disorders | ||||||
| Insomnia | 16 (7) | 1 (< 1) | 0 | 8 (3) | 0 | 0 |
| Key: R-CHOP=rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP=Борамилан ФС, rituximab, cyclophosphamide, doxorubicin, and prednisone. a Represents High Level Term Peripheral Neuropathies NEC | ||||||
The incidence of herpes zoster reactivation was 4.6% in the VcR-CAP arm and 0.8% in the R-CHOP arm. Antiviral prophylaxis was mandated by protocol amendment.
The incidences of Grade ≥ 3 bleeding events were similar between the 2 arms (3 patients in the VcR-CAP arm and 1 patient in the R-CHOP arm). All of the Grade ≥ 3 bleeding events resolved without sequelae in the VcR-CAP arm.
Adverse reactions leading to discontinuation occurred in 8% of patients in VcR-CAP group and 6% of patients in R-CHOP group. In the VcR-CAP group, the most commonly reported adverse reaction leading to discontinuation was peripheral sensory neuropathy (1%; 3 patients). The most commonly reported adverse reaction leading to discontinuation in the R-CHOP group was febrile neutropenia (< 1%; 2 patients).
Integrated Summary Of Safety (Relapsed Multiple Myeloma And Relapsed Mantle Cell Lymphoma)Safety data from phase 2 and 3 studies of single agent Борамилан ФС 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 Open-Label Study of Борамилан ФС subcutaneous versus intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of Борамилан ФС was similar in patients with multiple myeloma and mantle cell lymphoma.
In the integrated analysis, the most commonly reported (> 20%) adverse reactions were nausea (49%), diarrhea (46%), asthenic conditions including fatigue (41%) and weakness (11%), peripheral neuropathies (38%), thrombocytopenia (32%), vomiting (28%), constipation (25%), and pyrexia (21%). Eleven percent (11%) of patients experienced at least 1 episode of ≥ Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%).
In the Phase 2 relapsed multiple myeloma clinical trials of Борамилан ФС administered intravenously, local skin irritation was reported in 5% of patients, but extravasation of Борамилан ФС was not associated with tissue damage.
Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of SafetyA total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adver
Борамилан ФС® (bortezomib) is indicated for the treatment of patients with multiple myeloma.
Mantle Cell LymphomaБорамилан ФС is indicated for the treatment of patients with mantle cell lymphoma.
Following twice weekly administration of 1 mg/m2 and 1.3 mg/m2 bortezomib doses (n=12 per each dose level), the maximum inhibition of 20S proteasome activity (relative to baseline) in whole blood was observed 5 minutes after drug administration. Comparable maximum inhibition of 20S proteasome activity was observed between 1 and 1.3 mg/m2 doses. Maximal inhibition ranged from 70% to 84% and from 73% to 83% for the 1 mg/m2 and 1.3 mg/m2 dose regimens, respectively.
Following intravenous administration of 1 mg/m2 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n=12, per each dose level), the mean maximum plasma concentrations of bortezomib (Cmax) after the first dose (Day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the mean maximum observed plasma concentrations ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose. The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3mg/m2 dose. The mean total body clearances was 102 and 112 L/h following the first dose for doses of 1 mg/m2 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients (n = 14 for intravenous, n = 17 for subcutaneous) with multiple myeloma, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administration. The Cmax after subcutaneous administration (20.4 ng/mL) was lower than intravenous (223 ng/mL). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18% -122.80%.
DistributionThe mean distribution volume of bortezomib ranged from approximately 498 to 1884 L/m2 following single-or repeat-dose administration of 1 mg/m2 or 1.3mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.
MetabolismIn vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 min and 30 min after dosing indicate that the plasma levels of metabolites are low compared to the parent drug.
EliminationThe pathways of elimination of bortezomib have not been characterized in humans.
AgeAnalyses of data after the first dose of Cycle 1 (Day 1) in 39 multiple myeloma patients who had received intravenous doses of 1 mg/m2and 1.3 mg/m2 showed that both dose-normalized AUC and Cmax tend to be less in younger patients. Patients < 65 years of age (n=26) had about 25% lower mean dose-normalized AUC and Cmax than those ≥ 65 years of age (n=13).
GenderMean dose-normalized AUC and Cmax values were comparable between male (n=22) and female (n=17) patients after the first dose of Cycle 1 for the 1 and 1.3 mg/m2 doses.
RaceThe effect of race on exposure to bortezomib could not be assessed as most of the patients were Caucasian.
Hepatic ImpairmentThe effect of hepatic impairment (see Table 6 for definition of hepatic impairment) on the pharmacokinetics of bortezomib was assessed in 60 patients with cancer at bortezomib doses ranging from 0.5 to 1.3 mg/m2. When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be monitored closely.
Renal ImpairmentA pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCl) into the following groups: 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). A group of dialysis patients who were dosed after dialysis was also included in the study (N=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and Cmax) was comparable among all the groups.
PediatricSee Use In Specific Populations.
Cytochrome P450Bortezomib is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of > 30μM (> 11.5μg/mL). Bortezomib may inhibit 2C19 activity (IC50 = 18 μM, 6.9 μg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortezomib did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS Peripheral NeuropathyБорамилан ФС treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥ Grade 3) during treatment with Борамилан ФС. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing Борамилан ФС subcutaneous versus intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous. Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting Борамилан ФС subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during Борамилан ФС therapy may require a decrease in the dose and/or a less dose-intense schedule. In the Борамилан ФС versus dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥ Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥ Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
HypotensionThe incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.
Cardiac ToxicityAcute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during Борамилан ФС therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study of Борамилан ФС versus dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the Борамилан ФС and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤ 1% for each individual reaction in the Борамилан ФС group. In the dexamethasone group the incidence was ≤ 1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Pulmonary ToxicityAcute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving Борамилан ФС. Some of these events have been fatal.
In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and Борамилан ФС for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.
There have been reports of pulmonary hypertension associated with Борамилан ФС administration in the absence of left heart failure or significant pulmonary disease.
In the event of new or worsening cardiopulmonary symptoms, consider interrupting Борамилан ФС until a prompt and comprehensive diagnostic evaluation is conducted.
Posterior Reversible Encephalopathy Syndrome (PRES)Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving Борамилан ФС. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Борамилан ФС. The safety of reinitiating Борамилан ФС therapy in patients previously experiencing PRES is not known.
Gastrointestinal ToxicityБорамилан ФС treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Борамилан ФС for severe symptoms.
Thrombocytopenia/NeutropeniaБорамилан ФС is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.
Monitor complete blood counts (CBC) frequently during treatment with Борамилан ФС. Measure platelet counts prior to each dose of Борамилан ФС. Adjust dose/schedule for thrombocytopenia. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with Борамилан ФС. Support with transfusions and supportive care, according to published guidelines.
In the single-agent, relapsed multiple myeloma study of Борамилан ФС versus dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 8. The incidence of bleeding (≥ Grade 3) was 2% on the Борамилан ФС arm and was < 1% in the dexamethasone arm.
Table 8: Severity of Thrombocytopenia Related to Pretreatment Platelet Count in the Relapsed Multiple Myeloma Study of Борамилан ФС versus Dexamethasone
| Pretreatment Platelet Count* | Number of Patients (N=331)** | Number (%) of Patients with Platelet Count < 10,000/ìL | Number (%) of Patients with Platelet Count 10,000-25,000/μL |
| ≥ 75,000/μL | 309 | 8 (3%) | 36 (12%) |
| ≥ 50,000/μL< 75,000/μL | 14 | 2 (14%) | 11 (79%) |
| ≥ 10,000/μL< 50,000/μL | 7 | 1 (14%) | 5 (71%) |
| * A baseline platelet count of 50,000/μL was required for study eligibility ** Data were missing at baseline for 1 patient |
In the combination study of Борамилан ФС with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥ Grade 4) was 32% versus 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12. The incidence of bleeding events (≥ Grade 3) was 1% in the VcR-CAP arm (3 patients) and was < 1% in the R-CHOP arm (1 patient).
Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the RCHOP arm.
The incidence of neutropenia (≥ Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥ Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the RCHOP arm.
Tumor Lysis SyndromeTumor lysis syndrome has been reported with Борамилан ФС therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
Hepatic ToxicityCases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Борамилан ФС therapy to assess reversibility. There is limited re-challenge information in these patients.
Embryo-Fetal ToxicityBased on the mechanism of action and findings in animals, Борамилан ФС can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.
Females of reproductive potential should avoid becoming pregnant while being treated with Борамилан ФС. Advise females and males of reproductive potential that they must use contraception during treatment with Борамилан ФС and for 2 months following treatment. If Борамилан ФС is used during pregnancy or if the patient becomes pregnant during Борамилан ФС treatment, the patient should be apprised of the potential risk to the fetus.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityCarcinogenicity studies have not been conducted with bortezomib.
Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.
Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses ≥ 0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2.
Use In Specific Populations Pregnancy Risk SummaryBased on its mechanism of action and findings in animals, Борамилан ФС can cause fetal harm when administered to a pregnant woman. There are no studies with the use of Борамилан ФС in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose. Advise pregnant women of the potential risk to the fetus.
Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
DataAnimal Data
Bortezomib was not teratogenic in nonclinical developmental toxicity studies in rats and rabbits at the highest dose tested (0.075 mg/kg; 0.5 mg/m2 in the rat and 0.05 mg/kg; 0.6 mg/m2 in the rabbit) when administered during organogenesis. These dosages are approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area.
Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose (approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area). Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/m2) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight.
Lactation Risk SummaryThere are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breast fed infant, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in breastfed infants from Борамилан ФС is unknown, advise nursing women not to breastfeed during treatment with Борамилан ФС and for 2 months after treatment.
Females And Males Of Reproductive PotentialBased on its mechanism of action and findings in animals, Борамилан ФС can cause fetal harm when administered to a pregnant woman.
Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to initiating Борамилан ФС treatment.
ContraceptionAdvise patients of reproductive potential to use effective contraception during treatment with Борамилан ФС and for at least 2 months after treatment.
InfertilityBased on the mechanism of action and findings in animals, Борамилан ФС may have an effect on either male or female fertility.
Pediatric UseThe effectiveness of Борамилан ФС in pediatric patients with relapsed pre-B acute lymphoblastic leukemia (ALL) has not been established.
The activity and safety of Борамилан ФС in combination with intensive reinduction chemotherapy was evaluated in pediatric and young adult patients with lymphoid malignancies (pre-B cell ALL 77%, 16% with T-cell ALL, and 7% T-cell lymphoblastic lymphoma (LL)), all of whom relapsed within 36 months of initial diagnosis in a single-arm multicenter, non-randomized cooperative group trial. An effective reinduction multiagent chemotherapy regimen was administered in 3 blocks. Block 1 included vincristine, prednisone, doxorubicin and pegaspargase; block 2 included cyclophosphamide, etoposide and methotrexate; block 3 included high dose cytosine arabinoside and asparaginase. Борамилан ФС was administered at a dose of 1.3 mg/m2 as a bolus intravenous injection on days 1, 4, 8, and 11 of block 1 and days 1, 4, and 8 of block 2. There were 140 patients with ALL or LL enrolled and evaluated for safety. The median age was 10 years (range 1 to 26), 57% were male, 70% were white, 14% were black, 4% were Asian, 2% were American Indian/ Alaska Native, 1% were Pacific Islander.
The activity was evaluated in a pre-specified subset of the first 60 evaluable patients enrolled on the study with pre-B ALL ≤ 21 years and relapsed < 36 months from diagnosis. The complete remission (CR) rate at day 36 was compared to that in a historical control set of patients who had received the identical backbone therapy without Борамилан ФС. There was no evidence that the addition of Борамилан ФС had any impact on the CR rate.
No new safety concerns were observed when Борамилан ФС was added to a chemotherapy backbone regimen as compared with a historical control group in which the backbone regimen was given without Борамилан ФС.
The BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
Geriatric UseOf the 669 patients enrolled in the relapsed multiple myeloma study, 245 (37%) were 65 years of age or older: 125 (38%) on the Борамилан ФС arm and 120 (36%) on the dexamethasone arm. Median time to progression and median duration of response for patients ≥ 65 were longer on Борамилан ФС compared to dexamethasone [5.5 moversus 4.3 mo, and 8.0 mo versus 4.9 mo, respectively]. On the Борамилан ФС arm, 40% (n=46) of evaluable patients aged ≥ 65 experienced response (CR+PR) versus 18% (n=21) on the dexamethasone arm. The incidence of Grade 3 and 4 events was 64%, 78% and 75% for Борамилан ФС patients ≤ 50, 51-64 and ≥ 65 years old, respectively.
No overall differences in safety or effectiveness were observed between patients ≥ age 65 and younger patients receiving Борамилан ФС; but greater sensitivity of some older individuals cannot be ruled out.
Patients With Renal ImpairmentThe pharmacokinetics of Борамилан ФС are not influenced by the degree of renal impairment. Therefore, dosing adjustments of Борамилан ФС are not necessary for patients with renal insufficiency. Since dialysis may reduce Борамилан ФС concentrations, Борамилан ФС should be administered after the dialysis procedure.
Patients With Hepatic ImpairmentThe exposure of bortezomib is increased in patients with moderate (bilirubin ≥ 1.5 – 3x ULN) and severe (bilirubin > 3 x ULN) hepatic impairment. Starting dose should be reduced in those patients.
Patients With DiabetesDuring clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral anti-diabetic agents receiving Борамилан ФС treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.
Борамилан ФС is for intravenous or subcutaneous use only. Борамилан ФС should not be administered by any other route.
Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
The recommended starting dose of Борамилан ФС is 1.3 mg/m2. Борамилан ФС may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL.
Борамилан ФС retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Борамилан ФС and who have relapsed at least 6 months after completing prior Борамилан ФС treatment. Treatment may be started at the last tolerated dose.
When administered intravenously, Борамилан ФС is administered as a 3 to 5 second bolus intravenous injection.
Dosage In Previously Untreated Multiple MyelomaБорамилан ФС is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Борамилан ФС is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Борамилан ФС is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Борамилан ФС.
Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma
| Twice Weekly Борамилан ФС (Cycles 1-4) | ||||||||||||
| Week | 1 | 2 | 3 | 4 | 5 | 6 | ||||||
| Борамилан ФС (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(9 mg/m2) Prednisone(60 mg/m2) | Day 1 | Day 2 | Day 3 | Day 4 | - | - | rest period | - | - | - | - | rest period |
| Once Weekly Борамилан ФС (Cycles 5-9 when used in combination with Melphalan and Prednisone) | ||||||||||||
| Week | 1 | 2 | 3 | 4 | 5 | 6 | ||||||
| Борамилан ФС (1.3 mg/m2) | Day 1 | - | - | Day 8 | rest period | Day 22 | Day 29 | rest period | ||||
| Melphalan(9 mg/m2) Prednisone(60 mg/m2) | Day 1 | Day 2 | Day 3 | Day 4 | - | - | rest period | - | - | - | - | rest period |
Prior to initiating any cycle of therapy with Борамилан ФС in combination with melphalan and prednisone:
Table 2: Dose Modifications during Cycles of Combination Борамилан ФС, Melphalan and Prednisone Therapy Toxicity Dose modification or delay
| Toxicity | Dose modification or delay |
| Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle | Consider reduction of the melphalan dose by 25% in the next cycle |
| If platelet count is not above 30 x 109/L or ANC is not above 0.75 x 109/L on a Борамилан ФС dosing day (other than day 1) | Withhold Борамилан ФС dose |
| If several Борамилан ФС doses in consecutive cycles are withheld due to toxicity | Reduce Борамилан ФС dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) |
| Grade 3 or higher non-hematological toxicities | Withhold Борамилан ФС therapy until symptomsof toxicity have resolved to Grade 1 orbaseline. Then, Борамилан ФС may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For Борамилан ФС-related neuropathic pain and/or peripheral neuropathy, hold or modify Борамилан ФС as outlined in Table 5. |
For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided.
Dosage In Previously Untreated Mantle Cell LymphomaБорамилан ФС (1.3 mg/m2) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for six 3-week treatment cycles as shown in Table 3. Борамилан ФС is administered first followed by rituximab. Борамилан ФС is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period on Days 12-21. For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of Борамилан ФС.
Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma
| Twice Weekly Борамилан ФС (Six 3-Week Cycles)a | ||||||||
| Week | 1 | 2 | 3 | |||||
| Борамилан ФС (1.3 mg/m2) | Day 1 | - | - | Day 4 | - | Day 8 | Day 11 | rest period |
| Rituximab (375 mg/m2) Cyclophosphamide (750 mg/m2) Doxorubicin (50 mg/m2) | Day 1 | - | - | - | - | rest period | ||
| Prednisone (100 mg/m2) | Day 1 | Day 2 | Day 3 | Day 4 | Day 5 | - | - | rest period |
| a Dosing may continue for 2 more cycles (for a total of 8 cycles) if response is first seen at cycle 6. | ||||||||
Prior to the first day of each cycle (other than Cycle 1):
Interrupt Борамилан ФС treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy. For dose adjustments, see Table 4 below.
Table 4: Dose Modifications on Days 4, 8, and 11 during Cycles of Combination Борамилан ФС, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy
| Toxicity | Dose modification or delay |
| Hematological toxicity | |
| Withhold Борамилан ФС therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 109/L and a platelet count at or above 25 × 109/L.
|
| Grade 3 or higher non-hematological toxicities | Withhold Борамилан ФС therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, Борамилан ФС may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For Борамилан ФС-related neuropathic pain and/or peripheral neuropathy, hold or modify Борамилан ФС as outlined in Table 5. |
For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information.
Dosage And Dose Modifications For Relapsed Multiple Myeloma And Relapsed Mantle Cell LymphomaБорамилан ФС (1.3 mg/m2/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21). For extended therapy of more than 8 cycles, Борамилан ФС may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22) followed by a 13-day rest period (Days 23 to 35). At least 72 hours should elapse between consecutive doses of Борамилан ФС.
Patients with multiple myeloma who have previously responded to treatment with Борамилан ФС (either alone or in combination) and who have relapsed at least 6 months after their prior Борамилан ФС therapy may be started on Борамилан ФС at the last tolerated dose. Retreated patients are administered Борамилан ФС twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of Борамилан ФС. Борамилан ФС may be administered either as a single agent or in combination with dexamethasone.
Борамилан ФС therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below. Once the symptoms of the toxicity have resolved, Борамилан ФС therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose).
For dose modifications guidelines for peripheral neuropathy see section 2.7.
Dose Modifications For Peripheral NeuropathyStarting Борамилан ФС subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with Борамилан ФС only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during Борамилан ФС therapy may require a decrease in the dose and/or a less dose-intense schedule.
For dose or schedule modification guidelines for patients who experience Борамилан ФС-related neuropathic pain and/or peripheral neuropathy see Table 5.
Table 5: Recommended Dose Modification for Борамилан ФС related Neuropathic Pain and/or PeripheralSensory or Motor Neuropathy
| Severity of Peripheral Neuropathy Signs and Symptoms* | Modification of Dose and Regimen |
| Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or lossof function | No action |
| Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities ofDaily Living (ADL)**) | Reduce Борамилан ФС to 1 mg/m2 |
| Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL ***) | Withhold Борамилан ФС therapy until toxicity resolves. When toxicity resolves reinitiate with areduced dose of Борамилан ФС at 0.7 mg/m2 once per week. |
| Grade 4 (life-threatening consequences; urgent intervention indicated) | Discontinue Борамилан ФС |
| *Grading based on NCI Common Terminology Criteria CTCAE v4.0 **Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money etc; ***Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden |
Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Борамилан ФС dose. Patients with moderate or severe hepatic impairment should be started on Борамилан ФС at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and a subsequent dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 may be considered based on patient tolerance (see Table 6).
Table 6: Recommended Starting Dose Modification for Борамилан ФС in Patients with Hepatic Impairment
| Bilirubin Level | SGOT (AST) Levels | Modification of Starting Dose | |
| Mild | Less than or equal to 1.0 x ULN | More than ULN | None |
| More than 1.0 x −1.5 x ULN | Any | None | |
| Moderate | More than 1.5 x −3 x ULN | Any | Reduce Борамилан ФС to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability. |
| Severe | More than 3 x ULN | Any | |
| Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range. |
The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.
When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
If local injection site reactions occur following Борамилан ФС administration subcutaneously, a less concentrated Борамилан ФС solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously. Alternatively, the intravenous route of administration should be considered.
Борамилан ФС is an antineoplastic. Procedures for proper handling and disposal should be considered.
Reconstitution/Preparation For Intravenous And Subcutaneous AdministrationProper aseptic technique should be used. Reconstitute only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.
Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
For each 3.5 mg single-use vial of bortezomib reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 7):
Table 7: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration
| Route of administration | Bortezomib (mg/vial) | Diluent (0.9% Sodium Chloride) | Final Bortezomib concentration (mg/mL) |
| Intravenous | 3.5 mg | 3.5 mg | 1 mg/mL |
| Subcutaneous | 3.5 mg | 1.4 mL | 2.5 mg/mL |
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Борамилан ФС to be administered:
| Борамилан ФС dose (mg/m2) x patient BSA (m2) 1 mg mL | = Total Борамилан ФС volume (mL) to be administered |
| Борамилан ФС dose (mg/m2) x patient BSA (m2) 2.5 mg mL | = Total Борамилан ФС volume (mL) to be administered |
Stickers that indicate the route of administration are provided with each Борамилан ФС vial. These stickers should be placed directly on the syringe of Борамилан ФС once Борамилан ФС is prepared to help alert practitioners of the correct route of administration for Борамилан ФС.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Stability: Unopened vials of Борамилан ФС are stable until the date indicated on the package when stored in the original package protected from light.
Борамилан ФС contains no antimicrobial preservative. Reconstituted Борамилан ФС should be administered within 8 hours of preparation. When reconstituted as directed, Борамилан ФС may be stored at 25°C (77°F). The reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not exceed 8 hours when exposed to normal indoor lighting.
