What is mechanism of action?

mechanism of action is Proteasome Inhibitors [MoA]

Bortezomib

Check Drug InteractionsCheck known drug interactions.

Bortezomib Prescribing Information

Platelet count should be at least 100 × 10⁹/L and absolute neutrophil count (ANC) should be at least 1.5 × 10⁹/L

Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)

Nonhematologic toxicity should have recovered to Grade 1 or baseline

Interrupt bortezomib treatment at the onset of any Grade 3 hematologic or nonhematological toxicities, excluding neuropathy

[see Table 5, Warnings and Precautions (5)]

. For dose adjustments, see

Table 4

below.

Indications and Usage, Mantle Cell Lymphoma (

1.2 Mantle Cell Lymphoma

Bortezomib for Injection is indicated for the treatment of adult patients with mantle cell lymphoma.

), Removed phrase “who have received at least 1 prior therapy”

12/2022

Dosage and Administration (

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

Bortezomib (1.3 mg/m²) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6, three week treatment cycles as shown in

Table 3

. Bortezomib is administered first followed by rituximab. Bortezomib is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 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 bortezomib.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly Bortezomib (6, Three Week Cycles)
Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6.
Week	1					2		3
Bortezomib (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

2.5 Dose Modification Guidelines for Bortezomib When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone

Prior to the first day of each cycle (other than Cycle 1):

If, after bortezomib has been withheld, the toxicity does not resolve, discontinue bortezomib.

If toxicity resolves such that the patient has an ANC at or above 0.75 × 10⁹/L and a platelet count at or above 25 × 10⁹/L, bortezomib dose should be reduced by 1 dose level (from 1.3 mg/m²to 1 mg/m², or from 1 mg/m²to 0.7 mg/m²).

Table 4: Dose Modifications on Days 4, 8, and 11 During Cycles of Combination Bortezomib, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy
Toxicity	Dose Modification or Delay
Hematological Toxicity
Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 10⁹/L	Withhold bortezomib 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 nonhematological toxicities	Withhold bortezomib therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m²to 1 mg/m², or from 1 mg/m²to 0.7 mg/m²). For bortezomib-related neuropathic pain and/or peripheral neuropathy, hold or modify bortezomib as outlined in Table 5 .

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information.

2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

Bortezomib for Injection (1.3 mg/m²/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, Bortezomib for Injection may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35)

[see Clinical Studies (14)]

. At least 72 hours should elapse between consecutive doses of Bortezomib for Injection.

Patients with multiple myeloma who have previously responded to treatment with Bortezomib for Injection (either alone or in combination) and who have relapsed at least six months after their prior Bortezomib for Injection therapy may be started on Bortezomib for Injection at the last tolerated dose. Retreated patients are administered Bortezomib for Injection twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of Bortezomib for Injection. Bortezomib for Injection may be administered either as a single agent or in combination with dexamethasone

[see Clinical Studies (14.1)]

Bortezomib for Injection therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below

[see Warnings and Precautions (5)]

. Once the symptoms of the toxicity have resolved, Bortezomib for Injection 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.

2.7 Dose Modifications for Peripheral Neuropathy

Starting Bortezomib for Injection 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 Bortezomib for Injection only after careful risk-benefit assessment.

Patients experiencing new or worsening peripheral neuropathy during Bortezomib for Injection 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 Bortezomib for Injection-related neuropathic pain and/or peripheral neuropathy, see

Table 5

Table 5: Recommended Dose Modification for Bortezomib for Injection related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy Signs and Symptoms Grading based on NCI Common Terminology Criteria CTCAE v4.0	Modification of Dose and Regimen
Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function	No action
Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL) Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc.; )	Reduce Bortezomib for Injection to 1 mg/m²
Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden )	Withhold Bortezomib for Injection therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of Bortezomib for Injection at 0.7 mg/m²once per week.
Grade 4 (life-threatening consequences; urgent intervention indicated)	Discontinue Bortezomib for Injection

2.8 Dosage in Patients with Hepatic Impairment

Do not adjust the starting dose for patients with mild hepatic impairment.

Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m²per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m²or further dose reduction to 0.5 mg/m²based on patient tolerance

(see Table 6)

[see Use in Specific Populations (8.7)

Clinical Pharmacology (12.3)]

Table 6: Recommended Starting Dose Modification for Bortezomib for Injection in Patients with Hepatic Impairment
	Bilirubin Level	SGOT (AST) Levels	Modification of Starting Dose
Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.
Mild	Less than or equal to 1× ULN	More than ULN	None
Mild	More than 1× to 1.5× ULN	Any	None
Moderate	More than 1.5× to 3× ULN	Any	Reduce dose to 0.7 mg/m²in the first cycle. Consider dose escalation to 1 mg/m²or further dose reduction to 0.5 mg/m²in subsequent cycles based on patient tolerability.
Severe	More than 3× ULN	Any

2.9 Administration Precautions

The drug quantity contained in one vial (1 mg or 2.5 mg) may exceed the usual dose required. Use caution when calculating the dose to prevent overdose

[see Dosage and Administration (2.10)]

When administered subcutaneously, rotate sites for each injection (thigh or abdomen). Give new injections 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 Bortezomib for Injection administration subcutaneously, a less concentrated Bortezomib for Injection solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously

[see Dosage and Administration (2.10)]

. Alternatively, consider use of the intravenous route of administration

[see Dosage and Administration (2.10)]

Bortezomib for Injection is a hazardous drug. Follow applicable special handling and disposal procedures. 1

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique. Reconstitute

only with 0.9% Sodium Chloride Injection, USP

. The reconstituted product should be a clear and colorless solution.

Different volumes of 0.9% Sodium Chloride Injection, USP 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, use caution when calculating the volume to be administered

[see Dosage and Administration (2.9)]

For each 1 mg or 2.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP 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 Injection, USP)	Final Bortezomib Concentration
Intravenous	1 mg	1 mL	1 mg/mL
Subcutaneous	1 mg	0.4 mL	2.5 mg/mL Actual vial content results in a final concentration of 1 mg/0.4 mL
Intravenous	2.5 mg	2.5 mL	1 mg/mL
Subcutaneous	2.5 mg	1 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 Bortezomib for Injection to be administered:

•
Intravenous Administration [1 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

1 mg/mL

•
Subcutaneous Administration [2.5 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

2.5 mg/mL

Stickers that indicate the route of administration are provided with each Bortezomib for Injection vial. These stickers should be placed directly on the syringe of Bortezomib for Injection once Bortezomib for Injection is prepared to help alert practitioners of the correct route of administration for Bortezomib for Injection.

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 Bortezomib for Injection are stable until the date indicated on the package when stored in the original package protected from light.

Bortezomib for Injection contains no antimicrobial preservative. Administer reconstituted Bortezomib for Injection within eight hours of preparation. When reconstituted as directed, Bortezomib for Injection 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 eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

)

12/2022

Warnings and Precautions, Thrombocytopenia/Neutropenia (

5.7 Thrombocytopenia/Neutropenia

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

Monitor complete blood counts (CBC) frequently during treatment with Bortezomib for Injection. Measure platelet counts prior to each dose of Bortezomib for Injection. Adjust dose/schedule for thrombocytopenia

[see Dosage and Administration (2.6)]

. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines.

In the single agent, relapsed multiple myeloma study of bortezomib vs 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 bortezomib 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 Bortezomib vs Dexamethasone
Pretreatment Platelet Count A baseline platelet count of 50,000/µL was required for study eligibility	Number of Patients (N=331) Data were missing at baseline for one patient	Number (%) of Patients with Platelet Count <10,000/µL	Number (%) of Patients with Platelet Count 10,000 to 25,000/µL
≥ 75,000/µL	309	8 (3%)	36 (12%)
≥ 50,000/µL to < 75,000/ µL	14	2 (14%)	11 (79%)
≥ 10,000/µL to < 50,000/ µL	7	1 (14%)	5 (71%)

In the combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 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 1.7% in the VcR-CAP arm (four patients) and was 1.2% in the R-CHOP arm (three patients).

Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.

The incidence of neutropenia (≥Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.

)

12/2022

Bortezomib for Injection is a proteasome inhibitor indicated for:

•Treatment of adult patients with multiple myeloma. (
1.1 Multiple Myeloma
Bortezomib for Injection is indicated for the treatment of adult patients with multiple myeloma.
)
•Treatment of adult patients with mantle cell lymphoma. (
1.2 Mantle Cell Lymphoma
Bortezomib for Injection is indicated for the treatment of adult patients with mantle cell lymphoma.
)

•For subcutaneous or intravenous use only. Each route of administration has a different reconstituted concentration; Exercise caution when calculating the volume to be administered. (

2.1 Important Dosing Guidelines

Bortezomib for Injection is for intravenous or subcutaneous use only. Do not administer Bortezomib for Injection by any other route.

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered.

The recommended starting dose of Bortezomib for Injection is 1.3 mg/m². Bortezomib for Injection is administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL

[see Dosage and Administration (2.10)].

Bortezomib for Injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezomib for Injection and who have relapsed at least six months after completing prior Bortezomib for Injection treatment. Treatment may be started at the last tolerated dose

[see Dosage and Administration (2.6)]

When administered intravenously, administer Bortezomib for Injection as a 3 to 5 second bolus intravenous injection.

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique. Reconstitute

only with 0.9% Sodium Chloride Injection, USP

. The reconstituted product should be a clear and colorless solution.

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered

[see Dosage and Administration (2.9)]

For each 1 mg or 2.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP 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 Injection, USP)	Final Bortezomib Concentration
Intravenous	1 mg	1 mL	1 mg/mL
Subcutaneous	1 mg	0.4 mL	2.5 mg/mL Actual vial content results in a final concentration of 1 mg/0.4 mL
Intravenous	2.5 mg	2.5 mL	1 mg/mL
Subcutaneous	2.5 mg	1 mL	2.5 mg/mL

•
Intravenous Administration [1 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

1 mg/mL

•
Subcutaneous Administration [2.5 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

2.5 mg/mL

Stability

Unopened vials of Bortezomib for Injection are stable until the date indicated on the package when stored in the original package protected from light.

)

•The recommended starting dose of Bortezomib for Injection is 1.3 mg/m² administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. (

2.2 Dosage in Previously Untreated Multiple Myeloma

Bortezomib for Injection is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in

Table 1

. In Cycles 1 to 4, Bortezomib for Injection is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, Bortezomib for Injection is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib for Injection.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma
Twice Weekly Bortezomib for Injection (Cycles 1 to 4)
Week	1				2		3	4		5		6
Bortezomib for Injection (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 Bortezomib for Injection (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)
Week	1				2		3	4		5		6
Bortezomib for Injection (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

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

Table 3

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly Bortezomib (6, Three Week Cycles)
Dosing may continue for two more cycles (for a total of eight cycles) if response is first seen at Cycle 6.
Week	1					2		3
Bortezomib (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

2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma

[see Clinical Studies (14)]

. At least 72 hours should elapse between consecutive doses of Bortezomib for Injection.

[see Clinical Studies (14.1)]

Bortezomib for Injection therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below

[see Warnings and Precautions (5)]

For dose modifications guidelines for peripheral neuropathy, see section 2.7.

)

•Retreatment for multiple myeloma: May retreat starting at the last tolerated dose. (
2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
Bortezomib for Injection (1.3 mg/m²/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, Bortezomib for Injection may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day rest period (Days 23 to 35)
[see Clinical Studies (14)]
. At least 72 hours should elapse between consecutive doses of Bortezomib for Injection.
Patients with multiple myeloma who have previously responded to treatment with Bortezomib for Injection (either alone or in combination) and who have relapsed at least six months after their prior Bortezomib for Injection therapy may be started on Bortezomib for Injection at the last tolerated dose. Retreated patients are administered Bortezomib for Injection twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of Bortezomib for Injection. Bortezomib for Injection may be administered either as a single agent or in combination with dexamethasone
[see Clinical Studies (14.1)]
.
Bortezomib for Injection therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below
[see Warnings and Precautions (5)]
. Once the symptoms of the toxicity have resolved, Bortezomib for Injection 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.
)

•Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (

2.8 Dosage in Patients with Hepatic Impairment

Do not adjust the starting dose for patients with mild hepatic impairment.

(see Table 6)

[see Use in Specific Populations (8.7)

Clinical Pharmacology (12.3)]

Table 6: Recommended Starting Dose Modification for Bortezomib for Injection in Patients with Hepatic Impairment
	Bilirubin Level	SGOT (AST) Levels	Modification of Starting Dose
Abbreviations: SGOT = serum glutamic oxaloacetic transaminase; AST = aspartate aminotransferase; ULN = upper limit of the normal range.
Mild	Less than or equal to 1× ULN	More than ULN	None
Mild	More than 1× to 1.5× ULN	Any	None
Moderate	More than 1.5× to 3× ULN	Any	Reduce dose to 0.7 mg/m²in the first cycle. Consider dose escalation to 1 mg/m²or further dose reduction to 0.5 mg/m²in subsequent cycles based on patient tolerability.
Severe	More than 3× ULN	Any

)

•Dose must be individualized to prevent overdose. (

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique. Reconstitute

only with 0.9% Sodium Chloride Injection, USP

. The reconstituted product should be a clear and colorless solution.

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered

[see Dosage and Administration (2.9)]

For each 1 mg or 2.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP 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 Injection, USP)	Final Bortezomib Concentration
Intravenous	1 mg	1 mL	1 mg/mL
Subcutaneous	1 mg	0.4 mL	2.5 mg/mL Actual vial content results in a final concentration of 1 mg/0.4 mL
Intravenous	2.5 mg	2.5 mL	1 mg/mL
Subcutaneous	2.5 mg	1 mL	2.5 mg/mL

•
Intravenous Administration [1 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

1 mg/mL

•
Subcutaneous Administration [2.5 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

2.5 mg/mL

Stability

Unopened vials of Bortezomib for Injection are stable until the date indicated on the package when stored in the original package protected from light.

)

For injection: Each single-dose vial of Bortezomib for Injection contains 1 mg or 2.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose

[see

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

Use proper aseptic technique. Reconstitute

only with 0.9% Sodium Chloride Injection, USP

. The reconstituted product should be a clear and colorless solution.

Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered

[see Dosage and Administration (2.9)]

For each 1 mg or 2.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP 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 Injection, USP)	Final Bortezomib Concentration
Intravenous	1 mg	1 mL	1 mg/mL
Subcutaneous	1 mg	0.4 mL	2.5 mg/mL Actual vial content results in a final concentration of 1 mg/0.4 mL
Intravenous	2.5 mg	2.5 mL	1 mg/mL
Subcutaneous	2.5 mg	1 mL	2.5 mg/mL

•
Intravenous Administration [1 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

1 mg/mL

•
Subcutaneous Administration [2.5 mg/mL concentration]

Bortezomib for Injection dose (mg/m²) × patient BSA (m²)

= Total Bortezomib for Injection volume (mL) to be administered

2.5 mg/mL

Stability

Unopened vials of Bortezomib for Injection are stable until the date indicated on the package when stored in the original package protected from light.

]

Patients with diabetes may require close monitoring of blood glucose and adjustment of antidiabetic medication. (

8.8 Patients with Diabetes

During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib for Injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

)

Bortezomib for Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions

[see

6.1 Clinical Trials Experience

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 Myeloma

Table 9

describes safety data from 340 patients with previously untreated multiple myeloma who received bortezomib (1.3 mg/m²) administered intravenously in combination with melphalan (9 mg/m²) and prednisone (60 mg/m²) in a prospective randomized study.

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

Table 9: Most Commonly Reported Adverse Reactions (≥10% in the Bortezomib, Melphalan and Prednisone Arm) with Grades 3 and ≥4 Intensity in the Previously Untreated Multiple Myeloma Study
	Bortezomib, Melphalan and Prednisone (n = 340)			Melphalan and Prednisone (n = 337)
Body System	Total	Toxicity Grade, n (%)		Total	Toxicity Grade, n (%)
Adverse Reaction	n (%)	3	≥4	n (%)	3	≥4
Blood and Lymphatic System Disorders
Thrombocytopenia	164 (48)	60 (18)	57 (17)	140 (42)	48 (14)	39 (12)
Neutropenia	160 (47)	101 (30)	33 (10)	143 (42)	77 (23)	42 (12)
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)
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 neuropathyRepresents High Level Term Peripheral Neuropathies NEC	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

Relapsed Multiple Myeloma Randomized Study of Bortezomib vs Dexamethasone

The safety data described below and in

Table 10

reflect exposure to either bortezomib (n=331) or dexamethasone (n=332) in a study of patients with relapsed multiple myeloma. Bortezomib was administered intravenously at doses of 1.3 mg/m²twice weekly for two out of three weeks (21 day cycle). After eight 21 day cycles patients continued therapy for three 35 day cycles on a weekly schedule. Duration of treatment was up to 11 cycles (nine months) with a median duration of six cycles (4.1 months). For inclusion in the trial, patients must have had measurable disease and one to three prior therapies. There was no upper age limit for entry. Creatinine clearance could be as low as 20 mL/min and bilirubin levels as high as 1.5 times the upper limit of normal. The overall frequency of adverse reactions was similar in men and women, and in patients <65 and ≥65 years of age. Most patients were Caucasian

[see Clinical Studies (14.1)]

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

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone

Serious adverse reactions are defined as any reaction that results in death, is life-threatening, requires hospitalization or prolongs a current hospitalization, results in a significant disability, or is deemed to be an important medical event. A total of 80 (24%) patients from the bortezomib treatment arm experienced a serious adverse reaction during the study, as did 83 (25%) dexamethasone-treated patients. The most commonly reported serious adverse reactions in the bortezomib treatment arm were diarrhea (3%), dehydration, herpes zoster, pyrexia, nausea, vomiting, dyspnea, and thrombocytopenia (2% each). In the dexamethasone treatment group, the most commonly reported serious adverse reactions were pneumonia (4%), hyperglycemia (3%), pyrexia, and psychotic disorder (2% each).

A total of 145 patients, including 84 (25%) of 331 patients in the bortezomib treatment group and 61 (18%) of 332 patients in the dexamethasone treatment group were discontinued from treatment due to adverse reactions. Among the 331 bortezomib-treated patients, the most commonly reported adverse reaction leading to discontinuation was peripheral neuropathy (8%). Among the 332 patients in the dexamethasone group, the most commonly reported adverse reactions leading to treatment discontinuation were psychotic disorder and hyperglycemia (2% each).

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

Most Commonly Reported Adverse Reactions in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone

The most common adverse reactions from the relapsed multiple myeloma study are shown in

Table 10

. All adverse reactions with incidence ≥10% in the bortezomib arm are included.

Table 10: Most Commonly Reported Adverse Reactions (≥10% in Bortezomib Arm), with Grades 3 and 4 Intensity in the Relapsed Multiple Myeloma Study of Bortezomib vs Dexamethasone (N=663)
	Bortezomib (N = 331)			Dexamethasone (N = 332)
Adverse Reactions	All	Grade 3	Grade 4	All	Grade 3	Grade 4
Any 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 neuropathiesRepresents High Level Term Peripheral Neuropathies NEC	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

Safety Experience from the Phase 2 Open-Label Extension Study in Relapsed Multiple Myeloma

In the Phase 2 extension study of 63 patients, no new cumulative or new long-term toxicities were observed with prolonged bortezomib treatment. These patients were treated for a total of 5.3 to 23 months, including time on bortezomib in the prior bortezomib study

[see Clinical Studies (14.1)]

Safety Experience from the Phase 3 Open-Label Study of Bortezomib Subcutaneous vs Intravenous in Relapsed Multiple Myeloma

The safety and efficacy of bortezomib administered subcutaneously were evaluated in one Phase 3 study at the recommended dose of 1.3 mg/m². This was a randomized, comparative study of bortezomib subcutaneous vs intravenous in 222 patients with relapsed multiple myeloma. The safety data described below and in

Table 11

reflect exposure to either bortezomib subcutaneous (N=147) or bortezomib intravenous (N=74)

[see Clinical Studies (14.1)]

Table 11: Most Commonly Reported Adverse Reactions (≥10%), with Grade 3 and ≥4 Intensity in the Relapsed Multiple Myeloma Study (N=221) of Bortezomib Subcutaneous vs Intravenous
	Subcutaneous (N = 147)			Intravenous (N = 74)
Body System	Total	Toxicity Grade, n (%)		Total	Toxicity Grade, n (%)
Adverse Reaction	n (%)	3	≥4	n (%)	3	≥4
Note: Safety population: 147 patients in the subcutaneous treatment group and 74 patients in the intravenous treatment group who received at least one dose of study medication
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 neuropathiesRepresents High Level Term Peripheral Neuropathies NEC	55 (37)	8 (5)	1 (1)	37 (50)	10 (14)	1 (1)

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 vs 9% intravenous), peripheral neuropathies (6% subcutaneous vs 15% intravenous), neutropenia (13% subcutaneous vs 18% intravenous), and thrombocytopenia (8% subcutaneous vs 16% intravenous).

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

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

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Relapsed Multiple Myeloma Study of Bortezomib Subcutaneous vs Intravenous

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

In the subcutaneous treatment group, 27 patients (18%) discontinued study treatment due to an adverse reaction compared with 17 patients (23%) in the intravenous treatment group

Among the 147 subcutaneously-treated patients, the most commonly reported adverse reactions leading to discontinuation were peripheral sensory neuropathy (5%) and neuralgia (5%). Among the 74 patients in the intravenous treatment group, the most commonly reported adverse reactions leading to treatment discontinuation were peripheral sensory neuropathy (9%) and neuralgia (9%).

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

Safety Experience from the Clinical Trial in Patients with Previously Untreated Mantle Cell Lymphoma

Table 12

describes safety data from 240 patients with previously untreated mantle cell lymphoma who received bortezomib (1.3 mg/m²) administered intravenously in combination with rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²), and prednisone (100 mg/m²) (VcR-CAP) in a prospective randomized study.

Infections were reported for 31% of patients in the VcR-CAP arm and 23% of the patients in the comparator (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]) arm, including the predominant preferred term of pneumonia (VcR-CAP 8% vs 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)
Body System	All	Toxicity Grade 3	Toxicity Grade ≥4	All	Toxicity Grade 3	Toxicity Grade ≥4
Adverse Reactions	n (%)	n (%)	n (%)	n (%)	n (%)	n (%)
Key: R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; VcR-CAP = bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.
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
neuropathyRepresents High Level Term Peripheral Neuropathies NEC.	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 (15)	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

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

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

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

Integrated Summary of Safety (Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma)

Safety data from Phase 2 and 3 studies of single agent bortezomib 1.3 mg/m²/dose twice weekly for two weeks followed by a ten day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. This analysis does not include data from the Phase 3 open-label study of bortezomib subcutaneous vs intravenous in relapsed multiple myeloma. In the integrated studies, the safety profile of bortezomib was similar in patients with multiple myeloma and mantle cell lymphoma.

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

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

Serious Adverse Reactions and Adverse Reactions Leading to Treatment Discontinuation in the Integrated Summary of Safety

A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each) and pneumonia, dyspnea, peripheral neuropathies, and herpes zoster (1% each).

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

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

Most Commonly Reported Adverse Reactions in the Integrated Summary of Safety

The most common adverse reactions are shown in

Table 13

. All adverse reactions occurring at ≥10% are included. In the absence of a randomized comparator arm, it is often not possible to distinguish between adverse events that are drug-caused and those that reflect the patient's underlying disease. Please see the discussion of specific adverse reactions that follows.

Table 13: Most Commonly Reported (≥ 10% Overall) Adverse Reactions in Integrated Analyses of Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma Studies Using the 1.3 mg/m²Dose (N=1163)
	All Patients (N=1163)		Multiple Myeloma (N=1008)		Mantle Cell Lymphoma (N=155)
Adverse Reactions	All	≥Grade 3	All	≥Grade 3	All	≥Grade 3
Nausea	567 (49)	36 (3)	511 (51)	32 (3)	56 (36)	4 (3)
Diarrhea NOS	530 (46)	83 (7)	470 (47)	72 (7)	60 (39)	11 (7)
Fatigue	477 (41)	86 (7)	396 (39)	71 (7)	81 (52)	15 (10)
Peripheral neuropathiesRepresents High Level Term Peripheral Neuropathies NEC	443 (38)	129 (11)	359 (36)	110 (11)	84 (54)	19 (12)
Thrombocytopenia	369 (32)	295 (25)	344 (34)	283 (28)	25 (16)	12 (8)
Vomiting NOS	321 (28)	44 (4)	286 (28)	40 (4)	35 (23)	4 (3)
Constipation	296 (25)	17 (1)	244 (24)	14 (1)	52 (34)	3 (2)
Pyrexia	249 (21)	16 (1)	233 (23)	15 (1)	16 (10)	1 (<1)
Anorexia	227 (20)	19 (2)	205 (20)	16 (2)	22 (14)	3 (2)
Anemia NOS	209 (18)	65 (6)	190 (19)	63 (6)	19 (12)	2 (1)
Headache NOS	175 (15)	8 (<1)	160 (16)	8 (<1)	15 (10)	0
Neutropenia	172 (15)	121 (10)	164 (16)	117 (12)	8 (5)	4 (3)
Rash NOS	156 (13)	8 (<1)	120 (12)	4 (<1)	36 (23)	4 (3)
Paresthesia	147 (13)	9 (<1)	136 (13)	8 (<1)	11 (7)	1 (<1)
Dizziness (excl vertigo)	129 (11)	13 (1)	101 (10)	9 (<1)	28 (18)	4 (3)
Weakness	124 (11)	31 (3)	106 (11)	28 (3)	18 (12)	3 (2)

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

Gastrointestinal Toxicity

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

Thrombocytopenia

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

[see Warnings and Precautions (5.7)]

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

Peripheral Neuropathy

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

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

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

Hypotension

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

Neutropenia

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

Asthenic Conditions (Fatigue, Malaise, Weakness, Asthenia)

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

Pyrexia

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

Herpes Virus Infection

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

Retreatment in Relapsed Multiple Myeloma

A single-arm trial was conducted in 130 patients with relapsed multiple myeloma to determine the efficacy and safety of retreatment with intravenous bortezomib. The safety profile of patients in this trial is consistent with the known safety profile of bortezomib-treated patients with relapsed multiple myeloma as demonstrated in

Tables 10, 11, and 13

; no cumulative toxicities were observed upon retreatment. The most common adverse drug reaction was thrombocytopenia which occurred in 52% of the patients. The incidence of ≥Grade 3 thrombocytopenia was 24%. Peripheral neuropathy occurred in 28% of patients, with the incidence of ≥Grade 3 peripheral neuropathy reported at 6%. The incidence of serious adverse reactions was 12.3%. The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), and herpes zoster and pneumonia (1.5% each).

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

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

Additional Adverse Reactions from Clinical Studies

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

Blood and Lymphatic System Disorders:

Anemia, disseminated intravascular coagulation, febrile neutropenia, lymphopenia, leukopenia

Cardiac Disorders:

Angina pectoris, atrial fibrillation aggravated, atrial flutter, bradycardia, sinus arrest, cardiac amyloidosis, complete atrioventricular block, myocardial ischemia, myocardial infarction, pericarditis, pericardial effusion,

Torsades de pointes

, ventricular tachycardia

Ear and Labyrinth Disorders:

Hearing impaired, vertigo

Eye Disorders:

Diplopia and blurred vision, conjunctival infection, irritation

Gastrointestinal Disorders:

Abdominal pain, ascites, dysphagia, fecal impaction, gastroenteritis, gastritis hemorrhagic, hematemesis, hemorrhagic duodenitis, ileus paralytic, large intestinal obstruction, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, large intestinal perforation, stomatitis, melena, pancreatitis acute, oral mucosal petechiae, gastroesophageal reflux

General Disorders and Administration Site Conditions:

Chills, edema, edema peripheral, injection site erythema, neuralgia, injection site pain, irritation, malaise, phlebitis

Hepatobiliary Disorders:

Cholestasis, hepatic hemorrhage, hyperbilirubinemia, portal vein thrombosis, hepatitis, liver failure

Immune System Disorders:

Anaphylactic reaction, drug hypersensitivity, immune complex mediated hypersensitivity, angioedema, laryngeal edema

Infections and Infestations:

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

Injury, Poisoning and Procedural Complications:

Catheter-related complication, skeletal fracture, subdural hematoma

Investigations:

Weight decreased

Metabolism and Nutrition Disorders:

Dehydration, hypocalcemia, hyperuricemia, hypokalemia, hyperkalemia, hyponatremia, hypernatremia

Musculoskeletal and Connective Tissue Disorders:

Arthralgia, back pain, bone pain, myalgia, pain in extremity

Nervous System Disorders:

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

Psychiatric Disorders:

Agitation, anxiety, confusion, insomnia, mental status change, psychotic disorder, suicidal ideation

Renal and Urinary Disorders:

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

Respiratory, Thoracic and Mediastinal Disorders:

Acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbated, cough, dysphagia, dyspnea, dyspnea exertional, epistaxis, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress, pulmonary hypertension

Skin and Subcutaneous Tissue Disorders:

Urticaria, face edema, rash (which may be pruritic), leukocytoclastic vasculitis, pruritus

Vascular Disorders:

Cerebrovascular accident, cerebral hemorrhage, deep venous thrombosis, hypertension, peripheral embolism, pulmonary embolism, pulmonary hypertension

]

Bortezomib for Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib products.

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