Bortezomib - Velcade®

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Usual Diluents

Dilution Data

The recommended dose of VELCADE is 1.3 mg/m2 administered as a 3 to 5 second bolus intravenous injection. Dose adjustment may be used to manage adverse events that occur during treatment.

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.

Reconstitute with 3.5 mL of 0.9% Sodium Chloride resulting in a final concentration of 1 mg/mL of bortezomib. The reconstituted product should be a clear and colorless solution.

Stability: Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light. VELCADE contains no antimicrobial preservative. Reconstituted VELCADE should be administered within 8 hours of preparation. When reconstituted as directed, VELCADE 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.

Updates:
Stability of unused reconstituted bortezomib in original manufacturer vials. Soruce: https://www.ncbi.nlm.nih.gov/pubmed/20926455

CONCLUSION: Unused reconstituted bortezomib is stable for up to 15 days stored at 4°C in the original manufacturer vial. Such use of bortezomib may improve cost efficiency by reducing bortezomib waste.

Stability of Bortezomib 2.5 mg/mL in Vials and Syringes Stored at 4°C and Room Temperature (23°C). Source: https://www.ncbi.nlm.nih.gov/pubmed/24799719

CONCLUSIONS: Bortezomib (3.5 mg in manufacturer's vial) reconstituted with 1.4 mL NS is physically and chemically stable for up to 21 days at 4°C or 23°C when stored in either the manufacturer's original glass vial or a syringe.

Stability / Miscellaneous

WARNINGS/PRECAUTIONS: See Package insert.	INDICATIONS	CONTRAINDICATIONS
DOSAGE AND ADMINISTRATION	ADMINISTRATION / DILUTION	HOW SUPPLIED
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1. INDICATIONS AND USAGE

1.1 Multiple Myeloma
VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

1.2 Mantle Cell Lymphoma
VELCADE (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

2. DOSAGE AND ADMINISTRATION

2.1 Dosage in Previously Untreated Multiple Myeloma
VELCADE (bortezomib) is administered as a 3-5 second bolus IV injection in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, VELCADE is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE.

Table 1-Dosage Regimen for Patients with Previously Untreated Multiple Myeloma

Twice Weekly VELCADE (Cycles 1-4)
Week	1				2		3	4		5		6
VELCADE (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 VELCADE (Cycles 5-9 when used in combination with Melphalan and Prednisone)
Week	1				2		3	4		5		6
VELCADE (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

2.2 Dose Modification Guidelines for Combination Therapy with VELCADE, Melphalan and Prednisone

Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone: Platelet count should be ≥70 x 109/L and the ANC should be ≥ 1.0 x 109/L Non-hematological toxicities should have resolved to Grade 1 or baseline Table 2-Dose Modifications During Cycles of Combination VELCADE, Melphalan and Prednisone Therapy

Toxicity	Dose modification or delay
For information concerning melphalan and prednisone, see manufacturer's prescribing information.
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 ≤30 x 109/L or ANC ≤0.75 x 109/L on a VELCADE dosing day (other than day 1)	VELCADE dose should be withheld
If several VELCADE doses in consecutive cycles are withheld due to toxicity	VELCADE dose should be reduced 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 non-hematological toxicities	VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, VELCADE 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 VELCADE-related neuropathic pain and/or peripheral neuropathy, hold or modify VELCADE as outlined in Table 3.

2.3 Dosage in Relapsed Multiple Myeloma and Mantle Cell Lymphoma
VELCADE (1.3 mg/m2/dose) is administered as a 3 to 5 second bolus intravenous injection 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, VELCADE may be administered on the standard schedule or 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) [see PACKAGE INSERT FOR Clinical Studies section (14) for a description of dose administration during the trials]. At least 72 hours should elapse between consecutive doses of VELCADE.

2.4 Dose Modification Guidelines for Relapsed Multiple Myeloma and Mantle Cell Lymphoma
VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see PACKAGE INSERT FOR Warnings and Precautions (5)]. Once the symptoms of the toxicity have resolved, VELCADE 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 the management of patients who experience VELCADE related neuropathic pain and/or peripheral neuropathy see Table 3. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.

Table 3: Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy

Severity of Peripheral Neuropathy Signs and Symptoms	Modification of Dose and Regimen
Grading based on NCI Common Toxicity Criteria CTCAE v3.0
Grade 1 (paresthesias, weakness and/or loss of reflexes) without pain or loss of function	No action
Grade 1 with pain or Grade 2 (interfering with function but not with activities of daily living)	Reduce VELCADE to 1 mg/m2
Grade 2 with pain or Grade 3 (interfering with activities of daily living)	Withhold VELCADE therapy until toxicity resolves. When toxicity resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m2 and change treatment schedule to once per week.
Grade 4 (sensory neuropathy which is disabling or motor neuropathy that is life threatening or leads to paralysis)	Discontinue VELCADE

2.5 Dosage in Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended VELCADE dose. Patients with moderate or severe hepatic impairment should be started on VELCADE 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 4). [see PACKAGE INSERT FOR Warnings and Precautions (5.11), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]

Table 4: Recommended Starting Dose Modification for VELCADE 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	≤ 1.0x ULN	> ULN	None
	> 1.0x-1.5x ULN	Any	None
Moderate	> 1.5x-3.0x ULN	Any	Reduce VELCADE 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	> 3x ULN	Any

2.6 Administration Precautions
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.

VELCADE is an antineoplastic. Procedures for proper handling and disposal should be considered. [see How Supplied/Storage and Handling]

In clinical trials, local skin irritation was reported in 5% of patients, but extravasation of VELCADE was not associated with tissue damage.

2.7 Reconstitution/Preparation for Intravenous Administration
Proper aseptic technique should be used. Reconstitute with 3.5 mL of 0.9% Sodium Chloride resulting in a final concentration of 1 mg/mL of bortezomib. The reconstituted product should be a clear and colorless solution.

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

VELCADE contains no antimicrobial preservative. Reconstituted VELCADE should be administered within 8 hours of preparation. When reconstituted as directed, VELCADE 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.

3. DOSAGE FORMS AND STRENGTHS
Each single use vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized powder.

4. CONTRAINDICATIONS
VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

HOW SUPPLIED/STORAGE AND HANDLING
VELCADE® (bortezomib) for Injection is supplied as individually cartoned 10 mL vials containing 3.5 mg of bortezomib as a white to off-white cake or powder.

NDC 63020-049-01
3.5 mg single use vial

Unopened vials may be stored at controlled room temperature 25°C (77°F); excursions permitted from 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature]. Retain in original package to protect from light.

Consider handling and disposal of VELCADE according to guidelines issued for cytotoxic drugs, including the use of gloves and other protective clothing to prevent skin contact.

VELCADE, and MILLENNIUM are registered trademarks of Millennium Pharmaceuticals, Inc.

Reference(s)

PRIMARY:
[PACKAGE INSERT DATA] : VELCADE (bortezomib) injection, powder, lyophilized, for solution. Millennium Pharmaceuticals, Inc. 40 Landsdowne Street. Cambridge, MA 02139. Revision Date 12/2009.

Other:
1. Bladé J, Samson D, Reece D, Apperley J, Bjorkstrand B, Gahrton G et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haematopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. British Journal of Haematology 1998;102(5):1115-1123.

2. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM et al. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. Journal of Clinical Oncology 1999; 17 (4):1244.

3. Preventing Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. NIOSH Alert 2004-165.

4. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999.
https://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html.

5. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. 2006;63:1172-1193.

6. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society