CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`021602Orig1s027
`
`Velcade
`
`Millennium Pharmaceuticals, Inc.
`
`
`Trade Name:
`
`bortezomib
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`01/23/2012
`
` VELCADE is a proteasome inhibitor indicated for:
`• treatment of patients with multiple myeloma
`• treatment of patients with mantle cell lymphoma who have
`received at least 1 prior therapy
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`021602Orig1s027
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
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`X
`X
`
`
`X
`X
`X
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`X
`X
`
`X
`
`
`X
`X
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`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`021602Orig1s027
`
`APPROVAL LETTER
`
`
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`
`
`

`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`
` NDA 021602/S-027
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`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`Millennium Pharmaceuticals, Inc.
`Attention: Eileen Bedell, M.P.H
`Director, Regulatory Affairs
`40 Landsdowne Street
`Cambridge, MA 02139
`
`Dear Ms. Bedell:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated March 23, 2011,
`received March 23, 2011, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for VELCADE® (bortezomib) for Injection.
`
`We acknowledge receipt of your amendments dated April 7 and 29, June 30, July 22, September
`14 and 20, October 4 and 13, November 15 and 16, and December 22, 2011.
`
`This “Prior Approval” supplemental new drug application provides for a subcutaneous route of
`administration as an alternative to the existing intravenous route of administration.
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`
`CONTENT OF LABELING
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling, with the addition of any labeling changes
`in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes
`not included in the enclosed labeling.
`
`Information on submitting SPL files using eLIST may be found in the guidance for industry
`
`titled “SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Reference ID: 3075367
`
`

`

`
`
` NDA 021602/S-027
`Page 2
`
`
`Also within 14 days, amend all pending supplemental applications for this NDA, including CBE
`supplements for which FDA has not yet issued an action letter, with the content of labeling
`[21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the changes approved in this
`supplemental application, as well as annual reportable changes and annotate each change. To
`facilitate review of your submission, provide a highlighted or marked-up copy that shows all
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annual report date(s).
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`
`Submit final printed carton and container labels that are identical to the enclosed carton and
`immediate container labels as soon as they are available, but no more than 30 days after they are
`printed.
`
`Please submit these labels electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Product
`Correspondence – Final Printed Carton and Container Labels for approved
`NDA 021602/S-027.” Approval of this submission by FDA is not required before the labeling is
`used.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`Reference ID: 3075367
`
`

`

`
`
` NDA 021602/S-027
`Page 3
`
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`You must submit final promotional materials and package insert(s), accompanied by a Form
`
`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
`
`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Amy Baird, Regulatory Project Manager, at (301) 796-4969.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`Edvardas Kaminskas, M.D.
`Acting Deputy Director
`Division of Hematology Products
`Office of Hematology and Oncology Products
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`
`
`
`
`Reference ID: 3075367
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`EDVARDAS KAMINSKAS
`01/23/2012
`
`Reference ID: 3075367
`
`

`

` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`021602Orig1s027
`
`LABELING
`
`
`
`
`
`

`

`HIGHLIGHTS OF PRESCRIBING INFORMATION
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`These highlights do not include all the information needed to use
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`VELCADE safely and effectively. See full prescribing information for
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`VELCADE.
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`VELCADE® (bortezomib) for Injection
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`Initial U.S. Approval: 2003
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`-------------------------------RECENT MAJOR CHANGES---------------------
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`Dosage and Administration
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`
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`Management of Peripheral Neuropathy (2.5)
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`Administration Precautions (27)
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`Reconstitution/Preparation for Intravenous and Subcutaneous
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`Administration (2.8)
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`Warnings and Precautions, Peripheral Neuropathy (5.1)
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`1/2012
`1/2012
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`1/2012
`1/2012
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`------------------------------INDICATIONS AND USAGE
`
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`VELCADE is a proteasome inhibitor indicated for:
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`0 treatment of patients with multiple myeloma ( 1.1)
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`0 treatment of patients with mantle cell lymphoma who have received at
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`least 1 prior therapy (1.2)
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`----------------------DOSAGE AND ADMINISTRATION---------------------
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`The recommended dose of VELCADE is 1.3 mg/m2 administered either as a
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`3 to 5 second bolus intravenous injection or subcutaneous injection. (2.1,
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`2.3)
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`--------------------DOSAGE FORMS AND STRENGTHS--------------------
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`1 single-use vial contains 3.5 mg of bortezomib. Dose must be
`o
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`individualized to prevent overdose. (3)
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`--------------------------CONTRAlNDICATIONS---------------------------------
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`o VELCADE is contraindicated in patients with hypersensitivity to
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`bortezomib, boron, or mannitol. (4)
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`o VELCADE is contraindicated for intrathecal administration. (4)
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`0 Hypotension can occur. Use caution when treating patients receiving
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`antihypertensives, those with a history of syncope, and those who are
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`dehydrated. (5 .2)
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`o Closely monitor patients with existing heart disease or risk factors for
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`heart disease. (5.3)
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`- Acute diffuse infiltrative pulmonary disease has been reported. (5 .4)
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`o Nausea, diarrhea, constipation, and vomiting have occurred and may
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`require use of antiemetic and antidiarrheal medications or fluid
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`replacement. (5.6)
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`o Thrombocytopenia or neutropenia can occur; complete blood counts
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`should be regularly monitored throughout treatment. (5.7)
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`0 Tumor Lysis Syndrome (5.8), Reversible Posterior Leukoencephalopathy
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`Syndrome (5.5), and acute hepatic failure (5.9) have been reported.
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`0 Women should avoid becoming pregnant while being treated with
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`VELCADE. Pregnant women should be apprised of the potential harm to
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`the fetus. (5.11, 8.1)
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`--------------------------ADVERSE REACTIONS---------------------------------
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`Most commonly reported adverse reactions (incidence Z 30%) in clinical
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`studies include asthenie conditions, diarrhea, nausea, constipation,
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`peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric
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`disorders, anorexia and decreased appetite, neutropenia, neuralgia,
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`leukopenia and anemia. (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Millennium
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`Pharmaceuticals at 1-866 VELCADE or FDA at 1—800-FDA-1088 or
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`www. (da.g0v/med1vatcl1.
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`--------------------------DRUG INTERACTIONS---------------------------------
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`o Closely monitor patients receiving VELCADE in combination with
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`strong CYP3A4 inhibitors. (7.1)
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`o Concomitant use of strong CYP3A4 inducers is not recommended. (7.3)
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`¥----------,----------USE IN SPECIFIC POPULATIONS------------------------
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`0 Patients with diabetes may require close monitoring of blood glucose and
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`adjustment of anti-diabetic medication. (8.8)
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`o Hepatic Impairnient: Use a lower starting dose for patients with moderate
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`or severe hepatic impairment. (2. 6, 5. 10,87, 12.3)
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`See 17 for PATIENT COUNSELING INFORMATION.
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`Revised: [1/2012]
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`--------------------------WARNINGS AND PRECAUTIONS-------------------
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`0 Peripheral neuropathy, including severe cases, may occur - manage with
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`dose modification or discontinuation. (2. 5) Patients with preexisting
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`severe neuropathy should be treated with VELCADE only after careful
`risk-benefit assessment. (2. 5: 5 1)
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`FULL PRESCRIBING INFORMATION: CONTENTS*
`6.2 Postmarketing Experience
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`7 DRUG INTERACTIONS
`INDICATIONS AND USAGE
`1
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`7.1 CYP3A4 inhibitors
`1.1 Multiple Myeloma
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`' 7.2 CYP2C19 inhibitors
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`' 1.2 Mantle Cell Lymphoma
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`7.3 CYP3A4 inducers
`2 DOSAGE AND ADMINISTRATION
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`7.4 Dexamethasone
`2.1 Dosage in Previously Untreated Multiple Myeloma
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`7.5 Melphalan-Prednisone
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`2.2 Dose Modification Guidelines for Combination Therapy with
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`8 USE IN SPECIFIC POPULATIONS
`VELCADE, Melphalan and Prednisone
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`8.1 Pregnancy
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`2.3 Dosage in Relapsed Multiple Myeloma and Mantle Cell
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`8.3 Nursing Mothers
`Lymphoma
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`_8.4 Pediatric Use
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`2.4 .Dose Modification Guidelines for Relapsed Multiple Myeloma
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`85 Geriatric Use
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`and Mantle Cell Lymphoma
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`8.6 Patients with Renal Impairment
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`2.5 Management of Peripheral Neuropathy
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`8.7 Patients with Hepatic Impairment
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`2.6 Dosagein Patients with Hepatic Impairment
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`2.7 Administration Precautions
`8.8 Patients with Diabetes
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`10 OVERDOSAGE
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`2.8 Reconstitution/Preparation for Intravenous and Subcutaneous
`11 DESCRIPTION
`Administration
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`12 CLINICAL PHARMACOLOGY
`3 DOSAGE FORMS AND STRENGTHS
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`12.1 Mechanism of Action
`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
`12.2 Pharmacodynamics
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`112.3 Pharmacokinetics
`5.] Peripheral Neuropathy
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`l3 NONCLINICAL TOXICOLOGY
`5.2 Hypotension
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`5.3 Cardiac Disorders
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`5.4 Pulmonary Disorders
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`13.2 Animal Toxicology and/or Pharmacology
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`l4 CLINICAL STUDIES
`5.5 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)
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`5.6 Gastrointestinal Adverse Events
`14.1 Multiple Myeloma
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`14.2 Mantle Cell Lymphoma
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`5.7 Thrombocytopenia/Neutropenia
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`15 REFERENCES
`5.8 Tumor Lysis Syndrome
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`16 HOW SUPPLIED/STORAGE AND HANDLING
`5.9 Hepatic Events
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`l7 PATIENT COUNSELING INFORMATION
`5.10 Hepatic Impairment
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`5.11 Use in Pregnancy
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`*Sections or subsections omitted from the full prescribing information are
`6 ADVERSE REACTIONS
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`not listed
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`6.1 Clinical Trials Safety Experience
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`Reference ID: 3075367
`Reference ID: 3075367
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`1/35
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`

`

`
`
`FULL PRESCRIBING INFORMATION
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`1
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`INDICATIONS AND USAGE
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`1.1 Multiple Myeloma
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`VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.
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`1.2 Mantle Cell Lymphoma
`VELCADE (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who
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`have received at least 1 prior therapy.
`2 DOSAGE AND ADMINISTRATION
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`The recommended starting dose of VELCADE is 1.3 mg/mz. VELCADE may be administered intravenously at
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`a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL [see
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`Reconstitution/Preparationfor Intravenous and Subcutaneous Administration (2.8)]. When administered
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`intravenously, VELCADE is administered as a 3 to 5 second bolus intravenous injection. VELCADE is for
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`intravenous or subcutaneous use only. VELCADE should not be administered by any other route.
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`Because each route of administration has a different reconstituted concentration, caution should be used
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`when calculating the volume to be administered.
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`2.1 Dosage in Previously Untreated Multiple Myeloma
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`11
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`29
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`32
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`rest
`period
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`rest
`period
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`VELCADE (bortezomib) for Injection is administered in combination with oral melphalan and oral prednisone
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`for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, VELCADE is administered twice weekly
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`(days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, VELCADE is administered once weekly (days 1, 8, 22 and
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`29). At least 72 hours should elapse between consecutive doses of VELCADE.
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`le M eloma
`Table 1: Dosa e Re imen for Patients with Previous] Untreated Multi
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Day
`Day Day2 Day rest
`Day Day Day Day rest
`
`
`
`
`
`
`
`
`
`
` VELCADE
`
`
`
`
`
`
`
`
`
`
`
`period 22
`25
`
`(1.3 mg/mz)
`
`
`
`
`
`
`
`Day Day Day Day
`Melphalan(9 mg/m )
`
`
`
`
`
`
`
`1
`2
`3
`4
`Prednisone(60 mg/m2)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Once Weekly VELCADE (Cycles 5-9 when used in combination with Melphalan and
`
`Prednisone
`
`
`_—---
`
`
`
`
`
`
`
`
`
`
`
`
`
` VELCADE
`
`
`Day
`Day
`Day
`rest
`Day
`
`
`
`
`
`period 22
`29
`
`(1.3 mg/mz)
`
`
`
`
`
`
`
`Melphalan(9 mg/mz) Day Day Day Day
`
`
`
`
`
`
`
`2
`l
`2
`3
`4
`
`Prednisone(60 mg/m )
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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:
`o Platelet count should be at least 70 x 109/L and the absolute neutrophil count (ANC) should be at
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`least 1 0 x 10%
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`o Non-hematological toxicities should have resolved to Grade 1 or baseline
`
`
`
`
`
`
`
`Reference ID: 3075367
`Reference ID: 3075367
`
`2/35
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`Table 2: Dose Modifications during Cycles of Combination VELCADE, Melphalan and Prednisone
`
`Therapy
`
`
`
`Dose modification or delay
`
`. T
`
`
`
`
`
`oxicity
`
`
`
`
`
`Hematological toxicity during a cycle:
`
`
`
`
`
`
`If prolonged Grade 4 neutropenia or
`
`
`
`thrombocytopenia, or thrombocytopenia with
`
`
`
`
`
`
`
`bleeding is observed in the previous cycle
`If platelet count is not above 30 x 109/L or
`
`
`
`
`
`
`
`
`
`ANC15 not above 075 x 109/L on a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VELCADE closing day (other than day 1)
`
`
`
`
`
`If several VELCADE doses in consecutive
`
`
`
`
`
`
`cycles are withheld due to toxicity
`V
`
`
`
`
`
`
`
`
`
`Consider reduction of the melphalan dose by
`
`
`
`
`
`25% in the next cycle
`
`
`
`
`
`VELCADE dose should be withheld
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VELCADE dose should be reduced by 1 dose
`
`
`
`
`
`
`
`
`level (fr20m 1.3 mg/m: to 1 mg/mz, or from
`
`
`1mg/m2 t00.27mg/m)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Grade 3 or higher 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 withone dose level reduction (from
`
`
`
`
`
`
`
`
`
`1.3 mg/m: to l mg/mz, 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.
`
`
`
`
`
`
`
`
`
`For information concerning melphalan and prednisone, see manufacturer's prescribing information.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`For dose modifications guidelines for peripheral neuropathy see Management of Peripheral Neuropathy section
`
`"(2.5).
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.3 Dosage in Relapsed Multiple Myeloma and Mantle Cell Lymphoma
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VELCADE (1.3 mg/mz/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, 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 Clinical Studies section (14) for a description ofdose
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 Warnings and Precautions (5)] Once the symptoms of
`the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (13 mg/mz/dose
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`reduced to 1 mg/mz/dose; 1 mg/mZ/dose reduced to 0.7 mg/mz/dose).
`
`
`
`
`
`-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`For dose modifications guidelines for peripheral neuropathy see Management of Peripheral Neuropathy section
`
`(2.5).
`
`
`
`
`
`
`
`
`2.5 Management of Peripheral Neuropathy '
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Starting VELCADE 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 VELCADE only
`
`
`
`
`after careful risk-benefit assessment.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Patients experiencing new or worsening peripheral neuropathy during VELCADE 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 VELCADE-related neuropathic pain
`
`
`
`
`
`
`and/or peripheral neuropathy see Table 3.
`
`
`
`Reference ID: 3075367
`Reference ID: 3075367
`
`3/35
`
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`Table 3: Recommended Dose Modification for VELCADE related Neuropathic Pain and/or Peripheral
`
`
`
`
`Sensory or Motor Neuropathy
`
`
`
`
`
`
`
`
`
`
`Severity of Peripheral Neuropathy
`Modification of Dose and Regimen
`
`
`
`Signs and Symptoms*
`
`
`
`
`
`
`Grade 1 (asymptomatic; loss of deep tendon
`
`
`
`
`
`
`
`reflexes or paresthesia) without pain or loss
`
`
`of function
`__—.'_—.—__———___—__—__—‘——2_—-__
`
`
`
`
`
`
`
`
`
`
`
`
`
`Grade 1 w1th pa1n or Grade 2 (moderate
`Reduce VELCADE to 1 mg/m
`
`
`
`
`symptoms; limiting instrumental Activities of
`
`
`
`Daily Livin (ADL)**)
`
`
`
`
`
`
`
`
`Grade 2 with pain or Grade 3 (severe
`
`
`
`
`
`symptoms; limiting self care ADL ***)
`
`
`
`
`
`
`No action
`
`
`
`
`
`
`
`
`
`
`
`
`Withhold VELCADE therapy until toxicity
`
`
`
`
`
`
`resolves. When toxicity resolves reinitiatze with a
`
`
`
`
`
`
`
`reduced dose of VELCADE at 0.7 mg/m2 once
`
`
`per week.
`
`
`
`
`
`
`Discontinue VELCADE
`Grade 4 (life-threatening consequences;
`
`
`
`
`urgent intervention indicated)
`
`
`
`
`
`
`
`
`
`*Grading based on NCI Common Terminology Criteria CTCAE v4.0
`
`
`
`
`
`
`
`
`
`
`
`
`
`**Instrumenta1ADL: 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`2.6 Dosage in Patients with Hepatic Impairment I
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 Warnings and Precautions (5.10), 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)
`Modification of Starting Dose
`I
`
`
`
`
`
`
`
`
`
`Levels
`_
`'
`-
`'
`
`
`
`
`
`
`
`Morethan3XULN- 1.0mg/morfurtherdosereductlont00.5
`
`
`
`
`
`
`
`Less than or equal to
`
`
`1.0x ULN
`
`
`
`More than ULN
`’
`
`
`
`None
`
`
`
`Any
`
`
`
`.
`
`None
`
`
`
`'
`
`
`
`More than
`
`1.0x—1.5x ULN
`
`
`
`
`
`More than 1. 5x—3x
`
`ULN
`
`
`
`
`
`
`
`
`
`
`
`Mild
`
`
`
`
`
`
`Moderate
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reduce VELCADE to 0.7 mg/m in the
`
`
`
`
`
`
`first cyclez. Consider dose escalation to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`mg/m 1n subsequent cycles based on
`
`
`
`
`patient tolerability.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Abbreviations: SGOT——~ serum glutamic oxaloacetic transaminase;
`
`
`
`
`
`
`
`
`
`AST = aspartate aminotransferase; ULN = upper limit of the normal range.
`
`
`
`Reference ID: 3075367
`Reference ID: 3075367
`
`4/35
`
`
`

`

`
`
`2.7 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.
`[see Reconstitution/Preparation for Intravenous and Subcutaneous
`
`
`Administration (2.8)]
`'
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 VELCADE administration subcutaneously, a less concentrated
`
`
`
`
`
`
`
`
`
`
`
`
`‘ VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see
`
`
`
`
`
`
`
`
`
`
`Reconstitution/Preparation for Intravenous and Subcutaneous Administration (2. 8) and follow reconstitution
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`instructions for 1 mg/mL]. Alternatively, the intravenous route of administration should be considered [see
`
`
`
`
`
`
`
`
`Reconstitution/Preparation for Intravenous and Subcutaneous Administration (2.8)]
`
`
`
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VELCADE is an antineoplastic. Procedures for proper handling and disposal should be considered.
`
`
`
`
`Supplied/Starage and Handling (16)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`In clinical trials of VELCADE intravenous, local skin irritation was reported in 5% of patients, but
`
`
`
`
`
`
`
`
`
`
`
`
`extravasation of VELCADE was not associated with tissue damage. In a clinical trial of subcutaneous
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`VELCADE, a local reaction was reported in 6% of patients as an adverse event, mostly redness.
`
`
`
`
`
`
`[see How
`
`
`
`
`
`
`
`
`
`
`2.8 Reconstitution/Preparation for Intravenous and Subcutaneous Administration
`Proper aseptic technique 'should be used. Reconstitute only with 0.91% 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 [see Administration Precautions (2.7)]
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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 5):
`
`
`
`
`
`
`
`
`
`
`Table 5: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous
`
`Administration
`
`
`
`
`
`
`
`
`
`
`
`
`Route of
`administration
`
`
`
`Bortezomib
`
`
`(mg/vial)
`
`
`
`
`
`
`
`
`
`
`
`
`
`Diluent
`
`(0.9% Sodium
`
`Chloride
`
`
`
`
`
`
`
`
`
`
`
`m_/mL
`
`
`
`
`Final Bortezomib
`
`concentration
`
`
`
`
`
`,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`After determining patient body surface area (BSA) in square meters, use the following equations to calculate the
`
`
`
`
`
`
`
`
`
`total volume (mL) of reconstituted VELCADE to be administered:
`
`
`
`
`0
`
`
`
`
`
`Intravenous Administration [1 mg/mL concentration]
`
`
`
`
`
`
`
`VELCADE dose (mg/m2) x patient BSA (m2)
`
`
`
`
`1 mg/mL
`
`
`
`
`
`
`
`= Total VELCADE volume (mL) to be administered
`
`
`
`
`
`
`
`
`0 Subcutaneous Administration [2.5 mg/mL concentration]
`
`
`
`
`
`
`
`VELCADE dose (mg/m2) x patient BSA (H12)
`
`
`
`
`25 mg/mL
`
`
`
`
`
`
`
`= Total VELCADE volume (mL) to be administered
`
`
`
`Reference ID: 3075367
`Reference ID: 3075367
`
`5/35 .
`
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Stickers that indicate the route of administration are provided with each VELCADE vial. These stickers should
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`be placed directly on the syringe of VELCADE Once VELCADE is prepared to help alert practitioners of the
`
`
`
`
`
`
`correct route of administration for VELCADE.
`.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Stability: Unopened vials of VELCADE are stable until the date indicated on the package when stored in the
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`original package protected from light.
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`VELCADE contains no antimicrobial preservative. Reconstituted VELCADE should be administered within 8
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`hours of preparation. When reconstituted as directed, VELCADE may be stored at 25°C (77°F). The
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`reconstituted material may be stored in the original vial and/or the syringe prior to administration. The product
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`may be stored for up to 8 hours in a syringe; however, total storage time for the reconstituted material must not
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`exceed 8 hours when exposed to normal indoor lighting.
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`3 DOSAGE FORMS AND STRENGTHS
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`Each single-use vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized powder.
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`4 CONTRAINDICATIONS
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`VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.
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`VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal
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`administration of VELCADE.
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`5 WARNINGS AND PRECAUTIONS
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`VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic
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`therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE.
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`5.1 Peripheral Neuropathy
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`VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe
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`sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness,
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`pain or a burning feeling in the feet or' hands) and/or signs of peripheral neuropathy may experience worsening
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`peripheral neuropathy (including 2 Grade 3) during treatment with VELCADE. Patients should be monitored
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`for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort,
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`neuropathic pain or weakness.
`In- the Phase 3 relapsed multiple myeloma trial comparing VELCADE
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`subcutaneous vs. intravenous the incidence of Grade 2 2 peripheral neuropathy events was 24% for
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