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VELCADE (bortezomib) for injection, for subcutaneous

2015-10-08 03:46:34 来源: 作者: 【大中小】浏览:923次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use VELCADE safely and effectively. See full prescribing information for VELCADE.

VELCADE ® (bortezomib) for injection, for subcutaneous or intravenous use
Initial U.S. Approval: 2003
RECENT MAJOR CHANGES

Indications and Usage (1.2)	10/2014
Dosage and Administration (2)	10/2014
Warnings and Precautions, Thrombocytopenia/Neutropenia (5.7)	10/2014

INDICATIONS AND USAGE

VELCADE is a proteasome inhibitor indicated for:

treatment of patients with multiple myeloma (1.1)
treatment of patients with mantle cell lymphoma (1.2)

DOSAGE AND ADMINISTRATION

For subcutaneous or intravenous use only (2.1)
The recommended starting dose of VELCADE is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection. (2.2, 2.4, 2.6)
Retreatment for multiple myeloma: May retreat starting at the last tolerated dose. (2.6)
Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. (2.8)
Dose must be individualized to prevent overdose (2.10)

DOSAGE FORMS AND STRENGTHS

Single-use vial contains 3.5 mg of bortezomib as lyophilized powder. (3)

CONTRAINDICATIONS

Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. (4)
Contraindicated for intrathecal administration. (4)

WARNINGS AND PRECAUTIONS

Peripheral Neuropathy: Manage with dose modification or discontinuation. (2.7) Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. (2.7, 5.1)
Hypotension: Use caution when treating patients taking anti-hypertensives, with a history of syncope, or with dehydration. (5.2)
Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. (5.3)
Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. (5.4)
Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. (5.5).
Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. (5.6)
Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. (5.7)
Tumor Lysis Syndrome: Closely monitor patients with high tumor burden (5.8).
Hepatic Toxicity: Monitor hepatic enzymes during treatment.(5.9).
Embryo-fetal Risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. (5.10)

ADVERSE REACTIONS

Most commonly reported adverse reactions (incidence ≥ 20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Millennium Pharmaceuticals at 1-866 VELCADE or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Co-administration with strong CYP3A4 inhibitors can increase VELCADE exposure. Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. (7.1)
Co-administration with strong CYP3A4 inducers can decrease VELCADE exposure. Avoid concomitant use of strong CYP3A4 inducers. (7.3)

USE IN SPECIFIC POPULATIONS

Patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication. (8.8)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 9/2015

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

1.2 Mantle Cell Lymphoma

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Guidelines

2.2 Dosage in Previously Untreated Multiple Myeloma

2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone

2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

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

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

2.7 Dose Modifications for Peripheral Neuropathy

2.8 Dosage in Patients with Hepatic Impairment

2.9 Administration Precautions

2.10 Reconstitution/Preparation for Intravenous and Subcutaneous Administration

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

5.2 Hypotension

5.3 Cardiac Toxicity

5.4 Pulmonary Toxicity

5.5 Posterior Reversible Encephalopathy Syndrome (PRES)

5.6 Gastrointestinal Toxicity

5.7 Thrombocytopenia/Neutropenia

5.8 Tumor Lysis Syndrome

5.9 Hepatic Toxicity

5.10 Embryo-fetal Risk

6 ADVERSE REACTIONS

6.1 Clinical Trials Safety Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 CYP3A4 inhibitors

7.2 CYP2C19 inhibitors

7.3 CYP3A4 inducers

7.4 Dexamethasone

7.5 Melphalan-Prednisone

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Patients with Renal Impairment

8.7 Patients with Hepatic Impairment

8.8 Patients with Diabetes

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Multiple Myeloma

14.2 Mantle Cell Lymphoma

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*: Sections or subsections omitted from the full prescribing information are not listed.

1 INDICATIONS AND USAGE

1.1 Multiple Myeloma

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

1.2 Mantle Cell Lymphoma

VELCADE is indicated for the treatment of patients with mantle cell lymphoma.

2 DOSAGE AND ADMINISTRATION

2.1 General Dosing Guidelines

The recommended starting dose of VELCADE is 1.3 mg/m2. VELCADE may be 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)].

VELCADE retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with VELCADE and who have relapsed at least 6 months after completing prior VELCADE treatment. Treatment may be started at the last tolerated dose [see Dosage and Administration (2.6)].

When administered intravenously, VELCADE is administered as a 3 to 5 second bolus intravenous injection. VELCADE is for intravenous or subcutaneous use only. VELCADE should not be administered by any other route.

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

2.2 Dosage in Previously Untreated Multiple Myeloma

VELCADE is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, 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

2.3 Dose Modification Guidelines for VELCADE When Given in Combination with Melphalan and Prednisone

Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone:

Platelet count should be at least 70 × 109/L and the absolute neutrophil count (ANC) should be at least 1.0 × 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 is not above 30 × 109/L or ANC is not above 0.75 × 109/L on a VELCADE dosing day (other than day 1)

Withhold VELCADE dose

If several VELCADE doses in consecutive cycles are withheld due to toxicity

Reduce VELCADE dose by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)

Grade 3 or hig