INDICATIONS AND USAGE:

Multiple Myeloma

Bortezomib for injection is indicated for the treatment of adult patients with multiple myeloma.

Mantle Cell Lymphoma

Bortezomib for injection is indicated for the treatment of adult patients with mantle cell lymphoma who have received at least 1 prior therapy.

DOSAGE FORMS AND STRENGTHS:

For injection: Each single-dose vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose.

DOSAGE AND ADMINISTRATION:

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

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.

Retreatment for multiple myeloma: May retreat starting at the last tolerated dose.

Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment. Dose must be individualized to prevent overdose.

WARNINGS AND PRECAUTIONS:

Peripheral Neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.

Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

Cardiac Toxicity: Worsening of and development of cardiac failure has occurred. Closely monitor patients with existing heart disease or risk factors for heart disease.

Pulmonary Toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms and consider interrupting VELCADE therapy.

Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected.

Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.

Thrombocytopenia and Neutropenia: Monitor complete blood counts regularly throughout treatment.

Tumor Lysis Syndrome: Closely monitor patients with high tumor burden.

Hepatic Toxicity: Monitor hepatic enzymes during treatment. Interrupt VELCADE therapy to assess reversibility.

Thrombotic Microangiopathy: Monitor for signs and symptoms. Discontinue VELCADE if suspected.

Embryo-fetal Toxicity: VELCADE can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to avoid pregnancy.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with bortezomib.

Bortezomib showed clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames test) and in vivo micronucleus assay in mice.

Fertility studies with bortezomib were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the six month rat toxicity study, degenerative effects in the ovary were observed at doses ≥0.3 mg/m2 (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/m2. Animal Toxicology and/or Pharmacology

Cardiovascular Toxicity

Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses ≥1.2 mg/m2 induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. In a repeated dosing toxicity study in the monkey, myocardial hemorrhage, inflammation, and necrosis were also observed.

Chronic Administration

In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for two weeks followed by one week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed.

DRUG INTERACTIONS

Effects of Other Drugs on VELCADE

Strong CYP3A4 Inducers

Coadministration with a strong CYP3A4 inducer decreases the exposure of bortezomib which may decrease VELCADE efficacy. Avoid coadministration with strong CYP3A4 inducers.

Strong CYP3A4 Inhibitors

Coadministration with a strong CYP3A4 inhibitor increases the exposure of bortezomib which may increase the risk of VELCADE toxicities. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors.

Drugs Without Clinically Significant Interactions with VELCADE

No clinically significant drug interactions have been observed when VELCADE was coadministered with dexamethasone, omeprazole, or melphalan in combination with prednisone.