Bortezomib

VELCADE is a proteasome inhibitor indicated for: treatment of adult patients with multiple myeloma treatment of adult patients with mantle cell lymphoma

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.

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/m 2 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.

VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. Contraindicated for intrathecal administration.

Peripheral Neuropathy: Manage with dose modification or discontinuation. Patients with pre-existing 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.

The following clinically significant adverse reactions are also discussed in other sections of the labeling: Peripheral Neuropathy Hypotension Cardiac Toxicity Pulmonary Toxicity Posterior Reversible Encephalopathy Syndrome (PRES) Gastrointestinal Toxicity Thrombocytopenia/Neutropenia Tumor Lysis Syndrome Hepatic Toxicity Thrombotic Microangiopathy 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.

Strong CYP3A4 Inhibitors: Closely monitor patients with concomitant use. Strong CYP3A4 Inducers: Avoid concomitant use. 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.

Unopened vials may be stored at controlled room temperature 25°C (77°F), excursions permitted from 15°C to 30°C (59°F to 86°F). Retain in original package to protect from light.