Velcade-Generic, bortezomib 1mg x 1 vial

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

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

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 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 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.

2.5 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 (16.]

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

2.6 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.

5 WARNINGS AND PRECAUTIONS

Velcade should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with Velcade.

5.1 Use in Pregnancy

Pregnancy Category D

Women of childbearing potential should avoid becoming pregnant while being treated with Velcade. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. [see Use in Specific Populations (8.1)]

5.2 Peripheral Neuropathy

Velcade treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with Velcade. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of Velcade [see Dosage and Administration (2.2, 2.4)]. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies [see Adverse Reactions (6)]. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

5.3 Hypotension

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. [see Adverse Reactions(6)]

5.4 Cardiac Disorders

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the Velcade and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the Velcade and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

5.5 Pulmonary Disorders

There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving Velcade. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2g/m2 per day) by continuous infusion with daunorubicin and Velcade for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy.

There have been reports of pulmonary hypertension associated with Velcade administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

5.6 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)

There have been reports of RPLS in patients receiving Velcade. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue Velcade. The safety of reinitiating Velcade therapy in patients previously experiencing RPLS is not known.

5.7 Gastrointestinal Adverse Events

Velcade treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

5.8 Thrombocytopenia/Neutropenia

Velcade is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 4. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the Velcade (4%) and dexamethasone (5%) arms. Platelet count should be monitored prior to each dose of Velcade. Patients experiencing thrombocytopenia may require change in the dose and schedule of Velcade [see Table 2 and Dosage and Administration (2.4)]. There have been reports of gastrointestinal and intracerebral hemorrhage in association with Velcade. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

5.9 Tumor Lysis Syndrome

Because Velcade is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

5.10 Hepatic Events

Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of Velcade. There is limited re-challenge information in these patients.

Patients with Hepatic Impairment: Bortezomib is metabolized by liver enzymes and bortezomib clearance may decrease in patients with hepatic impairment. These patients should be closely monitored for toxicities when treated with Velcade. [Use In Specific Populations (8.7)]

6 ADVERSE REACTIONS

The following adverse reactions are also discussed in other sections of the labeling:

• Peripheral Neuropathy [see Warnings and Precautions (5.2); Dosage and Administration (Table 3)]
• Hypotension [see Warnings and Precautions (5.3)]
• Cardiac Disorders [see Warnings and Precautions (5.4)]
• Pulmonary Disorders [see Warnings and Precautions (5.5)]
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS) [see Warnings and Precautions (5.6)]
• Gastrointestinal Adverse Events [see Warnings and Precautions (5.7)]
• Thrombocytopenia/Neutropenia [see Warnings and Precautions (5.8)]
• Tumor Lysis Syndrome [see Warnings and Precautions (5.9)]
• Hepatic Events [see Warnings and Precautions (5.10)]