Bortezomib (Page 2 of 8)

2.9 Administration Precautions

The drug quantity contained in one vial may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose [see Dosage and Administration (2.10)].

Bortezomib Injection is a hazardous drug. Follow applicable special handling and disposal procedures. ¹

2.10 Instructions for Intravenous Administration

Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of Bortezomib Injection to be administered based on the drug product concentration:

A sticker that indicates the route of administration is provided with each Bortezomib Injection vial. Place this sticker directly on the syringe once the required volume of Bortezomib Injection has been withrdrawn from the vial to help alert the practitioners of the correct route of administration for Bortezomib Injection

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 product should not be used. Discard any unused portion.

Stability

Unopened vials of Bortezomib Injection are stable until the date indicated on the package when stored refrigerated at 2 to 8ºC (36 ºF to 46 °F) in the original package protected from light.

Bortezomib Injection contains no antimicrobial preservative. Unopened vials may be stored at room temperature (20ºC to 25ºC [68 ºF to 77 ºF]) for up to 7 days prior to use.

3 DOSAGE FORMS AND STRENGTHS

Injection: Bortezomib Injection is a clear, colorless to slightly yellow sterile solution available as:

• 3.5 mg/3.5 mL (1 mg/mL) in a ready-to-use single-dose vial
• 3.5 mg/1.4 mL (2.5 mg/mL) in a ready-to-use single-dose vial

4 CONTRAINDICATIONS

Bortezomib Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions [see Adverse Reactions (6.1)].

Bortezomib Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib.

5 WARNINGS AND PRECAUTIONS

5.1 Peripheral Neuropathy

Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with preexisting 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 Bortezomib Injection. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial, the incidence of Grade ≥2 peripheral neuropathy was 39% for intravenous administration. Grade ≥3 peripheral neuropathy occurred in 15% of patients in the intravenous treatment group ​[see Adverse Reactions (6.1)].

Patients experiencing new or worsening peripheral neuropathy during Bortezomib Injection therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.7)]. In the bortezomib vs dexamethasone Phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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. The long- term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

5.2 Hypotension

The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8% ​[see Adverse Reactions (6.1)]. These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

5.3 Cardiac Toxicity

Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. ​[see Adverse Reactions (6.1)] Patients with risk factors for, or existing heart disease should be frequently monitored. In the relapsed multiple myeloma study of bortezomib vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the bortezomib group. In the dexamethasone group the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

5.4 Pulmonary Toxicity

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

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

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

In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib Injection until a prompt and comprehensive diagnostic evaluation is conducted

5.5 Posterior Reversible Encephalopathy Syndrome (PRES)

Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. PRES 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 PRES, discontinue bortezomib. The safety of reinitiating Bortezomib Injection therapy in patients previously experiencing PRES is not known.

5.6 Gastrointestinal Toxicity

Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting [see Adverse Reactions (6.1)] sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib Injection for severe symptoms.

5.7 Thrombocytopenia/Neutropenia

Bortezomib 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 remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.

Monitor complete blood counts (CBC) frequently during treatment with Bortezomib Injection. Measure platelet counts prior to each dose of Bortezomib Injection. Adjust dose/schedule for thrombocytopenia [see Tables 2 and 4, Dosage and Administration (2.6)]. Gastrointestinal and intracerebral hemorrhage has occurred during thrombocytopenia in association with bortezomib. Support with transfusions and supportive care, according to published guidelines.

In the single-agent, relapsed multiple myeloma study of bortezomib vs dexamethasone, the mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia related to pretreatment platelet count is shown in Table 7. The incidence of bleeding (≥Grade 3) was 2% on the bortezomib arm and was <1% in the dexamethasone arm.

In the combination study of bortezomib with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) in previously untreated mantle cell lymphoma patients, the incidence of thrombocytopenia (≥Grade 4) was 32% vs 1% for the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) arm as shown in Table 12. The incidence of bleeding events (≥Grade 3) was 1.7% in the VcR-CAP arm (four patients) and was 1.2% in the R-CHOP arm (three patients).

Platelet transfusions were given to 23% of the patients in the VcR-CAP arm and 3% of the patients in the R-CHOP arm.

The incidence of neutropenia (≥Grade 4) was 70% in the VcR-CAP arm and was 52% in the R-CHOP arm. The incidence of febrile neutropenia (≥Grade 4) was 5% in the VcR-CAP arm and was 6% in the R-CHOP arm. Myeloid growth factor support was provided at a rate of 78% in the VcR-CAP arm and 61% in the R-CHOP arm.