Bortezomib (Page 2 of 8)

2.6 Dosage in Patients with Hepatic Impairment

Do not adjust the starting dose for patients with mild hepatic impairment. Start patients with moderate or severe hepatic impairment at a reduced dose of 0.7 mg/m2 per injection during the first cycle, and consider subsequent dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 based on patient tolerance (see Table 4) [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

Table 4: Recommended Starting Dose Modification for Bortezomib for injection in Patients with Hepatic Impairment

Bilirubin Level SGOT (AST) Levels Modification of Starting Dose
Mild Less than or equal to 1x ULN More than ULN None
More than 1x−1.5x ULN Any None
Moderate More than 1.5x−3x ULN Any Reduce Bortezomib for injection to 0.7 mg/m2 in the first cycle. Consider dose escalation to 1 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.
Severe More than 3x ULN Any

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase;

AST = aspartate aminotransferase; ULN = upper limit of the normal range.

2.7 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 [see Dosage and Administration (2.8)].

Bortezomib for injection is a cytotoxic drug. Follow applicable special handling and disposal procedures.1

2.8 Reconstitution/Preparation for Intravenous Administration

Use proper aseptic technique. Reconstitute only with 0.9% Sodium Chloride Injection, USP. The reconstituted product should be a clear and colorless solution.

For each 3.5 mg single-dose vial of Bortezomib for injection reconstitute with the following volume of 0.9% Sodium Chloride Injection, USP (Table: 5)

Table 5: Reconstitution Volumes and Final Concentration for Intravenous Administration

Route of Administration Bortezomib (mg/vial) Diluent (0.9% Sodium Chloride Injection, USP) Final Bortezomib Concentration (mg/mL)
Intravenous 3.5 mg 3.5 mL 1 mg/mL

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 reconstituted Bortezomib for injection to be administered:

Intravenous Administration [1 mg/mL concentration ]

Bortezomib for injection dose (mg/m2) x patient BSA(m2) = Total Bortezomib for injection (mL) to be administered

1 mg/mL

A sticker that indicates the route of administration is provided with each Bortezomib for injection vial. Place this sticker directly on the syringe of Bortezomib for injection once it is prepared to help alert practitioners of the correct route of administration for Bortezomib for 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 reconstituted product should not be used.

Stability

Unopened vials of Bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.

Bortezomib for injection contains no antimicrobial preservative. Administer reconstituted Bortezomib for injection within 8 hours of preparation. When reconstituted as directed, Bortezomib for injection may be stored at 20°-25°C (68°-77°F). The reconstituted material should be stored in the original vial and/or the syringe prior to administration. The product may be stored for up to eight hours in a syringe; however, total storage time for the reconstituted material must not exceed eight hours when exposed to normal indoor lighting.

3 DOSAGE FORMS AND STRENGTHS

For Injection: Each single-dose vial of Bortezomib for injection 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 [see Dosage and Administration (2.8)].

4 CONTRAINDICATIONS

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

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

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 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 Bortezomib for 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 the intravenous treatment group. Grade ≥ 3 peripheral neuropathy occurred in 15% in the intravenous treatment group [see Adverse Reactions (6.1)].

Patients experiencing new or worsening peripheral neuropathy during Bortezomib for injection therapy may require a decrease in the dose and/or a less dose-intense schedule [see Dosage and Administration (2.5)]. In the bortezomib versus 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 [see Adverse Reactions (6.1)]. 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 versus 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.

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