Bortezomib - Warnings and Precautions

5 WARNINGS AND PRECAUTIONS Peripheral Neuropathy: Manage with dose modification or discontinuation.

Patients with pre-existing severe neuropathy should be treated with Bortezomib for injection only after careful risk-benefit assessment. ( 2.7 , 5.1 ) 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 Bortezomib for injection therapy.

Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib for injection 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 Bortezomib for injection therapy to assess reversibility.

Thrombotic Microangiopathy: Monitor for signs and symptoms.

Discontinue Bortezomib for injection if suspected.

Embryo-Fetal Toxicity: Bortezomib for injection can cause fetal harm.

Advise females of reproductive potential and males with female partners of reproductive potential of the potential risk to a fetus and to use effective contraception.

5.1 Peripheral Neuropathy Bortezomib for injection 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 comparing Bortezomib for injection subcutaneous vs intravenous the incidence of Grade ≥ 2 peripheral neuropathy was 24% for subcutaneous and 39% for intravenous.

Grade ≥ 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group [ see Adverse Reactions ] .

Starting Bortezomib for injection subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy.

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 ].

In the Bortezomib for injection 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.