Bortez IV/SC Injection

Bortez is a proteasome inhibitor indicated for:

• Treatment of adult patients with multiple myeloma
• Treatment of adult patients with mantle cell lymphoma

Bortezomib for Injection is an antineoplastic agent available for intravenous (IV) and subcutaneous injection use. It 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.

Distribution: The distribution volume of Bortezomib as a single agent was not assessed at the recommended dose in patients with multiple myeloma.The binding of Bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1000 ng/mL.

Metabolism: Bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1 A2. Bortezomib metabolism by CYP 2D6 and 2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated Bortezomib metabolites are inactive as 26S proteasome inhibitors.

Elimination: The mean elimination half-life of Bortezomib after first dose ranged from 9 to 15 hours at doses ranging from 1.45 to 2.00 mg/m2 in patients with advanced malignancies. The pathways of elimination of Bortezomib have not been characterized in humans.

The recommended dose of Bortezomib is 1.3 mg/m2/dose administered as a 3 to 5 second bolus intravenous and subcutaneous 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, Bortezomib 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).

Bortezomib retreatment may be considered for patients with multiple myeloma who has previously responded to treatment with Bortezomib and who has relapsed at least 6 months after completing prior Bortezomib treatment. Treatment may be started at the last tolerated dose. Bortezomib is for intravenous or subcutaneous use only. Bortezomib should not be administered by any other route.

No formal drug interaction studies have been conducted with Bortez. In vitro studies with human liver microsomes indicate that Bortez is primarily a substrate of cytochrome P450 3A4, 2C19, and 1A2. Bortez is a poor inhibitor of human liver microsome cytochrome P450 1A2, 2C9, 2D6, and 3A4, with IC50 values of >30µM (>11.5 µg/mL). Bortez may inhibit 2C19 activity (IC50= 18 µM, 6.9 µg/mL) and increase exposure to drugs that are substrates for this enzyme. Bortez did not induce the activities of cytochrome P450 3A4 and 1A2 in primary cultured human hepatocytes.

Bortezomib is contraindicated in patients with hypersensitivity to Bortezomib, boron or mannitol. Reactions have included anaphylactic reactions. Bortezomib is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib.

The following adverse reactions can be occurred during Bortez therapy: Peripheral Neuropathy, Hypotension, Cardiac Toxicity, Pulmonary Toxicity, Posterior Reversible Encephalopathy Syndrome (PRES), Gastrointestinal Toxicity, Thrombocytopenia /Neutropenia,Tumor Lysis Syndrome, Hepatic Toxicity.

Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib. No placental transfer studies have been conducted with Bortezomib. There are no adequate and well-controlled studies in pregnant women. If Bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus.

Bortez should be administered under the supervision of a physician experienced in the use of antineoplastic therapy.

Peripheral Neuropathy: Bortez treatment causes a peripheral neuropathy that is predominantly sensory, although cases of motor neuropathy have also 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 Bortez. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort or neuropathic pain. Patients experiencing new or worsening peripheral neuropathy may require changes in thedose and schedule of Bortez. Starting Bortez subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: 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.

Cardiac Disorders: The acute development or exacerbation of congestive heart failure has been seen in patients with risk factors for, or existing heart disease. Such patients should be closely monitored. In clinical studies, isolated cases of QT-interval prolongation have been observed; causality has not been established.

Gastrointestinal Adverse Events: Bortez treatment can cause nausea, diarrhea, constipation, and vomiting with sometimes requiring use of antiemetic and antidiarrheal medications. Fluid and electrolyte replacement should be administered to prevent dehydration.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving Bortez. Some of these events have been fatal. There have been reports of pulmonary hypertension associated with Bortez administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortez until a prompt and comprehensive diagnostic evaluation is conducted.

Thrombocytopenia: Bortez 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 Bortez. Measure platelet counts prior to each dose of Bortez. Adjust dose/schedule for thrombocytopenia. There have been reports of gastrointestinal and intracerebral hemorrhage in association with Bortez. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with Bortez therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortez therapy to assess reversibility. There is limited re-challenge information in these patients.

Renal Impairment: The pharmacokinetics of Bortez is not influenced by the degree of renal impairment. Therefore, dosing adjustments of Bortez are not necessary for patients with renal insufficiency. Since dialysis may reduce Bortez concentrations, Bortez should be administered after the dialysis procedure.

Pediatric: The safety and effectiveness of Bortez in children have not been established.

Patients with Diabetes: Patients on oral anti-diabetic agents receiving Bortez treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their anti-diabetic medication.

Overdosage more than twice the recommended dose can be associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for Bortez overdosage. In the event of an overdosage, the patient's vital signs should be monitored and
appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature.

Targeted Cancer Therapy

Unopened vial: Do not store above 25°C temperature. Keep in outer box in order to protect from light. Reconstituted solution: Do not store above 2°C-8°C temperature. Use within 8 hours of reconstitution. Do not use if any particulate matter is observed or if the solution is discolored.