Uses of Bortez 1: - Multiple myeloma - Mantle-cell lymphoma Mantle Cell Lymphoma, Multiple Myeloma, Hypersensitivity. Child. Pregnancy and lactation.

Targeted Cancer Therapy

Bortezomib 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.

How to use Bortezomib: Your doctor or nurse will give you this medicine. Kindly do not self administer. Administration: IV or SC Preparation Reconstitute vial with 0.9% NaCl IV administration: Add 3.5 mL to vial for final concentration of 1 mg/mL SC administration: 2.5 mg/mL: Add 1.4 mL to vial for final concentration of 2.5 mg/mL If local injection site reactions occur following SC administration, a less concentrated solution (1 mg/mL) may be administered subcutaneously IV or SC Administration Not for intrathecal (IT) use; inadvertent IT has resulted in death and is contraindicated Separate consecutive doses by at least 72 hr Give IV as a bolus over 3-5 seconds or as SC injection Give SC injection in thigh or abdomen; rotate injection site with each dose Monitor hydration status Use cytotoxic handling procedures for preparation, administration, and disposal Adult Dose: Mantle Cell Lymphoma Indicated for treatment of patients with mantle cell lymphoma as first-line in previously untreated patients or those who have relapsed Previously untreated MCL 1.3 mg/m²/dose IV twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21) for six 3-week cycles; may continue for 8 cycles if response is first seen at cycle 6 Give with rituximab 375 mg/m² IV, cyclophosphamide 750 mg/m² IV, and doxorubicin 50 mg/m² IV on day 1, plus prednisone 100 mg/m² IV on days 1-5 Relapsed MCL 1.3 mg/m²/dose IV/SC twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21) Therapy extending beyond 8 cycles: Give standard schedule Multiple Myeloma Previously untreated multiple myeloma Administer in combination with prednisone and melphalan as part of 6-wk treatment cycles for 9 cycles Cycles 1-4 (twice weekly): 1.3 mg/m² IV/SC on Days 1, 4, 8, 11, 22, 25, 29, and 32 Cycles 5-9 (once weekly): 1.3 mg/m² IV/SC on Days 1, 8, 22, and 29 Relapsed multiple myeloma 1.3 mg/m²/dose IV/SC twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21) Therapy extending beyond 8 cycles: Standard schedule or 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) Re-treatment Indicated for re-treatment of adults with multiple myeloma who had previously responded to bortezomib and relapsed at least 6 months following completion of prior bortezomib treatment Treatment may be started at the last tolerated dose Administer twice weekly for 2 weeks (days 1, 4, 8, 11) followed by a 10-day rest period (days 12 to 21) Hepatic impairment Moderate-to-severe (bilirubin >1.5x ULN): Reduce 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 tolerability

Concurrent use of amiodarone, antivirals, isoniazid, nitrofurantoin, statins may increase the chance of peripheral neuropathy. Concurrent use of antihypertensives increases the chance of hypotension.

Hypersensitivity. Child. Pregnancy and lactation.

Common - Low blood platelets - Fatigue - Peripheral neuropathy (tingling and numbness of feet and hand) - Psychiatric disturbances - Nausea - Vomiting - Loss of appetite - Fever - Anemia (low number of red blood cells) - Diarrhea - Decreased appetite - Decreased white blood cell count (neutrophils) - Constipation >10% Asthenia (61-65%) Nausea (61-65%) Diarrhea (51-55%) Anorexia (41-45%) Constipation (41-45%) Thrombocytopenia (41-45%) Peripheral neuropathy (IV: 16-41%; SC: 6-24%) Pyrexia (36-40%) Vomiting (36-40%) Anemia (31-35%) Arthralgia (26-30%) Headache (26-30%) Insomnia (26-30%) Limb pain (26-30%) Dizziness (21-25%) Dyspnea (21-25%) Edema (21-25%) Neutropenia (21-25%) Paresthesia (21-25%) Rash (21-25%) Cough (15-20%) Dehydration (15-20%) URI (15-20%) Rigors, grade 4 toxicity (10-15%)

Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib. 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.

Precaution: Hepatic or renal impairment; history of syncope, orthostatic hypotension; dehydration. Impairs ability to drive or operate machinery. Monitor for symptoms of peripheral neuropathy. Monitor closely the blood glucose levels in patients receiving oral antidiabetic agents.

Unopened vials may be stored at controlled room temperature 25º C

Targeted Cancer Therapy

Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26-S proteasome. It prevents targeted proteolysis that affects multiple signaling cascades responsible for normal homeostatic functions within the cell, leading to cell death.

Pregnancy Based on mechanism of action and findings in animals, therapy can cause fetal harm when administered to a pregnant woman; there are no studies in pregnant women to inform drug-associated risks; therapy caused embryo-fetal lethality in rabbits at doses lower than the clinical dose; advise pregnant women of potential risk to fetus Verify pregnancy status of females of reproductive potential prior to initiating treatment Advise patients of reproductive potential to use effective contraception during treatment with therapy and for at least 2 months after treatment Lactation There are no data on presence of bortezomib or metabolites in human milk, the effects of the drug on the breast fed infant or on milk production Many drugs are excreted in human milk and potential for serious adverse reactions in breastfed infants from therapy is unknown Advise nursing women not to breastfeed during treatment and for 2 months after treatment