Bortezomib 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 administered intravenously (IV) or subcutaneously. It acts as a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a protein complex responsible for degrading ubiquitinated proteins. The ubiquitin-proteasome pathway is essential for regulating intracellular protein levels and maintaining cellular homeostasis. By inhibiting the 26S proteasome, Bortezomib disrupts targeted protein degradation, affecting multiple signaling pathways within the cell. This disruption interferes with normal cellular processes and ultimately leads to apoptosis (cell death). Studies have shown that Bortezomib is cytotoxic to various cancer cell types in vitro and delays tumor growth in vivo in experimental models, including multiple myeloma.

Distribution: The distribution volume of Bortezomib as a single agent has not been fully evaluated at recommended doses in patients with multiple myeloma. It is approximately 83% bound to human plasma proteins over a concentration range of 100–1000 ng/mL.

Metabolism: Bortezomib is mainly metabolized through oxidative pathways involving cytochrome P450 enzymes such as CYP3A4, CYP2C19, and CYP1A2. Minor metabolism occurs via CYP2D6 and CYP2C9. The primary metabolic process involves deboronation, forming two deboronated metabolites that are further hydroxylated. These metabolites are inactive as 26S proteasome inhibitors.

Elimination: The mean elimination half-life of Bortezomib after the first dose ranges from approximately 9 to 15 hours at doses between 1.45 and 2.00 mg/m² in patients with advanced malignancies. The exact elimination pathways in humans have not been fully established.

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 Bortezomib. In vitro studies using human liver microsomes suggest that Bortezomib is mainly a substrate of cytochrome P450 enzymes, including CYP3A4, CYP2C19, and CYP1A2. It shows weak inhibitory effects on CYP1A2, CYP2C9, CYP2D6, and CYP3A4 at higher concentrations. Bortezomib may inhibit CYP2C19 activity and could increase exposure to drugs metabolized by this enzyme. However, it does not appear to induce CYP3A4 or CYP1A2 activity in primary cultured human hepatocytes.

Bortezomib is contraindicated in patients with known hypersensitivity to Bortezomib, boron, or mannitol. Severe allergic reactions, including anaphylaxis, have been reported. It must not be administered via the intrathecal route, as this has resulted in fatal outcomes.

Adverse effects associated with Bortezomib therapy may include peripheral neuropathy, hypotension, cardiac toxicity, pulmonary toxicity, posterior reversible encephalopathy syndrome (PRES), gastrointestinal toxicity, thrombocytopenia or neutropenia, tumor lysis syndrome, and hepatic toxicity.

Bortezomib is classified as Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant during treatment. There are no adequate and well-controlled studies in pregnant women, and no placental transfer studies have been conducted. If Bortezomib is used during pregnancy, or if a patient becomes pregnant while receiving treatment, she should be informed about the potential risk to the fetus.

Bortezomib should be administered under the supervision of a physician experienced in anticancer therapy.

Peripheral Neuropathy: Bortezomib commonly causes sensory peripheral neuropathy, although motor neuropathy may also occur. Patients with pre-existing symptoms such as numbness, tingling, or burning sensations in the hands or feet may experience worsening. Regular monitoring is required, and dose modification may be necessary if symptoms progress. Switching to subcutaneous administration may be considered in patients at risk.

Hypotension: Use caution in patients with a history of syncope, dehydration, or those receiving medications associated with hypotension. Management may include adjusting antihypertensive therapy, ensuring adequate hydration, and using supportive medications such as mineralocorticoids or sympathomimetics.

Cardiac Disorders: New or worsening congestive heart failure has been observed in some patients. Close monitoring is recommended, especially in those with pre-existing cardiac conditions. QT interval prolongation has been reported in isolated cases, though a direct causal relationship has not been confirmed.

Gastrointestinal Adverse Events: Treatment may cause nausea, vomiting, diarrhea, or constipation. Supportive care with antiemetics, antidiarrheals, and fluid/electrolyte replacement may be required to prevent dehydration.

Pulmonary Toxicity: Serious pulmonary conditions, including ARDS, pneumonitis, interstitial pneumonia, and lung infiltration, have been reported and may be fatal. Pulmonary hypertension has also occurred. If new or worsening respiratory symptoms develop, treatment interruption and prompt evaluation are advised.

Thrombocytopenia: Bortezomib may cause cyclical decreases in platelet and neutrophil counts. Regular monitoring of complete blood counts is essential. Dose adjustments or delays may be required in cases of severe thrombocytopenia. Bleeding complications, including gastrointestinal and intracranial hemorrhage, have been reported.

Tumor Lysis Syndrome: Patients with high tumor burden are at risk of tumor lysis syndrome. Preventive measures and close monitoring are recommended.

Hepatic Toxicity: Cases of acute liver failure and other hepatic reactions (e.g., hepatitis, elevated liver enzymes, hyperbilirubinemia) have been reported. Treatment interruption may be required to assess reversibility.

Renal impairment: The pharmacokinetics of Bortezomib are not significantly affected by renal dysfunction; therefore, dose adjustment is generally not required. However, as dialysis may reduce drug levels, Bortezomib should be administered after dialysis sessions.

Pediatric: The safety and efficacy of Bortezomib in children have not been established.

Patients with diabetes: Patients receiving oral antidiabetic therapy may require close monitoring of blood glucose levels and possible adjustment of their antidiabetic medications during Bortezomib treatment.

Overdose exceeding twice the recommended dose has been associated with acute symptomatic hypotension and thrombocytopenia, which may be life-threatening. There is no specific antidote for Bortezomib overdose. In case of overdose, patients should be closely monitored, and supportive treatment should be provided to maintain vital functions such as blood pressure and body temperature.

Targeted Cancer Therapy

Unopened vial: Store below 25°C and keep in the original carton to protect from light.

Reconstituted solution: Store at 2°C–8°C and use within 8 hours after preparation. Do not use if the solution appears discolored or contains visible particles.