Bortezomib

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Contents

[edit] BRAND NAMES

[edit] STRUCTURE

Bortezomib.jpg

[edit] MECHANISM OF ACTION

Bortezomib, is a proteasome inhibitor. It blocks the proteasome, which is a system within the cells that breaks down proteins when they are no longer needed. When the proteins in the cancer cells, such as the proteins that control the growth of the cells, are not broken down, the cells are affected and they eventually die.

More specifically, 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.

[edit] INDICATIONS

  • treatment of patients with multiple myeloma
  • treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy

[edit] DOSAGE

  • For subcutaneous or intravenous use only
  • The recommended dose of Bortezomib is 1.3 mg/m2 administered either as a 3 to 5 second bolus intravenous injection or subcutaneous injection.
  • Hepatic Impairment: Use a lower starting dose for patients with moderate or severe hepatic impairment.
  • Dose must be individualized to prevent overdose

[edit] CONTRAINDICATIONS

  • Patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions.
  • Contraindicated for intrathecal administration.

[edit] WARNINGS AND PRECAUTIONS

  • Peripheral Neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with Bortezomib only after careful risk-benefit assessment.
  • 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.
  • Posterior Reversible Encephalopathy Syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue Bortezomib if suspected.
  • Gastrointestinal Toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement.
  • Thrombocytopenia or 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.
  • Embryo-fetal Risk: Women should avoid becoming pregnant while being treated with Bortezomib. Advise pregnant women of potential embryo-fetal harm
  • Patients with diabetes may require close monitoring of blood glucose and adjustment of anti-diabetic medication.

[edit] INTERACTIONS

Co-administration with strong CYP3A4 inhibitors can increase Bortezomib exposure. Closely monitor patients receiving Bortezomib in combination with strong CYP3A4 inhibitors. (7.1) Co-administration with strong CYP3A4 inducers can decrease Bortezomib exposure. Avoid concomitant use of strong CYP3A4 inducers

[edit] PREGNANCY AND LACTATION

  • Pregnancy Category D (US). 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.
  • Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Bortezomib, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

[edit] SIDE EFFECTS

Most commonly reported adverse reactions (incidence ≥ 20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy (nerve damage in the hands and feet), fatigue, neuralgia, anaemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

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[edit] REFERENCES