bortezomib

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bortezomib

Velcade

Pharmacologic class: Proteasome inhibitor

Therapeutic class: Antineoplastic

Pregnancy risk category D

Action

Inhibits proteasomes (enzyme complexes that regulate protein homeostasis within cells). Reversibly inhibits chymotrypsin-like activity at 26S proteasome, leading to activation of signaling cascades, cell-cycle arrest, and apoptosis.

Availability

Powder for reconstitution (preservative-free): 3.5 mg (contains 35 mg of mannitol)

Indications and dosages

Multiple myeloma, patients with mantle cell lymphoma who have received at least one prior therapy

Adults: 1.3 mg/m2 I.V. or subcutaneously twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by 10-day rest period (days 12 to 21). Allow at least 72 hours to elapse

between doses. One treatment cycle equals 21 days (3 weeks).

Dosage adjustment

• Moderate or severe hepatic impairment
• Peripheral neuropathy
• Grade 3 nonhematologic events
• Grade 4 hematologic events

Contraindications

• Hypersensitivity to drug, mannitol, or boron

Precautions

Use cautiously in:
• peripheral neuropathy, dehydration, hepatic or renal impairment
• history of syncope or cardiovascular disorders
• pregnant or breastfeeding patients
• children.

Administration

• Be aware that drug is for I.V. or subcutaneous use only. Because each route of administration has a different reconstituted concentration, use caution when calculating volume to be administered.
• Reconstitute drug in vial with 3.5 ml of normal saline for injection to yield a concentration of 1 mg/ml for I.V. use.
• Reconstitute drug in vial with 1.4 ml of normal saline for injection to yield a concentration of 2.5 mg/ml for subcutaneous use.
• Give by I.V. push over 3 to 5 seconds or subcutaneously.
• Reconstituted solution must be used within 8 hours.

Adverse reactions

CNS: headache, insomnia, dizziness, anxiety, peripheral neuropathy, reversible posterior leukoen-cephalopathy syndrome

CV: tachycardia, hypotension

EENT: throat tightness

GI: nausea, vomiting, diarrhea, abdominal pain, dyspepsia

Hematologic: eosinophilia, anemia, thrombocytopenia, neutropenia

Hepatic: hyperbilirubinemia, hepatitis, acute liver failure

Metabolic: dehydration, pyrexia

Respiratory: cough, dyspnea, upper respiratory tract infection, acute diffuse infiltrative pulmonary disease (pneumonitis, interstitial pneumonia, acute respiratory distress syndrome)

Skin: rash, pruritus, urticaria

Other: altered taste, increased or decreased appetite, fever, chills, edema, tumor lysis syndrome

Interactions

Drug-drug.CYP3A4 inducers (including amiodarone, carbamazepine, nevi-rapine, phenobarbital, phenytoin, and rifampin): possible decrease in bortezomid serum level and efficacy

CYP3A4 inhibitors (including amiodarone, cimetidine, clarithromycin, delavirdine, diltiazem, disulfiram, erythromycin, fluoxetine, fluvoxamine, nefazodone, nevirapine, propoxyphene, quinupristin, verapamil, zafirlukast, and zileuton): possible increase in bortezomib serum level and efficacy

Drug-diagnostic tests.Liver function

tests: increased levels

Drug-food.Grapefruit juice: increased bortezomib blood level, greater risk of toxicity

Patient monitoring

Monitor vital signs and temperature. Especially watch for tachycardia, fever, and hypotension.

Stay alert for and discontinue drug if posterior leukoencephalopathy (headache, seizures, lethargy, confusion, blindness) or tumor lysis syndrome occurs (irregular heartbeat, shortness of breath, high potassium level, high uric acid level, impairment of mental ability, kidney failure).

Closely monitor liver function tests and watch for signs and symptoms of hepatitis or liver failure.
• Monitor nutritional and hydration status for changes caused by GI adverse effects.
• Monitor CBC with white cell differential, and watch for signs and symptoms of blood dyscrasias.

Monitor respiratory status, watching for dyspnea, cough, and other signs and symptoms of upper respiratory tract infection.

Patient teaching

Inform patient that drug can cause serious blood dyscrasias. Teach him which signs and symptoms to report right away.
• Tell patient that drug may cause other significant adverse reactions. Reassure him he will be closely monitored.
• Instruct patient to move slowly when sitting or standing up to avoid dizziness or light-headedness from sudden blood pressure drop.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration and alertness.
• Advise patient to minimize adverse GI effects by eating small frequent servings of healthy food and ensuring adequate fluid intake.
• Tell patient to immediately report signs and symptoms of upper respiratory tract infection.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and foods mentioned above.

bortezomib

a miscellaneous antineoplastic.
indications This drug is used to treat multiple myeloma when at least two other treatments have failed.
contraindications Pregnancy and known hypersensitivity to this drug, boron, or Mannitol prohibit its use.
adverse effects Adverse effects of this drug include hypotension, edema, anemia, fatigue, malaise, weakness, arthralgia, bone pain, muscle cramps, myalgia, back pain, abdominal pain, constipation, diarrhea, dyspepsia, nausea, vomiting, anorexia, anxiety, insomnia, dizziness, headache, peripheral neuropathy, rigors, paresthesia, cough, pneumonia, dyspnea, upper respiratory infection, dehydration, weight loss, herpes zoster, rash, pruritus, and blurred vision. Life-threatening side effects include neutropenia and thrombocytopenia.

bortezomib

A proteasome inhibitor which induces apoptosis in cancer cells, and inhibits binding to stromal cells and production of growth and survival factors.

Indications
Treatment-refractory myeloma (35% response rate), mantle cell lymphoma.
 
Adverse effects
Thrombocytopaenia, fatigue, peripheral neuropathy, neutropaenia. 

bortezomib

The first of a new class of anticancer drugs that act by inhibition of the action of PROTEASOMES. When proteasomes in tumour cells are inhibited, these cells become greatly sensitized to the action of cytotoxic drugs. The drug has been found to produce a 35 per cent response rate in patients with relapsed and refractive multiple MYELOMATOSIS. A brand name is Velcade.
References in periodicals archive ?
Phase 1 trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies.
Adams, a recognized leader in drug discovery and development, was selected to receive the Cain Award for his groundbreaking research and development of PS-341, now marketed as VELCADE(R), for the treatment of multiple myeloma.
Most patients with refractory or relapsing multiple myeloma stabilized or significantly improved when they took a novel agent known as PS-341, Dr.
Taking another approach, researchers are examining a new drug called PS-341.
PS-341 has shown significant activity in preclinical murine tumor models (3) where the antitumor activity was positively correlated with the degree of proteasome inhibition measured both in leukocyte and tumor biopsy material.
PS-341 or a combination of arsenic trioxide and interferon-alpha inhibit growth and induce caspase-dependent apoptosis in KSHV/HHV8-infected primary effusion lymphoma cells.
The poster was titled "Synergistic Activity of the Proteasome Inhibitor PS-341 with Non-Myeloablative 153-Sm-EDTMP in a Syngeneic, Orthotopic Model of Multiple Myeloma.
The abstract, entitled: "Synergistic Activity of the Proteasome Inhibitor PS-341 with Non-Myeloablative 153-Sm-EDTMP in a Syngeneic, Orthotopic Model of Multiple Myeloma" (A.
Based on these results, a Phase II clinical trial of PS-341 along with standard chemotherapeutic agents is planned to begin later this year at NCI and other institutions.
The first presentation, entitled "The Proteasome Inhibitor PS-341 Inhibits Growth, Induces Apoptosis and Overcomes Drug Resistance in Human Multiple Myeloma (MM) Cells," was based on research conducted by Teru Hideshima, Ph.
of New York University, in a poster entitled "Effect of the Proteasome Inhibitor PS-341 on Cell Cycle Progression and Potentially Unique Mechanism of Action.
The acquisition of ProScript provides LeukoSite with two additional compounds: PS-341, an anti-cancer compound in Phase I clinical trials and PS- 519, an anti-inflammatory agent in advanced preclinical development.