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 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 ?
(Nasdaq: MLNM), Cambridge, Mass., has announced updated preliminary findings of a phase II clinical trial of its investigational drug MLN341 (formerly known as LDP-341 and PS-341) in patients with multiple myeloma, the second most common hematologic cancer, whose disease has relapsed and not responded following multiple prior treatments.
MLN341 has been shown in this study to arrest the course of the disease and delay disease progression in study patients while avoiding many of the more toxic and debilitating side effects common with standard treatments."
MLN341 is designed to specifically inhibit the proteasome, which is an enzyme complex in the cell responsible for breaking down a variety of proteins, including many that regulate cell division.
About the study MLN341 - the only proteasome inhibitor in clinical trials for oncology - has been evaluated in over 250 patients with relapsed and/or refractory multiple myeloma in clinical trials to date.
* The 77 percent of patients receiving MLN341 experienced a reduction or stabilization in their M protein, a substance in the blood that physicians use to evaluate multiple myeloma tumor burden;
* Overall, 77 percent of patients (54 of 70 evaluable patients) in the study experienced stabilization of the disease or a reduction in their M protein levels after receiving MLN341 for up to 24 weeks;
Side effects with MLN341 were manageable and predictable and included fatigue, diarrhea, reduced platelets, and peripheral neuropathy (numbness and tingling and occasionally pain in the extremities).
"These findings are a significant advance in our development of MLN341 which is an exciting new therapy that could provide hope to many seriously ill cancer patients," said Mark Levin, chief executive officer, Millennium Pharmaceuticals.
Researchers are scheduled to present additional data concerning MLN341 at the annual meeting of the American Society of Hematology, December 6-10 in Philadelphia, PA.