Bortezomib

Trade Names:
Velcade
- Injection, lyophilized powder for solution 3.5 mg

Pharmacology

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Inhibits 26S proteasome, which disrupts normal homeostatic mechanisms and leads to cell death.

Pharmacokinetics

Absorption

C _max is 89 to 120 ng/mL following IV administration of 1.3 mg/m ² .

Distribution

83% bound to plasma protein. Vd is approximately 498 to 1,884 L/m ² .

Metabolism

In vitro studies indicate metabolism is primarily oxidative via CYP1A2, 2C9, 2C19, 2D6, and 3A4.

Elimination

Mean elimination half-life is 76 to 108 h and mean total body Cl after first dose is 112 L/h after 1.3 mg/m ² dose.

Special Populations

Pharmacokinetics are comparable among patients with healthy renal function compared with patients with moderate or severe renal impairment or patients who are on dialysis. Administer bortezomib after dialysis.

No pharmacokinetic studies have been conducted.

Patients younger than 65 yr of age have about 25% lower mean dose-normalized AUC and C _max than those 65 yr of age and older.

Pharmacokinetics are comparable between men and women.

Effects of pharmacokinetics based on race have not been assessed.

Indications and Usage

Treatment of multiple myeloma; treatment of mantle cell lymphoma in patients who have received at least 1 prior therapy.

Unlabeled Uses

Treatment of myelomatous pleural effusion.

Contraindications

Hypersensitivity to boron, mannitol, or any component of the product.

Dosage and Administration

IV 1.3 mg/m ² as a 3- to 5-sec bolus in combination with oral melphalan and oral prednisone for nine 6-wk treatment cycles. In cycles 1 to 4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29, and 32). In cycles 5 to 9, bortezomib is administered weekly (days 1, 8, 22, and 29). At least 72 h should elapse between consecutive doses.

IV Prior to starting any cycle with bortezomib in combination with melphalan and prednisone, platelet count should be at least 70 × 10 ⁹ /L, and the absolute neutrophil count (ANC) should be at least 1 × 10 ⁹ /L; nonhematological toxicities should have resolved to grade 1 or baseline. If prolonged grade 4 neutropenia or thrombocytopenia or thrombocytopenia with bleeding is observed in the previous cycle, consider reducing the melphalan dose by 25% in the next cycle. If platelet count is 30 × 10 ⁹ /L or less or if ANC is 0.75 × 10 ⁹ /L or less on a bortezomib dosing day (other than day 1), withhold bortezomib. If several bortezomib doses in consecutive cycles are withheld because of toxicity, reduce the bortezomib dose by 1 dose level (eg, from 1.3 to 1 mg/m ² , or from 1 to 0.7 mg/m ² ). For grade 3 or higher nonhematological toxicities, withhold bortezomib therapy until toxicity symptoms have resolved to grade 1 or baseline. Then, reinitiate bortezomib with 1 dose level reduction (eg, from 1.3 to 1 mg/m ² , or from 1 to 0.7 mg/m ² ). For bortezomib-related neuropathic pain and/or peripheral neuropathy, hold or modify bortezomib as discussed under Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy.

IV 1.3 mg/m ² /dose administered as a 3- to 5-sec bolus twice weekly for 2 wk (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12 to 21). For extended therapy of more than 8 cycles, bortezomib may be administered in the standard schedule or on a maintenance schedule of once weekly for 4 wk (days 1, 8, 15, and 22) followed by a 13-day rest period (days 23 to 35). At least 72 h should elapse between consecutive doses of bortezomib.

IV Withhold bortezomib therapy at the onset of any grade 3 nonhematological or grade 4 hematological toxicities, excluding neuropathy. Once symptoms of toxicity have resolved, bortezomib therapy may be reinitiated at a 25% reduced dose (eg, from 1.3 to 1 mg/m ² , or from 1 to 0.7 mg/m ² ). For management of patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy, see Dose Modification for Bortezomib-Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy.

IV There is no dose modification for grade 1 peripheral neuropathy (paresthesias, weakness, and/or loss of reflexes) without pain or loss of function. For grade 1 peripheral neuropathy with pain or grade 2 (interfering with function but not with activities of daily living), reduce dose to 1 mg/m ² . For grade 2 peripheral neuropathy with pain or grade 3 (interfering with activities of daily living), withhold therapy until toxicity resolves, then reinitiate therapy with a reduced dose of 0.7 mg/m ² and change treatment schedule to once weekly. Discontinue therapy for grade 4 (sensory neuropathy that is disabling or motor neuropathy that is life-threatening or leads to paralysis).

General Advice

• Follow manufacturer's instructions for reconstituting powder. Use caution during handling and preparation. Use gloves and other protective clothing to prevent skin contact.
• Administer fluid and electrolyte replacement to prevent dehydration.
• Inspect solution visually before administration. Do not administer if solution is cloudy, discolored, or contains particulate matter.
• Discard any unused product. Vials are for single-use only. Do not save medication for future use.

Storage/Stability

Store unopened vials 59° to 86°F in original package to protect from light. Reconstituted solution may be stored at 77°F for up to 8 h. Reconstituted solution may be stored for up to 8 h in syringe prior to administration; however, the total storage time for reconstituted solution must not exceed 8 h when exposed to indoor lighting.

Drug Interactions

Bortezomib plasma concentrations may be reduced; closely monitor patient for decreased bortezomib efficacy.

Bortezomib plasma concentrations may be increased; closely monitor patient for bortezomib toxicity.

Because hypoglycemia and hyperglycemia were reported in trials, adjustment of antidiabetic dosages may be necessary.

Laboratory Test Interactions

None well documented.

Adverse Reactions

The following adverse reactions have been reported with bortezomib administered as monotherapy or in combination with other chemotherapeutic agents.

Cardiovascular

Hypotension (15%); hypertension (13%); aggravated atrial fibrillation, angina pectoris, atrial flutter, bradycardia, cardiac amyloidosis, cerebral hemorrhage, cerebrovascular accident, complete AV block, deep venous thrombosis, MI, myocardial ischemia, pericardial effusion, pericarditis, peripheral embolism, pulmonary embolism, pulmonary hypertension, sinus arrest, torsades de pointes, ventricular tachycardia; cardiac tamponade (postmarketing).

CNS

Asthenic conditions including fatigue, malaise, and weakness (64%); peripheral nephropathy (47%); neuralgia (36%); psychiatric disorders (35%); paresthesia and dysesthesia (27%); headache (26%); asthenia (21%); insomnia (20%); dizziness (17%); anxiety (10%); agitation, ataxia, coma, confusion, cranial palsy, dysarthria, dysautonomia, encephalopathy, grand mal convulsion, hemorrhagic stroke, herpes meningoencephaliti (postmarketing); mental status change, motor dysfunction, paralysis, postherpetic neuralgia, reversible posterior leukoencephalopathy syndrome, spinal cord compression, subdural hematoma, suicidal ideation, transient ischemic attack, vertigo.

Dermatologic

Rash (19%); pruritus (10%); face edema, leukocytoclastic vasculitis, urticaria; toxic epidermal necrolysis (postmarketing).

EENT

Nasopharyngitis (14%); conjunctival infection, diplopia and blurred vision, eye irritation; bilateral deafness, ophthalmic herpes, sinusitis (postmarketing).

GI

Diarrhea, nausea (57%); constipation (42%); appetite decreased (36%); vomiting (35%); anorexia (34%); abdominal pain (16%); upper abdominal pain (12%); acute pancreatitis, ascites, dysgeusia, dyspepsia, dysphagia, fecal impaction, gastroenteritis, gastroesophageal reflux, hematemesis, hemorrhagic duodenitis, hemorrhagic gastritis, large intestinal obstruction, large intestinal perforation, melena, oral mucosal petechiae, paralytic ileus, paralytic intestinal obstruction, peritonitis, small intestinal obstruction, stomatitis; ischemic colitis (postmarketing).

Genitourinary

Bilateral hydronephrosis, bladder spasm, glomerular nephritis proliferation, hematuria, hemorrhagic cystitis, renal calculus, renal failure, urinary incontinence, urinary retention, UTI.

Hematologic-Lymphatic

Thrombocytopenia (52%); neutropenia (49%); anemia (43%); leukopenia (33%); lymphopenia (24%); DIC.

Hepatic

Cholestasis, hepatic hemorrhage, hepatitis, hyperbilirubinemia, liver failure, portal vein thrombosis.

Hypersensitivity

Anaphylactic reaction, angioedema, drug hypersensitivity, immune complex–mediated hypersensitivity, laryngeal edema.

Local

Injection-site erythema, injection-site pain, irritation, phlebitis.

Metabolic-Nutritional

Hypokalemia (13%); dehydration (10%); hypercalcemia (2%); hyperkalemia, hypernatremia, hyperuricemia, hypocalcemia, hyponatremia.

Musculoskeletal

Arthralgia, back pain (17%); bone pain (16%); limb pain (15%); pain in extremities (14%); muscle cramps, myalgia (12%); rigors (11%); skeletal fracture.

Respiratory

Cough, dyspnea (21%); pneumonia (16%); lower respiratory lung infections (15%); bronchitis (13%); upper respiratory tract infection (12%); acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbation, dysphagia, dyspnea, epistaxis, exertional dyspnea, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, pulmonary hypertension, respiratory distress; acute diffuse infiltrative pulmonary disease (postmarketing).

Miscellaneous

Pyrexia (35%); edema (23%); peripheral edema (20%); herpes zoster (13%); lower limb edema (11%); herpes simplex (2% to 8%); aspergillosis, bacteremia, catheter-related complication, herpes viral infection, impaired hearing, listeriosis, oral candidiasis, septic shock, toxoplasmosis.

Precautions

Pregnancy

Category D .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

No differences in safety and efficacy have been observed between patients 65 yr of age and older compared with younger patients.

Hepatic Function

Cl may be reduced in patients with hepatic impairment. Closely monitor patients for toxicities.

Cardiac disorders

Acute development or exacerbation of CHF and new onset of decreased left ventricular ejection fraction may occur.

GI

Constipation, diarrhea, nausea, and vomiting, sometimes requiring use of antiemetics and antidiarrheals, may occur. Ileus can occur.

Hepatic events

Acute liver failure has been reported.

Hypotension

Because orthostatic/postural hypotension can occur, use with caution when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated.

Peripheral neuropathy

Peripheral neuropathy that is predominantly sensory may occur, although severe sensory and motor peripheral neuropathy has been reported.

Pulmonary disorders

Acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome has been reported.

Reversible posterior leukoencephalopathy syndrome

Has been reported rarely.

Thrombocytopenia/Neutropenia

May occur throughout therapy, but is most common in cycles 1 and 2.

Tumor lysis syndrome

Because malignant cells may be killed rapidly, complications of tumor lysis syndrome may occur.

Overdosage

Symptoms

Hypotension, thrombocytopenia.

Patient Information

• Ensure that patient, family, or caregiver understands that medication is administered in treatment cycles.
• Advise patient, family, or caregiver that medication will be prepared and administered by health care provider in a health care setting.
• Advise patient that drug may cause fatigue, dizziness, fainting, and/or vision changes, and to use caution while driving or performing other tasks requiring alertness until tolerance is determined.
• Instruct breast-feeding women to discontinue breast-feeding while undergoing treatment.
• Advise patient to notify health care provider if any of the following occur: abnormal skin sensations, dizziness, fainting, fever, light-headedness, nerve pain, persistent vomiting or diarrhea, or other symptoms of infection.
• Instruct diabetic patients to monitor blood glucose more frequently during therapy and to inform health care provider of significant changes in readings.
• Advise patients regarding appropriate measures to avoid dehydration because therapy is associated with vomiting and diarrhea.
• Advise patient to notify health care provider of new or worsening symptoms of tingling, numbness, pain, a burning feeling in the feet or hands, or weakness in the arms or legs.

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