Class: Proteasome inhibitor
- Injection, lyophilized powder for solution 3.5 mg
Inhibits 26S proteasome, which disrupts normal homeostatic mechanisms and leads to cell death.
C max is 89 to 120 ng/mL following IV administration of 1.3 mg/m 2 .
83% bound to plasma protein. Vd is approximately 498 to 1,884 L/m 2 .
In vitro studies indicate metabolism is primarily oxidative via CYP1A2, 2C9, 2C19, 2D6, and 3A4.
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 PopulationsRenal Function Impairment
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.Hepatic Function Impairment
Dose-normalized mean AUC levels were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in these patients and monitor them closely.Elderly
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.Children
There are no pharmacokinetic data in children.Gender
Pharmacokinetics are comparable between men and women.Race
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.
Treatment of myelomatous pleural effusion.
Hypersensitivity to bortezomib, boron, or mannitol.
Dosage and AdministrationPreviously Untreated Multiple Myeloma
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.Dose Modification for Combination Therapy With Bortezomib, Melphalan, and Prednisone
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.Relapsed Multiple Myeloma and Mantle Cell Lymphoma
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.Dose Modification for Relapsed Multiple Myeloma and Mantle Cell Lymphoma
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.Dose Modification for Bortezomib-Related Neutropenic 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).Hepatic function impairment
IV Starting dose should be reduced in patients with moderate and severe hepatic impairment. Start with 0.7 mg/m 2 in the first cycle. Consider escalation to 1 mg/m 2 or further dose reduction to 0.5 mg/m 2 in subsequent cycles based on patient tolerability.
- Reconstitute vial with 3.5 mL of sodium chloride 0.9%.
- 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 or discolored, or contains particulate matter.
- Discard any unused product. Vials are for single-use only. Do not save medication for future use.
Store unopened vials at 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 InteractionsAntihypertensive agents
May potentiate hypotension. Adjust the dose of the antihypertensive agent as needed.Cyclosporine
Bortezomib may enhance the neurotoxic effect of cyclosporine. Closely monitor the patient. If an interaction is suspected, adjust the cyclosporine dose and continue monitoring for neurotoxic effects.CYP3A4 inducers (eg, carbamazepine)
Bortezomib plasma concentrations may be reduced; closely monitor patient for decreased bortezomib efficacy. Adjust the bortezomib dose as needed.CYP3A4 inhibitors (eg, ketoconazole, ritonavir)
Bortezomib plasma concentrations may be increased; closely monitor patient for bortezomib toxicity. Adjust the bortezomib dose as needed.Melphalan-Prednisolone
Coadministration of melphalan-prednisolone with bortezomib resulted in a 17% increase in bortezomib AUC. This increase is unlikely to be clinically important.Oral hypoglycemic agents (eg, glipizide)
Bortezomib administration has resulted in hyperglycemia. In patients receiving oral hypoglycemic agents, closely monitor blood glucose levels and adjust the dose of the hypoglycemic agent as necessary.
The following adverse reactions have been reported with bortezomib as monotherapy or in combination with other chemotherapeutic agents.
Hypotension (15%); hypertension (13%); aggravated atrial fibrillation, angina pectoris, atrial flutter, bradycardia, cardiac amyloidosis, cerebral hemorrhage, cerebrovascular accident, complete AV block, deep venous thrombosis, hemorrhagic stroke, MI, myocardial ischemia, pericardial effusion, pericarditis, peripheral embolism, pulmonary embolism, pulmonary hypertension, sinus arrest, transient ischemic attack, torsades de pointes, ventricular tachycardia; cardiac tamponade (postmarketing).
Asthenic conditions including fatigue, malaise, and weakness (72%); peripheral nephropathy (55%); neuralgia (36%); psychiatric disorders (35%); paresthesia and dysesthesia (27%); headache (26%); dizziness (23%); asthenia, insomnia (21%); anxiety (11%); agitation, ataxia, coma, confusion, cranial palsy, dysarthria, dysautonomia, encephalopathy, generalized tonic-clonic seizure, mental status change, motor dysfunction, paralysis, postherpetic neuralgia, reversible posterior leukoencephalopathy syndrome, spinal cord compression, suicidal ideation, vertigo; herpes meningoencephalitis (postmarketing).
Rash (28%); pruritus (10%); leukocytoclastic vasculitis, urticaria; TEN (postmarketing).
Nasopharyngitis (14%); conjunctival infection, diplopia and blurred vision, eye irritation, hearing impaired, sinusitis; bilateral deafness, ophthalmic herpes (postmarketing).
Diarrhea, nausea (57%); constipation (50%); appetite decreased (39%); vomiting (35%); anorexia (34%); abdominal pain (16%); upper abdominal pain (12%); dyspepsia (11%); acute pancreatitis, ascites, dysgeusia, 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).
Bilateral hydronephrosis, bladder spasm, glomerular nephritis proliferation, hematuria, hemorrhagic cystitis, renal calculus, renal failure, urinary incontinence, urinary retention, UTI.
Thrombocytopenia (52%); neutropenia (49%); anemia (43%); leukopenia (33%); lymphopenia (24%); DIC.
Cholestasis, hepatic hemorrhage, hepatitis, hyperbilirubinemia, liver failure, portal vein thrombosis.
Anaphylactic reaction, angioedema, drug hypersensitivity, immune complex–mediated hypersensitivity, laryngeal edema.
Injection-site erythema, injection-site pain, irritation, phlebitis.
Hypokalemia (13%); dehydration (11%); hypercalcemia (2%); hyperkalemia, hypernatremia, hyperuricemia, hypocalcemia, hyponatremia.
Arthralgia (18%); back pain, limb pain (17%); bone pain (16%); pain in extremities (14%); muscle cramps, myalgia (12%); rigors (11%); skeletal fracture.
Dyspnea (23%); cough (21%); pneumonia (16%); lower respiratory lung infection, upper respiratory tract infection (15%); bronchitis (13%); acute respiratory distress syndrome, aspiration pneumonia, atelectasis, chronic obstructive airways disease exacerbation, dyspnea, epistaxis, exertional dyspnea, hemoptysis, hypoxia, lung infiltration, pleural effusion, pneumonitis, respiratory distress; acute diffuse infiltrative pulmonary disease (postmarketing).
Pyrexia (35%); edema (28%); peripheral edema (20%); herpes zoster (13%); lower limb edema (11%); herpes simplex (2% to 8%); aspergillosis, bacteremia, catheter-related complication or infection, face edema, herpes viral infection, listeriosis, oral candidiasis, septic shock, subdural hematoma, toxoplasmosis.
Monitor patient for symptoms of neuropathy (eg, burning sensation, discomfort, hyperesthesia, hypoesthesia, neuropathic pain or weakness, paresthesia). Monitor CBC frequently throughout therapy. Monitor platelet counts prior to each dose of bortezomib. Monitor BP, especially in patients concurrently receiving medications known to lower BP. Closely monitor blood glucose levels in patients receiving oral hypoglycemic agents. Closely monitor patients with risk factors for heart disease and those with existing heart disease. Monitor patients with high tumor burden closely for tumor lysis syndrome. Closely monitor patients with moderate or severe hepatic impairment for toxicities.
Category D .
Safety and efficacy not established.
No differences in safety and efficacy have been observed between patients 65 yr of age and older compared with younger patients.
Administer dose after dialysis procedure.
Exposure is increased in patients with moderate or severe hepatic impairment; treat these patients at reduced starting doses and closely monitor for toxicities.
Acute development or exacerbation of CHF and new onset of decreased left ventricular ejection fraction may occur.
Constipation, diarrhea, nausea, and vomiting, sometimes requiring use of antiemetics and antidiarrheals, may occur. Ileus can occur.
Acute liver failure has been reported.
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 that is predominantly sensory may occur, although severe sensory and motor peripheral neuropathy has been reported.
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.
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.
- 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 women of childbearing potential to take measures to prevent pregnancy during 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 patients with diabetes 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, burning feeling in the feet or hands, or weakness in the arms or legs.
Copyright © 2009 Wolters Kluwer Health.