Verify pregnancy status. Baseline studies indicated; see Monitor.
Previously untreated multiple myeloma:
1.3 mg/M2/dose as an IV bolus. Given in combination with oral melphalan and oral prednisone for nine 6-week cycles as outlined in the following chart. For Cycles 1 to 4, administer twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32). For Cycles 5 to 9, administer once weekly (Days 1, 8, 22, 29). At least 72 hours should elapse between consecutive doses of bortezomib.
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Previously untreated mantle cell lymphoma:
1.3 mg/M2/dose as an IV bolus. Given in combination with intravenous rituximab, cyclophosphamide, doxorubicin, and oral prednisone (VcR-CAP) for six 3-week cycles as outlined in the following chart. Bortezomib is administered first, followed by rituximab. Bortezomib is administered twice weekly for 2 weeks (Days 1, 4, 8, 11), followed by a 10-day rest period on Days 12 to 21. For patients with a response first documented at Cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of bortezomib.
a Dosing may continue for 2 more cycles (for a total of 8 cycles) if response is first seen at Cycle 6. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
Relapsed multiple myeloma and relapsed mantle cell lymphoma:
1.3 mg/M2/dose as an IV bolus 2 times a week for 2 weeks (Days 1, 4, 8, and 11). Follow with a 10-day rest period (Days 12 through 21). At least 72 hours should elapse between doses of bortezomib (e.g., Days 1, 4, 8, and 11). A treatment cycle is 21 days. See Dose Adjustments. For extended therapy of more than 8 cycles, bortezomib may be administered on the above standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4 weeks (Days 1, 8, 15, and 22), followed by a 13-day rest period (Days 23 to 35).
Patients with multiple myeloma who have previously responded to treatment with bortezomib (either alone or in combination) and who have relapsed at least 6 months after their prior therapy may be started on bortezomib at the last tolerated dose. Retreated patients are administered bortezomib twice weekly (Days 1, 4, 8, and 11) every 3 weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of bortezomib. Bortezomib may be administered either alone or in combination with dexamethasone.
Combination therapy in multiple myeloma (unlabeled in bortezomib prescribing information):
Administer 1.3 mg/M2 as an IV bolus on Days 1, 4, 8, and 11 every 3 weeks.
Administer 30 mg/M2 on Day 4 following bortezomib. Continue for up to 8 cycles until disease progression or the occurrence of unacceptable toxicity.
Dose adjustments are based on clinical toxicities. ■ Starting dose adjustments are not required for patients with renal insufficiency, including those requiring dialysis. Bortezomib may be partially removed by dialysis. Administer after dialysis. ■ No significant difference in the pharmacokinetics of bortezomib based on age, sex, or renal impairment; see Precautions. ■ See the following charts for recommended starting dose modifications for patients with moderate to severe hepatic impairment; dose adjustments in combination therapy with melphalan and prednisone; dose adjustments in combination therapy with rituximab, cyclophosphamide, doxorubicin, and prednisone; dose adjustments in relapsed multiple myeloma and mantle cell lymphoma; and dose modifications for bortezomib-related neuropathic pain and/or peripheral sensory or motor neuropathy.
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Combination therapy with melphalan and prednisone in previously untreated multiple myeloma:
Before each treatment cycle, platelet count should be equal to or greater than 70 × 109/L, and ANC should be equal to or greater than 1 × 109/L. Nonhematologic toxicities should have resolved to Grade 1 or baseline. Dose modifications for subsequent cycles are outlined in the following chart.
a Graded according to Common Terminology Criteria for Adverse Events (CTCAE). | ||||||||||||||||||||||||
Combination therapy with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone in previously untreated mantle cell lymphoma:
Before the first day of each cycle (other than Cycle 1), platelet count should be equal to or greater than 100 × 109/L, and ANC should be equal to or greater than 1.5 × 109/L. Hemoglobin should be equal to or greater than 8 g/dL, and nonhematologic toxicities should have resolved to Grade 1 or baseline. Dose modifications for Days 4, 8, and 11 are outlined in the following chart.
For information concerning rituximab, cyclophosphamide, doxorubicin, and prednisone, see manufacturer’s prescribing information.
Relapsed multiple myeloma and relapsed mantle cell lymphoma:
Withhold dose if a Grade 3 nonhematologic toxicity (e.g., 6 to 10 emeses/24 hr, severe infection) or a Grade 4 hematologic toxicity (e.g., thrombocytopenia less than 25,000/mm3) occurs. When symptoms have resolved, resume treatment with a dose reduced by 25% (1.3 mg/M2/dose reduced to 1 mg/M2/dose, 1 mg/M2/dose reduced to 0.7 mg/M2/dose). ■ See doxorubicin monograph for additional dose adjustments required in Doxil and bortezomib combination therapy for treatment of multiple myeloma. ■ Reduce dose in patients who develop bortezomib-related neuropathic pain and/or peripheral sensory or motor neuropathy according to the following chart.
aGraded according to Common Terminology Criteria for Adverse Events (CTCAE), v. 4.0. bInstrumental ADL (e.g., preparing meals, shopping for groceries or clothes, using telephone, managing money). cSelf-care ADL (e.g., bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden). | ||||||||||||||||||||||||
Specific techniques required; see Precautions.
For IV use, reconstitute each 3.5-mg vial only with 3.5 mL NS. Concentration equals 1 mg/mL. The SC route uses less diluent and results in a different concentration (2.5 mg/mL). To prevent overdosage, use caution when diluting and calculating volume to administer. Manufacturer supplies a sticker that specifies indicated route of administration. Place sticker on syringe of prepared bortezomib.
Stable until expiration date when stored at CRT in original package and protected from light. Reconstituted solution stable at 25° C (77° F) for up to 8 hours in a syringe or in original vial when exposed to normal indoor lighting. Must be given within 8 hours.
A single dose as an IV bolus injection over 3 to 5 seconds. May be given into a peripheral vein. To ensure the full dose is administered, flush with NS after injection.
May also be given through an IV port if the primary IV is temporarily discontinued. Flush with NS before and after administration.
A reversible inhibitor of the 26S proteasome, which is a large protein complex that degrades ubiquitinated proteins. The blocking of this proteasome disrupts numerous biologic pathways related to the growth and survival of cancer cells and can lead to cell death. Distributes widely to peripheral tissues. Over 80% is bound to plasma proteins. Mean elimination half-life after multiple doses ranges from 76 to 108 hours after the 1.3 mg/M2 dose. Metabolized in the liver via selected cytochrome P450 enzymes. Pathways of elimination in humans have not been determined.
Treatment of patients with multiple myeloma. ■ Treatment of patients with mantle cell lymphoma.
Treatment of multiple myeloma in combination with doxorubicin liposomal injection in patients who have received one prior therapy but have not previously received bortezomib.
Hypersensitivity to bortezomib or any component of the formulation (e.g., boron or mannitol), not including local reactions. ■ Intrathecal administration.
Follow guidelines for handling cytotoxic agents. See Appendix A. ■ Velcade may be given IV or SC depending on dilution. Generic formulations of bortezomib are for IV use only. ■ Administered by or under the supervision of a physician experienced in the use of antineoplastic therapy in a facility equipped to monitor the patient and respond to any medical emergency. ■ Bortezomib therapy causes peripheral neuropathy. Both sensory and motor peripheral neuropathy have been reported. Use caution in patients with pre-existing peripheral neuropathy; symptoms may worsen. Many have been treated previously with neurotoxic agents. Incidence of peripheral neuropathy may be less with SC administration. Use of the SC route may be considered for patients who have pre-existing or are at high risk for peripheral neuropathy. ■ May cause orthostatic/postural hypotension. Use with caution in patients with a history of syncope, in patients receiving concomitant medications that may cause hypotension, and in patients who are dehydrated. ■ Hypersensitivity reactions (including anaphylactic reactions) have been reported. ■ Thrombocytopenia and neutropenia have been reported; see Monitor. ■ Gastrointestinal and intracerebral hemorrhages have occurred during thrombocytopenia in association with bortezomib. ■ Acute development or exacerbation of CHF and/or new onset of decreased left ventricular ejection fraction has been reported. ■ Acute respiratory distress syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred. ■ Pulmonary hypertension in the absence of left heart failure or significant pulmonary disease has been reported. ■ Posterior reversible encephalopathy syndrome (PRES), formerly termed reversible posterior leukoencephalopathy syndrome (RPLS), has occurred. Patients may present with visual or neurologic disturbances. MRI may be used to confirm diagnosis. ■ Use caution in patients with moderate to severe liver impairment. Clearance decreased; see Monitor and Dose Adjustments. ■ Use caution in patients who are receiving multiple concomitant medications and/or who have serious underlying medical conditions; asymptomatic increases in liver enzymes, hyperbilirubinemia, hepatitis, and rare cases of acute liver failure have been reported. May be reversible if bortezomib is discontinued. Information on rechallenging these patients is limited. ■ Tumor lysis syndrome has been reported; patients with a high tumor burden are at increased risk. ■ Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported. ■ GI adverse events, including constipation, diarrhea, ileus, nausea, and vomiting, have been reported and may require treatment. ■ Consider antiviral prophylaxis. Herpes simplex and herpes zoster reactivation have been reported.
Obtain baseline CBC with differential and platelet count; repeat before each cycle and monitor as needed during treatment. Monitor platelet count before each dose. ■ Obtain baseline electrolytes, including serum calcium and potassium. Monitor fluid and electrolyte balance and replace as indicated. Prevent dehydration. ■ Obtain baseline bilirubin and AST and repeat as indicated; see Dose Adjustments. Monitor patients with impaired liver function closely for S/S of bortezomib toxicity. ■ Monitor BP closely. Dehydration and/or concomitant medications may contribute to hypotension. Assist with ambulation. ■ Monitor patients at risk for or with existing heart disease closely for S/S of CHF (e.g., exertional dyspnea, orthopnea, edema, tachycardia, pulmonary rales, a third heart sound, jugular venous distention) and/or for new onset of decreased left ventricular ejection fraction. ■ Use prophylactic antiemetics to reduce nausea and vomiting and increase patient comfort. ■ Antidiarrheal medication (e.g., loperamide [Imodium]) may be indicated. ■ Monitor for S/S of peripheral neuropathy (e.g., burning sensation, discomfort, hyperesthesia [sensitivity of skin], hypoesthesia [impairment of any sense, especially touch], neuropathic pain or weakness, paresthesia [abnormal sensation such as burning, prickling]). Incidence may be increased in patients treated previously with neurotoxic agents (e.g., cisplatin, thalidomide [Thalomid], vinca alkaloids [e.g., vincristine]). See Dose Adjustments; may require change of dose or schedule. Improvement in or a resolution of peripheral neuropathy has been reported following dose adjustment or discontinuation of bortezomib. ■ Monitor for neutropenia and thrombocytopenia (platelet count less than 50,000/mm3). Occurs in a cyclical pattern with nadirs occurring after the last dose of each cycle and typically recovering before initiation of the next cycle. Initiate precautions to prevent excessive bleeding (e.g., inspect IV sites, skin, and mucous membranes; use extreme care during invasive procedures; test urine, emesis, stool, and secretions for occult blood). ■ Monitor uric acid levels before and during therapy. Hydration and uric acid–lowering drugs (e.g., allopurinol [Aloprim]) may be indicated for serious tumor lysis syndrome. ■ Monitor for S/S of TTP/HUS (e.g., fever, microangiopathic hemolytic anemia [see schistocytes in a blood smear], renal failure, thrombocytopenia, and neurologic manifestations). ■ Hypoglycemia and hyperglycemia have been reported in patients taking oral diabetic agents. Monitor blood glucose levels and adjust antidiabetic medications as indicated; see Drug/Lab Interactions. ■ Monitor respiratory status closely. Any change in condition should be evaluated promptly and treated as indicated. ■ Monitor for S/S associated with development of PRES (e.g., blindness, confusion, headache, hypertension, lethargy, seizures, and other visual and neurologic disturbances).
Verify pregnancy status of females of reproductive potential before initiating therapy. ■ Avoid pregnancy. Females of reproductive potential should use effective contraception during treatment with bortezomib and for 7 months after treatment. Males with female sexual partners of reproductive potential should use effective contraception during treatment with bortezomib and for 4 months after treatment. Should pregnancy occur, notify physician immediately and discuss potential hazards. ■ May have an effect on male and female fertility. ■ May cause dizziness, fatigue, hypotension, or syncope; use caution when driving or operating machinery. ■ Review all medications with your physician and/or pharmacist; effects of medications for high blood pressure and other medications that may lower blood pressure may increase hypotension. Other agents may increase peripheral neuropathy. May interfere with medications for diabetes. ■ Promptly report bleeding, constipation, decreased appetite, fever, or an increase in blood pressure ■ Review of monitoring requirements and adverse events before therapy is imperative. ■ Avoid dehydration; promptly report diarrhea, dizziness, fainting spells, light-headedness, muscle cramps, and vomiting. ■ Promptly report any signs of infection (e.g., chills, fever, night sweats) or signs of bleeding (e.g., bruising, tarry stools, blood in urine, pinpoint red spots on skin). ■ Promptly report symptoms of peripheral neuropathy (e.g., burning sensation [feet or hands], numbness, pain, tingling, or weakness in the arms or legs). If these symptoms pre-existed, report if they seem to be worse. ■ Promptly report shortness of breath, cough, or other lung problems. ■ Promptly report swelling of the ankles, feet, or legs. ■ Report any visual or neurologic disturbances. ■ Promptly report jaundice or right upper quadrant pain. ■ Promptly report rash, severe injection site reactions, or skin pain. ■ See Appendix D, p. 1311.
Based on the mechanism of action and findings in animals, bortezomib can cause fetal harm. Use of effective contraception required. ■ Discontinue breast-feeding during treatment and for up to 2 months after treatment. ■ Safety and effectiveness for use in pediatric patients not established.
Safety and effectiveness similar to other age-groups; however, greater sensitivity in the elderly cannot be ruled out. In clinical trials, patients over 65 years of age had a slightly increased incidence of Grade 3 or 4 toxicity.
Drug interaction studies are limited. ■ Bortezomib is a substrate of CYP3A4, 2C19, and 1A2; concomitant administration of inhibitors or inducers of selected cytochrome P450 enzymes may cause toxicity or reduce effectiveness of bortezomib. Consult pharmacist. Inhibitors may reduce metabolism and increase serum levels of bortezomib. ■ Coadministration with ketoconazole, an inhibitor, increases bortezomib exposure. Monitor for toxicity. Other examples of inhibitors include cimetidine, erythromycins, grapefruit juice, antifungal agents (e.g., itraconazole), nefazodone, and ritonavir. Patients receiving bortezomib in conjunction with a strong CYP3A4 inhibitor should be closely monitored. ■ Inducers may increase metabolism and decrease serum levels and effectiveness of bortezomib. Examples of inducers may include carbamazepine, phenobarbital, phenytoin, and rifampin. Concomitant use of strong CYP3A4 inducers (e.g., rifampin) is not recommended. ■ Hypotension may be increased by agents that induce hypotension (e.g., alcohol, antihypertensives [e.g., ACE inhibitors (e.g., lisinopril)], beta-blockers [e.g., atenolol]). ■ May increase or decrease the effects of oral antidiabetic agents (e.g., glyburide, glipizide). Monitor blood glucose levels and adjust dose of antidiabetic medication as indicated.
Diarrhea, fatigue, peripheral neuropathy, excessive vomiting, and thrombocytopenia may be dose limiting. Most common side effects reported include anemia, anorexia, constipation, diarrhea, fatigue, fever, leukopenia, lymphopenia, nausea and vomiting, neuralgia, neutropenia, peripheral neuropathy, rash, and thrombocytopenia. Abdominal distention, abdominal pain, alopecia, arthralgia, asthenia, bronchitis, cardiac failure, chills, cough, decreased appetite, dehydration, dizziness, dysesthesia, edema, febrile neutropenia, headache, hypertension, hypoesthesia, hypotension, hyperglycemia, malaise, nasopharyngitis, paresthesia, peripheral edema, pneumonia, psychotic disorders (e.g., anxiety, agitation, confusion, insomnia, mental status change, suicidal ideation), reactivation of herpesvirus infections (zoster and simplex), respiratory tract infections, stomatitis, upper abdominal pain, weakness, and weight loss have also been reported. Numerous other side effects have been reported that may or may not be related to bortezomib and include hypersensitivity reactions (including anaphylaxis and immune complex–mediated hypersensitivity), ARDS and other pulmonary disorders, bleeding (e.g., GI, intracerebral), CVA, GI disorders (serious [e.g., acute pancreatitis, ischemic colitis, paralytic ileus]), hepatic disorders (e.g., cholestasis, liver failure, portal vein thrombosis), hyperbilirubinemia, hypernatremia, hyperuricemia, hypocalcemia, hypokalemia, hyponatremia, infections (e.g., aspergillosis, bacteremia, herpes, listeriosis, oral candidiasis, septic shock, toxoplasmosis, URI), MI, pleural effusion, PRES, pulmonary embolism, pulmonary hypertension, renal disorders (e.g., acute or chronic renal failure, calculus, hemorrhagic cystitis, hydronephrosis), respiratory distress, and tumor lysis syndrome. See prescribing information for additional side effects.
Acute diffuse infiltrative pulmonary disease, acute febrile neutrophilic dermatosis (Sweet’s syndrome), blindness, cardiac tamponade, chalazion/blepharitis, deafness (bilateral), herpes meningoencephalitis, ischemic colitis, ophthalmic herpes, optic neuropathy, PRES, progressive multifocal leukoencephalopathy (PML), and Stevens-Johnson syndrome/toxic epidermal necrolysis.
Profound progressive hypotension, tachycardia, and decreased cardiac contractility. Symptomatic hypotension and thrombocytopenia with fatal outcomes have been reported in patients who received more than twice the recommended dose.
Keep physician informed of all side effects. Most will be treated symptomatically as indicated. See Dose Adjustments for dosing modifications based on toxicity. Temporarily discontinue bortezomib if severe thrombocytopenia occurs (less than 25,000 or 30,000/mm3, depending on indication); may be resumed at a reduced dose after thrombocytopenia is resolved. Severe thrombocytopenia may require platelet transfusions. Reduce dose, withhold dose, or discontinue based on S/S of peripheral neuropathy. Symptoms of peripheral neuropathy may improve or return to baseline if bortezomib is discontinued. Hypotension may respond to adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids and/or sympathomimetics. Withhold bortezomib for Grade 3 neutropenia. Recovery from neutropenia may be spontaneous or may be treated with filgrastim (Neupogen, Zarxio) or pegfilgrastim (Neulasta). Treat anemia as indicated with whole blood products (e.g., packed RBCs) or blood modifiers (e.g., darbepoetin alfa [Aranesp], epoetin alfa [Epogen]). For new or worsening cardiopulmonary symptoms, consider interrupting bortezomib until a prompt and comprehensive diagnostic evaluation is conducted. For symptoms of serious liver dysfunction, interrupt bortezomib to assess reversibility. Discontinue bortezomib in patients who develop PRES. In overdose, monitor V/S continuously and provide supportive care. Maintain BP with dopamine, epinephrine, or norepinephrine (Levophed) as needed. Maintain body temperature. If diagnosis of TTP/HUS is suspected, stop treatment and evaluate. If diagnosis is excluded, consider restarting There is no specific antidote; supportive therapy will help sustain the patient in toxicity. Resuscitate as indicated.