bortezomib

bor-TEZ-o-mib

Therapeutic Classification: antineoplastics

Pharmacologic Classification: proteasome inhibitors

High Alert

Multiple myeloma (as initial therapy or after progression) (in combination with melphalan and prednisone).
Mantle cell lymphoma.

Inhibits proteasome, a regulator of intracellular protein catabolism, resulting in disruption of various intracellular processes.
Cytotoxic to a variety of cancerous cells.

Therapeutic effects:

Decreased progression and improved survival in multiple myeloma and mantle cell lymphoma.

Absorption: IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues.

Metabolism/Excretion: Mostly metabolized by the liver via the CYP2C19, CYP3A4, and CYP1A2 isoenzymes, and to a lesser extent by the CYP2D6 and CYP2C9 isoenzymes; excretion pathway unknown.

Half-Life: 9–15 hr.

ROUTE	ONSET	PEAK	DURATION
IV	unknown	38 days*	unknown

*Median time to response based on clinical parameters.

Contraindicated in:

Hypersensitivity to bortezomib, boron, or mannitol;
Intrathecal administration (may cause death);
OB: Pregnancy;
Lactation: Lactation.

Use Cautiously in:

History of or risk factors for HF;
Moderate or severe hepatic impairment;
Rep: Women of reproductive potential and men with female partners of reproductive potential;
Pedi: Safety and effectiveness not established in children.

CV: hypotension, HF

Derm: STEVENS-JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

EENT: blurred vision, diplopia

GI: anorexia, constipation, diarrhea, nausea, vomiting, LIVER FAILURE

Hemat: anemia, neutropenia, thrombocytopenia, BLEEDING, THROMBOTIC THROMBOCYTOPENIC PURPURA/HEMOLYTIC UREMIC SYNDROME

Neuro: fatigue, malaise, peripheral neuropathy, weakness, dizziness, POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES), syncope

Resp: pneumonia

Misc: fever, tumor lysis syndrome

Drug-drug:

Neurotoxic medications including amiodarone, some antivirals, nitrofurantoin, isoniazid, or HMG-CoA reductase inhibitors may ↑ risk of peripheral neuropathy.

Previously Untreated Multiple Myeloma

IV SUBQ (Adults ): 1.3 mg/m² twice weekly on Days 1, 4, 8, 11, 22, 25, 29, and 32 for Cycles 1–4 ), then once weekly on Days 1, 8, 22, and 29 for Cycles 5–9); further cycles/doses depend on response and toxicity.

Hepatic Impairment

IV (Adults ): Moderate or severe hepatic impairment: 0.7 mg/m² per injection for the 1st cycle, then may ↑ to 1 mg/m² per injection or ↓ further to 0.5 mg/m² per injection, based on tolerability.

Previously Untreated Mantle Cell Lymphoma

IV SUBQ (Adults ): 1.3 mg/m² twice weekly on Days 1, 4, 8, and 11, followed by a 10-day rest (days 12–21); repeat for 5 additional cycles; further cycles/doses depend on response and toxicity.

Hepatic Impairment

IV (Adults ): Moderate or severe hepatic impairment: 0.7 mg/m² per injection for the 1st cycle, then may ↑ to 1 mg/m² per injection or ↓ further to 0.5 mg/m² per injection, based on tolerability.

Relapsed Multiple Myeloma and Mantle Cell Lymphoma

IV SUBQ (Adults ): 1.3 mg/m² twice weekly on Days 1, 4, 8, and 11 for 2 wk , followed by a 10-day rest; further cycles/doses depend on response and toxicity. Patients with multiple myeloma who have previously responded to bortezomib therapy and who have relapsed ≥6 mo after prior bortezomib therapy can be started on their last tolerated dose; dose should be given twice weekly on Days 1, 4, 8, and 11 every 3 wk for a max of 8 cycles.

Hepatic Impairment

IV (Adults ): Moderate or severe hepatic impairment: 0.7 mg/m² per injection for the 1st cycle, then may ↑ to 1 mg/m² per injection or ↓ further to 0.5 mg/m² per injection, based on tolerability.

(Generic available)

Lyophilized powder for injection: 1 mg/vial; 2 mg/vial; 3.5 mg/vial
Solution for injection: 2.5 mg/mL

Monitor vital signs frequently during therapy. May cause fever and orthostatic hypotension requiring adjustment of antihypertensives, hydration, or administration of mineralocorticoids.
Monitor for GI adverse effects. May require antidiarrheals, antiemetics, and fluid and electrolyte replacement to prevent dehydration. Weigh weekly; modify diet as tolerated.
Monitor for signs/symptoms of peripheral neuropathy (burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain, weakness) during therapy. If Grade 1 peripheral neuropathy occurs, continue prescribed dose. If Grade 1 paresthesia with pain or Grade 2 peripheral neuropathy occurs,↓ dose to 1 mg/m². If Grade 2 peripheral neuropathy with pain or Grade 3 peripheral neuropathy occurs, hold bortezomib until toxicity resolves, then restart with a ↓ dose of 0.7 mg/m² and ↓ frequency to once weekly. If Grade 4 peripheral neuropathy occurs, discontinue bortezomib.
Monitor for signs/symptoms of tumor lysis syndrome (tachypnea, tachycardia, hypotension, pulmonary edema). Patients with high tumor burden before treatment are at ↑ risk.
Monitor for signs/symptoms of PRES (headache, seizure, lethargy, confusion, blindness). Hypertension may or may not be present. May occur within 16 hr–1 yr of initiation of therapy. Treat hypertension if present and discontinue bortezomib therapy. Symptoms usually resolve within days.
Monitor for signs/symptoms of thrombotic angiopathy (thrombocytopenia, microangiopathic hemolytic anemia, thrombotic thrombocytopenic purpura/hemolytic uremic syndrome, acute kidney injury). If thrombotic angiopathy occurs, discontinue bortezomib.

Lab Test Considerations:

Verify negative pregnancy test before starting therapy.
Monitor blood glucose levels closely in patients taking PO hypoglycemic agents; may require adjustment of antidiabetic agent dose.
Monitor CBC frequently during therapy. Assess platelet count before each dose. Dose modifications for hematologic toxicity are made based on indication and concurrent drug therapy; see manufacturer's recommendations. The nadir of thrombocytopenia is day 11 and recovery is usually by next cycle. Occurs more commonly in Cycles 1 and 2, but may occur throughout therapy. May require discontinuation of therapy.
Before starting any cycle of therapy in combination with melphalan and prednisone: Platelet count should be >70 x 10⁹/L and ANC should be >1 x 10⁹/L. Nonhematologic toxicities should have resolved to Grade ≤1.
If bortezomib is given in combination with rituximab, cyclophosphamide, doxorubicin and prednisone,Before the 1st day of each cycle (other than Cycle 1): Platelet count should be >100 x 10⁹/L and ANC should be >1.5 x 10⁹/L. Hemoglobin should be >8 g/dL (>4.96 mmol/L). Nonhematologic toxicity should have recovered to Grade ≤1.

Administer under the supervision of a physician experienced in the use of antineoplastic therapy.
- Wear gloves, gown, and mask while handling medication. Discard IV equipment in specially designated containers.
Dosage modifications during cycles of combination bortezomib, melphalan and prednisone therapy. Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle,Consider ↓melphalan dose by 25% in the next cycle. If platelet count is not >30 × 10⁹/L or ANC is not >0.75 x 10⁹/L on a bortezomib dosing day (other than Day 1), hold bortezomib dose. If several bortezomib doses in consecutive cycles are held due to toxicity, ↓bortezomib dose by 1 dose level (from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²). If Grade ≥3 nonhematologic toxicities, hold bortezomib therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Restart bortezomib with 1 dose level ↓(from 1.3 mg/m²to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²).
Dosage modification for bortezomib when given in combination with rituximab, cyclophosphamide, doxorubicin and prednisone: For hematological toxicity. If Grade 3 or higher neutropenia, or platelet count not ≥25 x 10⁹/L, hold bortezomib therapy for up to 2 wk until ANC ≥0.75 x 10⁹/L and platelet count ≥25 x 10⁹/L. If bortezomib has been held, the toxicity does not resolve, discontinue bortezomib. If toxicity resolves and ANC ≥0.75 x 10⁹/L and platelet count ≥25 x 10⁹/L, ↓bortezomib dose by 1 dose level (from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²). If Grade ≥3 nonhematologic toxicities, hold bortezomib therapy until symptoms of toxicity resolve to Grade 2 or better. Restart bortezomib with 1 dose level ↓(from 1.3 mg/m² to 1 mg/m², or from 1 mg/m² to 0.7 mg/m²).
Dose modifications for relapsed multiple myeloma and relapsed mantle cell lymphoma: If any Grade 3 nonhematologic or Grade 4 hematologic toxicities excluding neuropathy, hold bortezomib therapy. Once symptoms of toxicity have resolved, restart at a 25% ↓dose (1.3 mg/m²/dose ↓to 1 mg/m²/dose; 1 mg/m²/dose ↓to 0.7 mg/m²/dose).
Dosage modifications for peripheral neuropathy:If Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function, No action. If Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental ADLs), ↓bortezomib to 1 mg/m². If Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADLs), hold bortezomib until toxicity resolves. When resolved, start at ↓dose of bortezomib at 0.7 mg/m² once per wk. If Grade 4 (life-threatening consequences; urgent intervention indicated),discontinue bortezomib.
Recommended starting dose modification with hepatic impairment:For mild (bilirubin ≤1 × ULN with SGOT [AST] > ULN, or bilirubin >1 × to 1.5 × ULN and any SGOT [AST]), no action. For moderate (bilirubin >1.5 × to 3 × ULN) or severe (bilirubin >3 × ULN), and any SGOT [AST] , ↓ dose to 0.7 mg/m²in Cycle 1; based on tolerability, dose may be ↑ to 1 mg/m²or ↓ to 0.5 mg/m² in subsequent cycles.

IV Administration:

SUBQ: Reconstitution: Reconstitute each vial with 1.4 mL of 0.9% NaCl.Concentration: 2.5 mg/mL. Solution should be clear and colorless; do not administer solutions that are discolored or contain particulate matter. May inject into thigh or abdomen; rotate injection sites. Inject into sites >1 inch from other sites and avoid tender, bruised, erythematous, or indurated sites. If local injection site reactions occur, may inject a less concentrated (1 mg/mL) solution.
IV Push: Reconstitution: Reconstitute each vial with 3.5 mL of 0.9% NaCl. Solution should be clear and colorless; do not administer solutions that are discolored or contain particulate matter.Concentration: 1 mg/mL. Administer reconstituted solution within 8 hr at room temperature; 3 of the 8 hr may be stored in a syringe.
Rate: Administer as a 3–5 sec bolus injection twice weekly for 2 wk followed by a 10-day rest period. ≥72 hr should elapse between consecutive doses.

Explain purpose and side effects of medication to patient. Advise patient to read Patient Information before starting therapy.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Advise the patient that dehydration may occur with vomiting or diarrhea. Advise patient to maintain fluid intake and to notify health care professional if dizziness or fainting occurs.
Advise patient to contact health care professional if they experience new or worsening signs/symptoms of peripheral neuropathy (tingling, numbness, pain, burning feeling in the feet or hands, weakness in the arms or legs), PML (progressive weakness on one side of the body or clumsiness of limbs; disturbance of vision; changes in thinking, memory, and orientation leading to confusion and personality changes), or if symptoms of dehydration (dizziness, fainting) due to vomiting or diarrhea; rash; shortness of breath; cough; swelling of feet, ankles, or legs; bleeding, infection, convulsions; persistent headache; ↓ eyesight; ↑ BP or blurred vision occur.
May cause dizziness and blurred vision. Advise patient to avoid driving or other activities requiring alertness until response to medication is known.
Advise patients with diabetes taking PO hypoglycemic agents to monitor blood glucose frequently and notify health care professional of changes in blood sugar.
Rep: Advise women of reproductive potential to use effective contraception during and for 7 mo after last dose and to avoid breastfeeding during therapy and for 2 mo after therapy. Advise men with female partners of reproductive potential to use effective contraception for 4 mo after last dose of bortezomib. Patient should notify health care professional immediately if pregnancy is suspected. May impair fertility in men and women.

Decreased progression and improved survival in multiple myeloma and mantle cell lymphoma.

Boruzu, Velcade

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