Special pediatric considerations are noted when applicable, otherwise adult provisions apply.

MECHANISM OF ACTION

: Bortezomib is a reversible inhibitor of the 26S proteasome, a protein complex that degrades ubiquitinated proteins. This inhibition affects cancer cells in a number of ways, including altering regulatory proteins, which control cell cycle progression and Nuclear Factor kappa B activation. Inhibition of the proteasome results in cell cycle arrest and apotosis.1

PHARMACOKINETICS:

SPECIAL PRECAUTIONS:

Contraindicated 1

in patients who have a history of hypersensitivity reaction to bortezomib, boron, or any components of the formulation.

Hepatitis B (HBV) reactivation:

All lymphoma and myeloma patients should be tested for both HBsAg and HBcAb. If either test is positive, such patients should be treated with lamivudine 100 mg/day orally, for the entire duration of chemotherapy and for six months afterwards. Such patients should also be monitored with frequent liver function tests and HBV DNA at least every two months. If the HBV DNA level rises during this monitoring, management

should be reviewed with an appropriate specialist with experience managing hepatitis and consideration given to halting chemotherapy.4

Carcinogenicity:

Mutagenicity: Not mutagenic in Ames test and in the mammalian in vivo mutation test. Bortezomib is clastogenic in mammalian in vitro chromosome tests.1

Fertility: 1

Fertility studies have not been performed. Degenerative effects in ovaries and testes suggest a potential effect on fertility.

Pregnancy: FDA Pregnancy Category D.5 There is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Breastfeeding 1

Drugs associated with peripheral neuropathy: 5

An increased risk of peripheral neuropathy may occur when bortezomib is used concomitantly with other drugs associated with peripheral neuropathy; (e.g., amiodarone, antiviral agents, isoniazid, nitrofurantoin, and HMG-CoA reductase inhibitors.)

Overdosage with as little as twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes.1 In the event of an overdosage, monitor vital signs and provide supportive care to maintain blood pressure and body temperature.1 Special Populations: Greater sensitivity of elderly patients cannot be ruled out; however, no overall differences in safety or effectiveness were observed between younger patients and patients >65 years of age.1 Patients on oral antidiabetic agents receiving bortezomib may experience hypo and hyperglycemia; monitor blood glucose levels closely.1 An increased risk of hypotension exists when bortezomib is used with medications that can cause hypotension.5 Dosage adjustment of hypotensive agents may be necessary.5 Patients with amyloidosis should be treated with caution as the impact of proteasome inhibition on disorders associated with protein accumulation is unknown.1 Potentially life-threatening transfusion-related graft-versus-host-disease can occur in previously treated myeloma patients. Patients receiving bortezomib for myeloma should receive irradiated blood products, effectively eliminating this risk.

SIDE EFFECTS:

The table includes adverse events that presented during drug treatment but may not necessarily have a causal relationship with the drug. Because clinical trials are conducted under very specific conditions, the adverse event rates observed may not reflect the rates observed in clinical practice. Adverse events are generally included if they were reported in more than 1% of patients in the product monograph or pivotal trials, and/or determined to be clinically important.6 When placebo-controlled trials are available, adverse events are included if the incidence is > 5% higher in the treatment group.7-10

ORGAN SITE	SIDE EFFECT	ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
allergy/immunology	hypersensitivity reactions (<1%)	I	E
allergy/immunology	cutaneous vasculitis 11-13		E 12	D 11
blood/bone marrow/ febrile neutropenia	anemia (26-32%, severe 9-10%)		E
blood/bone marrow/ febrile neutropenia	neutropenia (19-24%, severe 14-16%)		E

ORGAN SITE	SIDE EFFECT	ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
	thrombocytopenia (35-43%, severe 30%); nadir day 11		E 1
auditory/hearing	hearing loss (<1%) 14			D 14
cardiovascular (arrhythmia)	arrhythmias (<1%)		E
cardiovascular (general)	congestive heart failure; decreased left ventricular ejection fraction (<1%)	I	E
	hypotension (11-12%, severe 4%)	I	E
	ischemia, infarction, angina (<1%)	I	E
	pulmonary hypertension (<1%)	I	E
coagulation	disseminated intravascular coagulation (<1%)		E
constitutional symptoms	fatigue (61-65%, severe 12-18%)		E 15
	fever (35-36%, severe 4-6%)	I	E
	insomnia (18%)		E
	rigors (11-12%)	I
dermatology/skin	extravasation hazard: irritant 1
	pruritis (12%)	I	E
	rash, urticaria 16 (24-28%, severe 2%)	I	E
endocrine	ADH secretion abnormalities (<1%)		E
gastrointestinal	emetogenic potential: rare 17
	anorexia (34-43%, severe 2-3%)	I		E
	constipation (42-43%, severe 2%)	I 1		E 1
	dehydration (18%, severe 7%)	I 1		E 1
	diarrhea (55-58%, severe 7-8%)	I 1		E 1
	dyspepsia (10-13%)	I		E
	enteritis (<1%) 18			E
	ileus, obstruction (<1%)			E
	nausea (57-64%, severe 2-7%)	I 1
	stomatitis (<1%)			E
	taste alterations, dysgeusia (13%)	I
	vomiting (35-36%, severe 3-7%)	I 1
hemorrhage	epistaxis (10%)			E
hemorrhage	severe hemorrhage (<1%)			E
hepatobiliary/pancreas	liver failure (<1%) 19				D
hepatobiliary/pancreas	acute pancreatitis (<1%)			E
infection	febrile neutropenia (<1%) 15			E
infection	herpes zoster (11-13%, severe 1%)			E

ORGAN SITE	SIDE EFFECT	ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
	nasopharyngitis (14%)		E
	pneumonia (10%, severe 5%)		E
	sepsis (<1%)		E
	upper respiratory tract infection (18%)		E
lymphatics	peripheral edema (17-21%, severe 1%)		E
metabolic/laboratory	asymptomatic increases in liver enzymes (<1%)		E
	electrolyte abnormalities (<1%)		E
	hyperbilirubinemia (<1%)		E
	hyperuricemia; during periods of active cell lysis (<1%)		E
musculoskeletal	arthralgia (15-28%, severe 5%)		E
musculoskeletal	muscle cramps (24%)		E
neurology	dizziness excluding vertigo (14-21%, severe 1%)	I	E
	encephalopathy (<1%)		E
	headache (28%, severe 4%)	I	E
	insomnia (18-27%, severe 1%)	I	E
	hypoesthesia (11%)		E
	mood alterations, anxiety (14%)		E	D
	peripheral neuropathy (36-37%, severe 8-14%)		E 15	D 15
	psychosis (<1%)		E
	seizures (<1%)		E
	sensory neuropathy, paresthesias (14-21%, severe 2%)		E
ocular/visual	blurred vision (11%, severe 1%)		E
ocular/visual	diplopia (<1%)		E
pain	abdominal pain (16-20%, severe 2%)		E
	back pain (14%, severe 3-4%)		E
	bone pain (16-17%, severe 4-5%)		E
	limb pain (15%, severe 2%)		E
	musculoskeletal pain (10%)		E
	not otherwise specified (10%, severe 1-2%)		E
pulmonary	cough (17-21%)		E
	dyspnea (25-29%, severe 5%)	I	E
	pulmonary toxicity, respiratory failure (<1%) 20		E
renal/genitourinary	renal failure (<1%)		E
sexual/reproductive function	infertility, sterility		E	D

ORGAN SITE	SIDE EFFECT	ONSET
Clinically important side effects are in bold, italics I = immediate (onset in hours to days); E = early (days to weeks); D = delayed (weeks to months); L = late (months to years)
syndromes	Sweet syndrome (<1%) 21,22		E
syndromes	tumor lysis syndrome (<1%) 23,24		E

Adapted from standard reference1 unless specified otherwise.

Peripheral Neuropathy:

This is a common, and often dose limiting side effect. It is predominantly sensory, characterized by pain, paresthesias, burning dysethesias, and numbness, with feet affected more often than

hands.25 Cases of mixed sensorimotor neuropathy have also been reported.1 The mechanism underlying bortezomib-induced peripheral neuropathy is not known.1 Patients with baseline symptoms are at a greater risk of developing severe neuropathy.2 Early detection and appropriate dosage adjustments may prevent development of severe neuropathies.2,25 The development of even mildly painful peripheral neuropathy should prompt a dose reduction. Autonomic neuropathy may contribute to postural hypotension, diarrhea, constipation with ileus, and pyrexia caused by bortezomib.1 Thrombocytopenia: Patients receiving bortezomib experience a median 60% decrease in platelet count regardless of initial baseline platelet count, baseline serum myeloma protein level, or degree of bone marrow involvement.2 This pattern of thrombocytopenia is not consistent with the pattern typically observed with conventional chemotherapy.9 The onset of thrombocytopenia most commonly occurs after cycle 1 or 2 and continues throughout therapy,2 with no evidence of cumulative thrombocytopenia.25 Platelet counts typically reach a nadir on day 11 and rise to a normal count by day 21.2 In responding patients, platelet counts at baseline appear to increase progressively with successive cycles of treatment from the second cycle onwards.25 The mechanism underlying bortezomib-induced thrombocytopenia is not known, but it is unlikely to be related to marrow injury or decreased thrombopoietin production; 26 therefore supportive care rather than discontinuation of bortezomib therapy may be appropriate.2 Bortezomib should be temporarily discontinued in patients with a platelet count less than 25, (NCI Grade 4 thrombocytopenia) until the platelet count returns to normal. Bortezomib can then be reinitiated at a 25% dose reduction.2 There have been reports of GI and intracerebral hemorrhage in association with bortezomib-induced thrombocytopenia.5

Diarrhea:

Diarrhea is a common side effect in patients receiving bortezomib; severe diarrhea occurs in 7-8% of patients. Management of diarrhea should include, maintaining adequate fluid intake and prompt treatment with loperamide. Patients with severe diarrhea should be carefully monitored for dehydration and given fluid and

electrolyte replacement as needed.1 Premedication with loperamide prior to bortezomib treatment is not required. However, patients should be instructed to have loperamide on hand and start treatment at the first poorly formed or loose stool, or earliest onset of more frequent bowel movement than usual. If NCI Grade 3 diarrhea occurs,1 or if diarrhea is associate with mucus or dehydration,27 discontinue treatment until diarrhea resolves, then reinitiate at a 25% dose reduction. Hypotension: Hypotension occurs in up to 12% of patients receiving bortezomib. Risk factors include history of syncope, concomitant use of medications known to lower blood pressure, and dehydration.2 Hydration status should be assessed and corrected before and if necessary throughout bortezomib therapy, especially in patients experiencing vomiting and diarrhea.2 Additionally, dosage adjustment of hypotensive agents may be necessary.5 Mineralocorticoids and/or sympathomimetics may be effective in minimizing the hypotensive effects of bortezomib.1 Patients should be instructed to report signs and symptoms of hypotension (lightheadedness, dizziness, syncope) immediately.1 In patients experiencing NCI Grade 3 hypotension, discontinue bortezomib until symptoms resolve, and then reinitiate at a 25% dose reduction.1 Liver failure: Rare cases of acute liver failure have been reported in bortezomib-treated patients on multiple concomitant medications and with serious underlying medical conditions.1 Other reported hepatic events include asymptomatic increases in liver enzymes, hyperbilirubinemia, and hepatitis.1 These changes may be reversible upon discontinuation of bortezomib.1

Hyperuricemia1,24 may result from cell lysis by cytotoxic chemotherapy and may lead to electrolyte disturbances or acute renal failure.28 It is most likely with highly proliferative tumors of massive burden, such as leukemias, high-grade lymphomas and myeloproliferative diseases. The risk may be increased in patients with preexisting renal dysfunction, especially ureteral obstruction. Suggested prophylactic treatment for high-risk patients29:

aggressive hydration: 3 L/m2/24 hr with target urine output > 100 mL/hr
if possible, discontinuation of drugs that cause hyperuricemia (e.g., thiazide diuretics) or acidic urine (e.g., salicylates)
monitoring of electrolytes, calcium, phosphate, renal function, LDH and uric acid q6h x 24-48 hours
electrolyte replacement as required
allopurinol 600 mg po initially, then 300 mg po q6h x 6 doses, then 300 mg po daily x 5-7 days

Urine should be alkalinized only if the uric acid level is elevated, using sodium bicarbonate IV or PO titrated to maintain urine pH > 7. Rasburicase (FASTURTEC(r)) is a novel uricolytic agent that catalyzes the oxidation of uric acid to a water-soluble metabolite, removing the need for alkalinization of the urine.30 It may be used for treatment or prophylaxis of hyperuricemia, 0.2 mg/kg IV daily for up to 7 days; however, its place in therapy has not yet been established.

INTERACTIONS:

Bortezomib may inhibit CYP450 isoenzyme 2C19 and increase the levels/effects of CYP2C19 substrates.5

Bortezomib is a substrate mainly for CYP3A4 and CYP2C19. Patients receiving bortezomib with inhibitors or inducers of CYP 3A4 and 2C19 should be monitored for potential toxicities or reduced efficacy assiociated with concomitant use.1

SUPPLY AND STORAGE:

Injection: supplied as a 3.5 mg sterile preservative free lyophilized powder for injection.1 Unopened vials should be stored at room temperature and protected from light.5

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

Compatibility of selected drugs:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Refer to protocol by which patient is being treated. Numerous dosing schedules exist and depend on disease, response and concomitant therapy. Guidelines for dosing also include consideration of absolute neutrophil count (ANC). Dosage may be reduced, delayed or discontinued in patients with bone marrow depression due to cytotoxic/radiation therapy or with other toxicities.

Intravenous: 3 weeks27: 1.3 mg/m2 (range 1-1.3 mg/m2) IV for one dose on days 1, 4, 8, and 11. Consecutive doses should be separated by at least 72 hours1

(total dose per cycle 5.2 mg/m2 [range 4-5.2 mg/m2])

For maintenance therapy (beyond 8 cycles) standard doses may be used, or 1.3 mg/m2 (range 1-1.3 mg/m2) IV for one dose on days 1, 8, 15, and 22 of a 5 week cycle.1 (total dose per cycle 5.2 mg/m2 [range 4-5.2 mg/m2]) 3 weeks27: 1 mg/m2 IV for one dose on days 1, 4, 8, and 11 when given in combination with other chemotherapy. Consecutive doses should be separated by at least 72 hours.27 (total dose per cycle 4 mg/m2)

Dosage in myelosuppression1: at the onset of any NCI Grade 4 hematological toxicities, discontinue bortezomib until symptoms resolve; reinitiate at a 25% dose reduction

Dosage in renal failure1: use with caution in patients with renal impairment Dosage in hepatic failure1: use with caution in patients with hepatic impairment Dosage in dialysis31: has been given safely to patients on hemodialysis Dosage in neuropathy1: Peripheral neuropathy

Grade 1 without pain or loss of function maintain dose Grade 1 with pain or Grade 2 reduce dose25 by 25% Grade 2 with pain or Grade 3 hold until symptoms resolve; reinitiate at 0.7 mg/m2 once weekly Grade 4 discontinue bortezomib

Dosage in diarrhea27: delay next cycle until diarrhea resolves(< 2 watery bowel movements/day)

reduce dose27,32 by 20-25% of that used in the last course (if two dose reductions have already occurred, further treatment must be individualized and should only continue if a clearly useful clinical response has occurred)

Dosage in other non- hematological toxicities1: at the onset of any NCI Grade 3 non-hematological toxicities, discontinue bortezomib until symptoms resolve; reinitiate at a 25% dose reduction

safety and efficacy have not been established in children and adolescent patients

REFERENCES:

Jaskiewicz AD, Herrington JD, Wong L. Tumor lysis syndrome after bortezomib therapy for plasma cell leukemia. Pharmacotherapy 2005; 25(12 I):1820-1825.

Terpos E, Politou M, Rahemtulla A. Tumour lysis syndrome in multiple myeloma after bortezomib (VELCADE) administration. Journal of Cancer Research & Clinical Oncology 2004; 130(10):623-625.

San Miguel J, Blade J, Boccadoro M, et al. A practical update on the use of bortezomib in the management of multiple myeloma. Oncologist 2006; 11(1):51-61.

Lonial S, Waller EK, Richardson PG, et al. Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 2005; 106(12):3777-84.

BC Cancer Agency Lymphoma Tumour Group. BCCA Protocol summary for the treatment of Multiple Myeloma with Bortezomib. Vancouver: BC Cancer Agency; UMYBORTEZ, 2005.

DeVita VT, Hellman S, Rosenberg SA. Cancer Principles & Practice of Oncology. 6th ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2001. p. 2640.

Leukemia/Bone Marrow Transplant Program of British Columbia. Leukemia/BMT Manual. 4th ed. Vancouver, British Columbia: Vancouver Hospital and Health Sciences Centre / BC Cancer Agency; 2003. p. 27.

Sanofi-Synthelabo. Rasburicase product information package. Markham, Ontario; 2004.

Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. 6 2007; 109(6):2604-6.

Rose BD editor. Bortezomib. www.uptodate.com ed. Waltham, Massachusetts: UpToDate; 2006.

Interpatient variability	wide interpatient variability in plasma concentration
Distribution	distribution half life is less than 10 minutes 2
	cross blood brain barrier?	no information found
	volume of distribution 3	>500 L
	plasma protein binding	no information found
Metabolism	oxidative deboronation via CYP 3A4 and 2C19; other CYP 450 enzymes (1A2, 2C9, 2D6) have minor roles
	active metabolite(s)	none
	inactive metabolite(s) 2	>30
Excretion	urine	no information found
	feces	no information found
	terminal half life	9-15 h
	clearance	no information found

AGENT	EFFECT	MECHANISM	MANAGEMENT
docetaxel 2	no effect on bortezomib or docetaxel pharmacokinetics or pharmacodynamics
gemcitabine 2	no effect on bortezomib or gemcitabine pharmacokinetics or pharmacodynamics
irinotecan 2	no effect on bortezomib or irinotecan pharmacokinetics or pharmacodynamics

BCCA administration guideline noted in bold , italics
Subcutaneous	no information found
Intramuscular	no information found
Direct intravenous	over 3-5 seconds
Intermittent infusion	no information found
Continuous infusion	no information found
Intraperitoneal	no information found
Intrapleural	no information found
Intrathecal	no information found
Intra-arterial	no information found
Intravesical	no information found

DRUG NAME: Bortezomib

CLASSIFICATION:

MECHANISM OF ACTION

PHARMACOKINETICS:

USES:

Primary uses: Other uses:

SPECIAL PRECAUTIONS:

Contraindicated 1

Hepatitis B (HBV) reactivation:

Carcinogenicity:

Fertility: 1

Breastfeeding 1

Drugs associated with peripheral neuropathy: 5

SIDE EFFECTS:

Peripheral Neuropathy:

Diarrhea:

INTERACTIONS:

SUPPLY AND STORAGE:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

SOLUTION PREPARATION AND COMPATIBILITY:

Compatibility of selected drugs:

For basic information on the current brand used at the BC Cancer Agency, see Chemotherapy Preparation and Stability Chart in Appendix.

PARENTERAL ADMINISTRATION:

DOSAGE GUIDELINES:

Intravenous: 3 weeks27: 1.3 mg/m2 (range 1-1.3 mg/m2) IV for one dose on days 1, 4, 8, and 11. Consecutive doses should be separated by at least 72 hours1

(total dose per cycle 5.2 mg/m2 [range 4-5.2 mg/m2])

REFERENCES: