The solubility of bortezomib, as the monomeric boronic acid, is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.In water, 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5 (as the monomeric boronic acid)5.32e-02 g/LSoluble in chloroform, dimethyl sulfoxide, ethanol and methanol.
Human Drugs
Breast FeedingLactationMilk, HumanAntineoplastic AgentsProteasome InhibitorsFDA approved drugs -> Active ingredientEMA approved medicines: Human medicine
DangerH300 (86.7%): Fatal if swallowed [Danger Acute toxicity, oral]P203, P260, P264, P264+P265, P270, P273, P280, P301+P316, P302+P352, P305+P351+P338, P318, P319, P321, P330, P332+P317, P337+P317, P362+P364, P391, P405, and P501 (click each P-code to see the statement)Aggregated GHS information provided per 45 reports by companies from 12 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.
FDA-Anforderungen
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl bortezomib, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
Hazard Classes and Categories
Acute Tox. 2 (86.7%)
Shipment Methods and Regulations
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Methods for transporting hazardous drugs to the health-care setting should be consistent with environmental protection and national or local regulations for transporting hazardous substances. When hazardous drugs are being transported to the home-care setting, appropriate containers (eg, lined cardboard boxes) and procedures should be used to prevent breakage and contain leakage. ... The drugs must be securely capped or sealed and properly packaged and protected during transport to reduce further the chance of breakage and spillage in a public area such as a corridor or elevator. /Antineoplastic agents/
Lagerbedingungen
Unopened vials may be stored at controlled room temperature 25 °C (77 °F)excursions permitted from 15 to 30 °C (59 to 86 °F). Retain in original package to protect from light.
Reinigungsverfahren
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Spill kits containing all materials needed to clean up spills of hazardous drugs should be assembled or purchased. These kits should be readily available in all areas where hazardous drugs are routinely handled. If hazardous drugs are being prepared or administered in a nonroutine area (home setting or unusual patient-care area), a spill kit should be obtained by the drug handler. The kit should include two pairs of disposable gloves (one outer pair of utility gloves and one inner latex pair)low-permeability, disposable protective garments (coveralls or gown and shoe covers)
Anwendungen & Verwendung
Verwenden
Bortezomib is the first proteasome inhibitor to be approved b the US FDA for multiple myeloma, a blood cancer. A reversible inhibitor of the 26S proteasome-a barrel-shaped multiprotein particle found in the nucleus and cytosol of all eukaryotic cells. T
safety glasses or splash goggles
respirator
absorbent, plastic-backed sheets or spill pads
disposable toweling
at least 2 sealable thick plastic hazardous waste disposal bags (prelabeled with an appropriate warning label)
a disposable scoop for collecting glass fragments
and a puncture-resistant container for glass fragments. All individuals who routinely handle hazardous drugs must be trained in proper spill management and cleanup procedures. Spills and breakages must be cleaned up immediately according to the following procedures. If the spill is not located in a confined space, the spill area should be identified and other people should be prevented from approaching and spreading the contamination. Wearing protective apparel from the spill kit, workers should remove any broken glass fragments and place them in the puncture-resistant container. Liquids should be absorbed with a spill pad
powder should be removed with damp disposable gauze pads or soft toweling. The hazardous material should be completely removed and the area rinsed with water and then cleaned with detergent. The spill cleanup should proceed progressively from areas of lesser to greater contamination. The detergent should be thoroughly rinsed and removed. All contaminated materials should be placed in the disposal bags provided and sealed and transported to a designated containment receptacle. Spills occurring in the biohazard cabinet should be cleaned up immediately
a spill kit should be used if the volume exceeds 150 ml or the contents of one drug vial or ampule. If there is broken glass, utility gloves should be worn to remove it and place it in the puncture-resistant container located in the biohazard cabinet. The biological safety cabinet, including the drain spillage trough, should be thoroughly cleaned. If the spill is not easily and thoroughly contained, the biological safety cabinet should be decontaminated after cleanup. If the spill contaminates the high efficiency particulate air filter, use of the biological safety cabinet should be suspended until the cabinet has been decontaminated and the high efficiency particulate air filter replaced. /Antineoplastic agents/
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ If hazardous drugs are routinely prepared or administered in carpeted areas, special equipment is necessary to remove the spill. Absorbent powder should be substituted for pads or sheets and left in place on the spill for the time recommended by the manufacturer. The powder should then be picked up with a small vacuum unit reserved for hazardous drug cleanup. The carpet should then be cleaned according to usual procedures. The vacuum bag should be removed and discarded or cleaned, and the exterior of the vacuum cleaner should be washed with detergent and rinsed before being covered and stored. The contaminated powder should be discarded into a sealable plastic bag and segregated with other contaminated waste materials. Alternatively, inexpensive wet or dry vacuum units may be purchased for this express use and used with appropriate cleaners. All such units are contaminated, once used, and must be cleaned, stored, and ultimately discarded /properly/ ... The circumstances and handling of spills should be documented. Health-care personnel exposed during spill management should also complete an incident report or exposure form. /Antineoplastic agents/
Entsorgungsverfahren
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices./PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All contaminated disposables should be contained in sealable bags for transfer to larger waste containers. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ All bottles must be discarded as contaminated waste after decontamination of the biohazard cabinet. All protective apparel (gown, gloves, goggles, and respirator) should be discarded as contaminated waste. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The contaminated filters must be removed, bagged in thick plastic and prepared for disposal in a hazardous waste dump site or incinerator licensed by the Environmental Protection Agency (EPA). /Antineoplastic agents/For more Disposal Methods (Complete) data for BORTEZOMIB (8 total), please visit the HSDB record page.
Preventive Measures
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Accidental contamination of the health-care environment, resulting in exposure of personnel, patients, visitors, and family members to hazardous substances, is prevented by maintaining the physical integrity and security of packages of hazardous drugs. 1. Access to all areas where hazardous drugs are stored is limited to specified authorized staff. 2. A method should be present for identifying to personnel those drugs that require special precautions (eg, cytotoxics). One way to accomplish this is to apply appropriate warning labels to all hazardous drug containers, shelves, and bins where the drug products are stored. ... 3. A method of identifying, for patients and family members, those drugs that require special precautions in the home should be in place. This may be accomplished in the health-care setting, by providing specific labeling for discharge medications, along with written instructions. 4. Methods for identifying shipping cartons of hazardous drugs should be required from manufacturers and distributors of these drugs. 5. Written procedures for handling damaged packages of hazardous drugs should be maintained. Personnel involved in shipping and receiving hazardous drugs should be trained in these procedures, including the proper use of protective garments and equipment. Damaged shipping cartons of hazardous drugs should be received and opened in an isolated area (eg, in a laboratory fume hood, if available, not in a vertical laminar airflow biological safety cabinet used for preparing sterile products). /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Facilities (eg, shelves, carts, counters, and trays) for storing hazardous drugs are designed to prevent breakage and to limit contamination in the event of leakage. Bins, shelves with barriers at the front, or other design features that reduce the chance of drug containers falling to the floor should be used. Hazardous drugs requiring refrigeration should be stored separately from nonhazardous drugs in individual bins designed to prevent breakage and to contain leakage. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Until the reproductive risks (or lack thereof) associated with handling hazardous drugs within a safety program have been substantiated, staff who are pregnant or breast-feeding should be allowed to avoid contact with these drugs. Policies should be in effect that provide these individuals with alternative tasks or responsibilities if they so desire. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ The pharmacy should provide access to information on toxicity, treatment of acute exposure (if available), chemical inactivators, solubility and stability of hazardous drugs (including investigational agents) used in the workplace. /Antineoplastic agents/For more Preventive Measures (Complete) data for BORTEZOMIB (19 total), please visit the HSDB record page.
Personal Protective Equipment (PPE)
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Protective apparel: Disposable closed-front gown or coveralls, disposable utility gloves over disposable latex gloves, NIOSH-approved air-purifying half-mask respirator equipped with a high efficiency filter, and eye protection should be worn. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Class 100 clean-air work stations, both horizontal and vertical airflow (with no containment characteristics), are inappropriate engineering controls for handling hazardous drugs because they provide no personnel protection and permit environmental contamination. Although there are no engineering controls designed specifically for the safe handling of hazardous chemicals as sterile products, Class II contained vertical-flow biological safety cabinets (biohazard cabinets) have been adopted for this use. Biohazard cabinetry is, however, designed for the handling of infectious agents, not hazardous chemicals. ... Based on design, ease of use, and cost considerations, Class II contained-vertical-flow biohazard cabinetry is currently recommended for use in preparing sterile doses of hazardous drugs. Class II cabinetry design and performance specifications are defined in NSF Standard 49. Biological safety cabinets selected for use with hazardous drugs should meet NSF Standard 49 specifications to ensure the maximum protection from these engineering controls. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers should wear powder free, disposable surgical latex gloves of good quality when preparing hazardous drugs. Selection criteria for gloves should include thickness (especially at the fingertips where stress is the greatest), fit, length, and tactile sensation. ... The practice of double gloving is supported by research that indicates that many glove materials vary in drug permeability even within lotstherefore, double gloving is recommended. ... In general, surgical latex gloves fit better, have appropriate elasticity for double gloving and maintaining the integrity of the glove-gown interface, and have sufficient tactile sensation (even during double gloving) for stringent aseptic procedures. ... Powdered gloves should be avoided. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ Workers who are not protected by the containment environment of a biohazard cabinet should use respiratory protection when handling hazardous drugs. Respiratory protection should be an adjunct to and not a substitute for engineering controls. Surgical masks of all types provide no respiratory protection against powdered or liquid aerosols of hazardous drugs. In situations where workers may be exposed to potential eye contact with hazardous drugs, an appropriate plastic face shield or splash goggles should be worn. /Antineoplastic agents//PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ During compounding of hazardous drugs (eg, crushing, dissolving, and preparing an ointment), workers should wear low permeability gowns and double gloves. Compounding should take place in a protective area such as a disposable glove box. If compounding must be done in the open, an area away from drafts and traffic must be selected, and the worker should use appropriate respiratory protection. /Antineoplastic agents/
Wechselwirkungen
Hypoglycemia and hyperglycemia have been reported in patients with diabetes mellitus who received bortezomib concomitantly with oral antidiabetic agents. If bortezomib is used concomitantly with oral antidiabetic agents, blood glucose concentrations should be monitored carefully and dosage of the antidiabetic agent adjusted as necessary.Potential interaction (increased risk of peripheral neuropathy) when bortezomib is used concomitantly with other drugs associated with peripheral neuropathy (eg, amiodarone, antiviral agents, isoniazid, nitrofurantoin, hydroxymethylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors [statins]).Potential interaction (increased risk of hypotension) when bortezomib is used with drugs that can cause hypotension. Dosage adjustment of hypotensive agents may be necessary.... In a preclinical toxicology study, bortezomib-treated rats resulted in liver enlargement (35%). Ex vivo analyses of the liver samples showed an 18% decrease in cytochrome P450 (P450) content, a 60% increase in palmitoyl coenzyme A beta-oxidation activity, and a 41 and 23% decrease in CYP3A protein expression and activity, respectively. Furthermore, liver samples of bortezomib-treated rats had little change in CYP2B and CYP4A protein levels and activities. To address the likelihood of clinical drug-drug interactions, the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2 and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. Bortezomib, M1, and M2 were found to be mild inhibitors of CYP2C19 (IC(50) approximately 18.0, 10.0, and 13.2 microM, respectively), and M1 was also a mild inhibitor of CYP2C9 (IC(50) approximately 11.5 microM). However, bortezomib, M1, M2, M3, and M4 did not inhibit other P450s (IC(50) values > 30 microM). There also was no time-dependent inhibition of CYP3A4/5 by bortezomib or its major metabolites. Based on these results, no major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major metabolites. ...
Hepatotoxicity
In large clinical trials of bortezomib, elevations in serum aminotransferase levels were common, occurring in ~10% of patients. However, values greater than 5 times the upper limit of normal (ULN) were rare, occurring in
Unerwünschte Wirkungen
The following are adverse events seen with bortezomib:
Milk Concentrations
It is not known whether bortezomib is excreted in human milk.
Toxizitätsübersicht
Bortezomib should be withheld at the onset of grade 3 non-hematological or grade 4 hematological toxicity until the toxicity resolves. Treatment is then treatment restarted at a lower adjusted dose. There is no antidote available to reverse the toxic effects of the drug.
Medical Surveillance
/PRECAUTIONS FOR ANTINEOPLASTIC AGENTS:/ There is no method available for routine monitoring of personnel for evidence of hazardous drug exposure. Tests for the presence of mutagens or chromosomal damage are not drug specific and are of value only in controlled studies. Chemical analysis of urine for the presence of hazardous drugs at the sensitivity level needed to detect occupational exposure is limited to a few drugs and is not yet commercially available. /Antineoplastic agents/
Human Toxicity Excerpts
/SIGNS AND SYMPTOMS/ In humans, fatal outcomes following the administration of more than twice the recommended therapeutic dose have been reported, which were associated with the acute onset of symptomatic hypotension and thrombocytopenia. In the event of an overdosage, the patient's vital signs should be monitored and appropriate supportive care given./CASE REPORTS/ ... /Investigators/ describe the case of a patient with plasma cell leukemia treated with bortezomib who developed tumor lysis syndrome (TLS). Bortezomib was begun as single-agent therapy that resulted in the development of TLS after the third dose of the first cycle. Evaluation with the Naranjo Adverse Drug Reaction Probability Scale indicated a probable relationship between TLS and bortezomib in this patient. Patients receiving bortezomib may be at risk for TLS, especially if they have high tumor burden, rapidly proliferative disease, and unfavorable cytogenetics./CASE REPORTS/ ... Between June 2004 and September 2005, 13 Japanese patients with multiple myeloma were treated with bortezomib in Toranomon Hospital, Juntendo University School of Medicine, and Jichi Medical School. Four of them developed severe pulmonary complications, and 2 died of respiratory failure without progression of underlying disease. ... Previous clinical studies on bortezomib, mostly in the United States and Europe, have shown low incidences of pulmonary adverse effects. /This/ study suggests that bortezomib can cause serious lung injury, and that its incidence might vary among different ethnicities. .../CASE REPORTS/ ... /Investigators/ present here a case of severe, but reversible, congestive cardiac failure in a lung cancer patient who had no prior cardiac history, after receiving an experimental treatment of bortezomib combined with chemotherapy. Elevated levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP), as retrospectively measured in archived serum samples, were suggestive of pre-existent (sub-clinical) left ventricular dysfunction. Based on literature, /The authors/ hypothesize that baseline presence of sub clinical cardiomyopathy, characterized by a dysregulation of the ubiquitin-proteasome system, could have predisposed this patient for a cardiac side effect induced by systemic proteasome inhibition. ...For more Human Toxicity Excerpts (Complete) data for BORTEZOMIB (14 total), please visit the HSDB record page.
Drug Induced Liver Injury
Drug Induced Liver Injury Rank (DILIrank 2.0)BortezomibvMost-DILI-concern7Warnings & precautionsDOI:10.1016/j.drudis.2016.02.015
Non-Human Toxicity Excerpts
/LABORATORY ANIMALS: Acute Exposure/ Studies in monkeys showed that administration of dosages approximately twice the recommended clinical dose resulted in heart rate elevations, followed by profound progressive hypotension, bradycardia, and death 12 to 14 hours post dose. Doses =1.2 mg/sq m induced dose-proportional changes in cardiac parameters. Bortezomib has been shown to distribute to most tissues in the body, including the myocardium. Bortezomib doses as low as 2 times the recommended clinical dose on a mg/sq m basis were associated with increases in heart rate, decreases in contractility, hypotension, and death./LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In animal studies at a dose and schedule similar to that recommended for patients (twice weekly dosing for 2 weeks followed by 1-week rest), toxicities observed included severe anemia and thrombocytopenia, and gastrointestinal, neurological and lymphoid system toxicities. Neurotoxic effects of bortezomib in animal studies included axonal swelling and degeneration in peripheral nerves, dorsal spinal roots, and tracts of the spinal cord. Additionally, multifocal hemorrhage and necrosis in the brain, eye, and heart were observed./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant rabbits given bortezomib during organogenesis at a dose of 0.05 mg/kg (0.6 mg/sq m) experienced significant post-implantation loss and decreased number of live fetuses. Live fetuses from these litters also showed significant decreases in fetal weight. The dose is approximately 0.5 times the clinical dose of 1.3 mg/sq m based on body surface area./LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In the 6-month rat toxicity study, degenerative effects in the ovary were observed at doses =0.3 mg/sq m (one-fourth of the recommended clinical dose), and degenerative changes in the testes occurred at 1.2 mg/sq m. Bortezomib could have a potential effect on either male or female fertility.For more Non-Human Toxicity Excerpts (Complete) data for BORTEZOMIB (6 total), please visit the HSDB record page.
Populations at Special Risk
Although no overall differences in efficacy or safety were observed between geriatric and younger patients receiving bortezomib, the possibility that some older patients may exhibit increased sensitivity to the drug cannot be ruled out. ... Approximately 35% of the 202 patients enrolled in the phase II study of bortezomib were 65 years of age or older. Overall (complete plus partial) responses were observed in approximately 19% of patients 65 years of age or older. Grade 3 or 4 adverse effects were reported in 74% of patients 50 years of age or younger, 80% of patients 51-65 years of age, and 85% of patients older than 65 years of age.Safety and efficacy of bortezomib have not been established in patients with creatinine clearance of less than 13 mL/minute or in patients who are undergoing hemodialysis. In 2 phase II studies, partial responses to bortezomib were observed in 2 of 10 patients with a creatinine clearance of 30 mL/minute or less. The manufacturer states that patients with renal impairment should be closely monitored for evidence of toxicity.
Antidote and Emergency Treatment
Maintain an open airway and assist ventilation if necessary. Treat coma, seizures, hypotension, and arrhythmias if they occur. Treat nausea and vomiting with metoclopramide and fluid loss caused by gastroenteritis with intravenous crystalloid fluids. Bone marrow depression should be treated with the assistance of an experienced hematologist or oncologist. Extravasation: Immediately stop the infusion and withdraw as much fluid as possible by negative pressure on the syringe. ... /For/ decontamination administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. Because of the rapid intracellular incorporation of these agents, dialysis and other extracorporeal removal procedures are generally not effective.Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/
