Bortezomib Injection, a proteasome inhibitor, contains bortezomib which is an antineoplastic agent. Bortezomib is a modified dipeptidyl boronic acid. The chemical name for bortezomib, the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid.
The molecular weight is 384.24. The molecular formula is C19H25BN4O4. The solubility of bortezomib, as the mannitol boronic acid ester, in water is 3.3 to 3.8 mg/mL in a pH range of 2 to 6.5.
Bortezomib Injection is available for intravenous injection use only. Each single-dose vial contains 2.5 mg/mL of bortezomib as a sterile, clear, colorless aqueous solution. It also contains the inactive ingredient: 50 mg mannitol, USP. The product is provided as a mannitol boronic ester which consists of the mannitol ester in equilibrium with its hydrolysis product, the monomeric boronic acid. The drug substance exists in its cyclic anhydride form as a trimeric boroxine.
Bortezomib Injection INDICATIONS AND USAGE
- Bortezomib Injection is indicated for the treatment of adult patients with multiple myeloma.
Mantle Cell Lymphoma
- Bortezomib Injection is indicated for the treatment of adult patients with mantle cell lymphoma.
Bortezomib Injection Mechanism of Action
Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death.
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Bortezomib Injection DOSAGE AND ADMINISTRATION
Bortezomib Injection is for intravenous use only. Do not administer Bortezomib Injection by any other route.
The recommended starting dose of Bortezomib Injection is 1.3 mg/m2. Bortezomib Injection is administered intravenously at a concentration of 1 mg/mL.
Bortezomib Injection retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezomib Injection and who have relapsed at least six months after completing prior Bortezomib Injection treatment. Treatment may be started at the last tolerated dose.
Administer Bortezomib Injection as a 3 to 5 second bolus intravenous injection.
The drug quantity contained in one vial (2.5 mg/mL or 3.5 mg/1.4 mL) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose.
Bortezomib Injection is a hazardous drug. Follow applicable special handling and disposal procedures.
Bortezomib Injection CONTRAINDICATIONS
Bortezomib Injection is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions.
Bortezomib Injection is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of bortezomib.
Bortezomib Injection WARNINGS AND PRECAUTIONS
Peripheral Neuropathy: Bortezomib treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with Bortezomib Injection. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness.
Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated may be at increased risk of hypotension. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.
Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during bortezomib therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be frequently monitored.
Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration have occurred in patients receiving bortezomib. Some of these events have been fatal.
There have been reports of pulmonary hypertension associated with bortezomib administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, consider interrupting Bortezomib Injection until a prompt and comprehensive diagnostic evaluation is conducted.
Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving bortezomib. PRES is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue Bortezomib Injection. The safety of reinitiating Bortezomib Injection therapy in patients previously experiencing PRES is not known.
Gastrointestinal Toxicity: Bortezomib treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt Bortezomib Injection for severe symptoms.
Thrombocytopenia/Neutropenia: Bortezomib is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remain consistent in the studies of multiple myeloma and mantle cell lymphoma, with no evidence of cumulative thrombocytopenia or neutropenia in the treatment regimens studied.
Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with bortezomib therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt Bortezomib Injection therapy to assess reversibility. There is limited re-challenge information in these patients.
Thrombotic Microangiopathy: Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in the postmarketing setting in patients who received bortezomib. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop Bortezomib Injection and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting Bortezomib Injection. The safety of reinitiating Bortezomib Injection therapy in patients previously experiencing TTP/HUS is not known.
Embryo-Fetal Toxicity: Based on the mechanism of action and findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused postimplantation loss and a decreased number of live fetuses.
Advise females of reproductive potential to use effective contraception during treatment with Bortezomib Injection and for seven months following treatment. Advise males with female partners of reproductive potential to use effective contraception during treatment with Bortezomib Injection and for four months following treatment. If Bortezomib Injection is used during pregnancy or if the patient becomes pregnant during Bortezomib Injection treatment, the patient should be apprised of the potential risk to the fetus.
Bortezomib Injection USE IN SPECIFIC POPULATIONS
Pregnancy: Based on its mechanism of actionand findings in animals, Bortezomib Injection can cause fetal harm when administered to a pregnant woman. There are no studies with the use of bortezomib in pregnant women to inform drug-associated risks. Bortezomib caused embryo-fetal lethality in rabbits at doses lower than the clinical dose.
Advise pregnant women of the potential risk to the fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications.
Lactation: There are no data on the presence of bortezomib or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. Because many drugs are excreted in human milk and because the potential for serious adverse reactions in a breastfed child from bortezomib is unknown, advise nursing women not to breastfeed during treatment with Bortezomib Injection and for two months after treatment.
Pediatric Use: Safety and effectiveness have not been established in pediatric patients.
Renal Impairment: No starting dosage adjustment of Bortezomib Injection is recommended for patients with renal impairment. In patients requiring dialysis, Bortezomib Injection should be administered after the dialysis procedure.
Hepatic Impairment: No starting dosage adjustment of Bortezomib Injection is recommended for patients with mild hepatic impairment (total bilirubin ≤1x ULN and AST >ULN, or total bilirubin >1 to 1.5x ULN and any AST). The exposure of bortezomib is increased in patients with moderate (total bilirubin ≥1.5 to 3x ULN and any AST) and severe (total bilirubin >3x ULN and any AST) hepatic impairment. Reduce the starting dose in patients with moderate or severe hepatic impairment.
Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib Injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Bortezomib Injection OVERDOSAGE
There is no known specific antidote for bortezomib overdosage. 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 (5.2) and thrombocytopenia (5.7). In the event of an overdosage, the patient’s vital signs should be monitored and appropriate supportive care given.
Studies in monkeys and dogs showed that intravenous bortezomib doses as low as two times the recommended clinical dose on a mg/m basis were associated with increases in heart rate, decreases in contractility, hypotension, and death. In dog studies, a slight increase in the corrected QT interval was observed at doses resulting in death. In monkeys, doses of 3.0 mg/m and greater (approximately twice the recommended clinical dose) resulted in hypotension starting at one hour post administration, with progression to death in 12 to 14 hours following drug administration.