Bortero

Bortero

bortezomib

Manufacturer:

Camber

Distributor:

Camber
Full Prescribing Info
Contents
Bortezomib.
Description
Each vial contains 3.5 mg of Bortezomib.
Bortero is an antineoplastic agent available for intravenous injection or subcutaneous use. Each single use vial contains 3.5 mg of bortezomib as a sterile lyophilized powder. Inactive ingredient 35 mg mannitol.
Bortezomib is a modified dipeptidyl boronic acid. The product is provided as a mannitol boronic ester which, in reconstituted form, 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.
Action
Pharmacology: Pharmacodynamics: Bortezomib, an antineoplastic agent, 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.
Pharmacokinetics: Absorption/Distribution: Following IV administration of 1 and 1.3 mg/m2 doses to 24 patients with multiple myeloma (n = 12 per each dose level), the mean maximum plasma concentrations (Cmax) of bortezomib after the first dose (day 1) were 57 and 112 ng/mL, respectively. In subsequent doses, when administered twice weekly, the observed Cmax ranged from 67 to 106 ng/mL for the 1 mg/m2 dose and 89 to 120 ng/mL for the 1.3 mg/m2 dose.
The mean distribution volume of bortezomib ranged from approximately 498 to 1,884 L/m2 following single- or repeat-dose administration of 1 or 1.3 mg/m2 to patients with multiple myeloma. This suggests bortezomib distributes widely to peripheral tissues. The binding of bortezomib to human plasma proteins averaged 83% over the concentration range of 100 to 1,000 ng/mL.
Metabolism: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 (CYP-450) isozymes indicate that bortezomib is primarily oxidatively metabolized via CYP-450 enzymes 3A4, 2C19, and 1A2. Bortezomib metabolism by CYP2D6 and CYP2C9 enzymes is minor. The major metabolic pathway is deboronation to form 2 deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated bortezomib metabolites are inactive as 26S proteasome inhibitors. Pooled plasma data from 8 patients at 10 and 30 minutes after dosing indicate that the plasma levels of metabolites are low compared with the parent drug.
Excretion: The mean elimination half-life of bortezomib upon multiple dosing ranged from 40 to 193 hours after the 1 mg/m2 dose and 76 to 108 hours after the 1.3 mg/m2 dose. The mean total body clearances were 102 and 112 L/h following the first dose for doses of 1 and 1.3 mg/m2, respectively, and ranged from 15 to 32 L/h following subsequent doses for doses of 1 and 1.3 mg/m2, respectively.
Indications/Uses
Mantle cell lymphoma: For the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.
Multiple myeloma: For the treatment of patients with multiple myeloma.
Dosage/Direction for Use
General dosing consideration: Because each route of administration has a different reconstituted concentration, and because the drug quantity contained in 1 vial may exceed the usual single dose required, caution should be used when calculating the volume to be administered.
Administer with fluid and electrolyte replacement to prevent dehydration.
Starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy. Patients with preexisting severe neuropathy should be treated with bortezomib only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may require a decrease in the dose and/or a less dose intense schedule.
Adults: Mantle cell lymphoma: Usual dosage: 1.3 mg/m2/dose twice weekly for 2 weeks (days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21).
Maintenance dosage: For extended therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or 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). At least 72 hours should elapse between consecutive doses of bortezomib.
Dosage adjustment: Bortezomib should be withheld at the onset of any grade 3 nonhematological or grade 4 hematological toxicities, excluding neuropathy. Once the symptoms of the toxicity have resolved, bortezomib may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose). (See Table 1.)

Click on icon to see table/diagram/image

Multiple myeloma, previously untreated: Usual dosage: See Table 2.

Click on icon to see table/diagram/image

Dosage adjustment: Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone, platelet count should be 70 x 109/L or more and the absolute neutrophil count (ANC) should be 1 x 109/L or more; nonhematological toxicities should have resolved to grade 1 or baseline. (See Table 3.)

Click on icon to see table/diagram/image

Multiple myeloma, relapsed: Refer to Mantle Cell Lymphoma for dosing.
Renal function impairment: Because dialysis may reduce bortezomib concentrations, the drug should be administered after the dialysis procedure.
Hepatic function impairment: See Table 4.

Click on icon to see table/diagram/image
Overdosage
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.
Treatment: There is no known specific antidote for bortezomib overdosage. In the event of overdosage, monitor patient's vital signs and give appropriate supportive care.
Contraindications
Hypersensitivity to bortezomib, boron, mannitol, or any component of the formulation; administration via the intrathecal route.
Warnings
This medicine can be harmful. Please use under a doctor's supervision.
Special 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 preexisting 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 or higher) during treatment with bortezomib. Monitor patients for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypesthesia, paresthesia, discomfort, neuropathic pain, or weakness. In the phase 3 relapsed multiple myeloma trial comparing bortezomib subcutaneous versus IV, the incidence of grade 2 or more peripheral neuropathy events was 24% for subcutaneous and 41% for IV. Grade 3 or more peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the IV treatment group. Starting bortezomib subcutaneously may be considered for patients with preexisting or at high risk of peripheral neuropathy.
Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may benefit from a decrease in the dose and/or a less dose-intense schedule. In the single agent phase 3 relapsed multiple myeloma study of bortezomib versus dexamethasone, following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with at least grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued because of grade 2 neuropathy or who had at least grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.
Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension not otherwise specified) was 13%. These reactions are observed throughout therapy. Use caution when treating patients who have a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, or administration of mineralocorticoids and/or sympathomimetics.
Cardiac effects: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reported in patients with no risk factors for decreased left ventricular ejection fraction. Closely monitor patients with risk factors for heart disease and those with existing heart disease. In the relapsed multiple myeloma study, the incidence of any treatment-emergent cardiac disorder was 15% and 13% in the bortezomib and dexamethasone groups, respectively. The incidence of heart failure events (eg, acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the bortezomib and dexamethasone groups (5% and 4%, respectively). There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.
Pulmonary effects: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) 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 conducting a prompt comprehensive diagnostic evaluation.
GI effects: Bortezomib treatment can cause constipation, diarrhea, nausea, and vomiting, sometimes requiring use of antiemetics and antidiarrheal medications. Ileus can occur. Administer fluid and electrolyte replacement to prevent dehydration.
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 remained consistent over the 8 cycles of twice-weekly dosing, and there were no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. In the relapsed multiple myeloma study of bortezomib versus dexamethasone, the incidence of significant bleeding events (grade 3 or higher) was similar on the bortezomib (4%) and dexamethasone (5%) arms. Monitor platelet counts prior to each dose of bortezomib. Patients experiencing thrombocytopenia may require a change in the dose and schedule of bortezomib.
Tumor lysis syndrome: Because bortezomib is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor these patients closely and take appropriate precautions.
Hepatic effects: Causes of acute liver failure have been reported in patients receiving multiple concomitant medications and those with serious underlying medical conditions. Other reported hepatic events include increase in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib. There is limited rechallenge information in these patients.
Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.
Renal function impairment: Because dialysis may reduce bortezomib concentrations, administer the drug after the dialysis procedure.
Hepatic function impairment: Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; treat these patients with bortezomib at reduced starting doses and closely monitor for toxicities.
Use in Children: The safety and efficacy of bortezomib in children have not been established.
Use in the Elderly: No overall differences in safety or efficacy were observed between patients 65 years of age and older and younger patients receiving bortezomib; however, greater sensitivity of some older patients cannot be ruled out.
Use In Pregnancy & Lactation
Pregnancy: Pregnancy Category D.
Advise women of childbearing potential to avoid becoming pregnant while being treated with bortezomib. There are no adequate and well-controlled studies in pregnant women. It is not known if bortezomib crosses the human placenta. The molecular weight (approximately 384), long elimination half-life, moderate plasma protein binding, and lack of rapid metabolism all suggest that the drug will cross to the embryo and/or fetus. If bortezomib is used during pregnancy, or if the patients becomes pregnant while receiving this drug, apprise the patient of the potential hazard to the fetus.
Lactation: It is not known whether bortezomib is excreted in human milk. Bortezomib's long elimination half-life, low molecular weight, and moderate protein binding suggest that it would be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breast-feeding infants from bortezomib, decide whether to discontinue breast-feeding or the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Adverse reactions and incidences reported are associated with monotherapy.
Incidence > 10%: Central Nervous System: Fatigue, fever, headache, dizziness.
Dermatologic: Rash.
Gastrointestinal: Diarrhea, nausea, constipation, vomiting, anorexia, abdominal pain, appetite decreased.
Hematologic: Thrombocytopenia, neutropenia, anemia, leukopenia.
Neuromuscular & skeletal: Peripheral neuropathy, neuralgia, paresthesia, weakness.
Respiratory: Dyspnea.
Incidence 1 - 10%: Cardiovascular: Cardiac disorder, hypotension, heart failure.
Endocrine & metabolic: Dehydration.
Hematologic: Bleeding.
Local: Injection site irritation.
Respiratory: Pneumonia.
Miscellaneous: Herpes zoster.
Incidence < 1%: Acute diffuse infiltrative pulmonary disease, acute respiratory distress syndrome (ARDS), alkaline phosphatase increased, amyloidosis, anaphylaxis, angina, angina pectoris, angioedema, ascites, aspergillosis, atelectasis, atrial fibrillation exacerbation, atrial flutter, AV block, bacteremia, blindness, bone pain, bradycardia, cardiac amyloidosis, cardiac arrest, cardiac tamponade, cardiopulmonary arrest, catheter-related infection, cerebral hemorrhage, cerebrovascular accident, coma, conjunctival infection/irritation, cranial palsy, deep vein thrombosis, diplopia, disseminated intravascular coagulation (DIC), duodenitis (hemorrhagic), dysautonomia, dysgeusia, dyspepsia, dysphagia, edema, embolism, encephalopathy, epistaxis, fecal impaction, gastritis (hemorrhagic), gastroenteritis, gastroesophageal reflux, GGT increased, glomerular nephritis, hearing impairment, hematemesis, hematuria, hemoptysis, hemorrhagic cystitis, hepatic failure, hepatic hemorrhage, hepatitis, hepatocellular damage, herpes meningoencephalitis, hyperbilirubinemia, hyper-/ hypoglycemia, hyper-/hypokalemia, hyper-/hyponatremia, hypersensitivity, hyperuricemia, hypocalcemia, hypoxia, ileus, interstitial pneumonia, intestinal perforation, intracerebral hemorrhage, ischemic colitis, ischemic stroke, laryngeal edema, left ventricular ejection fraction decreased, leukocytoclastic vasculitis, limb pain, listeriosis, lymphopenia, melena, MI, myalgia, myocardial ischemia, nasopharyngitis, neutropenic fever, ophthalmic herpes, optic neuritis, oral candidiasis, oral mucosal petechiae, pancreatitis, paralytic ileus, pericardial effusion, pericarditis, peritonitis, phlebitis, pleural effusion, pneumonitis, portal vein thrombosis, posterior reversible encephalopathy syndrome (PRES), proliferative glomerular nephritis, pruritis, psychosis, pulmonary embolism, pulmonary hypertension, pulmonary infiltrate, QTc prolongation, renal failure, respiratory failure, respiratory insufficiency, respiratory tract infection, seizure, sepsis, septic shock, SIADH, sinus arrest, sinusitis, spinal cord compression, Stevens-Johnson syndrome, stomatitis, stroke (hemorrhagic), subarachnoid hemorrhage, subdural hematoma, suicidal ideation, Sweet’s syndrome (acute febrile neutrophilic dermatosis), syncope, tachycardia, torsade de pointes, toxic epidermal necrolysis, toxoplasmosis, transaminases increased, transient ischemic attack, tumor lysis syndrome, ventricular tachycardia, weight loss.
Drug Interactions
Cytochrome P450: Bortezomib is metabolized by CYP-450 3A4, 2C19, and 1A2. Therefore, closely monitor patients receiving bortezomib concomitantly with potent CYP3A4 inhibitors or inducers for toxicities or reduced efficacy. Bortezomib may inhibit CYP2C19 activity and increase exposure to drugs that are substrates for this enzyme. (See Table 5.)

Click on icon to see table/diagram/image
Caution For Usage
TO RECONSTITUTE: General precautions: Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of Bortezomib. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of Bortezomib, since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of Bortezomib. Bortezomib 3.5 mg powder for solution for injection is for intravenous or subcutaneous use only. Bortezomib should not be administered intrathecally.
Instructions for reconstitution: Bortezomib must be reconstituted by a healthcare professional.
Intravenous injection: Each 10 ml vial of Bortezomib must be reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 1 mg Bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
HANDLING AND DISPOSAL: Cytotoxic preparations should not be handled by pregnant staff. Trained personnel should reconstitute the drug. This should be performed in a designated area. The work surface should be covered with disposable plastic-backed absorbent paper. Adequate protective gloves, masks, and clothing should be worn.
Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. If accidental contamination occurs, the eye should be washed with water thoroughly and immediately.
Use Luer-lock fittings on all syringes and sets. Large bore needles are recommended to minimize pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.
Adequate care and precaution should be taken in the disposal of items used to reconstitute bortezomib. Any unused dry product or contaminated materials should be placed in a high-risk waste bag. Sharp objects (needles, syringes, vials, etc) should be placed in a suitable rigid container.
Personnel concerned with the collection and disposal of this waste should be aware of the hazard involved. Waste material should be destroyed by incineration. Any excess drug solution should be flushed directly into a drain with copious amounts of water. Any unused product or waste material should be disposed of in accordance with local requirements.
Storage
Do not store above 30°C. Protect from light.
ATC Classification
L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.
Presentation/Packing
Powd for inj (vial) 3.5 mg (white powder) x 10 mL x 1's.
Register or sign in to continue
Asia's one-stop resource for medical news, clinical reference and education
Sign up for free
Already a member? Sign in