Myborte

Myborte

bortezomib

Manufacturer:

Dr. Reddy's

Distributor:

Zuellig Pharma

Marketer:

Dr. Reddy's
Full Prescribing Info
Contents
Bortezomib.
Description
Each vial contains Bortezomib 3.5 mg (Lyophilized).
Excipients/Inactive Ingredients: Mannitol (Pyrogen free), Tertiary butanol, Water for injection, Nitrogen NF (Process Aid).
Action
Pharmacology: Pharmacodynamics: Bortezomib an anti-neoplastic agent, is a reversible inhibitor of 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 affects 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 a 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 (Vd) of bortezomib ranged from 498 to 1884L/m2 following single- or repeated-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 average 83% over the concentration range of 100 to 1000 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-P450 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 compare 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.
Special populations: Elderly: Patients younger than 65 years of age (n=26) had about 25% lower mean dose normalized AUC and Cmax than those 65 years of age and older (n=13).
Indications/Uses
Bortezomib for Injection is indicated as follows: Mantle Cell Lymphoma: Bortezomib is used for treatment of mantle cell lymphoma in patients who have received at least one prior therapy.
Multiple Myeloma: Previously Untreated Multiple Myeloma: Bortezomib is used in combination with melphalan and prednisone for the treatment of Previously Untreated Multiple Myeloma.
Relapse Multiple Myeloma: Bortezomib is used alone for the treatment of relapse multiple myeloma in patients who have received at least one prior therapy.
Induction Therapy Prior to Stem-cell Transplantation: Bortezomib in combination with dexamethasone is indicated for the induction treatment of patients with newly diagnosed with multiple myeloma who are to undergo an autologous stem-cell transplant.
Dosage/Direction for Use
Adult: 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 extend therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or on a maintenance schedule of once weekly (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 initiated 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.)

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

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Dose adjustments: Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone, platelet counts should be 70 x 109/L or more and the absolute neutrophils count (ANC) should be 1.0 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: 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 4.)

Click on icon to see table/diagram/image

Induction Therapy Prior to Stem-Cell Transplantation: When used with dexamethasone as part of the bortezomib-dexamethasone regimen for induction therapy in patients newly diagnosed with multiple myeloma who were to undergo autologous stem-cell transplant, a bortezomib dosage of 1.3 mg/ml was administered by IV injection twice weekly for 2 weeks (days 1, 4, 8, and 11) followed by a 10-day rest period (days 12-21). In cycles 1 and 2, dexamethasone 40 mg was administered orally on days 1-4 and 9-12; in cycles 3 and 4, dexamethasone 40 mg was administered orally on days 1-4.
Renal function impairment: Dialysis may reduce bortezomib concentrations; administer after dialysis.
Hepatic function impairment: See Table 5.

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Preparation for administration: Different volumes of sodium chloride 0.9% are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration is greater than the reconstituted concentration of bortezomib for IV administration. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered. (See Table 6.)

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Administration: Administer IV at a concentration of 1 mg/mL or subcutaneously at a concentration of 2.5 mg/ml. When administered IV, bortezomib is administered as a 3- to 5-second bolus IV injection. Bortezomib is for IV or subcutaneous use only. Bortezomib should not be administered by any other route. Fatal events have occurred with intrathecal administration; bortezomib is contraindicated for intrathecal administration.
When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
If local injection-site reactions occur following bortezomib administration subcutaneously, a less concentrated bortezomib solution (1 mg/mL instead of 2.5 mg/ml) may be administered subcutaneously. Alternatively, the IV route of administration should be considered.
Overdosage
In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. There is no known specific antidote for bortezomib overdose. In the event of an overdose, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature.
Contraindications
Hypersensitivity (excluding local reactions) to bortezomib, boron, mannitol or any component of the formulation; intrathecal administration.
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 39% for IV. Grade 3 or more peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group compared with 15% 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 phase 3 relapsed multiple myeloma study of bortezomib versus dexamethasone following dose adjustments or interruptions, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with at least grade 2 peripheral neuropathy. 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 8%. 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 medication, hydration, or administration of mineralocorticoids and/or sympathomimetics. (See Adverse Reactions.)
Cardiac effects: Acute development or exacerbation of congestive heart failure (CHF) and new onset of decreased left ventricular ejection fraction have been reported, including reports 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 relapse multiple myeloma study, the incidence of any treatment- emergent cardiac disorder was 8% and 5% in the bortezomib and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (eg, acute pulmonary edema, cardiac failure, CHF, cardiogenic shock, pulmonary edema) was 1% or less for each individual reaction in the bortezomib group. In the dexamethasone group, the incidence was 1% or less for cardiac failure and CHF; there were no reported reaction of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT interval prolongation in clinical studies; causality has not been established.
Pulmonary disorder: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology (eg, pneumonitis, interstitial pneumonia, lung infiltration) and acute respiratory distress syndrome (ARDS) in patients receiving bortezomib. Some of these events have been fatal. In the event of new or worsening cardiopulmonary symptoms, consider interrupting bortezomib until a prompt comprehensive diagnostic evaluation is conducted.
Posterior Reversible Encephalopathy Syndrome: Posterior reversible encephalopathy syndrome (formerly reversible posterior leukoencephalopathy syndrome) has occurred in patients receiving bortezomib. Posterior reversible encephalopathy syndrome is a rare, reversible neurological disorder that can present with seizure, hypertension, headache, lethargy, confusion, blindness and other visual and neurological disturbances.
Brain imaging, preferably magnetic resonance imaging, is used to confirm the diagnosis.
Discontinue bortezomib in patients developing posterior reversible encephalopathy syndrome. The safety of reinitiating bortezomib therapy in patients previously experiencing posterior reversible encephalopathy syndrome is not known.
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. Interrupt bortezomib 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 remained consistent over the 8 cycles of twice-weekly dosing, and there was 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 bleeding (grade 3 or higher) was 2% in the bortezomib arm and was less than 1% in the dexamethasone arm. Monitor complete blood cell counts (CBC) frequently during treatment. 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: Tumor lysis syndrome has been reported. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions.
Hepatic effects: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and those with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Interrupt bortezomib therapy to excess reversibility.
Use In Pregnancy & Lactation
Pregnancy: Category D.
Adverse effects (fetal loss and decreased fetal weight) were observed in animal reproduction studies at doses less than the equivalent human dose (based on BSA). Women of reproductive potential should avoid becoming pregnant and should use effective contraception during treatment.
Lactation: It is not known whether bortezomib is excreted in human milk. Due to the potential for serious adverse reactions in the breast-feeding infant, the decision to discontinue bortezomib or breast-feeding should take into account the benefits of treatment to the mother.
Adverse Reactions
Common Adverse Effects: Adverse effects reported in 20% or more of patients with previously untreated multiple myeloma receiving bortezomib plus melphalan and prednisone (VMP) (in order of descending frequency) include thrombocytopenia, neutropenia, nausea, peripheral neuropathy, diarrhea, anemia, constipation, neuralgia, leukopenia, vomiting, pyrexia, fatigue, lymphopenia, anorexia, asthenia, cough, peripheral edema, and insomnia. Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving VMP include neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia, peripheral neuropathy, neuralgia, diarrhea, fatigue, asthenia, hypokalemia, and pneumonia.
Adverse effects reported in 20% or more of patients with relapsed multiple myeloma receiving bortezomib include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, paresthesia and dysesthesia, anemia, headache, cough, and dyspnea. Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving bortezomib include thrombocytopenia, asthenic condition, neutropenia, anemia, diarrhea, peripheral neuropathy, and dyspnea.
Adverse effects reported in 20% or more of patients with mantle cell lymphoma receiving bortezomib include asthenic conditions, peripheral neuropathy, constipation, diarrhea, nausea, decreased appetite, rash, dyspnea, dizziness (excluding vertigo), and insomnia. Serious (grade 3 or higher) adverse effects reported in 5% or more of patients receiving bortezomib include asthenic conditions, peripheral neuropathy, thrombocytopenia, diarrhea, dyspnea; abdominal pain, pneumonia, and dehydration.
Drug Interactions
Drugs Metabolized by Hepatic Microsomal Enzymes: Bortezomib may inhibit cytochrome P-450 (CYP) microsomal isoenzyme 2C19; potential pharmacokinetic interaction (increased exposure to drugs metabolized by CYP2C19). Bortezomib is a poor inhibitor of CYP1A2, CYP3A4, CYP2C9, and CYP2D6 and does not induce CYP1A2 or CYP3A4 in vitro.
Drugs Affecting Hepatic Microsomal Enzymes: In vitro studies indicate that bortezomib is a substrate mainly for CYP1A2, CYP3A4, and CYP2C19; the manufacturer states that patients receiving bortezomib with CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) or inducers should be closely monitored for potential toxicities or reduced efficacy associated with such concomitant therapy.
A 35% increase in mean bortezomib area under the concentration-time curve (AUC) was observed when the drug was administered concomitantly with ketoconazole, a potent CYP3A inhibitor, in 12 patients. However, concomitant administration of bortezomib and omeprazole, a potent inhibitor of CYP2C19 had no effect on bortezomib exposure in a study in 17 patients.
Melphalan and Prednisone: A 17% increase in mean bortezomib AUC was reported when the drug was administered concomitantly with melphalan and prednisone in 21 patients. However, the manufacturer states that this increase is unlikely to be clinically relevant.
Oral Antidiabetic Agents: In clinical studies, 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.
Hypotensive Agents: Potential interaction (increased risk of hypotension) when bortezomib is used with drugs that can cause hypotension. Dosage adjustment of hypotensive agents may be necessary.
Caution For Usage
Special precautions for disposal and other handling: 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.
Disposal of unused medicinal product or waste material: Bortezomib is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with the procedures for disposal of anticancer drugs.
Storage
Store below 30°C. Protect from light.
Shelf-Life: Unopened vials of bortezomib for injection are stable until the date indicated on the package when stored in the original package protected from light.
Bortezomib for injection contains no antimicrobial preservative.
When reconstituted bortezomib for injection as directed, the reconstituted material may be stored in the original vial and/or syringe prior to administration. The product may be stored at 20ºC - 25ºC up to 8 hours when exposed to normal indoor lighting, or stored at 2ºC - 8ºC up to 15 days.
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 (lyophilized, white to off white cake or powder) x 1's.
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