Biomib

Pharmacologic Classification: Antineoplastic.
Pharmacology: Mechanism of Action: Bortezomib, a modified dipeptidyl boronic acid, is an antineoplastic agent. The drug potently, reversibly, and specifically inhibits the proteolytic activity of mammalian 26S proteasome, a large protein complex that degrades ubiquitinated proteins. Bortezomib is highly selective for the proteasome; it is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The ubiquitin-proteasome pathway has a vital role in regulating the intracellular concentration of specific proteins, consequently maintaining homeostasis within cells.
The bortezomib-mediated proteasome inhibition impedes targeted proteolysis, affecting multiple intracellular signaling cascades. The disruption of normal homeostatic mechanisms can ultimately lead to cancer cell death.
Proteasome inhibition by bortezomib affects the cancer cells in various ways, including, but not limited to, the alteration of regulatory proteins responsible for the cell cycle progression and the activation of nuclear factor kappa B (NF-κB), a transcription factor. Inhibition of the proteasome leads to cell cycle arrest and apoptosis, while NF-κB activation is necessary for many phases of tumorigenesis, such as cell growth and survival, angiogenesis, cell-cell interactions, and metastasis.
In vitro studies demonstrated that bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment. It has also been shown that bortezomib is cytotoxic to different types of cancer cells, and has reduced tumor growth in vivo in several preclinical tumor models. Bortezomib has been also shown to cause a delay in tumor growth in in vivo tumor models, including multiple myeloma. Data from in vitro, ex-vivo, and animal models suggest that bortezomib increases osteoblast differentiation and activity, and inhibits osteoclast function. These effects have been observed in bortezomib-treated patients with multiple myeloma affected by an advanced osteolytic disease.
Pharmacokinetics: Bioavailability and Pharmacokinetics: Following the first-dose administration of bortezomib 1 mg/m² and 1.3 mg/m² via intravenous bolus to patients with multiple myeloma and creatinine clearance (CrCl) values >50 mL/min, the mean maximum plasma concentrations of bortezomib (C_max) were 57 and 112 ng/mL, respectively. In subsequent doses, the C_max of bortezomib doses of 1 mg/m² and 1.3 mg/m² ranged from 67 to 106 ng/mL and 89 to 120 ng/mL, respectively.
In patients with multiple myeloma, the total systemic exposure of bortezomib 1.3 mg/m² dose, as measured by the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC_last), was comparable for subcutaneous injection and intravenous bolus administration. The C_max of bortezomib was lower for subcutaneous injection (20.4 ng/mL) compared to intravenous administration (223 ng/mL).
The area under the plasma concentration-time curve (AUC) following subcutaneous injection (92.1 to 195 ng/hr/mL) of bortezomib was equivalent to that of the intravenous injection. An increase in the AUC was observed after multiple-dose intravenous administration at day 11, indicating an increased systemic exposure to bortezomib. The AUC values following intravenous injection of bortezomib ranged from 104 ng/hr/mL at day 1 to 241 ng/hr/mL at day 11. The same trend was also observed following subcutaneous administration of bortezomib.
Bortezomib pharmacokinetics is described by a two-compartment model. Following single- or repeated-dose intravenous administration of 1 mg/m² or 1.3 mg/m² to patients with multiple myeloma, the mean distribution volume (Vd) of bortezomib ranged from 1,659 L to 3,294 L. The mean pseudo-steady state Vd of subcutaneously administered bortezomib was relatively high (1,330 L). Both Vd values indicate that bortezomib is widely distributed to peripheral tissues. In human plasma, the average in-vitro protein of bortezomib in concentration range of 10 to 1,000 ng/mL was 82.9%. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes demonstrated that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes 3A4, 2C19, and 1A2. The two deboronated metabolites formed during deboronation (the major metabolic pathway) subsequently undergo hydroxylation to several metabolites. Deboronated metabolites of bortezomib are inactive as 26S proteasome inhibitors.
The mean half-life (t_½) values of bortezomib were 98.1 and 65.7 hours for the intravenous and subcutaneous administration, respectively, with a high degree of intersubject variability. Upon multiple dosing, the mean elimination t_½ of bortezomib ranged from 40 to 193 hours.
Bortezomib is eliminated more rapidly after the first dose compared to succeeding doses. The mean total body clearances following the initial administration of 1 mg/m² and 1.3 mg/m² (102 L/hr and 112 L/hr, respectively) were higher than those observed in subsequent doses (15 to 32 L/h and 18 to 32 L/h, respectively).
Special Populations: Hepatic Impairment: Mild hepatic impairment did not affect the AUC of bortezomib. However, the mean AUC values were increased by approximately 60% in patients with moderate to severe hepatic impairment compared to patients with normal liver function. A lower starting dose is recommended in patients with moderate to severe hepatic impairment (see Dosage & Administration).
Renal Impairment: The pharmacokinetics of bortezomib is not affected by mild to moderate renal impairment (CrCl >20 mL/min/1.73 m²). Exposure of bortezomib from intravenous doses of 0.7 to 1.3 mg/m² (as measured by dose-normalized AUC and C_max) was comparable in patients with mild, moderate, and severe renal impairment. Dialysis may reduce bortezomib concentrations.

As monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone for the treatment of adult patients with progressive multiple myeloma who have received at least one prior therapy and who have already undergone or are unsuitable for hematopoietic stem cell transplantation.
In combination with melphalan and prednisone for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
In combination with dexamethasone, or with dexamethasone and thalidomide for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
In combination with rituximab, cyclophosphamide, doxorubicin and prednisone for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for hematopoietic stem cell transplantation.

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents. Bortezomib has a narrow therapeutic index and should be used with caution.
For the treatment of adult patients with progressive multiple myeloma who have received at least one prior therapy: General Dosing Recommendations: The recommended dosage of bortezomib is 1.3 mg/m² body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
As monotherapy: It is recommended that patients should receive two cycles of bortezomib after a complete response is confirmed. It is also recommended that patients responding to treatment but who do not achieve a complete remission should receive a total of eight cycles of bortezomib therapy.
Dose adjustments during treatment and re-initiation of treatment for bortezomib monotherapy: Treatment with bortezomib must be withheld at the onset of any Grade 3 non-hematological or any Grade 4 hematological toxicities, excluding neuropathy. Once the symptoms of the toxicity have resolved, bortezomib treatment may be re-initiated at a 25% reduced dose (i.e., 1.3 mg/m² reduced to 1 mg/m²; 1 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of bortezomib therapy must be considered, unless the benefit of treatment clearly outweighs the risk.
Neuropathic pain and/or peripheral neuropathy: Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy should be managed accordingly (see Table 1). Patients with pre-existing severe neuropathy should only be treated with bortezomib after careful risk-benefit assessment. (See Table 1.)

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In combination with pegylated liposomal doxorubicin: Follow general dosing recommendation as previously mentioned.
The recommended dose of pegylated liposomal doxorubicin is 30 mg/m² to be administered as a one-hour intravenous infusion following bortezomib injection on day 4 of the treatment cycle.
Up to eight cycles of this combination therapy can be administered as long as patients have not progressed and can tolerate the treatment. Patients achieving a complete response can continue with the combination therapy for at least two cycles after the first evidence of complete response, even if this requires treatment for more than eight cycles. Patients whose paraprotein levels continue to decrease after eight cycles can still receive this combination therapy for as long as the patient can tolerate and respond with the treatment.
In combination with dexamethasone: Follow general dosing recommendation as previously mentioned.
Dexamethasone 20 mg is administered orally at days 1, 2, 4, 5, 8, 9, 11 and 12 of the bortezomib treatment cycle. Patients achieving a response or a stable disease after four cycles of this combination therapy may continue to be administered with the same combination for a maximum of four additional cycles.
Dose adjustments for combination therapy for patients with progressive multiple myeloma: For dosage adjustments of bortezomib in combination therapy, follow dose modification guidelines of bortezomib as monotherapy.
For the treatment of adult patients with progressive multiple myeloma who are unsuitable for hematopoietic stem cell transplantation: In combination with melphalan and prednisone: Bortezomib is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone (See Table 2). A six-week period is considered a treatment cycle. In Cycles 1 to 4, bortezomib is administered twice weekly (i.e., on days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, bortezomib is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of bortezomib.
Melphalan and prednisone should both be administered orally on days 1, 2, 3, and 4 of the first week of each bortezomib treatment cycle. Nine treatment cycles of this combination therapy are administered. (See Table 2.)

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Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisone: Prior to initiating a treatment cycle: Platelet counts should be ≥70 x 109/L and the absolute neutrophils count should be ≥1 x 109/L; Non-hematological toxicities should have resolved to Grade I or baseline. (See Table 3.)

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For previously untreated multiple myeloma patients eligible for hematopoietic stem cell transplantation (induction therapy): In combination therapy with dexamethasone: The recommended dosage of bortezomib is 1.3 mg/m2 body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone 40 mg is administered orally on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib treatment cycle. Four treatment cycles of this combination therapy are administered (See Table 4).
In combination therapy with dexamethasone and thalidomide: The recommended dosage of bortezomib is 1.3 mg/m2 body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a followed by a 17-day rest period (days 12 to 28) in a 28-day treatment cycle. This four-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
Dexamethasone 40 mg is orally administered on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib treatment cycle.
Thalidomide 50 mg is orally administered daily on days 1 to 14 and if tolerated, the dose is increased to 100 mg on days 15 to 28. Thereafter, the dose may be further increased to 200 mg daily from cycle 2 (see Table 5). Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response should receive two additional cycles. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed. (See Tables 4 & 5.)

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Dosage adjustments for transplant eligible patients: For dosage adjustments of bortezomib, dose modification guidelines described for monotherapy should be followed. In addition, when bortezomib is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the Summary of Product Characteristics.
For patients with previously untreated mantle cell lymphoma (MCL): Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone: The recommended dosage of bortezomib is 1.3 mg/m² body surface area to be administered via intravenous or subcutaneous injection twice weekly for two weeks (i.e., on days 1, 4, 8, and 11), followed by a 10-day rest period (days 12 to 21) in a 21-day treatment cycle. This three-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of bortezomib.
It is recommended to administer six bortezomib treatment cycles. For patients with a response first documented at cycle 6, two additional bortezomib treatment cycles may be given.
Prednisone is administered orally at 100 mg/m² on days 1, 2, 3, 4 and 5 of each bortezomib treatment cycle. The following medicinal products are administered on day 1 of each three-week treatment cycle as intravenous infusions: rituximab at 375 mg/m², cyclophosphamide at 750 mg/m², and doxorubicin at 50 mg/m².
Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma: Prior to initiating a new treatment cycle: Platelet counts should be ≥100,000 cells/mcL and the ANC should be ≥1,500 cells/mcL; Platelet counts should be ≥75,000 cells/mcL in patients with bone marrow filtration or splenic sequestration; Hemoglobin ≥8 g/dL; Non-hematological toxicities should have resolved to Grade 1 or baseline.
Bortezomib treatment must be withheld at the onset of any ≥Grade 3 bortezomib-related non-hematological toxicities (excluding neuropathy) or ≥Grade 3 hematological toxicities. Granulocyte colony stimulating factors may be given for hematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered if cycle administration is repeatedly delayed. Platelet transfusion should be considered as treatment of thrombocytopenia when clinically appropriate. (See Table 6.)

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In addition, when bortezomib is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.
Method of Administration: Bortezomib is available for intravenous or subcutaneous administration. It should not be administered by other routes. Intrathecal administration has resulted in death.
Intravenous injection: Bortezomib reconstituted solution is administered as three- to five-second bolus intravenous injection through a peripheral or central intravenous catheter, followed by a flush with 0.9% sodium chloride solution for injection. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous injection: Bortezomib reconstituted solution is administered either at the right or left thigh or right or left side of the abdomen. The solution should be injected subcutaneously at a 45° to 90° angle. Injection sites should be rotated for consecutive injections. If local injection site reactions occur, either a less concentrated solution (i.e., bortezomib 3.5 mg to be reconstituted to 1 mg/mL instead of 2.5 mg/mL) may be subcutaneously administered, or a switch to intravenous injection is recommended.
Instructions for Reconstitution: Since bortezomib is a cytotoxic agent, the handling and preparation of this product shall be performed with caution. Moreover, aseptic technique must be strictly observed, as this product does not contain preservatives. The use of gloves and other appropriate protective clothing is recommended to prevent possible skin contact.
Bortezomib should only be reconstituted by a healthcare professional. Prior to administration, the reconstituted solution must be visually inspected for particulate matter and discoloration. If any discoloration or particulate matter is observed, the reconstituted solution must be discarded.
For intravenous injection: Reconstitute the bortezomib 8 mL vial with 3.5 mL of 0.9% sodium chloride solution for injection. The dissolution of the lyophilized powder is completed in less than two minutes.
After reconstitution, 1 mL of solution for intravenous injection contains 1 mg bortezomib.
For subcutaneous injection: Reconstitute the bortezomib 8 ml vial with 1.4 mL of 0.9% sodium chloride solution for injection. The dissolution of the lyophilized powder is completed in less than two minutes.
After reconstitution, 1 mL of solution for subcutaneous injection contains 2.5 mg bortezomib.
Special Populations: Hepatic Impairment: Dose adjustments are not required in patients with mild hepatic impairment. Patients with moderate or severe hepatic impairment, however, should be administered with a reduced starting dose of bortezomib on 0.7 mg/m² per injection during the first treatment cycle. A subsequent dose escalation to 1 mg/m² or further dose reduction to 0.5 mg/m² may be considered, depending on the tolerability of the patient. (See Table 7.)

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Renal Impairment: Dose adjustments for patients with mild to moderate renal impairment are not necessary (CLCr >20 mL/min/1.73 m²). However, it is unknown if the pharmacodynamics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CLCr <20 mL/min/1.73 min²). Bortezomib should be administered after dialysis since it may reduce bortezomib concentrations (see Precautions).
Elderly: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma.
Since there are no studies on the use of bortezomib in elderly patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with hematopoietic stem cell transplantation, no dose recommendations can be made in this population.
In a study, 42.9% and 10.4% of previously untreated mantle cell lymphoma patients exposed to bortezomib were in the range 65 to 74 years and ≥75 years of age, respectively. Both bortezomib-rituximab-cyclophosphamide-doxorubicin-prednisone regimen and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are less tolerated by patients aged ≥75 years of age with mantle cell lymphoma.

Acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes occurred in patients administered with more than twice the recommended therapeutic dose.
There is no known specific antidote for bortezomib overdose. Management for bortezomib overdose includes the monitoring of vital signs and provision of appropriate supportive care to maintain blood pressure (e.g., fluids, pressors, and/or inotropic agents) and body temperature.

Hypersensitivity to bortezomib, boron, mannitol, or to any component in the product.
Acute diffuse infiltrative pulmonary and pericardial disease.
Intrathecal administration (See Dosage & Administration)

General: Bortezomib has a narrow therapeutic window and has demonstrated high acute toxicity in all animal species evaluated. Accidental administration of at least twice the recommended dose has been reported to cause fatalities. Careful attention should be observed to ensure that the recommended dose is not exceeded.
Hematologic Effects: Bortezomib treatment is commonly associated with neutropenia, anemia, thrombocytopenia, and other hematological toxicities (see Adverse Reactions). The potential benefit of the treatment should be carefully weighed against the risks, particularly in patients with moderate to severe thrombocytopenia and risk factors for bleeding.
Dose-related thrombocytopenia and neutropenia follow a cyclical pattern, with nadirs occurring after the last dose of each cycle. Neutrophil and platelet counts typically recover to baseline prior to initiation of the next cycle. Generally, the pattern of platelet count decrease and recovery remained constant over eight cycles of bortezomib administered twice weekly. There are no evidence of cumulative thrombocytopenia and neutropenia.
Platelet counts should be monitored prior to each dose of bortezomib. Moreover, complete blood counts (CBC) with differential and platelet counts should be frequently monitored throughout the treatment. The dose and schedule should be adjusted for thrombocytopenia. Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.
Since patients with neutropenia have an increased risk of infections, they should be monitored for signs and symptoms of infection and should be treated promptly. Granulocyte colony stimulating factors may be administered for hematologic toxicity if recommended by local guidelines. In case of repeated delays in cycle administration, the administration of granulocyte colony stimulating factors as prophylaxis should be considered.
Bortezomib therapy should be withheld when the platelet count is <25,000/mcL or ≤30,000/mcL during monotherapy or in combination with melphalan and prednisone, respectively, and shall only be re-initiated at a reduced dose upon resolution. Cases of gastrointestinal and intracerebral hemorrhage have been reported to occur. Transfusions and supportive care should be considered.
Neurologic Effects: Posterior Reversible Encephalopathy Syndrome: Posterior Reversible Encephalopathy Syndrome (PRES), a rare, often reversible, rapidly evolving neurological condition, has been associated with the use of bortezomib. Some manifestations of PRES include seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. Treatment with bortezomib should be discontinued in patients with developing PRES. The safety of reinitiating bortezomib therapy in patients previously experiencing PRES is not yet established.
Progressive Multifocal Leukoencephalopathy: Very rare cases of John Cunningham (JC) virus infection with unknown causality, leading to progressive multifocal leukoencephalopathy (PML) and death, have been reported in patients administered with bortezomib in combination with or following other therapies. Patients diagnosed with PML had immunosuppressive therapy before or during bortezomib therapy. Most cases of PML were diagnosed within 12 months after receiving their first dose of bortezomib.
Patients should be regularly monitored for any new or worsening neurological symptoms or signs that may be indicative of PML (e.g., confusion or problem thinking, loss of balance, blurred vision or loss of vision, decreased strength or weakness in an arm or leg, or change in the way of walking or talking). If these signs or symptoms occurred, PML should be considered in the differential diagnosis. Patients should also be referred to a specialist in PML (e.g., neurologist) and appropriate diagnostic measures and further evaluation should be conducted. Treatment with bortezomib should be discontinued if the diagnosis of PML is confirmed.
Peripheral Neuropathy: Treatment with bortezomib is commonly associated with peripheral neuropathy that is predominantly sensory. However, severe motor neuropathy with or without sensory peripheral neuropathy, including those with fatal outcomes, have also been reported to occur. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.
Pre-existing symptoms (e.g., numbness, pain, burning sensation in hands or feet) and/or signs (e.g., hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness) of peripheral neuropathy may worsen during bortezomib treatment. Thus, bortezomib should only be used in patients with existing peripheral neuropathy if the potential benefits outweigh the risks.
Early and regular monitoring for symptoms of neuropathy with neurological evaluation should be considered in patients receiving bortezomib in combination with drugs inducing neuropathy (e.g., thalidomide). Previous use of neurotoxic agents also increases the risk of developing or aggravating peripheral neuropathy. Since the worsening of existing neuropathy is dose-related and cumulative, the bortezomib dose or schedule in patients experiencing new or worsening symptoms or signs of peripheral neuropathy may be adjusted. Treatment with bortezomib may also be discontinued, if necessary. Subcutaneous administration of bortezomib may be considered in patients with pre-existing or at high risk of peripheral neuropathy (see Dosage & Administration). Neuropathy can be managed with supportive care and other therapies.
Autonomic Neuropathy: Autonomic neuropathy may influence some adverse events, such as postural hypotension and severe constipation with ileus. Severe autonomic neuropathy has been reported to results to interruption or discontinuation of bortezomib treatment. Information on the contribution of autonomic neuropathy in these undesirable effects is limited. Bortezomib should only be used in patients with existing autonomic neuropathy after a careful benefit-risk assessment.
Seizures: Rare cases of seizures have been reported in patients during bortezomib therapy, even in those without previous history of seizures or epilepsy. Caution is required when treating patients with any risk factors for seizures.
Cardiovascular Effects: Deaths from cardiogenic shock, congestive heart failure, or cardiac arrest, have been reported to occur in patients during bortezomib therapy.
Heart Failure: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction have occurred in patients during treatment with bortezomib. These adverse events are also reported to occur even in patients with few or no risk factors for decreased left ventricular ejection fraction. Bortezomib is also associated with adverse reactions suggestive of heart failure (e.g., acute pulmonary edema, fluid retention, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock).
Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors or existing heart disease should be closely monitored during bortezomib therapy.
QT Prolongation: There have been isolated cases of QT-interval prolongation in clinical studies. However, causality has not been established.
Hypotension: Orthostatic or postural hypotension is not an acute reaction and is observed throughout treatment with bortezomib. Although the exact mechanism is unknown, this adverse event may be due to bortezomib-induced autonomic neuropathy. Bortezomib may also worsen an underlying condition such as diabetic or amyloidotic neuropathy.
Most cases are mild to moderate in severity, and only a minority of patients with orthostatic hypotension experienced syncopal events. Moreover, hypotension may also occur in patients who did not have orthostatic hypotension prior to with bortezomib treatment. Bortezomib should be used with caution in patients with a history of syncope, patients receiving medications that may cause hypotension, and patients who are dehydrated due to recurrent diarrhea or vomiting. Patients should be instructed to seek medical advice if they experience dizziness, light-headedness or fainting spells. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration, or administration of mineralocorticoids and/or sympathomimetics.
Pulmonary Disorders: There are reported deaths of patients treated with bortezomib from respiratory insufficiency or respiratory failure. Moreover, rare cases of acute diffuse infiltrative pulmonary disease of unknown etiology, some of which were fatal [e.g., pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS)], have been reported in patients administered with bortezomib. A pre-treatment chest radiograph should be obtained to determine if additional diagnostic measures are necessary and to serve as a baseline for potential bortezomib-induced pulmonary changes.
In a clinical trial, two patients (out of 2) given high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours with daunorubicin and bortezomib for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours is not recommended.
If new pulmonary symptoms appear or current symptoms worsen (e.g., cough, dyspnea), a diagnostic evaluation should be performed immediately and patient should be treated appropriately. The benefit-risk ratio should be considered before continuing treatment with bortezomib.
There have been rare reports of pulmonary hypertension associated with bortezomib use in the absence of left heart failure or significant pulmonary disease. In the event of new or aggravated cardiopulmonary symptoms, interruption of bortezomib treatment should be considered until a comprehensive diagnostic evaluation is performed.
Gastrointestinal Toxicity: Symptoms of gastrointestinal toxicity, including nausea, diarrhea, vomiting and constipation, are frequently observed in patients treated with bortezomib. These adverse events usually occur earlier in treatment (Cycles 1 and 2) and may persist for subsequent cycles, sometimes requiring the administration of antiemetics and antidiarrheals. Fluid and electrolyte replacement should be given to prevent dehydration. Patients should also be instructed on the appropriate measures to avoid dehydration, which may be caused by vomiting and/or diarrhea. Since there are uncommonly reported cases of intestinal obstruction, including ileus, patients who experience constipation should be closely monitored. Treatment with bortezomib should be interrupted if severe symptoms occur.
Tumor Lysis Syndrome: Because bortezomib is a cytotoxic agent, the complications of tumor lysis syndrome may occur after rapid lysis of malignant cells. The risk of tumor lysis syndrome is increased in patients with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions should be taken.
Herpes zoster virus reactivation: In patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more frequent in patients treated with bortezomib plus melphalan and prednisone compared with those only treated with melphalan and prednisone. Herpes meningoencephalitis and ophthalmic herpes virus infection has been rarely reported in postmarketing studies. Physicians should consider giving antiviral prophylaxis in patients treated with bortezomib, since prophylaxis reduced the incidence of herpes zoster virus reactivation among patients receiving bortezomib plus melphalan and prednisone.
Hepatitis B Virus reactivation and infection: Hepatitis B virus (HBV) screening must always be conducted before initiation of bortezomib combination treatment with rituximab in patients at risk of HBV infection. Clinical and laboratory signs of active HBV infection must be closely monitored in carriers of hepatitis B and patients with a history of hepatitis B during and after bortezomib combination treatment with rituximab. Antiviral prophylaxis should be considered.
Amyloidosis: Only limited clinical information is available on the use of bortezomib in patients with previously treated light-chain (AL) amyloidosis. The potential risk of complications due to organ involvement must be considered in treating patients with concurrent multiple myeloma and AL amyloidosis. Organ function (cardiac, renal, hepatic, and nervous systems) should be closely and regularly monitored to guide dose adjustments and duration of therapy.
Potentially immune complex-mediated reactions: Occurrences of potentially immune complex-mediated reactions, including serum sickness-type reaction, polyarthritis with rash, and proliferative glomerulonephritis, have been reported uncommonly during bortezomib therapy. Treatment should be discontinued if these serious reactions occur.
Hepatic Effects: Bortezomib is metabolized by liver enzymes. Cases of hepatic failure have been rarely reported in bortezomib-treated patients receiving several concomitant medications and with serious underlying medical conditions. Other hepatic reactions associated with the use of bortezomib include asymptomatic increases in hepatic enzyme concentrations, hyperbilirubinemia, and hepatitis. These hepatic reactions may be reversible upon treatment discontinuation. Information on the results of rechallenge in these patients is limited.
Renal Effects: Renal complications are frequently observed in patients with multiple myeloma. Moreover, high tumor burden is also associated with complications such as hypercalcemia and renal failure. Supportive measures should be provided, including bisphosphonates (for hypercalcemia and myeloma bone disease) and hydration, depending on the patient's status and the type and severity of the complication to be treated. Patients with renal impairment should be closely monitored.
Carcinogenicity, Mutagenicity, and Impairment of Fertility: Carcinogenicity studies with bortezomib have not been conducted. Bortezomib exhibited clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary cells. As demonstrated in the Ames assay and in vivo micronucleus assay, bortezomib was not mutagenic in bacteria and in mice, respectively.
Malignant neoplasms associated with bortezomib have been very rarely reported.
Fertility studies with bortezomib have not been performed. However, its degenerative effects in ovaries and testes exhibited in rat general toxicity studies may indicate its potential effect on male and female fertility.
Embryo-Fetal Toxicity: Based on its mechanism of action and animal findings, bortezomib may cause fetal harm when administered to pregnant women. The administration of bortezomib, at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area, resulted to post-implementation loss and decreased number of live fetuses in rabbits during organogenesis (see Use in Pregnancy & Lactation).
Effects on ability to drive and use machines: Bortezomib may cause adverse effects that may moderately affect the ability to drive and use machines (e.g., fatigue, dizziness, syncope, orthostatic or postural hypotension, blurred vision). Patients should be cautioned to avoid these potentially hazardous tasks if they experience these adverse effects.
Hepatic Impairment: Dose adjustments are not needed in patients with mild hepatic impairment. Patients with moderate to severe hepatic impairment should be administered with lower initial dosages of bortezomib and should be closely monitored for adverse events (see Dosage & Administration).
Renal Impairment: Since the pharmacokinetics of bortezomib is not affected by mild to moderate renal impairment (CrCl >20 mL/min/1.73 m²), dose adjustments are not necessary for patients with renal impairment. Bortezomib should be administered after dialysis procedure, since dialysis may decrease bortezomib levels. Patients with renal impairment, especially if CrCl ≤30 mL/min, should be closely monitored, since the incidence of serious adverse events may be increased these patients.
Use in Children: The safety and efficacy of bortezomib in children below 18 years of age have not been established.
Use in the Elderly: Evidences suggest that dose adjustments are not necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma. There are no studies conducted on the use of bortezomib in elderly patients with previously untreated multiple myeloma eligible for high-dose chemotherapy with hematopoietic stem cell transplantation.
No overall differences in safety or effectiveness of bortezomib were observed between younger patients and patients ≥65 years of age. Greater sensitivity of some older individuals cannot be ruled out. The serious adverse event rate in patients with mantle cell lymphoma treated with bortezomib-rituximab-cyclophosphamide-doxorubicin-prednisone was higher compared to those patients in the R-CHOP group.

Pregnancy: Pregnancy Category D. Bortezomib may cause harm to the fetus. The administration of bortezomib in pregnant rabbits during organogenesis resulted to significant post-implementation loss and decreased number of live fetuses. Embryolethality and decreased fetal weight were demonstrated in rabbits. Placental transfer studies have not been conducted with bortezomib. To date, there are no adequate or well-controlled studies using bortezomib to establish its safety in pregnant women.
Bortezomib should not be used during pregnancy, unless the clinical condition of the woman requires treatment with bortezomib. If bortezomib is used during pregnancy, the patient should be informed of the potential effects of the treatment to the fetus. Thalidomide, a known human teratogenic active substance that causes severe life-threatening birth defects, is contraindicated during pregnancy. Patients receiving bortezomib with thalidomide should adhere to the pregnancy prevention program of thalidomide. (Refer to the Summary of Product Characteristics of thalidomide for additional information.)
Females and Males of Reproductive Potential: Men should be advised not to father a child during and up to three months after bortezomib treatment. Women of childbearing potential should be advised to avoid becoming pregnant during and three months after treatment with bortezomib. If the patient becomes pregnant while taking bortezomib or if the drug is administered during pregnancy, the patient should be informed of the potential harm to the fetus.
Lactation: It is not known whether bortezomib is distributed in human milk. Since there is a possibility of toxicity in nursing infants if the drug was distributed into milk, a decision should be made whether to discontinue bortezomib therapy or breastfeeding, considering that importance of the drug to the patient. Women should also be advised not to breastfeed two months after treatment with bortezomib.

The most commonly reported adverse effects during bortezomib treatment are nausea, diarrhea, constipation, vomiting, fatigue, asthenia, pyrexia, [transient] thrombocytopenia, anemia, neutropenia, peripheral neuropathy (including motor and sensory), headache, paresthesia, decreased appetite, dyspnea, rash, herpes zoster, and myalgia.
Infections and infestations: Aspergillosis, bacteremia (including staphylococcal), bronchitis, bronchopneumonia, candida infection, catheter-related infection, Clostridium difficile colitis, conjunctivitis, device-related infection, Epstein-Barr virus infection, erysipelas, eyelid infection, haemophilus infection, herpes simplex infection, herpes virus infection, herpes zoster (including multidermatomal, ophthalmic, or disseminated) infection, hepatitis B infection, herpes zoster virus reactivation, infection (bacterial, fungal, or viral), infectious mononucleosis, influenza, listeriosis, lower respiratory tract infection, oral candidiasis, periodontitis, pleural infection, pneumonia, pneumococcal pneumonia, post-viral fatigue syndrome, progressive multifocal leukoencephalopathy [John Cunningham (JC) virus infection], sepsis, septic shock, Staphylococcal infection, tonsillitis, toxoplasmosis, respiratory tract infection (including upper and lower), urinary tract infection, varicella.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Leukemia plasmacytic, mycosis fungoides, neoplasm benign, neoplasm malignant, renal cell carcinoma, tumor lysis syndrome.
Blood and lymphatic system disorders: Acute febrile neutrophilic dermatosis (Sweet's syndrome), anemia aggravated, blood disorder, coagulopathy, disseminated intravascular coagulation, erythrosis, febrile neutropenia, hemolytic anemia, hemorrhagic diathesis, hyperviscosity syndrome, Jessner's lymphocytic infiltration, leukocytosis, leukopenia, lymphadenopathy, lymphocytic infiltration, lymphopenia, neutropenia aggravated, pancytopenia, platelet disorder, thrombocytopenic purpura, thrombocytosis.
Immune system disorders: Amyloidosis, anaphylactic reaction, anaphylactic shock, angioedema, bronchospasm, drug hypersensitivity, erythema multiforme, face edema, hypersensitivity, serum sickness-type reaction, type III immune complex-mediated hypersensitivity.
Endocrine disorders: Cushing's syndrome, hyperthyroidism, hypothyroidism, inappropriate antidiuretic hormone secretion.
Metabolism and nutrition disorders: Acidosis, alcohol intolerance, anorexia, change in thirst, dehydration, diabetes mellitus, edema, edema at the lower limb, electrolyte imbalance, enzyme abnormality, fluid overload, fluid retention, gout, hyperammonemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hyperphosphatemia, hyperuricemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, hypovolemia, increased appetite, metabolic disorder, peripheral edema, respiratory alkalosis, vitamin B₁₂ deficiency, vitamin B complex deficiency.
Psychiatric disorders: Abnormal dreams, acute psychosis, adjustment disorder, anxiety disorder, cognitive disorder, confusion, delirium, depression, disturbance in attention, hallucinations, insomnia, mental disorder, mood disorders, mood disturbances, psychomotor hyperactivity, psychotic disorder, restlessness, sleep disorder, sleep disturbances, suicidal ideation.
Nervous system disorders: Abnormal reflexes, agitation, ataxia, autonomic nervous system imbalance, autonomic neuropathy, balance disorder, brain edema, brain stem syndrome, cerebellar coordination and balance disturbances, cerebral hemorrhage, cerebrovascular accident, cerebrovascular disorder, coma, convulsion, cranial palsy, dizziness, drooling, dysarthria, dysautonomia, dysesthesia, dyskinesia, encephalopathy, gait disturbance, grand mal convulsion, Guillain-Barré syndrome, hemorrhagic stroke, herpes meningoencephalitis, hyperesthesia, hypoesthesia, intracranial hemorrhage, loss of consciousness, memory loss, meningitis (including bacterial), mental status changes, migraine, mononeuropathy, motor dysfunction, motor neuropathy, nerve root lesion, neuralgia, neuropathy, neurotoxicity, paralysis, paraplegia, paresis, paresthesia, peripheral neuropathy aggravated, parosmia, photophobia, polyneuropathy, posterior reversible encephalopathy syndrome, postherpetic neuralgia, presyncope, radiculitis, restless legs syndrome, sciatica, seizure disorder, speech disorder, spinal cord compression, subarachnoid hemorrhage, subdural hematoma, tremor, vertigo, vestibular neuronitis.
Eye disorders: Acquired dacryoadenitis, blepharitis, blindness, conjunctival hyperemia, conjunctival infection, conjunctival irritation, corneal lesion, diplopia, dry eye, exophthalmos, eye discharge, eye edema, eye hemorrhage, eye inflammation, eye irritation, eye pain, eye swelling, hordeolum, increased lacrimation, ocular hyperemia, optic neuritis, optic neuropathy, periorbital edema, photopsia, retinitis, scotoma, vision blurred, visual impairment.
Ear and labyrinth disorders: Bilateral hearing loss, deafness, decreased hearing acuity, dysacusis, ear discomfort, ear hemorrhage, ear infection, hearing impaired, hypoacusis, mastoiditis, tinnitus.
Cardiac disorders: Aggravated atrial fibrillation, angina pectoris, angina unstable, arrhythmia, atrial fibrillation, atrial flutter, atrioventricular block, bradycardia, cardiac amyloidosis, cardiac arrest, cardiac failure (including left and right ventricular), cardiac fibrillation, cardiac tamponade, cardiac toxicity, cardiac valve disorders, cardiomyopathy, cardiopulmonary arrest, complete atrioventricular block, congestive heart failure, congestive heart failure (exacerbated), coronary artery insufficiency, exertional dyspnea, left ventricular failure, mitral valve incompetence, myocardial infarction, myocardial ischemia, palpitations, pericardial effusion, pericarditis, sinus arrest, supraventricular tachycardia, tachycardia, torsade de pointes, ventricular dysfunction, ventricular fibrillation (including left and right), ventricular hypokinesia, ventricular tachycardia, viral myocarditis.
Vascular disorders: Cardiogenic shock, circulatory collapse, deep vein thrombosis, embolism, erythromelalgia, flushing, hematoma (including perirenal), hemorrhage, hot flushes, hyperemia, hypertension, hypotension, hypovolemic shock, ischemic colitis, ischemic stroke, livedo reticularis, lymphedema, orthostatic hypotension, pallor, peripheral embolism, phlebitis, poor peripheral circulation, spinal cord ischemia, syncope, thrombophlebitis (including superficial), transient ischemic attack, vasculitis, vasodilatation, vein discoloration, venous insufficiency.
Respiratory, thoracic and mediastinal disorders: Acute diffuse infiltrative pulmonary disease, acute pulmonary edema, acute respiratory distress syndrome, apnea, aspiration pneumonia, atelectasis, bronchial disorder, bronchial hyperreactivity, chest discomfort, chronic obstructive airways disease exacerbated, chronic obstructive pulmonary disease, cough, dry throat, dysphonia, epistaxis, hemoptysis, hoarseness, hyperventilation, hypocapnia, hypoxia, increased upper airway secretion, interstitial lung disease, laryngeal edema, lung infiltration, nasal congestion, nasopharyngitis, orthopnea, pharyngolaryngeal pain, pleural effusion, pleurisy, pneumonitis, pneumothorax, productive cough, pulmonary alveolar hemorrhage, pulmonary edema, pulmonary embolism, pulmonary fibrosis, pulmonary hypertension, respiratory arrest, respiratory distress, respiratory failure, respiratory insufficiency, respiratory tract congestion, rhinorrhea, sinusitis, tachypnea, throat irritation, throat tightness, upper-airway cough syndrome, wheezing.
Gastrointestinal disorders: Abdominal discomfort, abdominal distension, abdominal pain, abnormal feces, acute pancreatitis, ageusia, aggravated constipation, aggravated diarrhea, aggravated nausea, anal fissure, anal sphincter atony, ascites, change of bowel habit, cheilitis, colitis, diverticular perforation, dry mouth, dysgeusia, dyspepsia, dysphagia, enteritis, eructation, esophagitis, fecal impaction, fecal incontinence, fecaloma, flatulence, gastritis, gastroenteritis, gastroesophageal reflux disease, gastrointestinal hemorrhage (lower or upper), gastrointestinal inflammation, gastrointestinal malformation, gastrointestinal motility disorder, gastrointestinal obstruction, gastrointestinal pain, gastrointestinal perforation, gastrointestinal ulceration, gingival bleeding, gingival hypertrophy, gingival pain, hematemesis, hemorrhagic diarrhea, hemorrhagic duodenitis, hemorrhagic gastritis, hiatus hernia, hiccups, ileus, intestinal obstruction, intestinal perforation, irritable bowel syndrome, ischemic colitis, large intestinal obstruction, large intestinal perforation, lip pain, lip swelling, loose stools, megacolon, melena, mouth ulceration, mucosal hemorrhage, oral disorder, oral mucosal petechiae, oral pain, oral ulceration, oropharyngeal blistering, oropharyngeal pain, pancreatitis (acute or chronic), paralytic intestinal obstruction, paralytic ileus, peritonitis, proctalgia, rectal discharge, rectal hemorrhage, retching, salivary gland disorder, small intestinal obstruction, spleen pain, stomatitis, tongue coated, tongue discoloration, tongue edema, tongue ulceration, upper abdominal pain.
Hepatobiliary disorders: Acute hepatic failure, Budd-Chiari syndrome, cholelithiasis, cholestasis, cytomegalovirus hepatitis, hepatic failure, hepatic hemorrhage, hepatitis, hepatocellular damage, hepatomegaly, hepatotoxicity, hyperbilirubinemia, liver disorder, portal vein thrombosis.
Skin and subcutaneous tissue disorders: Abnormal hair texture, acne, alopecia, atopic dermatitis, blister, cellulitis, contusion, decubitus ulcer, dermatitis, dry skin, ecchymosis, eczema, erythema, hair disorder, heat rash, ichthyoses, laceration, leukocytoclastic vasculitis, nail disorder, palmar-plantar erythrodysesthesia syndrome, papule, petechiae, photosensitivity reaction, pigmentation disorder, pruritus, psoriasis, purpura, rash (erythematous, generalized, pruritic, macular, papular), seborrhea, skin discoloration, skin disorder, skin induration, skin infection, skin irritation, skin lesion, skin mass, skin nodule, skin reaction, skin ulcer, Stevens-Johnson syndrome, subcutaneous hemorrhage, toxic epidermal necrolysis, toxic skin eruptions, urticaria.
Musculoskeletal and connective tissue disorders: Arthralgia, arthritis, back pain, bone disorder, bone pain, bone pain aggravated, buttock pain, chest wall pain, dactylitis, diffuse polyarthritis, fracture, fistula, groin pain, hypotonia, joint effusion, joint stiffness, joint swelling, loin pain, muscle cramps, muscle spasms, muscle stiffness, muscle twitching, musculoskeletal and connective tissue infections and inflammations, musculoskeletal pain, muscular weakness, myopathy, pain in extremity, pain in jaw, pain in the limb, polyarthritis, rhabdomyolysis, skeletal fracture, synovial cyst, temporomandibular joint syndrome.
Renal and urinary disorders: Azotemia, bilateral hydronephrosis, bladder irritation, bladder spasm, dysuria, hematuria, hemorrhagic cystitis, micturition disorder, micturition urgency, nephrolithiasis, oliguria, pollakiuria, proliferative glomerulonephritis, proteinuria, renal calculus, renal colic, renal failure (acute or chronic), renal impairment, urinary incontinence, urinary retention, urinary tract signs and symptoms, urine odor abnormal.
Reproductive system and breast disorders: Decreased libido, epididymal tenderness, epididymitis, erectile dysfunction, female breast disorder, genital herpes, genital pain, pelvic pain, prostatitis, testicular disorder, testicular pain, vaginal hemorrhage, vulval ulceration.
General disorders and administration site conditions: Aplasia, burning sensation at the injection site, cachexia, catheter-related complication, chest pain, chills, cold sweat, death, discomfort, effusion, extravasation, fatigue, fatigue aggravated, failure to thrive, feeling cold, feeling of body temperature change, general physical health deterioration, hernia, hyperhidrosis, impaired healing, influenza-like illness, inflammation, injection site erythema, injection site extravasation, injection site hemorrhage, injection site irritation, injection site pain, injection site phlebitis, injection site reaction, irritability, irritation, lethargy, malaise, mass, mucosal disorder, mucosal inflammation, multi-organ failure, night sweats, non-cardiac chest pain, pain, peripheral swelling, rigors, sensation of foreign body, sudden death, swelling, tenderness, ulcer, weakness.
Investigations: Abnormal blood gases, abnormal blood glucose levels, abnormal blood tests, abnormal electrocardiogram, abnormal hepatic function tests, abnormal international normalized ratio, abnormal protein analysis, abnormal uric acid levels, abnormal urine analysis, cytomegalovirus test, decreased absolute lymphocyte count, decreased blood bicarbonate, decreased blood creatinine, decreased blood phosphate, decreased blood testosterone, decreased gastric pH, decreased hemoglobin, decreased left ventricular ejection fraction, decreased megakaryocytes, decreased red blood cell count, decreased weight, decreased white blood cell count, increased absolute neutrophil count, increased alanine aminotransferase, increased alkaline phosphatase, increased aspartate aminotransferase, increased beta-2 microglobulin, increased blood amylase, increased blood bilirubin, increased blood creatinine, increased blood lactate dehydrogenase, increased blood urea, increased C-reactive protein, increased gamma-glutamyl transferase, increased hemoglobin, increased platelet aggregation, increased serum ferritin, increased transaminases, increased troponin I, increased urine pH, increased weight, irregular heart rate, prolonged QT, virus identification and serology.
Injury, poisoning and procedural complications: Blood blister, burns, catheter site pain, face injury, fall, joint injury, post-procedural hemorrhage, post-procedural pain, procedural pain, radiation injuries, skull fracture, transfusion reaction, wound hemorrhage.
Surgical and medical procedures: Macrophage activation.

CYP3A4 inhibitors (e.g., ketoconazole, ritonavir): The coadministration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib.
If concomitant administration of bortezomib with a strong CYP3A4 inhibitor is needed, patients should be monitored for signs of bortezomib toxicity. Reduction in bortezomib dose must also be considered.
CYP3A4 inducers [e.g., rifampicin, St. John's wort (Hypericum perforatum), carbamazepine, phenytoin, phenobarbital]: Since the exposure and efficacy of bortezomib may be decreased in an unpredictable manner, its coadministration with a strong CYP3A4 inducer is not recommended.
Oral antidiabetic agents: Due to the risk of hypoglycemia and/or hyperglycemia, patients concurrently administered with oral antidiabetic agents and bortezomib should be closely monitored for their blood glucose levels and adjustment of their antidiabetic medication dose.
Melphalan-prednisone: Melphalan-prednisone increased the bortezomib exposure. However, this interaction is considered to have no clinical relevance.
Drugs that are associated with peripheral neuropathy or decrease in blood pressure (e.g., amiodarone, anti-virals, isoniazid, nitrofurantoin, statins): Bortezomib should be used in caution with these drugs (See Precautions).

Incompatibilities: Bortezomib should not be mixed with other medicinal products.
Stability of Reconstituted Solution: The reconstituted solution should be used immediately after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.
Disposal: Bortezomib is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Do not store at temperatures exceeding 25°C.
Keep the vial in the outer carton in order to protect from light.

Targeted Cancer Therapy

L01XG01 - bortezomib ; Belongs to the class of proteasome inhibitors. Used in the treatment of cancer.

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