Biomib Special Precautions

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.