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When Bortezomib is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with Bortezomib. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed.
Intrathecal administration: There have been fatal cases of inadvertent intrathecal administration of Bortezomib. Bortezomib 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. Bortezomib should not be administered intrathecally.
Gastrointestinal toxicity: Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with Bortezomib treatment. Cases of ileus have been uncommonly reported. Therefore, patients who experience constipation should be closely monitored.
Haematological toxicity: Bortezomib treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In the Phase III study evaluating Bortezomib (injected intravenously) versus dexamethasone, the most common haematologic toxicity was transient thrombocytopenia. In a Phase II study, platelets were lowest at day 11 of each cycle of Bortezomib treatment. There was no evidence of cumulative thrombocytopenia, including in the Phase II extension study. The mean platelet count nadir measured was approximately 40% of baseline. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts <75,000/μl, 90% of 21 patients had a count ≤25,000/μl during the study, including 14% <10,000/μl; in contrast, with a baseline platelet count >75,000/μl, only 14% of 309 patients had a count ≤25 x 109/L during the study. Platelet counts should be monitored prior to each dose of Bortezomib. Bortezomib therapy should be withheld when the platelet count is <25,000/μl or in combination with melphalan and prednisone when the platelet count is ≤30,000/μl and re-initiated at a reduced dose after resolution. 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.
Therefore, complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with Bortezomib.
Herpes zoster virus reactivation: Antiviral prophylaxis should be considered in patients being treated with Bortezomib. In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with Bortezomib+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
Progressive multifocal leukoencephalopathy (PML): Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with Bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of Bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue Bortezomib if PML is diagnosed.
Peripheral neuropathy: Treatment with Bortezomib is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
In the Phase III study comparing Bortezomib administered intravenously versus subcutaneously, the incidence of Grade 2 peripheral neuropathy events was 24% for the subcutaneous injection group and 41% for the intravenous injection group (p=0.0124). Grade 3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group (p=0.0264). The incidence of all grade peripheral neuropathy with Bortezomib administered intravenously was lower in the historical studies with Bortezomib administered intravenously than in study MMY-3021.
Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to subcutaneous. Neuropathy has been managed with supportive care and other therapies.
Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological evaluation should be considered in patients receiving Bortezomib in combination with medicinal products known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction or treatment discontinuation should be considered.
In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.
Seizures: Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.
Hypotension: Bortezomib treatment is commonly associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on Bortezomib (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with Bortezomib. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of Bortezomib. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to Bortezomib or Bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.
Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving Bortezomib. PRES is a rare, often reversible, rapidly evolving neurological condition, which can present with 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. In patients developing PRES, Bortezomib should be discontinued.
Heart failure: Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during Bortezomib treatment. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.
Electrocardiogram investigations: There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.
Pulmonary disorders: There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving Bortezomib. Some of these events have been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential posttreatment pulmonary changes.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing Bortezomib therapy.
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.
Renal impairment: Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely.
Hepatic impairment: Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with Bortezomib at reduced doses and closely monitored for toxicities.
Hepatic reactions: Rare cases of hepatic failure have been reported in patients receiving Bortezomib and concomitant medicinal products and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib.
Tumour lysis syndrome: Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Concomitant medicinal products: Patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4 or CYP2C19 substrates. Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics.
Potentially immunocomplex-mediated reactions: Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.
Effects on ability to drive and use machines: Bortezomib may have a moderate influence on the ability to drive and use machines. Bortezomib may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines.
