Myborte

Bortezomib.

Each vial contains: Bortezomib 3.5 mg (lyophilized).
Bortezomib for Injection 3.5 mg is a White to Off White Cake or Powder filled in 10 mL single-use USP Type-I tubular glass vial stoppered with 13 mm two leg slotted bromobutyl rubber stopper and sealed with 13 mm aluminium flip-off seal.
Bortezomib Powder for Solution for Injection 3.5 mg/vial should be reconstituted with 0.9% Sodium Chloride Injection before administration.
Description of Reconstituted solution: Clear colorless solution free from visible extraneous matter.
Excipients/Inactive Ingredients: Mannitol (Pyrogen free), Tertiary Butanol, Water for Injection, Nitrogen NF (Process Aid).

Pharmacology: Mechanism of action: Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.
Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1500-fold more selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t_½ of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible.
Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment.
Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.
Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.
Pharmacokinetics: Absorption: Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to patients with multiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the 1.0 mg/m² dose and 89 to 120 ng/ml for the 1.3 mg/m² dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m² dose to patients with multiple myeloma (in intravenous and subcutaneous group), the total systemic exposure after repeat dose administration (AUC_last) was equivalent for subcutaneous and intravenous administrations. The C_max after subcutaneous administration (20.4 ng/ml) was lower than intravenous (223 ng/ml). The AUC_last geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.
Distribution: The mean distribution volume (V_d) of bortezomib ranged from 1659 l to 3294 l following single- or repeated-dose administration of 1.0 mg/m² or 1.3 mg/m² to patients with multiple myeloma. This suggests that bortezomib distributes widely to peripheral tissues. Over a bortezomib concentration range of 0.01 to 1.0 μg/ml, the in vitro protein binding averaged 82.9% in human plasma. The fraction of bortezomib bound to plasma proteins was not concentration-dependent.
Biotransformation: In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolized via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.
Elimination: The mean elimination half-life (t_½) of bortezomib upon multiple dosing ranged from 40-193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/m² and 1.3 mg/m², respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for doses of 1.0 mg/m² and 1.3 mg/m², respectively.
Special populations: Hepatic impairment: The effect of hepatic impairment on the pharmacokinetics of bortezomib during the first treatment cycle, including patients primarily with solid tumors and varying degrees of hepatic impairment at bortezomib doses ranging from 0.5 to 1.3 mg/m².
When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalized bortezomib AUC. However, the dose-normalized mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be closely monitored.
Renal impairment: In patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥ 60 ml/min/1.73 m²), Mild (CrCL = 40-59 ml/min/1.73 m²), Moderate (CrCL = 20-39 ml/min/1.73 m²), and Severe (CrCL < 20 ml/min/1.73 m²). Patients were administered intravenous doses of 0.7 to 1.3 mg/m² of bortezomib twice weekly. Exposure of bortezomib (dose-normalized AUC and C_max) was comparable among all the groups.
Age: The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m² doses to pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV) clearance was 7.79 L/hr/m², volume of distribution at steady-state was 834 L/m², and the elimination half-life was 100 hours. After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

Bortezomib is indicated for the treatment of patients with multiple myeloma. Bortezomib is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

General Dosing Guidelines: The recommended starting dose of bortezomib is 1.3 mg/m².
Bortezomib may be administered intravenously at a concentration of 1 mg/ml, or subcutaneously at a concentration of 2.5 mg/ml. When administered intravenously, Bortezomib is administered as a 3 to 5 second bolus intravenous injection. Bortezomib is for intravenous or subcutaneous use only. Bortezomib should not be administered by any other route. Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.
BORTEZOMIB IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY. Intrathecal administration has resulted in death.
Dosage in Previously Untreated Multiple Myeloma: Bortezomib is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1.
In Cycles 1-4, bortezomib is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32).
In Cycles 5-9, bortezomib is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of bortezomib. (See Table 1.)

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Dose Modification Guidelines for Combination Therapy with bortezomib, Melphalan and Prednisone: Prior to initiating any cycle of therapy with bortezomib in combination with melphalan and prednisone: Platelet count should be ≥ 70 x 10⁹/L and the ANC should be ≥ 1 x 10⁹/L; nonhematological toxicities should have resolved to Grade 1 or baseline. (See Table 2.)

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For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided.
Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma: Bortezomib (1.3 mg/m²/dose) is administered twice weekly for 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12 - 21). For extended therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or, for relapsed multiple myeloma, 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.
Bortezomib therapy should be withheld at the onset of any Grade 3 non hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows. Once the symptoms of the toxicity have resolved, bortezomib therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1.0 mg/m²/dose; 1.0 mg/m²/dose reduced to 0.7 mg/m²/dose).
For dose modifications guidelines for peripheral neuropathy, see Dose Modifications for Peripheral Neuropathy as follows.
Dose Modifications for Peripheral Neuropathy: Starting bortezomib subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with bortezomib only after careful risk-benefit assessment. Patients experiencing new or worsening peripheral neuropathy during bortezomib therapy may require a decrease in the dose and/or a less dose-intense schedule. For dose or schedule modification guidelines for patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy see Table 3. (See Table 3.)

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Special populations: Elderly: There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age.
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 haematopoietic stem cell transplantation. Therefore no dose recommendations can be made in this population.
Previously untreated mantle cell lymphoma patients, who exposed to bortezomib were in the range 65-74 years and ≥ 75 years of age, respectively. In patients aged ≥ 75 years, both regimens, Bortezomib-R-CAP as well as R-CHOP, were less tolerated.
Hepatic impairment: Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on bortezomib at a reduced dose of 0.7 mg/m² per injection during the first treatment cycle, and a subsequent dose escalation to 1.0 mg/m² or further dose reduction to 0.5 mg/m² may be considered based on patient tolerability (see Table 4).

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Renal impairment: The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance [Cr_CL] > 20 ml/min/1.73 m²); therefore, dose adjustments are not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (Cr_CL < 20 ml/min/1.73 m²). Since dialysis may reduce bortezomib concentrations, bortezomib should be administered after the dialysis procedure.
Paediatric population: The safety and efficacy of bortezomib in children below 18 years of age have not been established.
Method of administration: Bortezomib 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.
Bortezomib 1 mg powder for solution for injection is available for intravenous administration only.
Bortezomib should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous injection: Bortezomib 3.5 mg reconstituted solution is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/ml (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of bortezomib.
Subcutaneous injection: Bortezomib 3.5 mg reconstituted solution is administered subcutaneously through the thighs (right or left) or abdomen (right or left). The solution should be injected subcutaneously, at a 45-90° angle. Injection sites should be rotated for successive injections.
If local injection site reactions occur following bortezomib subcutaneous injection, either a less concentrated bortezomib solution (bortezomib 3.5 mg to be reconstituted to 1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously or a switch to intravenous injection is recommended.

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.

Hypersensitivity to the active substance, to any of the excipients.
Acute diffuse infiltrative pulmonary and pericardial disease.

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 1 mg powder for solution for injection is for intravenous use only, while 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). Bortezomib (injected intravenously) versus dexamethasone, the most common haematologic toxicity was transient thrombocytopenia. Platelets were lowest at day 11 of each cycle of bortezomib treatment. There was no evidence of cumulative thrombocytopenia. The mean platelet count nadir measured was approximately with baseline. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts < 75,000/μl, and ≤ 25,000/μl.
There was a higher incidence of Grade ≥ 3 thrombocytopenia in the bortezomib treatment group (BortezomibR-CAP) as compared to the non-bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence of all-grade bleeding events as well as Grade 3 and higher bleeding events. In the BortezomibR-CAP group, patients received platelet transfusions compared to lower in patients with R-CHOP group.
Gastrointestinal and intracerebral haemorrhage, have been reported in association with bortezomib treatment. Therefore, 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 the case of combination with melphalan and prednisone, when the platelet count is ≤ 30,000/μl. 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.
Complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with bortezomib. Platelet transfusion should be considered when clinically appropriate.
Transient neutropenia that was reversible between cycles was observed, with no evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of bortezomib treatment and typically recovered to baseline by the next cycle. Patients with neutropenia are at increased risk of infections, they should be monitored for signs and symptoms of infection and treated promptly. Granulocyte colony stimulating factors may be administered for haematologic toxicity according to local standard practice. Prophylactic use of granulocyte colony stimulating factors should be considered in case of repeated delays in cycle administration.
Herpes zoster virus reactivation: Antiviral prophylaxis should be considered in patients being treated with bortezomib. 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. The incidence of herpes zoster infection was higher in the BortezomibR-CAP arm and lower in the R-CHOP arm.
Hepatitis B Virus (HBV) reactivation and infection: When rituximab is used in combination with bortezomib, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with bortezomib. Antiviral prophylaxis should be considered.
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.
Bortezomib administered intravenously versus subcutaneously, the incidence of Grade ≥ 2 peripheral neuropathy events lower for the subcutaneous injection group and higher for the intravenous injection group. Grade ≥ 3 peripheral neuropathy occurred in less patients in the subcutaneous treatment group, compared with intravenous treatment group. The incidence of all grade peripheral neuropathy with bortezomib administered intravenously was lower.
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 post-treatment 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.
Daunorubicin and bortezomib with concomitant administration of high-dose cytarabine (2 g/m² per day) by continuous infusion over 24 hours is not recommended.
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.
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.

Contraception in males and females: Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.
Pregnancy: No clinical data are available for bortezomib with regard to exposure during pregnancy. The teratogenic potential of bortezomib has not been fully investigated.
In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib on parturition and post-natal development were not conducted. Bortezomib should not be used during pregnancy unless the clinical condition of the woman requires treatment with bortezomib.
If bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this medicinal product, the patient should be informed of potential for hazard to the foetus.
Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the thalidomide pregnancy prevention program are met. Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancy prevention program of thalidomide. Refer to the Summary of Product Characteristics of thalidomide for additional information.
Breast-feeding: It is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reaction in breast-fed infants, breast-feeding should be discontinued during treatment with bortezomib.
Fertility: Fertility studies were not conducted with bortezomib.

Summary of the safety profile: Serious adverse reactions uncommonly reported during treatment with bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.
The most commonly reported adverse reactions during treatment with bortezomib are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.
Tabulated summary of adverse reactions: Multiple myeloma: Adverse reactions are listed as follows by system organ class and frequency grouping. Frequencies are defined as: Very common; common; uncommon; rare; very rare, not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 5 has been generated using Version 14.1 of the MedDRA. (See Table 5.)

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Mantle Cell Lymphoma (MCL): The safety profile of bortezomib in patients treated with bortezomib at 1.3 mg/m² in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (Bortezomib-R-CAP) versus patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described as follows. Additional adverse drug reactions identified associated with the use of the combination therapy (Bortezomib-R-CAP) were hepatitis B infection and myocardial ischaemia. The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to bortezomib alone. Very common incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders were seen with patients in the multiple myeloma.
Adverse drug reactions identified as those with common incidence, similar or higher incidence in the bortezomib-R-CAP arm and with at least a possible or probable causal relationship to the components of the bortezomib-R-CAP arm, are listed in Table 6 as follows. Also included are adverse drug reactions identified in the bortezomib-R-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib based on historical data in the multiple myeloma studies.
Adverse reactions are listed as follows by system organ class and frequency grouping. Frequencies are defined as: Very common; common; uncommon; rare; very rare; not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 6 has been generated using Version 16 of the MedDRA. (See Table 6.)

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Description of selected adverse reactions: Retreatment of patients with relapsed multiple myeloma: Bortezomib retreatment was administered in patients with relapsed multiple myeloma, who previously had at least partial response on a bortezomib-containing regimen, the most common all-grade adverse events occurring in patients were thrombocytopenia, neuropathy, anaemia, diarrhoea, and constipation. All grade peripheral neuropathy and grade ≥ 3 peripheral neuropathy were observed.

In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.
Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
The concomitant use of bortezomib with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort) is not recommended, as efficacy may be reduced.
Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

Special precautions for disposal and other handling: General precautions: Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of bortezomib. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of bortezomib, since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib 1 mg powder for solution for injection is for intravenous use only, while bortezomib 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. Bortezomib should not be administered intrathecally.
Instructions for reconstitution: Bortezomib must be reconstituted by a healthcare professional.
Intravenous injection: Each 10 ml vial of bortezomib must be reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilized powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear and colorless, with a final pH of 4 to 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Subcutaneous injection: Each 10 ml vial of bortezomib should be reconstituted with 1.4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilized powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colorless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.
Disposal: Bortezomib is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store below 30°C. Protect from light.
Shelf Life: Unopened Vials: 30 months, Protect from light.
Reconstituted Solution: When reconstituted as directed, the reconstituted solution may be stored for 8 hours at 25°C in the original vial or a syringe prior to administration; however the total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration. At 2-8°C reconstituted drug product is stable for 15 days.

Targeted Cancer Therapy

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

B