Myborte

Bortezomib.

White to off-white cake or powder.
Dosage Form: Lyophilized Powder for injection.
Myborte 1.0 mg should be reconstituted with 0.9% Sodium Chloride Injection before administration.
Description of Reconstituted solution: Clear colorless solution free from visible extraneous matter.
Each vial contains: Bortezomib 1 mg (lyophilized).
Excipients/Inactive Ingredients: Mannitol (Pyrogen free), Tertiary Butanol, Water for Injection, Nitrogen NF (Process Aid).

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents. ATC code: L01XG01.
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 1,500-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 t½ 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.
It is 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.
It is suggested that Bortezomib 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, the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administrations. The Cmax after subcutaneous administration (20.4 ng/ml) was lower than intravenous (223 ng/ml). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.
Distribution: The mean distribution volume (Vd) of bortezomib ranged from 1,659 l to 3,294 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: It indicates 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 (t½) 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: When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalised bortezomib AUC. However, the dose-normalised 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: Exposure of Bortezomib (dose-normalised AUC and Cmax) was comparable among all the 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) and dialysis patients.
Age: 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 (39%) L/m², and the elimination half-life was 100 (44%) 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.

Myborte 1.0 mg is indicated for the treatment of patients with multiple myeloma. Myborte 1.0 mg is indicated for the treatment of patients with mantle cell lymphoma.

Important Dosing Guidelines: MYBORTE 1.0MG is for intravenous use only. Do not administer MYBORTE 1.0MG by any other route.
The recommended starting dose of MYBORTE 1.0MG is 1.3 mg/m². MYBORTE 1.0MG may be administered intravenously at a concentration of 1 mg/ml.
MYBORTE 1.0MG retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with MYBORTE 1.0MG and who have relapsed at least 6 months after completing prior MYBORTE 1.0MG treatment. Treatment may be started at the last tolerated dose.
When administered intravenously, administer MYBORTE 1.0MG as a 3 to 5 second bolus intravenous injection.
Dosage in Previously Untreated Multiple Myeloma: MYBORTE 1.0MG is administered in combination with oral melphalan and oral prednisone for 9, six-week treatment cycles as shown in Table 1. In Cycles 1 to 4, MYBORTE 1.0MG is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, MYBORTE 1.0MG is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of MYBORTE 1.0MG.

Click on icon to see table/diagram/image

Dose Modification Guidelines for MYBORTE 1.0MG when given in Combination with Melphalan and Prednisone: Prior to initiating any cycle of therapy with MYBORTE 1.0MG in combination with melphalan and prednisone: Platelet count should be at least 70 x 10⁹/L and the absolute neutrophil count (ANC) should be atleast 1.0 x 10⁹/L; Nonhematological toxicities should have resolved to Grade 1 or baseline. (See Table 2.)

Click on icon to see table/diagram/image

For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided.
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy): Combination therapy with dexamethasone: MYBORTE 1.0MG is administered via intravenous injection at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of MYBORTE 1.0MG. Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the MYBORTE 1.0MG treatment cycle.
Four treatment cycles of this combination therapy are administered.
Combination therapy with dexamethasone and thalidomide: MYBORTE 1.0MG is administered via intravenous at the recommended dose of 1.3 mg/m² body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 28-day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of MYBORTE 1.0MG. Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the MYBORTE 1.0MG treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see Table 3).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. (See Table 3.)

Click on icon to see table/diagram/image

Dosage adjustments for transplant eligible patients: For MYBORTE 1.0MG dosage adjustments, as described under previously mentioned "Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma" and "Dose Modifications for Peripheral Neuropathy" as follows should be followed.
In addition, when MYBORTE 1.0MG 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 local package inserts.
Dosage in Previously Untreated Mantle Cell Lymphoma: MYBORTE 1.0MG (1.3 mg/m²) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for 6 three week treatment cycles as shown in Table 4. MYBORTE 1.0MG is administered first followed by rituximab. MYBORTE 1.0MG is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period on Days 12 to 21. For patients with a response first documented at cycle 6, two additional VcR- CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of MYBORTE 1.0MG. (See Table 4.)

Click on icon to see table/diagram/image

Dose Modification Guidelines for MYBORTE 1.0MG When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone: Prior to the first day of each cycle (other than Cycle 1): Platelet count should be at least 100 x 10⁹/L and absolute neutrophil count (ANC) should be atleast 1.5 x 10⁹/L, Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L), Non-hematologic toxicity should have recovered to Grade 1 or baseline.
Interrupt MYBORTE 1.0MG treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy [see Table 6 as follows and Precautions]. For dose adjustments, see Table 5.

Click on icon to see table/diagram/image

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see manufacturer's prescribing information.
Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma: MYBORTE 1.0MG (1.3 mg/m²/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a tenday rest period (Days 12 to 21). For extended therapy of more than eight cycles, MYBORTE 1.0MG may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four 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 MYBORTE 1.0MG.
Patients with multiple myeloma who have previously responded to treatment with MYBORTE 1.0MG (either alone or in combination) and who have relapsed at least six months after their prior MYBORTE 1.0MG therapy may be started on MYBORTE 1.0MG at the last tolerated dose. Retreated patients are administered MYBORTE 1.0MG twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of eight cycles. At least 72 hours should elapse between consecutive doses of MYBORTE 1.0MG. MYBORTE 1.0MG may be administered either as a single agent or in combination with dexamethasone.
MYBORTE 1.0MG therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed as follows (see Precautions). Once the symptoms of the toxicity have resolved, MYBORTE 1.0MG therapy may be reinitiated at a 25% reduced dose (1.3 mg/m²/dose reduced to 1 mg/m²/dose; 1 mg/m²/dose reduced to 0.7 mg/m²/dose).
For dose modifications guidelines for peripheral neuropathy, see Dose modifications for peripheral neuropathy as follows.
Dose Modifications for Peripheral Neuropathy: Patients with pre-existing severe neuropathy should be treated with MYBORTE 1.0MG only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during MYBORTE 1.0MG 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 MYBORTE 1.0MG-related neuropathic pain and/or peripheral neuropathy, see Table 6.

Click on icon to see table/diagram/image

Special Populations: Patients with Renal Impairment: The pharmacokinetics of MYBORTE 1.0MG are not influenced by the degree of renal impairment. Therefore, dosing adjustments of MYBORTE 1.0MG are not necessary for patients with renal insufficiency. Since dialysis may reduce MYBORTE 1.0MG concentrations, the drug should be administered after the dialysis procedure (see Pharmacology: Pharmacokinetics under Actions).
Patients with Hepatic Impairment: Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended MYBORTE 1.0MG dose. For patients with moderate or severe hepatic impairment, see Table 7 as follows (also, see Pharmacology: Pharmacokinetics under Actions).

Click on icon to see table/diagram/image

Administration: MYBORTE 1.0MG is administered intravenously. When administered intravenously, MYBORTE 1.0MG is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with 0.9% sodium chloride solution for injection.
Route of Administration: Intravenous.
Method of administration: MYBORTE 1.0MG is available for intravenous administration only.
MYBORTE 1.0MG should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous injection: MYBORTE 1.0MG 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 0.9% solution for injection. At least 72 hours should elapse between consecutive doses of bortezomib.

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 boron or to any of the excipients in this product.
Acute diffuse infiltrative pulmonary and pericardial disease.
When MYBORTE 1.0MG is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.

When MYBORTE 1.0MG 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 MYBORTE 1.0MG. 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 MYBORTE 1.0MG. BORTEZOMIB 1 mg powder for solution for injection is for intravenous use only, while MYBORTE 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. MYBORTE 1.0MG should not be administered intrathecally.
Gastrointestinal toxicity: Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with MYBORTE 1.0MG treatment. Cases of ileus have been uncommonly reported. Therefore, patients who experience constipation should be closely monitored.
Haematological toxicity: MYBORTE 1.0MG treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). One of the most common haematologic toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of MYBORTE 1.0MG treatment and typically recovered to baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean platelet count nadir measured was approximately 40% of baseline for multiple myeloma use and 50% for MCL use. 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 patients had a count ≤25,000/μl, including 14% <10,000/μl; in contrast, with a baseline platelet count >75,000/μl, only 14% of patients had a count ≤25,000/μl.
In patients with MCL, there was a higher incidence of Grade ≥3 thrombocytopenia in the BORTEZOMIB treatment group 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.
Gastrointestinal and intracerebral haemorrhage, have been reported in association with BORTEZOMIB treatment. Therefore, platelet counts should be monitored prior to each dose of MYBORTE 1.0MG. MYBORTE 1.0MG 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 MYBORTE 1.0MG. Platelet transfusion should be considered when clinically appropriate.
In patients with MCL, 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. Since 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 is recommended in patients being treated with MYBORTE 1.0MG.
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.
Hepatitis B Virus (HBV) reactivation and infection: When rituximab is used in combination with MYBORTE 1.0MG, 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 MYBORTE 1.0MG. Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics of rituximab for more information.
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 MYBORTE 1.0MG if PML is diagnosed.
Peripheral neuropathy: Treatment with MYBORTE 1.0MG 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.
Comparing MYBORTE 1.0MG administered intravenously versus subcutaneously, the incidence of Grade ≥2 peripheral neuropathy events was 24% for the subcutaneous injection compared to 41% for the intravenous injection. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group.
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 MYBORTE 1.0MG 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 MYBORTE 1.0MG. 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 MYBORTE 1.0MG. 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, MYBORTE 1.0MG 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, 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 MYBORTE 1.0MG therapy.
The 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 MYBORTE 1.0MG at reduced doses and closely monitored for toxicities.
Hepatic reactions: Rare cases of hepatic failure have been reported in patients receiving MYBORTE 1.0MG 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 and MCL 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: MYBORTE 1.0MG may have a moderate influence on the ability to drive and use machines. MYBORTE 1.0MG 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 and should be advised not to drive or operate machinery if they experience these symptoms

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 data are available for bortezomib with regard to exposure during pregnancy. The teratogenic potential of bortezomib has not been fully investigated.
MYBORTE 1.0MG should not be used during pregnancy unless the clinical condition of the woman requires treatment with MYBORTE 1.0MG.
If MYBORTE 1.0MG 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 programme are met. Patients receiving MYBORTE 1.0MG in combination with thalidomide should adhere to the pregnancy prevention programme 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 MYBORTE 1.0MG.
Fertility: There is no data for effect of BORTEZOMIB to fertility available.

Summary of the safety profile: Serious adverse reactions uncommonly reported during treatment with MYBORTE 1.0MG 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 MYBORTE 1.0MG 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: Undesirable effects in Table 8 were considered to have at least a possible or probabale causal relationship to BORTEZOMIB. Overall, BORTEZOMIB was administered for the treatment of 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. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Tables 8a and 8b.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Mantle Cell Lymphoma (MCL): 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. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. (See Table 9.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Herpes zoster virus reactivation: Multiple myeloma: The incidence of herpes zoster among patients in the Vc+M+P treatment was higher for patients not administered antiviral prophylaxis compared to patients administered antiviral prophylaxis.
Mantle cell lymphoma: The incidence of herpes zoster among patients in the VcR-CAP was higher for patients not administered antiviral prophylaxis compared to patients administered antiviral prophylaxis.
Hepatitis B Virus (HBV) reactivation and infection: Mantle cell lymphoma: The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP.
Peripheral neuropathy in combination regimens: Multiple Myeloma: Where MYBORTE 1.0MG was administered as induction treatment in combination with dexamethasone, and dexamethasone-thalidomide, the incidence of peripheral neuropathy in the combination regimens is presented in Table 10: See Table 10.

Click on icon to see table/diagram/image

Mantle cell lymphoma: Where BORTEZOMIB was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in Table 11: See Table 11.

Click on icon to see table/diagram/image

Elderly MCL patients: Although in patients aged ≥75 years, both VcR-CAP and R-CHOP were less tolerated, the serious adverse event rate in the VcR-CAP groups was higher compared to R-CHOP group.
Retreatment of patients with relapsed multiple myeloma: Where 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.

Bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.
Assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), it showed a mean bortezomib AUC increase. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
Assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib.
Assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction. Therefore, 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.
Assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib.
Assessing the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase that is not considered clinically relevant.
Hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. 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.

Incompatibilities: This product must not be mixed with other medicinal products except those mentioned in Method of Administration under Dosage & Administration.
Special precautions for disposal and other handling: General precautions: Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of MYBORTE 1.0MG. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of MYBORTE 1.0MG, since it contains no preservative.
There have been fatal cases of inadvertent intrathecal administration of BORTEZOMIB. MYBORTE 1.0MG is for intravenous use. MYBORTE 1.0MG should not be administered intrathecally.
MYBORTE 1.0MG is available for intravenous administration.
Instructions for reconstitution: MYBORTE 1.0MG must be reconstituted by a healthcare professional.
Intravenous injection: Each 5 ml vial of bortezomib must be reconstituted with 1 ml of sodium chloride 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.
Disposal: MYBORTE 1.0MG is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Unopened vial: Store below 30°C. Protect from light.
Shelf Life: Unopened vial: 24 months.
Reconstituted Solution: From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

Targeted Cancer Therapy

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

B