Borvex

Bortezomib.

Each vial contains: Bortezomib 3.5 mg (as sterile freeze-dried powder for reconstitution).
Bortezomib is white to off white colour crystalline powder. It is soluble in methanol, ethanol and diethyl Sulfoxide & slightly soluble in water. The chemically, it is the monomeric boronic acid, is [(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl) amino]propyl]amino]butyl] boronic acid. The molecular formula is C₁₉H₂₅BN₄O₄ and the molecular weight is 384.24.

Pharmacologic classification: Antineoplastic agent (Proteasome inhibitor).
Pharmacology: Pharmacodynamics: Mechanism of Action: Bortezomib is a reversible inhibitor of 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 intracellular concentration of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis, which can affect multiple signaling cascades within the cell. This disruption of normal homeostatic mechanisms can lead to cell death. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types in vitro. Bortezomib causes a delay in tumor growth in vivo in nonclinical tumor models, including multiple myeloma.
Pharmacokinetics: Absorption: Following intravenous bolus administration of a 1.0 mg/m² and 1.3 mg/m² dose to 11 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 (n=14 in the intravenous group, n=17 in the 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 1,659 l to 3,294 l following single- or repeated-dose intravenous 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 metabolised 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 (t1/2) 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.

Bortezomib for injection as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.
Bortezomib for injection in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
Bortezomib for injection in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.

Treatment must be initiated and administered under the supervision of a physician qualified and experienced in the use of chemotherapeutic agents. Bortezomib for injection must be reconstituted by a healthcare professional.
Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy): Monotherapy: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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. It is recommended that patients receive 2 cycles of Bortezomib for injection following a confirmation of a complete response. It is also recommended that responding patients who do not achieve a complete remission receive a total of 8 cycles of Bortezomib for injection therapy. At least 72 hours should elapse between consecutive doses of Bortezomib for injection.
Dose adjustments during treatment and re-initiation of treatment for monotherapy: Bortezomib for injection treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed as follows. Once the symptoms of the toxicity have resolved, Bortezomib for injection treatment may be re-initiated at a 25% reduced dose (1.3 mg/m² reduced to 1.0 mg/m²; 1.0 mg/m² reduced to 0.7 mg/m²). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of Bortezomib for injection must be considered unless the benefit of treatment clearly outweighs the risk.
Neuropathic pain and/or peripheral neuropathy: Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1. Patients with pre-existing severe neuropathy may be treated with Bortezomib for injection only after careful risk/benefit assessment. (See Table 1.)

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Combination therapy with pegylated liposomal doxorubicin: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 Bortezomib for injection.
Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the Bortezomib for injection treatment cycle as a 1 hour intravenous infusion administered after the Bortezomib for injection.
Up to 8 cycles of this combination therapy can be administered as long as patients have not progressed and tolerate treatment. Patients achieving a complete response can continue treatment for at least 2 cycles after the first evidence of complete response, even if this requires treatment for more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue for as long as treatment is tolerated and they continue to respond.
Combination with dexamethasone: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 Bortezomib for injection.
Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib for injection treatment cycle.
Patients achieving a response or a stable disease after 4 cycles of this combination therapy can continue to receive the same combination for a maximum of 4 additional cycles.
Dose adjustments for combination therapy for patients with progressive multiple myeloma: For Bortezomib for injection dosage adjustments for combination therapy follow dose modification guidelines described under monotherapy previously.
Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation: Combination therapy with melphalan and prednisone: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone as shown in Table 2. A 6-week period is considered a treatment cycle. In Cycles 1-4, Bortezomib for injection is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, Bortezomib for injection is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of Bortezomib for injection.
Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each Bortezomib for injection treatment cycle. Nine treatment cycles of this combination therapy are administered. (See Table 2.)

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Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisone: Prior to initiating a new cycle of therapy: Platelet counts should be ≥70 x 109/L and the absolute neutrophils count should be ≥1.0 x 109/L; Non-haematological toxicities should have resolved to Grade 1 or baseline. (See Table 3.)

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Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy): Combination therapy with dexamethasone: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 Bortezomib for injection.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib for injection treatment cycle. Four treatment cycles of this combination therapy are administered.
Combination therapy with dexamethasone and thalidomide: Bortezomib for injection 3.5 mg powder for solution for injection is administered via intravenous or subcutaneous 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 28-day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib for injection.
Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib for injection 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 4).
Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles. (See Table 4).

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Dosage adjustments for transplant eligible patients: For Bortezomib for injection dosage adjustments for neuropathy refer to Table 1.
In addition, when Bortezomib for injection 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.
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 for injection 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.
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 for injection 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 5.)

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Renal impairment: The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance [CrCl] >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 (CrCl <20 mL/min/1.73 m²). Since dialysis may reduce bortezomib concentrations, Bortezomib for injection should be administered after the dialysis procedure.
Paediatric population: The safety and efficacy of Bortezomib for injection in children below 18 years of age have not been established. No data are available.
Method of administration: Bortezomib for injection 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration. Bortezomib for injection 1 mg powder for solution for injection is available for intravenous administration only.
Bortezomib for injection should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous injection: Bortezomib for injection 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 for injection.
Subcutaneous injection: Bortezomib for injection 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 for injection subcutaneous injection, either a less concentrated Bortezomib for injection solution (Bortezomib for injection 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 boron or to any of the excipients listed in this product. Acute diffuse infiltrative pulmonary and pericardial disease.

When Bortezomib for injection is given in combination with other medicinal products, see drug interaction with other medicinal products must be consulted prior to initiation of treatment with Bortezomib for injection. 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 for injection. 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 for injection should not be administered intrathecally.
Gastrointestinal toxicity: Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with Bortezomib for injection treatment. Cases of ileus have been uncommonly reported. Therefore, patients who experience constipation should be closely monitored.
Haematological toxicity: Bortezomib for injection treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In the Phase III study evaluating Bortezomib for injection (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 for injection 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 for injection. Bortezomib for injection 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 for injection.
Herpes zoster virus reactivation: Antiviral prophylaxis should be considered in patients being treated with Bortezomib for injection. 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 for injection+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 for injection. 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 for injection. 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 for injection if PML is diagnosed.
Peripheral neuropathy: Treatment with Bortezomib for injection 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 for injection 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 for injection administered intravenously was lower in the historical studies with Bortezomib for injection 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 for injection 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 for injection 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 for injection (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with Bortezomib for injection. 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 for injection. 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 for injection. 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 for injection 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 for injection. 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 for injection 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 injection 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 for injection at reduced doses and closely monitored for toxicities.
Hepatic reactions: Rare cases of hepatic failure have been reported in patients receiving Bortezomib for injection 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 for injection may have a moderate influence on the ability to drive and use machines. Bortezomib for injection 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.

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 for injection should not be used during pregnancy unless the clinical condition of the woman requires treatment with Bortezomib for injection.
If Bortezomib for injection 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 Bortezomib for injection 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 Bortezomib for injection.
Fertility: Fertility studies were not conducted with Bortezomib for injection.

Summary of the safety profile: Serious adverse reactions uncommonly reported during treatment with Bortezomib for injection 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 for injection 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: Undesirable effects in Table 6 were considered by the investigators to have at least a possible or probable causal relationship to Bortezomib for injection. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with Bortezomib for injection at 1.3 mg/m² and included in Table 6.
Overall, Bortezomib for injection was administered for the treatment of multiple myeloma in 3,974 patients.
Adverse reactions are listed as follows by system organ class and frequency grouping. Frequencies are defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), 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 14.1 of the MedDRA.
Post-marketing adverse reactions not seen in clinical trials are also included. (See Tables 6a and 6b.)

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Description of selected adverse reactions: Herpes zoster virus reactivation: Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence of herpes zoster among patients in the Vc+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
Peripheral neuropathy in combination regimens: In trials in which Bortezomib for injection was administered as induction treatment in combination with dexamethasone (study IFM-2005-01), and dexamethasone-thalidomide (study MMY-3010), the incidence of peripheral neuropathy in the combination regimens is presented in the table as follows: (see Table 7.)

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Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.
Notable differences in the safety profile of Bortezomib for injection administered subcutaneously versus intravenously as single agent: In the Phase III study patients who received Bortezomib for injection subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse reactions that were Grade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of Bortezomib for injection. The overall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections and peripheral neuropathies were 12%-15% lower in the subcutaneous group than in the intravenous group. In addition, the incidence of Grade 3 or higher peripheral neuropathies was 10% lower, and the discontinuation rate due to peripheral neuropathies 8% lower for the subcutaneous group as compared to the intravenous group.
Six percent of patients had an adverse local reaction to subcutaneous administration, mostly redness. Cases resolved in a median of 6 days, dose modification was required in two patients. Two (1%) of the patients had severe reactions; 1 case of pruritus and 1 case of redness.
The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in the intravenous treatment group. Incidence of death from "Progressive disease" was 18% in the subcutaneous group and 9% in the intravenous group.
Retreatment of patients with relapsed multiple myeloma: In a study in which Bortezomib for injection retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a Bortezomib for injection-containing regimen, the most common all-grade adverse events occurring in at least 25% of patients were thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation (28%). All grade peripheral neuropathy and grade ≥ 3 peripheral neuropathy were observed in 40% and 8.5% of patients, respectively.

A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study 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 based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of Bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. 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.
In the same drug-drug interaction study 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 based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of Bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on data from 21 patients. This is not considered clinically relevant.
During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving Bortezomib for injection treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
Interaction with other medicinal products and other forms of interaction: 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 (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.
A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).
In a drug-drug interaction study 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 based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. 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.
In the same drug-drug interaction study 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 based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on data from 21 patients. This is not considered clinically relevant. During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving BORVEX treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

Store at temperatures not exceeding 30ºC. Protect from light.
The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the reconstituted solution is stable for 8 hours at 25°C stored in the original vial and/or a syringe prior to administration, with a maximum of 8 hours in the syringe.
Discard unused portion.
Shelf-life: 2 years from manufacturing date.

Targeted Cancer Therapy

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

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