- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy)
MonotherapyVELCADE 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 VELCADE 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 VELCADE therapy. At least 72 hours should elapse between consecutive doses of VELCADE.
Dose adjustments during treatment and re-initiation of treatment for monotherapyVELCADE treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4). Once the symptoms of the toxicity have resolved, VELCADE 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 VELCADE must be considered unless the benefit of treatment clearly outweighs the risk.
Neuropathic pain and/or peripheral neuropathyPatients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1 (see section 4.4). Patients with pre-existing severe neuropathy may be treated with VELCADE only after careful risk/benefit assessment.
Table 1: Recommended* posology modifications for bortezomib-related neuropathy
|Severity of neuropathy||Posology modification|
|Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) with no pain or loss of function||None|
|Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**)||Reduce VELCADE to 1.0 mg/m2or Change VELCADE treatment schedule to 1.3 mg/m2 once per week|
|Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL***)||Withhold VELCADE treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate VELCADE treatment and reduce dose to 0.7 mg/m2 once per week.|
|Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathy||Discontinue VELCADE|
|* Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience. Grading based on NCI Common Toxicity Criteria CTCAE v 4.0. ** Instrumental ADL: refers to preparing meals, shopping for groceries or clothes, using telephone, managing money, etc; *** Self care ADL: refers to bathing, dressing and undressing, feeding self, using the toilet, taking medicinal products, and not bedridden.|
Combination therapy with pegylated liposomal doxorubicinVELCADE 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 VELCADE.Pegylated liposomal doxorubicin is administered at 30 mg/m² on day 4 of the VELCADE treatment cycle as a 1 hour intravenous infusion administered after the VELCADE 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.For additional information concerning pegylated liposomal doxorubicin, see the corresponding Summary of Product Characteristics.
Combination with dexamethasoneVELCADE 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 VELCADE.Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELCADE 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.For additional information concerning dexamethasone, see the corresponding Summary of Product Characteristics.
Dose adjustments for combination therapy for patients with progressive multiple myelomaFor VELCADE dosage adjustments for combination therapy follow dose modification guidelines described under monotherapy above.
Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation
Combination therapy with melphalan and prednisoneVELCADE 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, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, VELCADE is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of VELCADE.Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each VELCADE treatment cycle.Nine treatment cycles of this combination therapy are administered.
Table 2: Recommended posology for VELCADE in combination with melphalan and prednisone
|Twice weekly VELCADE (cycles 1-4)|
|Vc (1.3 mg/m2)||Day 1||--||--||Day 4||Day 8||Day 11||rest period||Day 22||Day 25||Day 29||Day 32||rest period|
|M (9 mg/m2) P (60 mg/m2)||Day 1||Day 2||Day 3||Day 4||--||--||rest period||--||--||--||--||rest period|
|Once weekly VELCADE (cycles 5-9)|
|Vc (1.3 mg/m2)||Day 1||--||--||--||Day 8||rest period||Day 22||Day 29||rest period|
|M (9 mg/m2) P (60 mg/m2)||Day 1||Day 2||Day 3||Day 4||--||rest period||--||rest period|
|Vc=VELCADE; M=melphalan, P=prednisone|
Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisonePrior 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
Table 3: Posology modifications during subsequent cycles of VELCADE therapy in combination with melphalan and prednisone
|Toxicity||Posology modification or delay|
|Haematological toxicity during a cycle|
|• If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle||Consider reduction of the melphalan dose by 25% in the next cycle.|
|• If platelet counts ≤ 30 x 109/l or ANC ≤ 0.75 x 109/l on a VELCADE dosing day (other than day 1)||VELCADE therapy should be withheld|
|• If several VELCADE doses in a cycle are withheld (≥ 3 doses during twice weekly administration or ≥ 2 doses during weekly administration)||VELCADE dose should be reduced by 1 dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)|
|Grade ≥ 3 non-haematological toxicities||VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, VELCADE may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELCADE as outlined in Table 1.|
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasoneVELCADE 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 VELCADE.Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.Four treatment cycles of this combination therapy are administered.
Combination therapy with dexamethasone and thalidomideVELCADE 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 VELCADE.Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE 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.Table 4: Posology for VELCADE combination therapy for patients with previously untreated multiple myeloma eligible for haematopoietic stem cell transplantation
|Vc+ Dx||Cycles 1 to 4|
|Vc (1.3 mg/m2)||Day 1, 4||Day 8, 11||Rest Period|
|Dx 40 mg||Day 1, 2, 3, 4||Day 8, 9, 10, 11||-|
|Vc (1.3 mg/m2)||Day 1, 4||Day 8, 11||Rest Period||Rest Period|
|T 50 mg||Daily||Daily||-||-|
|T 100 mga||-||-||Daily||Daily|
|Dx 40 mg||Day 1, 2, 3, 4||Day 8, 9, 10, 11||-||-|
|Cycles 2 to 4b|
|Vc (1.3 mg/m2)||Day 1, 4||Day 8, 11||Rest Period||Rest Period|
|T 200 mga||Daily||Daily||Daily||Daily|
|Dx 40 mg||Day 1, 2, 3, 4||Day 8, 9, 10, 11||-||-|
|Vc=VELCADE; Dx=dexamethasone; T=thalidomide a Thalidomide dose is increased to 100 mg from week 3 of Cycle 1 only if 50 mg is tolerated and to 200 mg from cycle 2 onwards if 100 mg is tolerated. b Up to 6 cycles may be given to patients who achieve at least a partial response after 4 cycles|
Dosage adjustments for transplant eligible patientsFor VELCADE dosage adjustments for neuropathy refer to Table 1.In addition, when VELCADE 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 Summary of Product Characteristics.
Posology for patients with previously untreated mantle cell lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)VELCADE 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, followed by a 10-day rest period on days 12-21. This 3-week period is considered a treatment cycle. Six VELCADE cycles are recommended, although for patients with a response first documented at cycle 6, two additional VELCADE cycles may be given. At least 72 hours should elapse between consecutive doses of VELCADE.The following medicinal products are administered on day 1 of each VELCADE 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2.Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each VELCADE treatment cycle.
Dose adjustments during treatment for patients with previously untreated mantle cell lymphomaPrior to initiating a new cycle of therapy:• Platelet counts should be ≥ 100,000 cells/μL and the absolute neutrophils count (ANC) should be ≥ 1,500 cells/μL• Platelet counts should be ≥ 75,000 cells/μL in patients with bone marrow infiltration or splenic sequestration• Haemoglobin ≥ 8 g/dL• Non-haematological toxicities should have resolved to Grade 1 or baseline.VELCADE treatment must be withheld at the onset of any ≥ Grade 3 VELCADE-related non-haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities (see also section 4.4). For dose adjustments, see Table 5 below.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. Platelet transfusion for the treatment of thrombocytopenia should be considered when clinically appropriate.
Table 5: Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma
|Toxicity||Posology modification or delay|
|• ≥ Grade 3 neutropenia with fever, Grade 4 neutropenia lasting more than 7 days, a platelet count < 10,000 cells/μL||VELCADE therapy should be withheld for up to 2 weeks until the patient has an ANC ≥ 750 cells/μL and a platelet count ≥ 25,000 cells/μL. • If, after VELCADE has been held, the toxicity does not resolve, as defined above, then VELCADE must be discontinued. • If toxicity resolves i.e. patient has an ANC ≥ 750 cells/μL and a platelet count ≥ 25,000 cells/μL, VELCADE may be reinitiated at a dose reduced by one dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).|
|• If platelet counts < 25,000 cells/μL. or ANC < 750 cells/μL on a VELCADE dosing day (other than Day 1 of each cycle)||VELCADE therapy should be withheld|
|Grade ≥ 3 non-haematological toxicities considered to be related to VELCADE||VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 2 or better. Then, VELCADE may be reinitiated at a dose reduced by one dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For VELCADE-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELCADE as outlined in Table 1.|
ElderlyThere is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma.There are no studies on the use of VELCADE 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.In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients exposed to VELCADE were in the range 65-74 years and ≥ 75 years of age, respectively. In patients aged ≥ 75 years, both regimens, VcR-CAP as well as R-CHOP, were less tolerated (see section 4.8).
Hepatic impairmentPatients 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 VELCADE 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 6 and sections 4.4 and 5.2).
Table 6: Recommended starting dose modification for VELCADE in patients with hepatic impairment
|Grade of hepatic impairment*||Bilirubin level||SGOT (AST) levels||Modification of starting dose|
|Mild||≤ 1.0 x ULN||> ULN||None|
|> 1.0 x −1.5 x ULN||Any||None|
|Moderate||> 1.5 x −3 x ULN||Any||Reduce VELCADE to 0.7 mg/m2 in the first treatment cycle. Consider dose escalation to 1.0 mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.|
|Severe||> 3 x ULN||Any|
|Abbreviations: SGOT=serum glutamic oxaloacetic transaminase; AST=aspartate aminotransferase; ULN=upper limit of the normal range. * Based on NCI Organ Dysfunction Working Group classification for categorising hepatic impairment (mild, moderate, severe).|
Renal impairmentThe 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, VELCADE should be administered after the dialysis procedure (see section 5.2).
Paediatric populationThe safety and efficacy of VELCADE in children below 18 years of age have not been established (see sections 5.1 and 5.2). No data are available.
Method of administrationVELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.VELCADE 1 mg powder for solution for injection is available for intravenous administration only.VELCADE should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous injectionVELCADE 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 VELCADE.
Subcutaneous injectionVELCADE 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 VELCADE subcutaneous injection, either a less concentrated VELCADE solution (VELCADE 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.When VELCADE is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.
Intrathecal administrationThere have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mg powder for solution for injection is for intravenous use only, while VELCADE 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Gastrointestinal toxicityGastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with VELCADE treatment. Cases of ileus have been uncommonly reported (see section 4.8). Therefore, patients who experience constipation should be closely monitored.
Haematological toxicityVELCADE treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with VELCADE and in patients with previously untreated MCL treated with VELCADE in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP), one of the most common haematologic toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of VELCADE 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 in the single-agent multiple myeloma studies and 50% in the MCL study. 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 ≤ 25,000/μl during the study.In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) of Grade ≥ 3 thrombocytopenia in the VELCADE treatment group (VcR-CAP) as compared to the non-VELCADE 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 (6.3% in the VcR-CAP group and 5.0% in the R-CHOP group) as well as Grade 3 and higher bleeding events (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the VcR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients in the R-CHOP group.Gastrointestinal and intracerebral haemorrhage, have been reported in association with VELCADE treatment. Therefore, platelet counts should be monitored prior to each dose of VELCADE. VELCADE 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 (see section 4.2). 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 VELCADE. Platelet transfusion should be considered when clinically appropriate (see section 4.2).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 VELCADE treatment and typically recovered to baseline by the next cycle. In study LYM-3002, colony stimulating factor support was given to 78% of patients in the VcR-CAP arm and 61% of patients in the R-CHOP arm. 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 (see section 4.2).
Herpes zoster virus reactivationAntiviral prophylaxis is recommended in patients being treated with VELCADE.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 VELCADE+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the VcR-CAP arm and 1.2% in the R-CHOP arm (see section 4.8).
Hepatitis B Virus (HBV) reactivation and infectionWhen rituximab is used in combination with VELCADE, 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 VELCADE. 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 VELCADE. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of VELCADE. 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 VELCADE if PML is diagnosed.
Peripheral neuropathyTreatment with VELCADE 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 VELCADE 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 VELCADE administered intravenously was lower in the historical studies with VELCADE 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 (see section 4.2). 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 VELCADE 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.
SeizuresSeizures 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.
HypotensionVELCADE 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 VELCADE (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with VELCADE. 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 VELCADE. 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 VELCADE. 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, VELCADE should be discontinued.
Heart failureAcute 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 investigationsThere have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.
Pulmonary disordersThere 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 VELCADE (see section 4.8). 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 VELCADE 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 VELCADE 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 impairmentRenal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).
Hepatic impairmentBortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with VELCADE at reduced doses and closely monitored for toxicities (see sections 4.2 and 5.2).
Hepatic reactionsRare cases of hepatic failure have been reported in patients receiving VELCADE 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 (see section 4.8).
Tumour lysis syndromeBecause 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 productsPatients 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 (see section 4.5).Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see section 4.5).
Potentially immunocomplex-mediated reactionsPotentially 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.
Contraception in males and femalesMale and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.
PregnancyNo 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 (see section 5.3). VELCADE should not be used during pregnancy unless the clinical condition of the woman requires treatment with VELCADE.If VELCADE 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 VELCADE 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-feedingIt is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with VELCADE.
FertilityFertility studies were not conducted with VELCADE (see section 5.3).
Summary of the safety profileSerious adverse reactions uncommonly reported during treatment with VELCADE 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 VELCADE 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 MyelomaUndesirable effects in Table 7 were considered by the investigators to have at least a possible or probable causal relationship to VELCADE. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with VELCADE at 1.3 mg/m2 and included in Table 7.Overall, VELCADE was administered for the treatment of multiple myeloma in 3,974 patients. Adverse reactions are listed below 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 7 has been generated using Version 14.1 of the MedDRA.Post-marketing adverse reactions not seen in clinical trials are also included.
Table 7: Adverse reactions in patients with Multiple Myeloma treated with VELCADE as single agent or in combination
|System Organ Class||Incidence||Adverse reaction|
|Infections and infestations||Common||Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, Herpes simplex*, Fungal infection*|
|Uncommon||Infection*, Bacterial infections*, Viral infections*, Sepsis (inc septic shock)*, Bronchopneumonia, Herpes virus infection*, Meningoencephalitis herpetic#, Bacteraemia (inc staphylococcal), Hordeolum, Influenza, Cellulitis, Device related infection, Skin infection*, Ear infection*, Staphylococcal infection, Tooth infection*|
|Rare||Meningitis (inc bacterial), Epstein-Barr virus infection, Genital herpes, Tonsillitis, Mastoiditis, Post viral fatigue syndrome|
|Neoplasms benign, malignant and unspecified (incl cysts and polyps)||Rare||Neoplasm malignant, Leukaemia plasmacytic, Renal cell carcinoma, Mass, Mycosis fungoides, Neoplasm benign*|
|Blood and lymphatic system disorders||Very Common||Thrombocytopenia*, Neutropenia*, Anaemia*|
|Uncommon||Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia#|
|Rare||Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombocytopenic purpura, Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration|
|Immune system disorders||Uncommon||Angioedema#, Hypersensitivity*|
|Rare||Anaphylactic shock, Amyloidosis, Type III immune complex mediated reaction|
|Endocrine disorders||Uncommon||Cushing's syndrome*, Hyperthyroidism*, Inappropriate antidiuretic hormone secretion|
|Metabolism and nutrition disorders||Very Common||Decreased appetite|
|Common||Dehydration, Hypokalaemia*, Hyponatraemia*, Blood glucose abnormal*, Hypocalcaemia*, Enzyme abnormality*|
|Uncommon||Tumour lysis syndrome, Failure to thrive*, Hypomagnesaemia*, Hypophosphataemia*, Hyperkalaemia*, Hypercalcaemia*, Hypernatraemia*, Uric acid abnormal*, Diabetes mellitus*, Fluid retention|
|Rare||Hypermagnesaemia*, Acidosis, Electrolyte imbalance*, Fluid overload, Hypochloraemia*, Hypovolaemia, Hyperchloraemia*, Hyperphosphataemia*, Metabolic disorder, Vitamin B complex deficiency, Vitamin B12 deficiency, Gout, Increased appetite, Alcohol intolerance|
|Psychiatric disorders||Common||Mood disorders and disturbances*, Anxiety disorder*, Sleep disorders and disturbances*|
|Uncommon||Mental disorder*, Hallucination*, Psychotic disorder*, Confusion*, Restlessness|
|Rare||Suicidal ideation*, Adjustment disorder, Delirium, Libido decreased|
|Nervous system disorders||Very Common||Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*|
|Common||Motor neuropathy*, Loss of consciousness (inc syncope), Dizziness*, Dysgeusia*, Lethargy, Headache*|
|Uncommon||Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*, Cerebellar coordination and balance disturbances*, Memory loss (exc dementia)*, Encephalopathy*, Posterior Reversible Encephalopathy Syndrome#, Neurotoxicity, Seizure disorders*, Post herpetic neuralgia, Speech disorder*, Restless legs syndrome, Migraine, Sciatica, Disturbance in attention, Reflexes abnormal*, Parosmia|
|Rare||Cerebral haemorrhage*, Haemorrhage intracranial (inc subarachnoid)*, Brain oedema, Transient ischaemic attack, Coma, Autonomic nervous system imbalance, Autonomic neuropathy, Cranial palsy*, Paralysis*, Paresis*, Presyncope, Brain stem syndrome, Cerebrovascular disorder, Nerve root lesion, Psychomotor hyperactivity, Spinal cord compression, Cognitive disorder NOS, Motor dysfunction, Nervous system disorder NOS, Radiculitis, Drooling, Hypotonia|
|Eye disorders||Common||Eye swelling*, Vision abnormal*, Conjunctivitis*|
|Uncommon||Eye haemorrhage*, Eyelid infection*, Eye inflammation*, Diplopia, Dry eye*, Eye irritation*, Eye pain, Lacrimation increased, Eye discharge|
|Rare||Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eye disorder (inc. eyelid) NOS, Dacryoadenitis acquired, Photophobia, Photopsia, Optic neuropathy#, Different degrees of visual impairment (up to blindness)*|
|Ear and labyrinth disorders||Common||Vertigo*|
|Uncommon||Dysacusis (inc tinnitus)*,Hearing impaired (up to and inc deafness), Ear discomfort*|
|Rare||Ear haemorrhage, Vestibular neuronitis, Ear disorder NOS|
|Cardiac disorders||Uncommon||Cardiac tamponade#, Cardio-pulmonary arrest*, Cardiac fibrillation (inc atrial), Cardiac failure (inc left and right ventricular)*, Arrhythmia*, Tachycardia*, Palpitations, Angina pectoris, Pericarditis (inc pericardial effusion)*, Cardiomyopathy*, Ventricular dysfunction*, Bradycardia|
|Rare||Atrial flutter, Myocardial infarction*, Atrioventricular block*, Cardiovascular disorder (inc cardiogenic shock), Torsade de pointes, Angina unstable, Cardiac valve disorders*, Coronary artery insufficiency, Sinus arrest|
|Vascular disorders||Common||Hypotension*, Orthostatic hypotension, Hypertension*|
|Uncommon||Cerebrovascular accident#, Deep vein thrombosis*, Haemorrhage*, Thrombophlebitis (inc superficial), Circulatory collapse (inc hypovolaemic shock), Phlebitis, Flushing*, Haematoma (inc perirenal)*, Poor peripheral circulation*, Vasculitis, Hyperaemia (inc ocular)*|
|Rare||Peripheral embolism, Lymphoedema, Pallor, Erythromelalgia, Vasodilatation, Vein discolouration, Venous insufficiency|
|Respiratory, thoracic and mediastinal disorders||Common||Dyspnoea*, Epistaxis, Upper/lower respiratory tract infection*, Cough*|
|Uncommon||Pulmonary embolism, Pleural effusion, Pulmonary oedema (inc acute), Pulmonary alveolar haemorrhage#, Bronchospasm, Chronic obstructive pulmonary disease*, Hypoxaemia*, Respiratory tract congestion*, Hypoxia, Pleurisy*, Hiccups, Rhinorrhoea, Dysphonia, Wheezing|
|Rare||Respiratory failure, Acute respiratory distress syndrome, Apnoea, Pneumothorax, Atelectasis, Pulmonary hypertension, Haemoptysis, Hyperventilation, Orthopnoea, Pneumonitis, Respiratory alkalosis, Tachypnoea, Pulmonary fibrosis, Bronchial disorder*, Hypocapnia*, Interstitial lung disease, Lung infiltration, Throat tightness, Dry throat, Increased upper airway secretion, Throat irritation, Upper-airway cough syndrome|
|Gastrointestinal disorders||Very Common||Nausea and vomiting symptoms*, Diarrhoea*, Constipation|
|Common||Gastrointestinal haemorrhage (inc mucosal)*, Dyspepsia, Stomatitis*, Abdominal distension, Oropharyngeal pain*, Abdominal pain (inc gastrointestinal and splenic pain)*, Oral disorder*, Flatulence|
|Uncommon||Pancreatitis (inc chronic)*, Haematemesis, Lip swelling*, Gastrointestinal obstruction (inc ileus)*, Abdominal discomfort, Oral ulceration*, Enteritis*, Gastritis*, Gingival bleeding, Gastrooesophageal reflux disease*, Colitis (inc clostridium difficile)*, Colitis ischaemic#, Gastrointestinal inflammation*, Dysphagia, Irritable bowel syndrome, Gastrointestinal disorder NOS, Tongue coated, Gastrointestinal motility disorder*, Salivary gland disorder*|
|Rare||Pancreatitis acute, Peritonitis*, Tongue oedema*, Ascites, Oesophagitis, Cheilitis, Faecal incontinence, Anal sphincter atony, Faecaloma*, Gastrointestinal ulceration and perforation*, Gingival hypertrophy, Megacolon, Rectal discharge, Oropharyngeal blistering*, Lip pain, Periodontitis, Anal fissure, Change of bowel habit, Proctalgia, Abnormal faeces|
|Hepatobiliary disorders||Common||Hepatic enzyme abnormality*|
|Uncommon||Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis|
|Rare||Hepatic failure, Hepatomegaly, Budd-Chiari syndrome, Cytomegalovirus hepatitis, Hepatic haemorrhage, Cholelithiasis|
|Skin and subcutaneous tissue disorders||Common||Rash*, Pruritus*, Erythema, Dry skin|
|Uncommon||Erythema multiforme, Urticaria, Acute febrile neutrophilic dermatosis, Toxic skin eruption, Toxic epidermal necrolysis#, Stevens-Johnson syndrome#, Dermatitis*, Hair disorder*, Petechiae, Ecchymosis, Skin lesion, Purpura, Skin mass*, Psoriasis, Hyperhidrosis, Night sweats, Decubitus ulcer#, Acne*, Blister*, Pigmentation disorder*|
|Rare||Skin reaction, Jessner's lymphocytic infiltration, Palmar-plantar erythrodysaesthesia syndrome, Haemorrhage subcutaneous, Livedo reticularis, Skin induration, Papule, Photosensitivity reaction, Seborrhoea, Cold sweat, Skin disorder NOS, Erythrosis, Skin ulcer, Nail disorder|
|Musculoskeletal and connective tissue disorders||Very Common||Musculoskeletal pain*|
|Common||Muscle spasms*, Pain in extremity, Muscular weakness|
|Uncommon||Muscle twitching, Joint swelling, Arthritis*, Joint stiffness, Myopathies*,Sensation of heaviness|
|Rare||Rhabdomyolysis, Temporomandibular joint syndrome, Fistula, Joint effusion, Pain in jaw, Bone disorder, Musculoskeletal and connective tissue infections and inflammations*, Synovial cyst|
|Renal and urinary disorders||Common||Renal impairment*|
|Uncommon||Renal failure acute, Renal failure chronic*, Urinary tract infection*, Urinary tract signs and symptoms*, Haematuria*, Urinary retention, Micturition disorder*, Proteinuria, Azotaemia, Oliguria*, Pollakiuria|
|Reproductive system and breast disorders||Uncommon||Vaginal haemorrhage, Genital pain*, Erectile dysfunction,|
|Rare||Testicular disorder*, Prostatitis, Breast disorder female, Epididymal tenderness, Epididymitis, Pelvic pain, Vulval ulceration|
|Congenital, familial and genetic disorders||Rare||Aplasia, Gastrointestinal malformation, Ichthyosis|
|General disorders and administration site conditions||Very Common||Pyrexia*, Fatigue, Asthenia|
|Common||Oedema (inc peripheral), Chills, Pain*, Malaise*|
|Uncommon||General physical health deterioration*, Face oedema*, Injection site reaction*, Mucosal disorder*, Chest pain, Gait disturbance, Feeling cold, Extravasation*, Catheter related complication*, Change in thirst*, Chest discomfort, Feeling of body temperature change*, Injection site pain*|
|Rare||Death (inc sudden), Multi-organ failure, Injection site haemorrhage*, Hernia(inc hiatus)*, Impaired healing*, Inflammation, Injection site phlebitis*, Tenderness, Ulcer, Irritability, Non-cardiac chest pain, Catheter site pain, Sensation of foreign body|
|Uncommon||Hyperbilirubinaemia*, Protein analyses abnormal*, Weight increased, Blood test abnormal*,C-reactive protein increased|
|Rare||Blood gases abnormal*, Electrocardiogram abnormalities (inc QT prolongation)*, International normalised ratio abnormal*, Gastric pH decreased, Platelet aggregation increased, Troponin I increased, Virus identification and serology*, Urine analysis abnormal*|
|Injury, poisoning and procedural complications||Uncommon||Fall, Contusion|
|Rare||Transfusion reaction, Fractures*, Rigors*, Face injury, Joint injury*, Burns, Laceration, Procedural pain, Radiation injuries*|
|Surgical and medical procedures||Rare||Macrophage activation|
|NOS=not otherwise specified * Grouping of more than one MedDRA preferred term. # Postmarketing adverse reaction|
Mantle Cell Lymphoma (MCL)The safety profile of VELCADE in 240 MCL patients treated with VELCADE at 1.3 mg/m2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP) versus 242 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 below. Additional adverse drug reactions identified associated with the use of the combination therapy (VcR-CAP) were hepatitis B infection (< 1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to VELCADE alone. Notable differences in the MCL patient population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence of the haematological adverse reactions (neutropenia, thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.Adverse drug reactions identified as those with a ≥ 1% incidence, similar or higher incidence in the VcR-CAP arm and with at least a possible or probable causal relationship to the components of the VcR-CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in the VcR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to VELCADE based on historical data in the multiple myeloma studies.Adverse reactions are listed below 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 8 has been generated using Version 16 of the MedDRA.
Table 8 Adverse reactions in patients with Mantle Cell Lymphoma treated with VcR-CAP
|System Organ Class||Incidence||Adverse reaction|
|Infections and infestations||Very Common||Pneumonia*|
|Common||Sepsis (inc septic shock)*, Herpes zoster (inc disseminated & ophthalmic), Herpes virus infection*, Bacterial infections*, Upper/lower respiratory tract infection*, Fungal infection*, Herpes simplex*|
|Uncommon||Hepatitis B, Infection*, Bronchopneumonia|
|Blood and lymphatic system disorders||Very Common||Thrombocytopenia*, Febrile neutropenia, Neutropenia*, Leukopenia*, Anaemia*, Lymphopenia*|
|Immune system disorders||Common||Hypersensitivity*|
|Metabolism and nutrition disorders||Very Common||Decreased appetite|
|Common||Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*, Diabetes mellitus*, Fluid retention|
|Uncommon||Tumour lysis syndrome|
|Psychiatric disorders||Common||Sleep disorders and disturbances*|
|Nervous system disorders||Very Common||Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*|
|Common||Neuropathies*, Motor neuropathy*, Loss of consciousness (inc syncope), Encephalopathy*, Peripheral sensorimotor neuropathy, Dizziness*, Dysgeusia*, Autonomic neuropathy|
|Uncommon||Autonomic nervous system imbalance|
|Eye disorders||Common||Vision abnormal*|
|Ear and labyrinth disorders||Common||Dysacusis (inc tinnitus)*|
|Uncommon||Vertigo*, Hearing impaired (up to and inc deafness)|
|Cardiac disorders||Common||Cardiac fibrillation (inc atrial), Arrhythmia*, Cardiac failure (inc left and right ventricular)*, Myocardial ischaemia, Ventricular dysfunction*|
|Uncommon||Cardiovascular disorder (inc cardiogenic shock)|
|Vascular disorders||Common||Hypertension*, Hypotension*, Orthostatic hypotension|
|Respiratory, thoracic and mediastinal disorders||Common||Dyspnoea*, Cough*, Hiccups|
|Uncommon||Acute respiratory distress syndrome, Pulmonary embolism, Pneumonitis, Pulmonary hypertension, Pulmonary oedema (inc acute)|
|Gastrointestinal disorders||Very Common||Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*, Constipation|
|Common||Gastrointestinal haemorrhage (inc mucosal)*, Abdominal distension, Dyspepsia, Oropharyngeal pain*, Gastritis*, Oral ulceration*, Abdominal discomfort, Dysphagia, Gastrointestinal inflammation*, Abdominal pain (inc gastrointestinal and splenic pain)*, Oral disorder*|
|Uncommon||Colitis (inc clostridium difficile)*|
|Hepatobiliary disorders||Common||Hepatotoxicity (inc liver disorder)|
|Skin and subcutaneous tissue disorders||Very Common||Hair disorder*|
|Common||Pruritus*, Dermatitis*, Rash*|
|Musculoskeletal and connective tissue disorders||Common||Muscle spasms*, Musculoskeletal pain*, Pain in extremity|
|Renal and urinary disorders||Common||Urinary tract infection*|
|General disorders and administration site conditions||Very Common||Pyrexia*, Fatigue, Asthenia|
|Common||Oedema (inc peripheral), Chills, Injection site reaction*, Malaise*|
|Investigations||Common||Hyperbilirubinaemia*, Protein analyses abnormal*, Weight decreased, Weight increased|
|* Grouping of more than one MedDRA preferred term.|
Description of selected adverse reactions
Herpes zoster virus reactivationMultiple MyelomaAntiviral 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.Mantle cell lymphomaAntiviral prophylaxis was administered to 137 of 240 patients (57%) in the VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis (see section 4.4).
Hepatitis B Virus (HBV) reactivation and infectionMantle cell lymphomaHBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non-VELCADE treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP ) and 0.4% (n=1) of patients receiving VELCADE in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).
Peripheral neuropathy in combination regimensMultiple MyelomaIn trials in which VELCADE 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 below:
Table 9: Incidence of peripheral neuropathy during induction treatment by toxicity and treatment discontinuation due to peripheral neuropathy
|VDDx (N=239)||VcDx (N=239)||TDx (N=126)||VcTDx (N=130)|
|Incidence of PN (%)|
|≥ Grade 2 PN||1||10||2||31|
|≥ Grade 3 PN||< 1||5||0||5|
|Discontinuation due to PN (%)||< 1||2||1||5|
|VDDx=vincristine, doxorubicin, dexamethasone; VcDx=VELCADE, dexamethasone; TDx=thalidomide, dexamethasone; VcTDx=VELCADE, thalidomide, dexamethasone; PN=peripheral neuropathy Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.|
Table 10: Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatment discontinuation due to peripheral neuropathy
|VcR-CAP (N=240)||R-CHOP (N=242)|
|Incidence of PN (%)|
|≥ Grade 2 PN||18||9|
|≥ Grade 3 PN||8||4|
|Discontinuation due to PN (%)||2||< 1|
|VcR-CAP=VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; PN=peripheral neuropathy Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy|
Elderly MCL patients42.9% and 10.4% of patients in the VcR-CAP arm were in the range 65-74 years and ≥ 75 years of age, respectively. 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 68%, compared to 42% in the R-CHOP group.
Notable differences in the safety profile of VELCADE administered subcutaneously versus intravenously as single agentIn the Phase III study patients who received VELCADE 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 VELCADE. 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 myelomaIn a study in which VELCADE retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a VELCADE-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.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:
United KingdomYellow Card SchemeWebsite: www.yellowcard.mhra.gov.uk
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Mechanism of actionBortezomib 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.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.
Clinical efficacy in previously untreated multiple myelomaA prospective Phase III, international, randomised (1:1), open-label clinical study (MMY-3002 VISTA) of 682 patients was conducted to determine whether VELCADE (1.3 mg/m2 injected intravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. The median age of the patients in the study was 71 years, 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/l, and a median platelet count of 221.5 x 109/l. Similar proportions of patients had creatinine clearance ≤ 30 ml/min (3% in each arm).At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the M+P arm were offered Vc+M+P treatment. Median follow-up was 16.3 months. The final survival update was performed with a median duration of follow-up of 60.1 months. A statistically significant survival benefit in favour of the Vc+M+P treatment group was observed (HR=0.695; p=0.00043) despite subsequent therapies including VELCADE-based regimens. Median survival for the Vc+M+P treatment group was 56.4 months compared to 43.1 for the M+P treatment group. Efficacy results are presented in Table 11:
Table 11: Efficacy results following the final survival update to VISTA study
|Time to progressionEvents n (%)||101 (29)||152 (45)|
|Mediana (95% CI)||20.7 mo (17.6, 24,7)||15.0 mo (14.1, 17.9)|
|Hazard ratiob(95% CI)||0.54 (0.42, 0.70)|
|Progression-free survivalEvents n (%)||135 (39)||190 (56)|
|Mediana (95% CI)||18.3 mo (16.6, 21.7)||14.0 mo (11.1, 15.0)|
|Hazard ratiob(95% CI)||0.61 (0.49, 0.76)|
|Overall survival*Events (deaths) n (%)||176 (51.2)||211 (62.4)|
|Mediana(95% CI)||56.4 mo (52.8, 60.9)||43.1 mo (35.3, 48.3)|
|Hazard ratiob(95% CI)||0.695 (0.567, 0.852)|
|Response ratepopulatione n=668||n=337||n=331|
|CRf n (%)||102 (30)||12 (4)|
|PRf n (%)||136 (40)||103 (31)|
|nCR n (%)||5 (1)||0|
|CR+PRf n (%)||238 (71)||115 (35)|
|Reduction in serum M-proteinpopulationg n=667||n=336||n=331|
|>=90% n (%)||151 (45)||34 (10)|
|Time to first response in CR + PR|
|Median||1.4 mo||4.2 mo|
|Mediana response duration|
|CRf||24.0 mo||12.8 mo|
|CR+PRf||19.9 mo||13.1 mo|
|Time to next therapyEvents n (%)||224 (65.1)||260 (76.9)|
|Mediana(95% CI)||27.0 mo (24.7, 31.1)||19.2 mo (17.0, 21.0)|
|Hazard ratiob(95% CI)||0.557 (0.462, 0.671)|
|a Kaplan-Meier estimate. b Hazard ratio estimate is based on a Cox proportional-hazard model adjusted for stratification factors: β2-microglobulin, albumin, and region. A hazard ratio less than 1 indicates an advantage for VMP c Nominal p-value based on the stratified log-rank test adjusted for stratification factors: β2-microglobulin, albumin, and region d p-value for Response Rate (CR+PR) from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors e Response population includes patients who had measurable disease at baseline f CR=Complete Response; PR=Partial Response. EBMT criteria g All randomised patients with secretory disease * Survival update based on a median duration of follow-up at 60.1 months mo: months CI=Confidence Interval|
Patients eligible for stem cell transplantationTwo randomised, open-label, multicenter Phase III trials (IFM-2005-01, MMY-3010) were conducted to demonstrate the safety and efficacy of VELCADE in dual and triple combinations with other chemotherapeutic agents, as induction therapy prior to stem cell transplantation in patients with previously untreated multiple myeloma.In study IFM-2005-01 VELCADE combined with dexamethasone [VcDx, n=240] was compared to vincristine- doxorubicin-dexamethasone [VDDx, n=242]. Patients in the VcDx group received four 21 day cycles, each consisting of VELCADE (1.3 mg/m2 administered intravenously twice weekly on days 1, 4, 8, and 11), and oral dexamethasone (40 mg/day on days 1 to 4 and days 9 to 12, in Cycles 1 and 2, and on days 1 to 4 in Cycles 3 and 4).Autologous stem cell transplants were received by 198 (82%) patients and 208 (87%) patients in the VDDx and VcDx groups respectively; the majority of patients underwent one single transplant procedure. Patient demographic and baseline disease charateristics were similar between the treatment groups. Median age of the patients in the study was 57 years, 55% were male and 48% of patients had high-risk cytogenetics. The median duration of treatment was 13 weeks for the VDDx group and 11 weeks for the VcDx group. The median number of cycles received for both groups was 4 cycles.The primary efficacy endpoint of the study was post-induction response rate (CR+nCR). A statistically significant difference in CR+nCR was observed in favour of the VELCADE combined with dexamethasone group. Secondary efficacy endpoints included post-transplant response rates (CR+nCR, CR+nCR+VGPR+PR), Progression Free Survival and Overall Survival. Main efficacy results are presented in Table 12.
Table 12: Efficacy results from study IFM-2005-01
|Endpoints||VcDx||VDDx||OR; 95% CI; P valuea|
|IFM-2005-01||N=240 (ITT population)||N=242 (ITT population)|
|RR (Post-induction )*CR+nCR CR+nCR+VGPR+PR % (95% CI)||14.6 (10.4, 19.7) 77.1 (71.2, 82.2)||6.2 (3.5, 10.0) 60.7 (54.3, 66.9)||2.58 (1.37, 4.85); 0.003 2.18 (1.46, 3.24); < 0.001|
|RR (Post-transplant)bCR+nCR CR+nCR+VGPR+PR % (95% CI)||37.5 (31.4, 44.0) 79.6 (73.9, 84.5)||23.1 (18.0, 29.0) 74.4 (68.4, 79.8)||1.98 (1.33, 2.95); 0.001 1.34 (0.87, 2.05); 0.179|
|CI=confidence interval; CR=complete response; nCR=near complete response; ITT=intent to treat; RR=response rate; Vc=VELCADE; VcDx=VELCADE, dexamethasone; VDDx=vincristine, doxorubicin, dexamethasone; VGPR=very good partial response; PR=partial response; OR=odds ratio. * Primary endpoint a OR for response rates based on Mantel-Haenszel estimate of the common odds ratio for stratified tables; p-values by Cochran Mantel-Haenszel test. b Refers to response rate after second transplant for subjects who received a second transplant (42/240 [18% ] in VcDx group and 52/242 [21%] in VDDx group). Note: An OR > 1 indicates an advantage for Vc-containing induction therapy.|
Table 13: Efficacy results from study MMY-3010
|Endpoints||VcTDx||TDx||OR; 95% CI; P valuea|
|MMY-3010||N=130 (ITT population)||N=127 (ITT population)|
|*RR (Post-induction)CR+nCR CR+nCR+PR % (95% CI)||49.2 (40.4, 58.1) 84.6 (77.2, 90.3)||17.3 (11.2, 25.0) 61.4 (52.4, 69.9)||4.63 (2.61, 8.22); < 0.001a3.46 (1.90, 6.27); < 0.001a|
|*RR (Post-transplant) CR+nCR CR+nCR+PR % (95% CI)||55.4 (46.4, 64.1) 77.7 (69.6, 84.5)||34.6 (26.4, 43.6) 56.7 (47.6, 65.5)||2.34 (1.42, 3.87); 0.001a2.66 (1.55, 4.57); < 0.001a|
|CI=confidence interval; CR=complete response; nCR=near complete response; ITT=intent to treat; RR=response rate; Vc=VELCADE; VcTDx=VELCADE, thalidomide, dexamethasone; TDx=thalidomide, dexamethasone; PR=partial response; OR=odds ratio * Primary endpoint a OR for response rates based on Mantel-Haenszel estimate of the common odds ratio for stratified tables; p-values by Cochran Mantel-Haenszel test. Note: An OR > 1 indicates an advantage for Vc-containing induction therapy|
Clinical efficacy in relapsed or refractory multiple myelomaThe safety and efficacy of VELCADE (injected intravenously) were evaluated in 2 studies at the recommended dose of 1.3 mg/m2: a Phase III randomised, comparative study (APEX), versus dexamethasone (Dex), of 669 patients with relapsed or refractory multiple myeloma who had received 1-3 prior lines of therapy, and a Phase II single-arm study of 202 patients with relapsed and refractory multiple myeloma, who had received at least 2 prior lines of treatment and who were progressing on their most recent treatment.In the Phase III study, treatment with VELCADE led to a significantly longer time to progression, a significantly prolonged survival and a significantly higher response rate, compared to treatment with dexamethasone (see Table 14), in all patients as well as in patients who have received 1 prior line of therapy. As a result of a pre-planned interim analysis, the dexamethasone arm was halted at the recommendation of the data monitoring committee and all patients randomised to dexamethasone were then offered VELCADE, regardless of disease status. Due to this early crossover, the median duration of follow-up for surviving patients is 8.3 months. Both in patients who were refractory to their last prior therapy and those who were not refractory, overall survival was significantly longer and response rate was significantly higher on the VELCADE arm.Of the 669 patients enrolled, 245 (37%) were 65 years of age or older. Response parameters as well as TTP remained significantly better for VELCADE independently of age. Regardless of β2-microglobulin levels at baseline, all efficacy parameters (time to progression and overall survival, as well as response rate) were significantly improved on the VELCADE arm.In the refractory population of the Phase II study, responses were determined by an independent review committee and the response criteria were those of the European Bone Marrow Transplant Group. The median survival of all patients enrolled was 17 months (range < 1 to 36+ months). This survival was greater than the six-to-nine month median survival anticipated by consultant clinical investigators for a similar patient population. By multivariate analysis, the response rate was independent of myeloma type, performance status, chromosome 13 deletion status, or the number or type of previous therapies. Patients who had received 2 to 3 prior therapeutic regimens had a response rate of 32% (10/32) and patients who received greater than 7 prior therapeutic regimens had a response rate of 31% (21/67).
Table 14: Summary of disease outcomes from the Phase III (APEX) and Phase II studies
|Phase III||Phase III||Phase III||Phase II|
|All patients||1 prior line of therapy||> 1 prior line of therapy||≥ 2 prior lines|
|Time related events||Vcn=333a||Dexn=336a||Vcn=132a||Dexn=119a||Vcn=200a||Dexn=217a||Vcn=202a|
|TTP, days [95% CI]||189b[148, 211]||106b[86, 128]||212d[188, 267]||169d[105, 191]||148b[129, 192]||87b[84, 107]||210 [154, 281]|
|1 year survival, % [95% CI]||80d[74,85]||66d[59,72]||89d[82,95]||72d[62,83]||73 [64,82]||62 [53,71]||60|
|Best response (%)||Vcn=315c||Dexn=312c||Vcn=128||Dexn=110||Vcn=187||Dexn=202||Vcn=193|
|CR||20 (6)b||2 (< 1)b||8 (6)||2 (2)||12 (6)||0 (0)||(4)**|
|CR+nCR||41 (13)b||5 (2)b||16 (13)||4 (4)||25 (13)||1 (< 1)||(10)**|
|CR+nCR+PR||121 (38)b||56 (18)b||57 (45)d||29 (26)d||64 (34)b||27 (13)b||(27)**|
|CR+nCR+ PR+MR||146 (46)||108 (35)||66 (52)||45 (41)||80 (43)||63 (31)||(35)**|
|Median durationDays (months)||242 (8.0)||169 (5.6)||246 (8.1)||189 (6.2)||238 (7.8)||126 (4.1)||385*|
|Time to responseCR+PR (days)||43||43||44||46||41||27||38*|
|a Intent to Treat (ITT) population b p-value from the stratified log-rank test; analysis by line of therapy excludes stratification for therapeutic history; p < 0.0001 c Response population includes patients who had measurable disease at baseline and received at least 1 dose of study medicinal product. d p-value from the Cochran Mantel-Haenszel chi-square test adjusted for the stratification factors; analysis by line of therapy excludes stratification for therapeutic history * CR+PR+MR **CR=CR, (IF-); nCR=CR (IF+) NA=not applicable, NE=not estimated TTP-Time to Progression CI=Confidence Interval Vc=VELCADE; Dex=dexamethasone CR=Complete Response; nCR=near Complete response PR=Partial Response; MR=Minimal response|
Clinical efficacy with subcutaneous administration of VELCADE in patients with relapsed/refractory multiple myelomaAn open label, randomised, Phase III non-inferiority study compared the efficacy and safety of the subcutaneous administration of VELCADE versus the intravenous administration. This study included 222 patients with relapsed/refractory multiple myeloma, who were randomised in a 2:1 ratio to receive 1.3 mg/m2 of VELCADE by either the subcutaneous or intravenous route for 8 cycles. Patients who did not obtain an optimal response (less than Complete Response [CR]) to therapy with VELCADE alone after 4 cycles were allowed to receive dexamethasone 20 mg daily on the day of and after VELCADE administration. Patients with baseline Grade ≥ 2 peripheral neuropathy or platelet counts < 50,000/µl were excluded. A total of 218 patients were evaluable for response.This study met its primary objective of non-inferiority for response rate (CR+PR) after 4 cycles of single agent VELCADE for both the subcutaneous and intravenous routes, 42% in both groups. In addition, secondary response-related and time to event related efficacy endpoints showed consistent results for subcutaneous and intravenous administration (Table 15).
Table 15: Summary of efficacy analyses comparing subcutaneous and intravenous administrations of VELCADE
|VELCADE intravenous arm||VELCADE subcutaneous arm|
|Response Evaluable Population||n=73||n=145|
|Response Rate at 4 cycles n (%)|
|ORR (CR+PR)||31 (42)||61 (42)|
|CR n (%)||6 (8)||9 (6)|
|PR n (%)||25 (34)||52 (36)|
|nCR n (%)||4 (5)||9 (6)|
|Response Rate at 8 cycles n (%)|
|ORR (CR+PR)||38 (52)||76 (52)|
|CR n (%)||9 (12)||15 (10)|
|PR n (%)||29 (40)||61 (42)|
|nCR n (%)||7 (10)||14 (10)|
|Intent to Treat Populationb||n=74||n=148|
|(95% CI)||(7.6, 10.6)||(8.5, 11.7)|
|Hazard ratio (95% CI)cp-valued||0.839 (0.564, 1.249) 0.38657|
|Progression Free Survival, months||8.0||10.2|
|(95% CI)||(6.7, 9.8)||(8.1, 10.8)|
|Hazard ratio (95% CI)cp-valued||0.824 (0.574, 1.183) 0.295|
|1-year Overall Survival (%)e||76.7||72.6|
|(95% CI)||(64.1, 85.4)||(63.1, 80.0)|
|a p-value is for the non-inferiority hypothesis that the SC arm retains at least 60% of the response rate in the IV arm. b 222 subjects were enrolled into the study; 221 subjects were treated with VELCADE c Hazards ratio estimate is based on a Cox model adjusted for stratification factors: ISS staging and number of prior lines. d Log rank test adjusted for stratification factors: ISS staging and number of prior lines. e Median duration of follow up is 11.8 months|
VELCADE combination treatment with pegylated liposomal doxorubicin (study DOXIL-MMY-3001)A Phase III randomised, parallel-group, open-label, multicentre study was conducted in 646 patients comparing the safety and efficacy of VELCADE plus pegylated liposomal doxorubicin versus VELCADE monotherapy in patients with multiple myeloma who had received at least 1 prior therapy and who did not progress while receiving anthracycline-based therapy. The primary efficacy endpoint was TTP while the secondary efficacy endpoints were OS and ORR (CR+PR), using the European Group for Blood and Marrow Transplantation (EBMT) criteria.A protocol-defined interim analysis (based on 249 TTP events) triggered early study termination for efficacy. This interim analysis showed a TTP risk reduction of 45% (95% CI; 29-57%, p < 0.0001) for patients treated with combination therapy of VELCADE and pegylated liposomal doxorubicin. The median TTP was 6.5 months for the VELCADE monotherapy patients compared with 9.3 months for the VELCADE plus pegylated liposomal doxorubicin combination therapy patients. These results, though not mature, constituted the protocol defined final analysis.
VELCADE combination treatment with dexamethasoneIn the absence of any direct comparison between VELCADE and VELCADE in combination with dexamethasone in patients with progressive multiple myeloma, a statistical matched-pair analysis was conducted to compare results from the non randomised arm of VELCADE in combination with dexamethasone (Phase II open-label study MMY-2045), with results obtained in the VELCADE monotherapy arms from different Phase III randomised studies (M34101-039 [APEX] and DOXIL MMY-3001) in the same indication.The matched-pair analysis is a statistical method in which patients in the treatment group (e.g. VELCADE in combination with dexamethasone) and patients in the comparison group (e.g. VELCADE) are made comparable with respect to confounding factors by individually pairing study subjects. This minimises the effects of observed confounders when estimating treatment effects using non-randomised data.One hundred and twenty seven matched pairs of patients were identified. The analysis demonstrated improved ORR (CR+PR) (odds ratio 3.769; 95% CI 2.045-6.947; p < 0.001), PFS (hazard ratio 0.511; 95% CI 0.309-0.845; p=0.008), TTP (hazard ratio 0.385; 95% CI 0.212-0.698; p=0.001) for VELCADE in combination with dexamethasone over VELCADE monotherapy.Limited information on VELCADE retreatment in relapsed multiple myeloma is available.Phase II study MMY-2036 (RETRIEVE), single arm, open-label study was conducted to determine the efficacy and safety of retreatment with VELCADE. One hundred and thirty patients (≥ 18 years of age) with multiple myeloma who previously had at least partial response on a VELCADE-containing regimen were retreated upon progression. At least 6 months after prior therapy, VELCADE was started at the last tolerated dose of 1.3 mg/m2 (n=93) or ≤ 1.0 mg/m2 (n=37) and given on days 1, 4, 8 and 11 every 3 weeks for maximum of 8 cycles either as single agent or in combination with dexamethasone in accordance with the standard of care. Dexamethasone was administered in combination with VELCADE to 83 patients in Cycle 1 with an additional 11 patients receiving dexamethasone during the course of VELCADE retreatment cycles.The primary endpoint was best confirmed response to retreatment as assessed by EBMT criteria. The overall best response rate (CR + PR), to retreatment in 130 patients was 38.5% (95% CI: 30.1, 47.4).
Clinical efficacy in previously untreated mantle cell lymphoma (MCL)Study LYM-3002 was a Phase III, randomised, open-label study comparing the efficacy and safety of the combination of VELCADE, rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP; n=243) to that of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; n=244) in adult patients with previously untreated MCL (Stage II, III or IV). Patients in the VcR-CAP treatment arm received VELCADE (1.3 mg/m2; on days 1, 4, 8, 11, rest period days 12-21), rituximab 375 mg/m2 IV on day 1; cyclophosphamide 750 mg/m2 IV on day 1; doxorubicin 50 mg/m2 IV on day 1; and prednisone 100 mg/m2 orally on day 1 through day 5 of the 21 day VELCADE treatment cycle. For patients with a response first documented at cycle 6, two additional treatment cycles were given.The primary efficacy endpoint was progression-free survival based on Independent Review Committee (IRC) assessment. Secondary endpoints included, time to progression (TTP), time to next anti-lymphoma treatment (TNT), duration of treatment free interval (TFI), overall response rate (ORR) and complete response (CR/CRu) rate, overall survival (OS) and response duration.The demographic and baseline disease characteristics were generally well balanced between the two treatment arms: median patient age was 66 years, 74% were male, 66% were Caucasian and 32% Asian, 69% of patients had a positive bone marrow aspirate and/or a positive bone marrow biopsy for MCL, 54% of patients had an International Prognostic Index (IPI) score of ≥ 3, and 76% had Stage IV disease. Treatment duration (median=17 weeks) and duration of follow-up (median=40 months) were comparable in both treatment arms. A median of 6 cycles was received by patients in both treatment arms with 14% of subjects in the VcR-CAP group and 17% of patients in the R-CHOP group receiving 2 additional cycles. The majority of the patients in both groups completed treatment, 80% in the VcR-CAP group and 82% in the R-CHOP group. Efficacy results are presented in Table 16:
Table 16: Efficacy results from study LYM-3002
|n: ITT patients||243||244|
|Progression free survival (IRC)a|
|Events n (%)||133 (54.7%)||165 (67.6%)||HRb (95% CI)=0.63 (0.50; 0.79) p-valued < 0.001|
|Medianc(95% CI) (months)||24.7 (19.8; 31.8)||14.4 (12; 16.9)|
|n: response-evaluable patients||229||228|
|Overall complete response (CR+CRu)f n(%)||122 (53.3%)||95 (41.7%)||ORe (95% CI)=1.688 (1.148; 2.481) p-valueg=0.007|
|Overall response (CR+CRu+PR)h n(%)||211 (92.1%)||204 (89.5%)||ORe (95% CI)=1.428 (0.749; 2.722) p-valueg=0.275|
|a Based on Independent Review Committee (IRC) assessment (radiological data only). b Hazard ratio estimate is based on a Cox's model stratified by IPI risk and stage of disease. A hazard ratio < 1 indicates an advantage for VcR-CAP. c Based on Kaplan-Meier product limit estimates. d Based on Log rank test stratified with IPI risk and stage of disease. e Mantel-Haenszel estimate of the common odds ratio for stratified tables is used, with IPI risk and stage of disease as stratification factors. An odds ratio (OR) > 1 indicates an advantage for VcR-CAP. f Include all CR+CRu, by IRC, bone marrow and LDH. g P-value from the Cochran Mantel-Haenszel chi-square test, with IPI and stage of disease as stratification factors. h Include all radiological CR+CRu+PR by IRC regardless the verification by bone marrow and LDH. CR=Complete Response; CRu=Complete Response unconfirmed; PR=Partial Response; CI=Confidence Interval, HR=Hazard Ratio; OR=Odds Ratio; ITT=Intent to Treat|
Patients with previously treated light-chain (AL) AmyloidosisAn open label non randomised Phase I/II study was conducted to determine the safety and efficacy of VELCADE in patients with previously treated light-chain (AL) Amyloidosis. No new safety concerns were observed during the study, and in particular VELCADE did not exacerbate target organ damage (heart, kidney and liver). In an exploratory efficacy analysis, a 67.3% response rate (including a 28.6% CR rate) as measured by hematologic response (M-protein) was reported in 49 evaluable patients treated with the maximum allowed doses of 1.6 mg/m2 weekly and 1.3 mg/m2 twice-weekly. For these dose cohorts, the combined 1-year survival rate was 88.1%.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with VELCADE in all subsets of the paediatric population in multiple myeloma and in mantle cell lymphoma (see section 4.2 for information on paediatric use).
AbsorptionFollowing 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 (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%.
DistributionThe mean distribution volume (Vd) 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.
BiotransformationIn 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.
EliminationThe 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.
Hepatic impairmentThe effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase I study during the first treatment cycle, including 61 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-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 (see section 4.2, Table 6).
Renal impairmentA pharmacokinetic study was conducted 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, n=12), Mild (CrCL=40-59 ml/min/1.73 m2, n=10), Moderate (CrCL=20-39 ml/min/1.73 m2, n=9), and Severe (CrCL < 20 ml/min/1.73 m2, n=3). A group of dialysis patients who were dosed after dialysis was also included in the study (n=8). Patients were administered intravenous doses of 0.7 to 1.3 mg/m2 of VELCADE twice weekly. Exposure of VELCADE (dose-normalised AUC and Cmax) was comparable among all the groups (see section 4.2).
Unopened vial3 years
Reconstituted solutionThe reconstituted solution should be used immediately after preparation. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user. However, the chemical and physical in-use stability of the reconstituted solution has been demonstrated for 8 hours at 25°C stored in the original vial and/or a syringe. The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.
General precautionsBortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of VELCADE. Use of gloves and other protective clothing to prevent skin contact is recommended.Aseptic technique must be strictly observed throughout the handling of VELCADE, since it contains no preservative.There have been fatal cases of inadvertent intrathecal administration of VELCADE. VELCADE 1 mg powder for solution for injection is for intravenous use only, while VELCADE 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. VELCADE should not be administered intrathecally.
Instructions for reconstitutionVELCADE must be reconstituted by a healthcare professional.
Intravenous injectionEach 10 ml vial of VELCADE must be reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear and colourless, 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 injectionEach 10 ml vial of VELCADE should be reconstituted with 1.4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. Dissolution of the lyophilised powder is completed in less than 2 minutes.After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colourless, 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.
DisposalVELCADE is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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