Summary of medicine characteristics - Velcade
1. NAME OF THE MEDICINAL PRODUCT
VELCADE 1 mg powder for solution for injection
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each vial contains 1 mg bortezomib (as a mannitol boronic ester).
After reconstitution, 1 ml of solution for intravenous injection contains 1 mg bortezomib.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder for solution for injection.
White to off-white cake or powder.
4. CLINICAL PARTICULARS4.1 Therapeutic indications
VELCADE 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.
VELCADE 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.
VELCADE 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.
VELCADE in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.
4.2 Posology and method of administration
VELCADE treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients, however VELCADE may be administered by a healthcare professional experienced in use of chemotherapeutic agents. VELCADE must be reconstituted by a healthcare professional (see section 6.6).
Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy)
Monotherapy
VELCADE 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. 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 monotherapy
VELCADE 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 neuropathy
Patients 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/m2 or 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 doxorubicin
VELCADE 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 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 dexamethasone
VELCADE 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21 day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 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 myeloma For 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 prednisone
VELCADE 1 mg powder for solution for injection is administered via intravenous 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) ____________________________
| Week | 1 | 2 | 3 | 4 | 5 | 6 | |||||
| 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 Day 2 3 | Day 4 | -- | -- | rest period | -- | -- | -- | -- | rest period |
Once weekly VELCADE (cycles 5–9)
| Week | 1 | 2 | 3 | 4 | 5 | 6 |
| 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 Day Day Day 12 3 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 prednisone
Prior to initiating a new cycle of therapy:
- • Platelet counts should be > 70 × 109/l and the absolute neutrophils count should be > 1.0 × 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
thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle | Consider reduction of the melphalan dose by 25% in the next cycle. |
< 0.75 × 109/l on a VELCADE dosing day (other than day 1) | VELCADE therapy should be withheld |
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. |
For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.
Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
VELCADE 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of 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 thalidomide
VELCADE 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11 in a 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 | ||||||
| Week | 1 | 2 | 3 | ||||
| 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+Dx+T | Cycle 1 | ||||||
| Week | 1 | 2 | 3 | 4 | |||
| 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
aThalidomide 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.
bUp to 6 cycles may be given to patients who achieve at least a partial response after 4 cycles
Dosage adjustments for transplant eligible patients
For VELCADE dosage adjustments, dose modification guidelines described for monotherapy should be followed.
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 1 mg powder for solution for injection is administered via intravenous injection at the recommended dose of 1.3 mg/m2 body surface area twice weekly for two weeks on days 1, 4, 8, and 11, 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 lymphoma Prior to initiating a new cycle of therapy:
- • Platelet counts should be > 100,000 cells/pL and the absolute neutrophils count (ANC) should
be > 1,500 cells/pL
- • Platelet counts should be > 75,000 cells/pL 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 |
| Haematological toxicity | |
neutropenia lasting more than 7 days, a platelet count < 10,000 cells/pL | VELCADE therapy should be withheld for up to 2 weeks until the patient has an ANC > 750 cells/pL and a platelet count > 25,000 cells/pL.
|
| 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. |
In addition, when VELCADE is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.
Special populations
Elderly
There 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 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 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 xULN | 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 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, VELCADE should be administered after the dialysis procedure (see section 5.2).
Paediatric population
The safety and efficacy of VELCADE in children below 18 years of age have not been established (see sections 5.1 and 5.2). Currently available data are described in section 5.1 but no recommendation on a posology can be made.
Method of administration
VELCADE 1 mg powder for solution for injection is available for intravenous administration only.
VELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.
VELCADE should not be given by other routes. Intrathecal administration has resulted in death.
Intravenous injection
VELCADE 1 mg powder for solution for injection is for intravenous administration only. The 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.
When VELCADE is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.
4.3 Contraindications
Hypersensitivity to the active substance, to boron or to any of the excipients listed in section 6.1. Acute diffuse infiltrative pulmonary and pericardial disease.
When VELCADE is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.
4.4 Special warnings and precautions for use
When VELCADE is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with VELCADE. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed (see section 4.6).
Intrathecal administration
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.
Gastrointestinal toxicity
Gastrointestinal 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 toxicity
VELCADE 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/pl, 90% of 21 patients had a count < 25,000/pl during the study, including 14% < 10,000/pl; in contrast, with a baseline platelet count > 75,000/pl, only 14% of 309 patients had a count < 25,000/pl 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/pl or, in the case of combination with melphalan and prednisone, when the platelet count is < 30,000/pl (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 reactivation
Antiviral 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 infection
When 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 neuropathy
Treatment 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.
Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose or schedule of VELCADE (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.
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
VELCADE 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 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 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 impairment
Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).
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 VELCADE at reduced doses and closely monitored for toxicities (see sections 4.2 and 5.2).
Hepatic reactions
Rare 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 syndrome
Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.
Concomitant medicinal products
Patients should be closely monitored when given bortezomib in combination with potent CYP3A4-inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4– or CYP2C19 substrates (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 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.
4.5 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 VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.
4.6 Fertility, pregnancy and lactation
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 (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-feeding
It 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.
Fertility
Fertility studies were not conducted with VELCADE (see section 5.3).
4.7 Effects on ability to drive and use machines
VELCADE may have a moderate influence on the ability to drive and use machines. VELCADE may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines and should be advised not to drive or operate machinery if they experience these symptoms (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
Serious 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 Myeloma
Undesirable 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 in clinical
____________ trials, and all post-marketing adverse reactions regardless of indication*
| 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* |
| Common | Leukopenia*, Lymphopenia* | |
| Uncommon | Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia# | |
| Rare | Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombotic microangiopathy (inc 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 |
| Rare | Hypothyroidism | |
| 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, GuillainBarre syndrome#, Demyelinating polyneuropathy# | |
| Eye disorders | Common | Eye swelling*, Vision abnormal*, Conjunctivitis* |
| Uncommon | Eye haemorrhage*, Eyelid infection*, Chalazion#, Blepharitis#, 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 small intestinal obstruction, 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, Palmarplantar 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 | |
| Rare | Bladder irritation | |
| 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 | |
| Investigations | Common | Weight decreased |
| 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.
# Post-marketing adverse reaction regardless of indication
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 in a
clinical trial
| 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* |
| Uncommon | Pancytopenia* | |
| Immune system disorders | Common | Hypersensitivity* |
| Uncommon | Anaphylactic reaction | |
| 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) |
| Uncommon | Hepatic failure | |
| 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 reactivation
Multiple Myeloma
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.
Mantle cell lymphoma
Antiviral 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 infection
Mantle cell lymphoma
HBV 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 regimens
Multiple Myeloma
In 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
| IFM-2005–01 | MMY-3010 | |||
| VDDx (N=239) | VcDx (N=239) | TDx (N=126) | VcTDx (N=130) | |
| Incidence of PN (%) All GradePN | 3 | 15 | 12 | 45 |
| > 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.
Mantle cell lymphoma
In study LYM-3002 in which VELCADE was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in the table below:
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 (%) All GradePN | 30 | 29 |
| > 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 patients
42.9% 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.
Retreatment of patients with relapsed multiple myeloma
In 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 reactions
Reporting 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 the national reporting system listed in Appendix V.
4.9 Overdose
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
5.2 Pharmacokinetic properties
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.
Distribution
The 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 ^g/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.
Special populations
Hepatic impairment
The 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 impairment
A 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).
Age
The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3 mg/m2 doses to 104 pediatric patients (2–16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area (BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/m2, volume of distribution at steady-state was 834 (39%) L/m2, and the elimination half-life was 100 (44%) hours. After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA-normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.
5.3 Preclinical safety data
Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as 3.125 tg/ml, which was the lowest concentration evaluated. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice.
Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally toxic doses, but no direct embryo-foetal toxicity below maternally toxic doses. Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have been observed. It is, therefore, likely that bortezomib could have a potential effect on either male or female fertility. Peri- and postnatal development studies were not conducted.
In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs included the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic and lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice and dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs have shown partial to full recovery following discontinuation of treatment.
Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to be limited, if any and the relevance to humans is unknown.
Cardiovascular safety pharmacology studies in monkeys and dogs show that intravenous doses approximately two to three times the recommended clinical dose on a mg/m2 basis are associated with increases in heart rate, decreases in contractility, hypotension and death. In dogs, the decreased cardiac contractility and hypotension responded to acute intervention with positive inotropic or pressor agents. Moreover, in dog studies, a slight increase in the corrected QT interval was observed.
6. PHARMACEUTICAL PARTICULARS6.1 List of excipients
Mannitol (E 421)
Nitrogen
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
6.3 Shelf life
Unopened vial
3 years
Reconstituted solution
The 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.
6.4 Special precautions for storage
Do not store above 30°C.
Keep the vial in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Type 1 glass 5 ml-vial with a grey bromobutyl stopper and an aluminium seal, with a green cap containing 1 mg bortezomib.
The vial is contained in a transparent blister pack consisting of a tray with a lid. Each pack contains 1 single-use vial.
6.6 Special precautions for disposal and other handling
General precautions
Bortezomib 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 reconstitution
VELCADE must be reconstituted by a healthcare professional.
Each 5 ml vial of VELCADE must be carefully reconstituted with 1 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by using a 1 ml syringe, without removing the vial stopper. 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.
Disposal
VELCADE is for single use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
JANSSEN-CILAG INTERNATIONAL NV
Turnhoutseweg 30
B-2340 Beerse
Belgium
8. MARKETING AUTHORISATION NUMBER
EU/1/04/274/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 26 April 2004
Date of latest renewal: 10 January 2014