Posology : מינונים

4   DOSAGE AND ADMINISTRATION
General Dosing Guidelines
VELCADE IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY. VELCADE must not be administered by any other route.
Intrathecal administration has resulted in death. Intrathecal administration has resulted in death.

Because each route of administration has a different reconstituted concentration, caution should be used when calculating the volume to be administered.

The recommended starting dose of VELCADE is 1.3 mg/m2. VELCADE may be administered intravenously at a concentration of 1mg/mL, or subcutaneously at a concentration of 2.5 mg/mL (see reconstitution /preparation for intravenous and subcutaneous administration section 4.8). When administered intravenously, VELCADE is administered as a 3 to 5 second bolus intravenous injection.

4.1 Dosage in Previously Untreated Multiple Myeloma
VELCADE is administered in combination with oral melphalan and oral prednisone for 9, six week treatment cycles as shown in Table 1. In Cycles 1 to 4, VELCADE is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, VELCADE is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of VELCADE.
Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly VELCADE (Cycles 1 to 4)


Week                         1                          2           3            4               5           6 VELCADE          Day                          Day    Day       Day   rest     Day       Day   Day       Day   rest (1.3 mg/m2)         1                            4      8        11    period   22        25    29        32    period Melphalan
(9 mg/m2)                                          Day                    rest                                     rest Day 1   Day 2       Day 3
Prednisone                                          4                     period                                   period (60 mg/m2)
Once Weekly VELCADE (Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week                         1                          2           3            4               5           6 VELCADE          Day                                 Day             rest     Day             Day             rest (1.3 mg/m2)         1                                   8              period   22              29              period Melphalan
(9 mg/m2)         Day     Day        Day       Day                    rest                                     rest Prednisone          1       2          3         4                     period                                   period (60 mg/m2)

4.2 Dose Modification Guidelines for Combination Therapy with VELCADE Melphalan and Prednisone
Prior to initiating any cycle of therapy with VELCADE in combination with melphalan and prednisone: •    Platelet count should be ≥70 x 109/L and the absolute neutrophil count (ANC) should be ≥ 1.0 x 109/L •    Nonhematological toxicities should have resolved to Grade 1 or baseline 
Table 2: Dose Modifications During Cycles of Combination VELCADE, Melphalan and Prednisone Therapy Toxicity                                            Dose Modification or Delay Hematological toxicity during a cycle:              Consider reduction of the melphalan dose by 25% in the next cycle If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle
If platelet count is not above 30 x 109/L or        Withhold VELCADE dose ANC is not above 0.75 x 109/L on a VELCADE dosing day (other than Day 1)
If several VELCADE doses in consecutive             Reduce VELCADE dose by one dose level (from 1.3 mg/m2 to cycles are withheld due to toxicity                 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) Grade 3 or higher nonhematological                  Withhold VELCADE therapy until symptoms of toxicity have toxicities                                          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 or modify VELCADE as outlined in Table 5.

For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (4.5)].

4.3 Posology for patients with previously untreated mantle cell lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) VELCADE 3.5mg 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 1221. 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/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. For dose adjustments, see Table 3 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 3: Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma Toxicity                              Posology modification or delay

Haematological toxicity
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.
•         ≥ Grade 3 neutropenia      • If, after VELCADE has been held, the toxicity does not resolve, as defined above, with fever, Grade 4 neutropenia         then VELCADE must be discontinued.
lasting more than 7 days, a platelet count < 10,000 cells/μL      •          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                                       VELCADE therapy should be withheld dosing day (other than Day 1 of each cycle)
If several VELCADE doses in           Reduce VELCADE dose by one dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 consecutive cycles are withheld       to 0.7 mg/m2) due to toxicity
)
Grade ≥ 3 non-haematological          VELCADE therapy should be withheld until symptoms of the toxicity have resolved to toxicities considered to be related   Grade 2 or better. Then, VELCADE may be reinitiated at a dose reduced by one dose to VELCADE                            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.
4.4 Dosage in Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
VELCADE (1.3 mg/m2/dose) is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a ten day rest period (Days 12 to 21). For extended therapy of more than eight cycles, VELCADE may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for four weeks (Days 1, 8, 15, and 22) followed by a 13 day 
rest period (Days 23 to 35) [see Clinical Studies section (13) for a description of dose administration during the trials]. At least 72 hours should elapse between consecutive doses of VELCADE.


4.5 Dose Modification Guidelines for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
VELCADE therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below [see Warnings and Precautions (7)]. Once the symptoms of the toxicity have resolved, VELCADE therapy may be reinitiated at a 25% reduced dose (1.3 mg/m2/dose reduced to 1 mg/m2/dose; 1 mg/m2/dose reduced to 0.7 mg/m2/dose.
For dose modifications guidelines for peripheral neuropathy, see Management of peripheral neuropathy section 4.5) 4.6 Dose Modifications of Peripheral Neuropathy
Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule.
For dose or schedule modification guidelines for patients who experience VELCADE-related neuropathic pain and/or peripheral neuropathy, see Table 4.

Table 4 – Recommended Dose Modification for VELCADE -Related Neuropathic Pain and/or Peripheral Sensory or Motor Neuropathy
Severity of Peripheral Neuropathy
Modification of Dose and Regimen
Signs and Symptoms*
Grade 1 (asymptomatic; loss of deep tendon           No action reflexes or paresthesia) without pain or loss of function
Grade 1 with pain or Grade 2 (moderate                                   Reduce VELCADE to 1 mg/m2 symptoms; limiting instrumental Activities of                                        OR Daily Living (ADL))**                                                Change VELCADE treatment schedule to 1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (severe           Withhold VELCADE therapy until toxicity resolves. When toxicity symptoms; limiting self care ADL *** )          resolves reinitiate with a reduced dose of VELCADE at 0.7 mg/m2 once per week.

Grade 4 (life-threatening consequences; urgent Discontinue VELCADE intervention indicated)
*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 medications, and not bedridden

4.7 Dosage in Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended VELCADE 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 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 tolerance (see Table 5). [see Warnings and Precautions (7.8), Use in Specific Populations (10.7) and Clinical Pharmacology (13.3)]


Table 5: Recommended Starting Dose Modification for VELCADE in Patients with Hepatic Impairment 

Grade of hepatic            Bilirubin Level                 SGOT (AST)               Modification of Starting dose impairment*                                                   Levels


Mild                     less than or equal to         > ULN                                          None 1.0x ULN

More than 1.0x to 1.5x                Any                                    None ULN

Moderate                 More than 1.5x to 3x                  Any             Reduce VELCADE to 0.7 mg/m2 in the first ULN                                                   treatment cycle. Consider dose escalation to 1 Severe                   More than 3x ULN                      Any             mg/m2 or further dose reduction to 0.5 mg/m2 in subsequent cycles based on patient tolerability.


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).

4.8 Administration Precautions
The drug quantity contained in one vial (3.5 mg) may exceed the usual dose required. Caution should be used in calculating the dose to prevent overdose. (see reconstitution /preparation for intravenous and subcutaneous administration section 4.8).
VELCADE is authorized for intravenous or subcutaneous use only. Intrathecal administration has resulted in death.
When administered subcutaneously, sites for each injection (thigh or abdomen) should be rotated. New injections should be given at least one inch from an old site and never into areas where the site is tender, bruised, erythematous, or indurated.
If local injection site reactions occur following VELCADE administration subcutaneously, a less concentrated VELCADE solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see reconstitution /preparation for intravenous and subcutaneous administration section 4.8) and follow reconstitution instructions for 1 mg/mL]. Alternatively, the intravenous route of administration should be considered [see reconstitution /preparation for intravenous and subcutaneous administration section 4.8].

VELCADE is a cytotoxic drug. Follow applicable special handling and disposal procedures [ See How Supplied/Storage and Handling (16)].


4.9 Reconstitution/Preparation for Intravenous and Subcutaneous Administration
Use proper aseptic technique. Reconstitute only with 0.9% sodium chloride. The reconstituted product should be a clear and colorless solution.
Different volumes of 0.9% sodium chloride are used to reconstitute the product for the different routes of administration. The reconstituted concentration of bortezomib for subcutaneous administration (2.5 mg/mL) is greater than the reconstituted concentration of bortezomib for intravenous administration (1 mg/mL). Because each route of administration has a different reconstituted concentration, use caution when calculating the volume to be administered (see Administration Precautions section 4.8).
For each 3.5 mg single-dose vial of bortezomib, reconstitute with the following volume of 0.9% sodium chloride based on route of administration (Table 6):Table 6: Reconstitution Volumes and Final Concentration for Intravenous and Subcutaneous Administration


Route of                 Bortezomib                    Diluent                            Final Bortezomib Concentration Administration              (mg/vial)            (0.9% Sodium Chloride)                                 (mg/mL) Intravenous                3.5 mg                       3.5 mL                                        1 mg/mL Subcutaneous                 3.5 mg                       1.4 mL                                       2.5 mg/mL 
Dose must be individualized to prevent overdosage. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted VELCADE to be administered: 
•   Intravenous Administration [1 mg/mL concentration]
VELCADE dose (mg/m2) x patient BSA (m2)
_____________________________________ = Total VELCADE volume (mL) to be administered 1 mg/mL

•   Subcutaneous Administration [2.5 mg/mL concentration]
VELCADE dose (mg/m2) x patient BSA (m2)
_____________________________________ = Total VELCADE volume (mL) to be administered 2.5 mg/mL

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. If any discoloration or particulate matter is observed, the reconstituted product should not be used.
Stability
Unopened vials of VELCADE are stable until the date indicated on the package when stored in the original package protected from light. Do not store above 30°C.
VELCADE contains no antimicrobial preservative.
The reconstituted solution should be used immediately after preparation. If the reconstituted solution is not used immediately, in- use storage times and conditions prior to use are the responsibility of the user. However, the 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 prior to administration.

The total storage time for the reconstituted medicinal product should not exceed 8 hours prior to administration.
5 DOSAGE FORMS AND STRENGTHS
Each single dose vial of VELCADE contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration (section 4)].