Posology : מינונים

5     DOSAGE AND ADMINISTRATION
General Dosing Guidelines
BORTEZOMIB FRESENIUS KABI IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY. BORTEZOMIB FRESENIUS KABI must not be administered by any other route. 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 BORTEZOMIB FRESENIUS KABI is 1.3mg/m2. BORTEZOMIB FRESENIUS KABI 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 5.9). When administered intravenously, BORTEZOMIB FRESENIUS KABI is administered as a 3 to 5 second bolus intravenous injection.

5.1 Dosage in Previously Untreated Multiple Myeloma
BORTEZOMIB FRESENIUS KABI 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, BORTEZOMIB FRESENIUS KABI is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, BORTEZOMIB FRESENIUS KABI is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of BORTEZOMIB FRESENIUS KABI.
Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly BORTEZOMIB
FRESENIUS KABI (Cycles 1 to 4)
Week                            1                   2            3              4               5           6 BORTEZOMIB          Day                         Day    Day    Day   rest      Day       Day   Day       Day   rest FRESENIUS KABI        1                           4      8     11    period    22        25    29        32    period (1.3 mg/m2)
Melphalan
(9 mg/m2)                                     Day                 rest                                      rest Day 1    Day 2     Day 3
Prednisone                                     4                  period                                    period (60 mg/m2)
Once Weekly BORTEZOMIB FRESENIUS KABI (Cycles 5 to 9 when used in combination with Melphalan and Prednisone)
Week                     1                       2       3          4           5          6 BORTEZOMIB          Day                                Day          rest      Day             Day             rest FRESENIUS KABI        1                                  8           period    22              29              period (1.3 mg/m2)
Melphalan
(9 mg/m2)         Day      Day       Day      Day                 rest                                      rest Prednisone         1        2         3        4                  period                                    period (60 mg/m2)

5.2 Dose Modification Guidelines for Combination Therapy with BORTEZOMIB FRESENIUS KABI, Melphalan and Prednisone Prior to initiating any cycle of therapy with BORTEZOMIB FRESENIUS KABI in combination with melphalan and prednisone: •    Platelet count should be at least ≥70 x 109/L and the absolute neutrophil count (ANC) should be at least ≥ 1.0 x 109/L •    Nonhematological toxicities should have resolved to Grade 1 or baseline 
Table 2: Dose Modifications During Cycles of Combination BORTEZOMIB FRESENIUS KABI, 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 BORTEZOMIB FRESENIUS KABI dose ANC is not above 0.75 x 109/L on a
BORTEZOMIB FRESENIUS KABI dosing day
(other than Day 1)
If several BORTEZOMIB FRESENIUS KABI                Reduce BORTEZOMIB FRESENIUS KABI dose by one dose doses in consecutive cycles are withheld due        level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 to toxicity                                         mg/m2)
Grade 3 or higher nonhematological                  Withhold BORTEZOMIB FRESENIUS KABI therapy until symptoms of toxicities                                          toxicity have resolved to Grade 1 or baseline. Then, BORTEZOMIB FRESENIUS KABI 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
BORTEZOMIB FRESENIUS KABI-related neuropathic pain and/or peripheral neuropathy, hold or modify BORTEZOMIB FRESENIUS
KABI as outlined in Table 4.
For information concerning melphalan and prednisone, see manufacturer's prescribing information.
Dose modifications guidelines for peripheral neuropathy are provided [see Dosage and Administration (5.6)].


5.3 Posology for patients with previously untreated mantle cell lymphoma (MCL) Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP) BORTEZOMIB FRESENIUS KABI 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 12- 21. This 3-week period is considered a treatment cycle. Six BORTEZOMIB FRESENIUS KABI cycles are recommended, although for patients with a response first documented at cycle 6, two additional BORTEZOMIB FRESENIUS KABI cycles may be given. At least 72 hours should elapse between consecutive doses of BORTEZOMIB FRESENIUS KABI.
The following medicinal products are administered on day 1 of each BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB FRESENIUS KABI 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.

BORTEZOMIB FRESENIUS KABI treatment must be withheld at the onset of any ≥ Grade 3 BORTEZOMIB FRESENIUS KABI-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
BORTEZOMIB FRESENIUS KABI 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 with           - If, after BORTEZOMIB FRESENIUS KABI has been held, the toxicity does not fever, Grade 4 neutropenia           resolve, as defined above, then BORTEZOMIB FRESENIUS KABI must be lasting more than 7 days, a platelet discontinued.
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, BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB                         BORTEZOMIB FRESENIUS KABI therapy should be withheld FRESENIUS KABI dosing day (other than Day 1 of each cycle)
If several BORTEZOMIB FRESENIUS      Reduce BORTEZOMIB FRESENIUS KABI dose by one dose level (from 1.3 mg/m2 to 1 KABI doses in consecutive cycles     mg/m2, or from 1 mg/m2 to 0.7 mg/m2) are withheld due to toxicity
Grade ≥ 3 non-haematological          BORTEZOMIB FRESENIUS KABI therapy should be withheld until symptoms of the toxicities considered to be related   toxicity have resolved to Grade 2 or better. Then, BORTEZOMIB FRESENIUS KABI may be to BORTEZOMIB FRESENIUS KABI          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 BORTEZOMIB FRESENIUS KABI-related neuropathic pain and/or peripheral neuropathy, hold and/or modify BORTEZOMIB FRESENIUS KABI as outlined in Table 4.

In addition, when BORTEZOMIB FRESENIUS KABI 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.
5.4 Dosage in Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma BORTEZOMIB FRESENIUS KABI (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, BORTEZOMIB FRESENIUS KABI 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 (16) for a description of dose administration during the trials]. At least 72 hours should elapse between consecutive doses of BORTEZOMIB FRESENIUS KABI.

5.5 Dose Modification Guidelines for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma BORTEZOMIB FRESENIUS KABI 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 (8)]. Once the symptoms of the toxicity have resolved, BORTEZOMIB FRESENIUS KABI 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 5.6.

5.6 Dose Modifications of Peripheral Neuropathy
Starting BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB FRESENIUS KABI only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB FRESENIUS KABI-related neuropathic pain and/or peripheral neuropathy, see Table 4.

Table 4 – Recommended Dose Modification for BORTEZOMIB FRESENIUS KABI-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 BORTEZOMIB FRESENIUS KABI to 1 mg/m2 symptoms; limiting instrumental Activities of                                    OR Daily Living (ADL)]**                                    Change BORTEZOMIB FRESENIUS KABI treatment schedule to 1.3mg/m2 once per week
Grade 2 with pain or Grade 3 (severe         Withhold BORTEZOMIB FRESENIUS KABI therapy until toxicity resolves.
symptoms; limiting self care ADL *** )        When toxicity resolves reinitiate with a reduced dose of BORTEZOMIB FRESENIUS KABI at 0.7 mg/m2 once per week.

Grade 4 (life-threatening consequences; urgent      Discontinue BORTEZOMIB FRESENIUS KABI 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.

5.7 Dosage in Patients with Hepatic Impairment
Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended BORTEZOMIB FRESENIUS KABI dose. Patients with moderate or severe hepatic impairment should be started on BORTEZOMIB FRESENIUS KABI 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 (8.8), Use in Specific Populations (11.7) and Clinical Pharmacology (14.3)] 
Table 5: Recommended Starting Dose Modification for BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB FRESENIUS KABI to 0.7 ULN                                                      mg/m2 in the first treatment cycle. Consider dose Severe                   More than 3x ULN                        Any              escalation to 1 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).


5.8 Adminitration 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 5.9).
BORTEZOMIB FRESENIUS KABI 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 BORTEZOMIB FRESENIUS KABI administration subcutaneously, a less concentrated BORTEZOMIB FRESENIUS KABI solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously [see reconstitution/ preparation for intravenous and subcutaneous administration (section 5.9) 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 5.9].

BORTEZOMIB FRESENIUS KABI is a cytotoxic drug. Follow applicable special handling and disposal procedures [ See How Supplied/Storage and Handling (17)].
5.9 Reconsitution/ 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 5.8).

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 BORTEZOMIB FRESENIUS KABI to be administered: 
•   Intravenous Administration [1 mg/mL concentration]
BORTEZOMIB FRESENIUS KABI dose (mg/m2) x patient BSA (m2)
___________________________________________________________
=             Total BORTEZOMIB FRESENIUS KABI
1 mg/mL                                                         volume (mL) to be administered 

•   Subcutaneous Administration [2.5 mg/mL concentration]
BORTEZOMIB FRESENIUS KABI dose (mg/m2) x patient BSA (m2)
________________                       =                Total BORTEZOMIB FRESENIUS KABI 2.5 mg/mL                                                            volume (mL) to be administered 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 vial
The expiry date of the product is indicated on the packaging materials.
Store below 250C. Keep the vial in the outer carton in order to protect from light.

Reconstituted solution
The chemical and physical in-use stability of the reconstituted solution has been demonstrated at concentrations of 1 mg/ml and 2.5 mg/ml for 96 hours at 250C and 8 days at 2-80C, when stored in the original vial and/or a syringe.
From a microbiological point of view, 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. The total storage time for the reconstituted medicinal product should not exceed 96 hours (if stored at 250C) and 8 days (if stored at 2-80C) prior to administration.

6 DOSAGE FORMS AND STRENGTHS
Each vial of BORTEZOMIB FRESENIUS KABI contains 3.5 mg of bortezomib as white to off-white lyophilized powder or cake.