Posology : מינונים

4   DOSAGE AND ADMINISTRATION
General Dosing Guidelines
BORTEZOMIB S.K IS FOR INTRAVENOUS OR SUBCUTANEOUS USE ONLY.
BORTEZOMIB S.K 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 S.K is 1.3mg/m2. BORTEZOMIB S.K 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, BORTEZOMIB S.K is administered as a 3 to 5 second bolus intravenous injection.

4.1 Dosage in Previously Untreated Multiple Myeloma
BORTEZOMIB S.K 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 S.K is administered twice weekly (Days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5 to 9, BORTEZOMIB S.K is administered once weekly (Days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of BORTEZOMIB S.K.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly BORTEZOMIB S.K
(Cycles 1 to 4)
Week                       1                     2     3                  4              5         6 Bortezomib         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 BORTEZOMIB S.K (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 (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 Bortezomib Melphalan and Prednisone
Prior to initiating any cycle of therapy with Bortezomib 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 Bortezomib , 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 dose ANC is not above 0.75 x 109/L on a
Bortezomib dosing day (other than Day 1)
If several Bortezomib doses in consecutive           Reduce Bortezomib dose by one dose level (from 1.3 mg/m2 cycles are withheld due to toxicity                  to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) Grade 3 or higher nonhematological                   Withhold Bortezomib therapy until symptoms of toxicity have toxicities                                           resolved to Grade 1 or baseline. Then, Bortezomib 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 ‐related neuropathic pain and/or peripheral neuropathy, hold or modify
Bortezomib 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 (4.5)].

4.3 Posology for patients with previously untreated mantle cell lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR‐CAP) BORTEZOMIB S.K 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 cycles are recommended, although for patients with a response first documented at cycle 6, two additional Bortezomib cycles may be given. At least 72 hours should elapse between consecutive doses of Bortezomib. The following medicinal products are administered on day 1 of each Bortezomib 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 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 treatment must be withheld at the onset of any ≥ Grade 3 Bortezomib ‐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 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 Bortezomib has been held, the toxicity does not resolve, as defined with fever, Grade 4 neutropenia         above, then Bortezomib 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, Bortezomib 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 therapy should be dosing day (other than Day 1 of                                                withheld each cycle)
If several Bortezomib doses in        Reduce Bortezomib dose by one dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 consecutive cycles are withheld       mg/m2 to 0.7 mg/m2) due to toxicity

Grade ≥ 3 non‐haematological          Bortezomib therapy should be withheld until symptoms of the toxicity have resolved to toxicities considered to be related   Grade 2 or better. Then, Bortezomib may be reinitiated at a dose reduced by one dose to Bortezomib                         level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For Bortezomib ‐related neuropathic pain and/or peripheral neuropathy, hold and/or modify Bortezomib as outlined in Table 1.


In addition, when Bortezomib 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
Bortezomib (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 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 Bortezomib .


4.5 Dose Modification Guidelines for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
Bortezomib 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, Bortezomib 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 Bortezomib 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 only after careful risk‐benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during Bortezomib 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 ‐related neuropathic pain and/or peripheral neuropathy, see Table 4.

Table 4 – Recommended Dose Modification for Bortezomib ‐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 to 1 mg/m2 symptoms; limiting instrumental Activities of       OR
Daily Living (ADL))**                               Change Bortezomib treatment schedule to 1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (severe          Withhold Bortezomib therapy until toxicity resolves. When toxicity symptoms; limiting self care ADL *** )         resolves reinitiate with a reduced dose of BORTEZOMIB S.K at 0.7 mg/m2 once per week.
Grade 4 (life‐threatening consequences; urgent  Discontinue Bortezomib 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 Bortezomib dose.
Patients with moderate or severe hepatic impairment should be started on Bortezomib 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 Bortezomib 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 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).
BORTEZOMIB S.K 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 administration subcutaneously, a less concentrated Bortezomib 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].

BORTEZOMIB S.K 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 BORTEZOMIB S.K to be administered: 
•     Intravenous Administration [1 mg/mL concentration]
Bortezomib dose (mg/m2) x patient BSA (m2)
= Total BORTEZOMIB S.K volume (mL) to be administered
1 mg/mL

•     Subcutaneous Administration [2.5 mg/mL concentration]
Bortezomib dose (mg/m2) x patient BSA (m2)
= Total BORTEZOMIB S.K 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 BORTEZOMIB S.K are stable until the date indicated on the package when stored in the original package protected from light. Do not store above 25°C.
BORTEZOMIB S.K 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 use vial of BORTEZOMIB S.K contains 3.5 mg of bortezomib as a sterile lyophilized white to off‐white cake of powder for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration (section 4)].