Posology : מינונים

4.    DOSAGE AND ADMINISTRATION
General Dosing Guidelines
BORTEZOMIB TARO 3.5 MG IS FOR INTRAVENOUS OR SUBCUTANEOUS USE
ONLY. Bortezomib Taro 3.5 mg 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 Taro 3.5 mg is 1.3 mg/m2. Bortezomib Taro 3.5 mg may be administered intravenously at a concentration of 1 mg/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 Taro 3.5 mg is administered as a 3 to 5 second bolus intravenous injection.



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

TABLE 1 - Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib Taro (Cycles 1 to 4)
Week                   1                   2          3          4           5          6 Bortezomib
Day                Day Day Day           rest    Day Day Day Day           rest Taro (1.3
1                 4      8      11    period   22    25     29    32    period mg/m2)
Melphalan
(9 mg/m2)   Day Day Day Day                          rest                              rest Prednisone    1     2     3     4                   period                            period (60 mg/m2)
Once Weekly Bortezomib Taro (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
Taro (1.3     1
8            period   22           29          period mg/m )2

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 Taro,
Melphalan and Prednisone
Prior to initiating any cycle of therapy with Bortezomib Taro 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.
•   Non-hematological toxicities should have resolved to Grade 1 or baseline.

TABLE 2 – Dose Modifications During Cycles of Combination Bortezomib Taro, Melphalan and Prednisone Therapy
Toxicity                                                 Dose Modification or Delay Hematological toxicity during a cycle:                   Consider reduction of the melphalan dose If prolonged grade 4 neutropenia or thrombocytopenia, by 25% in the next cycle or thrombocytopenia with bleeding is observed in the previous cycle
If platelet count is not above 30 x 109/L or ANC is not Withhold Bortezomib Taro dose above 0.75 x 109/L on a Bortezomib dosing day (other than day 1)
If several Bortezomib Taro doses in consecutive cycles Reduce Bortezomib Taro dose by one are withheld due to toxicity                             dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2)
Grade 3 or higher non-hematological toxicities           Withhold Bortezomib Taro therapy until symptoms of toxicity have resolved to
Grade 1 or baseline. Then, Bortezomib

TABLE 2 – Dose Modifications During Cycles of Combination Bortezomib Taro, Melphalan and Prednisone Therapy
Toxicity                                          Dose Modification or Delay Taro 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 Taro-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib Taro 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 (4.6)].


4.3       Posology for Patients with Previously Untreated Mantle Cell Lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR- CAP)
Bortezomib Taro 3.5 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 Bortezomib Taro cycles are recommended, although for patients with a response first documented at cycle 6, two additional Bortezomib Taro cycles may be given. At least 72 hours should elapse between consecutive doses of Bortezomib Taro.
The following medicinal products are administered on day 1 of each Bortezomib Taro 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 Taro 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 Taro treatment must be withheld at the onset of any ≥ Grade 3 Bortezomib Taro- 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                            Dose modification or delay
Haematological toxicity
≥ Grade 3 neutropenia with fever,   Bortezomib therapy should be withheld for up to 2 weeks until Grade 4 neutropenia lasting more    the patient has an ANC ≥ 750 cells/μL and a platelet count ≥ than 7 days, a platelet count <     25,000 cells/μL.
10,000 cells/μL                      •If, after Bortezomib Taro has been held, the toxicity does not resolve, as defined above, then Bortezomib Taro must be discontinued.
•If toxicity resolves i.e., patient has an ANC ≥ 750 cells/μL and a platelet count ≥ 25,000 cells/μL, Bortezomib Taro 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 count < 25,000 cells/μL Bortezomib Taro therapy should be withheld.
or ANC < 750 cells/μL on a
Bortezomib Taro dosing day (other than Day 1 of each cycle)
If several Bortezomib Taro doses    Reduce Bortezomib Taro dose by one dose level (from 1.3 in consecutive cycles are withheld mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2) due to toxicity
Grade ≥ 3 non-hematological         Bortezomib Taro therapy should be withheld until symptoms toxicities considered to be related of the toxicity have resolved to Grade 2 or better. Then, to Bortezomib Taro                  Bortezomib Taro 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 Bortezomib Taro-related neuropathic pain and/or peripheral neuropathy, hold and/or modify Bortezomib
Taro as outlined in Table 1.
In addition, when Bortezomib Taro 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 Taro (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 Taro 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 (15) for a description of dose administration during the trials]. At least 72 hours should elapse between consecutive doses of Bortezomib Taro.


4.5    Dose Modification Guidelines for Relapsed Multiple Myeloma and Relapsed
Mantle Cell Lymphoma
Bortezomib Taro 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 (5)]. Once the symptoms of the toxicity have resolved, Bortezomib Taro 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 (4.6).
4.6     Dose Modifications of Peripheral Neuropathy
Starting Bortezomib Taro 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 Taro only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during Bortezomib Taro 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 Taro- related neuropathic pain and/or peripheral neuropathy, see Table 4.

TABLE 4 – Recommended Dose Modification for Bortezomib Taro-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                                  No action tendon reflexes or paresthesia) without pain or loss of function
Grade 1 with pain or Grade 2 (moderate                 Reduce Bortezomib Taro to 1 mg/m2 symptoms; limiting Instrumental                                        OR Activities of Daily Living (ADL))**             Change Bortezomib Taro treatment schedule to 1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (severe             Withhold Bortezomib Taro therapy until toxicity symptoms; limiting Self-care (ADL))***           resolves. When toxicity resolves reinitiate with a reduced dose of Bortezomib Taro at 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences;                    Discontinue Bortezomib Taro urgent 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 Taro dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib Taro 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 Taro in Patients with Hepatic Impairment
Grade of                        SGOT
Bilirubin hepatic                         (AST)     Modification of Starting Dose Level impairment*                     Levels
Less than or
Mild           equal to 1.0 x > ULN                          None
ULN

Grade of                             SGOT
Bilirubin hepatic                              (AST)      Modification of Starting Dose Level impairment*                          Levels
More than
1.0 x to 1.5 x      Any                           None
ULN
More than                   Reduce Bortezomib Taro to 0.7 mg/m2 in the Moderate            1.5 x to 3 x       Any      first treatment cycle. Consider dose ULN                      escalation to 1 mg/m2 or further dose
More than 3                  reduction to 0.5 mg/m2 in subsequent cycles Severe                                 Any x ULN                     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 4.9)).
Bortezomib Taro 3.5 mg 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 4.9) 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 4.9)].
Bortezomib Taro 3.5 mg 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
Final Bortezomib
Route of           Bortezomib Taro      Diluent (0.9%
Taro concentration
Administration          (mg/vial)      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 Taro 3.5 mg to be administered:
•Intravenous Administration [1 mg/mL concentration] Bortezomib dose (mg/m2) x patient BSA (m2)
1 mg/mL
= Total Bortezomib volume (mL) to be administered
•Subcutaneous Administration [2.5 mg/mL concentration] Bortezomib dose (mg/m2) x patient BSA (m2)
2.5 mg/mL
= Total Bortezomib 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 vials of Bortezomib Taro 3.5 mg 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 Taro 3.5 mg contains no antimicrobial preservative.
From a microbiological point of view, 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 Bortezomib Taro 3.5 mg contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder or cake for reconstitution and withdrawal of the appropriate individual patient dose [see Dosage and Administration (section 4)].