Posology : מינונים

4. DOSAGE AND ADMINISTRATION

General Dosing Guidelines
Bortez Teva 3.5 mg is for intravenous or subcutaneous use only.
Bortez Teva 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 Bortez Teva 3.5 mg (bortezomib) is 1.3mg/m2. Bortez 
Teva 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, Bortez Teva 3.5 mg is administered as a 3 to 5 second bolus intravenous injection.

4.1 Dosage in Previously Untreated Multiple Myeloma

Bortez Teva 3.5mg is administered in combination with oral melphalan and oral prednisone for nine 6-week treatment cycles as shown in Table 1. In Cycles 1-4, Bortez Teva 3.5mg is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortez Teva 3.5mg is administered once weekly (days 1, 8, 22 and 29).

At least 72 hours should elapse between consecutive doses of Bortez Teva 3.5mg.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortez Teva 3.5mg (Cycles 1 to 4)
Week                   1                   2         3         4                         5          6 
Bortezomib    Day                      Day   Day       Day rest Day            Day   Day       Day rest --         --
(1.3mg/m2)     1                        4     8        11 period 22            25    29        32 period 
Melphalan     Day    Day         Day   Day   --        --     rest    --       --    --        --    rest (9 mg/m2)      1      2           3     4                    period                                 period 
Prednisone
Once Weekly Bortez Teva 3.5mg
(Cycles 5 to 9 when used in combination with Melphalan and Prednisone) Week                       1                     2           3           4               5          6 Bortezomib
(1.3 mg/m2)    Day      --        --         Day              rest  Day              Day             rest 1                             8              period 22               29             period 

Melphalan     Day    Day        Day   Day    --        --    rest    --        --    --       --    rest (9 mg/m2)      1      2          3     4                    period                                 period 
Prednisone
(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.
• Non-hematological 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 If prolonged grade 4 neutropenia or       by 25% in the next cycle thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle.

If platelet count ≤30 x 109/L or ANC≤ 0.75 Withhold bortezomib dose x 109/L on a bortezomib dosing day (other than day 1).

If several bortezomib doses in consecutive   Reduce bortezomib dose by 1 dose level cycles are withheld due to toxicity          (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2.
Grade ≥ 3 non-hematological toxicities       Withhold bortezomib therapy until symptoms of the toxicity have 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.
For dose modifications guidelines for peripheral neuropathy (see Management of peripheral neuropathy section (4.5)).


4.3 Posology for Patients with Previously Untreated Mantle Cell Lymphoma (MCL)
Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (VcR-CAP)
Bortez Teva 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/L and the absolute neutrophil count (ANC) should be ≥1,500 cells/L.
• Platelet counts should be ≥ 75,000 cells/L 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
≥ Grade 3 neutropenia with fever, Bortezomib therapy should be withheld for up to Grade 4 neutropenia lasting more 2 weeks until the patient has an ANC ≥ 750 than 7 days, a platelet count < 10,000 cells/μL and a platelet count ≥ 25,000 cells/μL.
cells/L                                • If, after bortezomib has been held, the toxicity does not resolve, as defined above,
then bortezomib must be discontinued.
• 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/L Bortezomib therapy should be withheld or ANC < 750 cells/L on a bortezomib dosing day (other than
Day 1 of each cycle)
If several bortezomib doses in           Reduce bortezomib dose by one dose level consecutive cycles are withheld due      (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to toxicity                              to 0.7 mg/m2)

Grade ≥ 3 non-haematological             Bortezomib therapy should be withheld until toxicities considered to be related to   symptoms of the toxicity have resolved to Grade bortezomib                               2 or better. Then, 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). 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 2 weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period (Days 12-21).

For extended therapy of more than 8 cycles, bortezomib may be administered on the standard schedule or, for relapsed multiple myeloma, on a maintenance schedule of once weekly for 4 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 No action tendon 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 OR of 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 symptoms; limiting self-care ADL *** )      toxicity resolves. When toxicity resolves, reinitiate with a reduced dose of Bortez
Teva 3.5mg at 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences; Discontinue Bortezomib 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 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 impairment*                                 Levels                  Dose Mild                ≤1.0 x ULN             > ULN          None
> 1.0 x – 1.5 x ULN Any               None
Moderate            > 1.5x – 3x ULN        Any            Reduce bortezomib to 0.7 Severe              >3x ULN                Any            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.
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 of Bortez Teva 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)).

Bortez Teva 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 4.8) 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 .49)).

Bortez Teva 3.5mg 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 solution is clear and colourless, with a final pH of 4 to 7.

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 Bortez Teva 3.5 mg 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 administration       (mg/vial)    (0.9% Sodium Chloride)       concentration (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 overdose. After determining patient body surface area (BSA) in square meters, use the following equations to calculate the total volume (mL) of reconstituted Bortez Teva 3.5 mg to be administered:

•   Intravenous Administration [1 mg/mL concentration]

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ൌ            ୲୭ ୠୣ ୟୢ୫୧୬୧ୱ୲ୣ୰ୣୢ


•   Subcutaneous Administration [2.5 mg/mL concentration]

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ൌ            ୲୭ ୠୣ ୟୢ୫୧୬୧ୱ୲ୣ୰ୣୢ


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 Bortez Teva 3.5mg are stable until the date indicated on the package when stored in the original package protected from light.
Store below 30°C.
Bortez Teva 3.5 mg contains no antimicrobial preservative.

Reconstituted solution

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.
From a microbiological point of view, unless the method of reconstitution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

5. DOSAGE FORMS AND STRENGTHS

Each single-use vial of Bortez Teva 3.5mg contains 3.5 mg of bortezomib as a sterile lyophilized white to off-white powder.