Bortezomib TBM as monotherapy or in combination with pegylated liposomal doxorubicin or dexamethasone is indicated for the treatment of adult patients with progressive multiple myeloma who have received at least 1 prior therapy and who have already undergone or are unsuitable for haematopoietic stem cell transplantation.

Bortezomib TBM in combination with melphalan and prednisone is indicated for the treatment of adult patients with previously untreated multiple myeloma who are not eligible for high-dose chemotherapy with haematopoietic stem cell transplantation.
Bortezomib TBM in combination with dexamethasone, or with dexamethasone and thalidomide, is indicated for the induction treatment of adult patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. Bortezomib TBM in combination with rituximab, cyclophosphamide, doxorubicin and prednisone is indicated for the treatment of adult patients with previously untreated mantle cell lymphoma who are unsuitable for haematopoietic stem cell transplantation.

Bortezomib TBM treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients; however Bortezomib TBM may be administered by a healthcare professional experienced in use of chemotherapeutic agents.
Bortezomib TBM must be reconstituted by a healthcare professional (see section 6.6).

Posology for treatment of progressive multiple myeloma (patients who have received at least one prior therapy)
Monotherapy
Bortezomib TBM is administered via intravenous or subcutaneous 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 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. It is recommended that patients

receive 2 cycles of Bortezomib TBM following a confirmation of a complete response. It is also recommended that responding patients who do not
achieve a complete remission receive a total of 8 cycles of Bortezomib TBM therapy. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Dose adjustments during treatment and re-initiation of treatment for monotherapy

Bortezomib TBM treatment must be withheld at the onset of any Grade 3 non-haematological or any Grade 4 haematological toxicities, excluding neuropathy as discussed below (see also section 4.4). Once the symptoms of the toxicity have resolved, Bortezomib TBM treatment may be re- initiated at a 25% reduced dose (1.3 mg/m2 reduced to 1.0 mg/m2; 1.0 mg/m2 reduced to 0.7 mg/m2). If the toxicity is not resolved or if it recurs at the lowest dose, discontinuation of Bortezomib TBM must be considered unless the benefit of treatment clearly outweighs the risk.

Neuropathic pain and/or peripheral neuropathy
Patients who experience bortezomib-related neuropathic pain and/or peripheral neuropathy are to be managed as presented in Table 1 (see section 4.4). Patients with pre-existing severe neuropathy may be treated with Bortezomib TBM only after careful risk/benefit assessment.
Table 1: Recommended* posology modifications for bortezomib-related neuropathy

 

Severity of neuropathy	Posology Modication
Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) without pain or loss of function	None
Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**)	Reduce Bortezomib TBM to 1.0 mg/m2 or Change Bortezomib TBM treatment schedule to 1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (sever symptoms; limiting self care ADL***)	Withhold Bortezomib TBM therapy until symptoms of toxicity have resolved. When toxicity resolves reinitiate with a reduced dose of Bortezomib TBM at 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathy	Discontinue Bortezomib TBM

 

*Grading based on NCI Common Terminology Criteria CTCAE v4 .0* Based on posology modifications in Phase II and III multiple myeloma studies and post-marketing experience. 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 m medications, and not bedridden

Combination therapy with pegylated liposomal doxorubicin

Bortezomib TBM is administered via intravenous or subcutaneous 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 in a 21- day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Pegylated liposomal doxorubicin is administered at 30 mg/m2 on day 4 of the Bortezomib TBM treatment cycle as a 1 hour intravenous infusion administered after the Bortezomib TBM injection.

      

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Up to 8 cycles of this combination therapy can be administered as long as patients have not progressed and tolerate treatment. Patients achieving a complete response can continue treatment for at least 2 cycles after the first evidence of complete response, even if this requires treatment for more than 8 cycles. Patients whose levels of paraprotein continue to decrease after 8 cycles can also continue for as long as treatment is tolerated and they continue to respond.

For additional information concerning pegylated liposomal doxorubicin, see the corresponding Summary of Product Characteristics

Dose adjustments for combination therapy for patients with progressive multiple myeloma

For Bortezomib TBM dosage adjustments for combination therapy follow dose modification guidelines described under monotherapy above.

Posology for previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplantation
Combination therapy with melphalan and prednisone
Bortezomib TBM is administered via intravenous or subcutaneous injection in combination with oral melphalan and oral prednisone as shown in Table 2. A 6-week period is considered a treatment cycle. In Cycles 1-4, Bortezomib TBM is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, Bortezomib TBM is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each Bortezomib TBM treatment cycle.
Nine treatment cycles of this combination therapy are administered.

Table 2: Recommended posology for Bortezomib TBM in combination with melphalan and prednisone

Twice Weekly Bortezomib TBM (Cycles 1-4)
Week 1 2 3 4 5 6

         

Bz TBM (1.3 mg/m2)

M (9 mg/m2) P(60 mg/m2)

Day -- -- Day 1 4 Day Day Day Day

Day Day 8 11 -- --

rest period rest

Day Day Day Day rest 22 25 29 32 period

-- -- -- -- rest period

   

1234 period

 

Once Weekly Bortezomib TBM (Cycles 5-9)
Week 1 2 3 4 5 6

 

Bz TBM (1.3 mg/m2) M (9 mg/m2) P(60 mg/m2)

Day -- -- Day 18 Day Day Day Day --

1234

rest Day Day rest period 22 29 period rest -- -- rest period period

         

Bz TBM=Bortezomib TBM; M=melphalan, P=prednisone

Dose adjustments during treatment and re-initiation of treatment for combination therapy with melphalan and prednisone
Prior to initiating a new cycle of therapy:
• Platelet counts should be ≥ 70 x 109/l and the absolute neutrophils count should be ≥ 1.0 x 109/l

• Non-haematological toxicities should have resolved to Grade 1 or baseline.
Table 3: Posology modifications during subsequent cycles of Bortezomib TBM therapy in combination with melphalan and prednisone

Toxicity Dose modification or delay

Hematological toxicity during a cycle:

        

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Toxicity Dose modification or delay

Hematological toxicity during a cycle:

If platelet count is ≤not above 30 × 109 /L or Withhold Bortezomib TBM therapy should be ANC ≤is not above 0.75 × 109 /L on a withhelddose
Bortezomib TBM dosing day (other than day 1)

  

Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle

Consider reduction of the melphalan dose by 25% in the next cycle

     

If several Bortezomib TBM doses in a consecutive cycles are withheld (≥ 3 doses during twice weekly administration or ≥ 2 doses during weekly administration)due to toxicity	Reduce Bortezomib TBM dose should beby reduced by 1 dose level (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 TBM therapy should be withheld until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Bortezomib TBM 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 TBM-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib TBM as outlined in Table 15.

For additional information concerning melphalan and prednisone, see the corresponding Summary of Product Characteristics.

Posology for previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplantation (induction therapy)
Combination therapy with dexamethasone
Bortezomib TBM is administered via intravenous or subcutaneous 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 in a 21-day treatment cycle. This 3-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib TBM treatment cycle.
Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide

Bortezomib TBM is administered via intravenous or subcutaneous 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 in a 28-day treatment cycle. This 4-week period is considered a treatment cycle. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the Bortezomib TBM treatment cycle.
Thalidomide is administered orally at 50 mg daily on days 1-14 and if tolerated the dose is increased to 100 mg on days 15-28, and thereafter may be further increased to 200 mg daily from cycle 2 (see Table 4).

Four treatment cycles of this combination are administered. It is recommended that patients with at least partial response receive 2 additional cycles.
Table 4: Posology for Bortezomib TBM combination therapy for patients with previously untreated multiple myeloma eligible for haematopoietic stem cell transplantation

           

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Bz TBM+ Dx

Bz TBM +Dx+T

Cycles 1 to 4
Week 1 2 3

Bz TBM (1.3 mg/m2) Day 1, 4 Dx 40 mg Day 1, 2, 3, 4

Day 8, 11 Rest Period Day 8, 9, 10, 11 -

        

Cycle 1
Week 1 2 3 4

 

Bz TBM (1.3mg/m2)

T 50 mg T 100 mga Dx 40 mg

Bz TBM (1.3mg/m2) T 200 mga
Dx 40 mg

Day 1, 4

Daily -

Day 1, 2, 3, 4

Day 1, 4 Daily
Day 1, 2, 3, 4

Day 8, 11

Daily
-
Day 8, 9, 10, 11

Cycles 2 to 4b

Day 8, 11 Daily
Day 8, 9, 10, 11

Rest Period - Daily
-

Rest Period Daily
-

Rest Period - Daily
-

Rest Period Daily
-

                          

Bz TBM =Bortezomib TBM; Dx=dexamethasone; T=thalidomide
a Thalidomide dose is increased to 100 mg from week 3 of Cycle 1 only if 50 mg is tolerated and to 200 mg from cycle 2 onwards if 100 mg is tolerated.
b Up to 6 cycles may be given to patients who achieve at least a partial response after 4 cycles

Dosage adjustments for transplant eligible patients
For Bortezomib TBM dosage adjustments, dose modification guidelines described for monotherapy should be followed.
In addition, when Bortezomib TBM is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these products should be considered in the event of toxicities according to the recommendations in the Summary of Product Characteristics.

Posology for patients with previously untreated mantle cell lymphoma (MCL)

Combination therapy with rituximab, cyclophosphamide, doxorubicin and prednisone (BzR-CAP)

Bortezomib TBM is administered via intravenous or subcutaneous 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 TBM cycles are recommended, although for patients with a response first documented at cycle 6, two additional Bortezomib TBM cycles may be given. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

The following medicinal products are administered on day 1 of each Bortezomib TBM 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 TBM 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.

            

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Bortezomib for injection 3.5mg/vial

Bortezomib TBM treatment must be withheld at the onset of any ≥Grade 3 Bortezomib TBM- related non-haematological toxicities (excluding neuropathy) or ≥Grade 3 haematological toxicities (see also section 4.4). For dose adjustments, see Table 5 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 5: Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma

   

Toxicity

Hematological toxicity

Dose modification or delay

  

• ≥Grade 3 neutropenia with fever, Grade 4 neutropenia lasting more than 7 days, a platelet count < 10,000 cells/μL

Bortezomib TBM 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. • If, after Bortezomib TBM has been held, the toxicity does not resolve, as defined above, then Bortezomib TBM must be discontinued. • If toxicity resolves i.e. patient has an ANC ≥ 750 cells/μL and a platelet count ≥ 25,000 cells/μL, Bortezomib TBM 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 TBM dosing day (other than Day 1 of each cycle)

Bortezomib TBM therapy should be withheld

  

Grade ≥ 3 non-haematological toxicities considered to be related to Bortezomib TBM

Bortezomib TBM therapy should be withheld until symptoms of the toxicity have resolved to Grade 2 or better. Then, Bortezomib TBM may be reinitiated at a dose reduced by one dose level (from1.3mg/m2 to1mg/m2,orfrom1mg/m2 to 0.7 mg/m2). For Bortezomib TBM -related neuropathic pain and/or peripheral neuropathy, hold and/or modify Bortezomib TBM as outlined in Table 1

In addition, when Bortezomib TBM 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.

Special populations

Elderly

There is no evidence to suggest that dose adjustments are necessary in patients over 65 years of age with multiple myeloma or with mantle cell lymphoma.
There are no studies on the use of Bortezomib TBM in elderly patients with previously untreated multiple myeloma who are eligible for high-dose chemotherapy with haematopoietic stem cell transplantation. Therefore no dose recommendations can be made in this population.

In a study in previously untreated mantle cell lymphoma patients, 42.9% and 10.4% of patients exposed to Bortezomib TBM were in the range 65-74 years and ≥ 75 years of age, respectively. In patients aged ≥ 75 years, both regimens, BzR-CAP as well as R-CHOP, were less tolerated (see section 4.8).

     

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Bortezomib for injection 3.5mg/vial

Hepatic impairment

Patients with mild hepatic impairment do not require a dose adjustment and should be treated per the recommended dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib TBM at a reduced dose of 0.7 mg/ m2 per injection during the first treatment 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 tolerability (see Table 6 and sections 4.4 and 5.2).

Table 6: Recommended starting dose modification for Bortezomib TBM in patients with hepatic impairment

  

Grade of hepatic impairment* Mild

Moderate

Bilirubin level

≤ 1.0 x ULN
> 1.0 x -1.5 x ULN >1.5x-3xULN

SGOT (AST) levels
> ULN Any
Any

Modification of starting dose

None

None

ReduceBortezomibTBMto0.7mg/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.

         

Severe

> 3 x ULN

Any

    

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).

Renal impairment

The pharmacokinetics of bortezomib are not influenced in patients with mild to moderate renal impairment (Creatinine Clearance [CrCL] > 20 ml/min/1.73 m2); therefore, dose adjustments are not necessary for these patients. It is unknown if the pharmacokinetics of bortezomib are influenced in patients with severe renal impairment not undergoing dialysis (CrCL < 20 ml/min/1.73 m2). Since dialysis may reduce bortezomib concentrations, Bortezomib TBM should be administered after the dialysis procedure (see section 5.2).

Paediatric population

The safety and efficacy of bortezomib in children below 18 years of age have not been established (see sections 5.1 and 5.2). Currently available data are described in section 5.1 but no recommendation on a posology can be made.

Method of administration
Bortezomib TBM is available for intravenous or subcutaneous administration.
Bortezomib TBM should not be given by other routes. Intrathecal administration has resulted in death.

Intravenous injection

Bortezomib TBM is administered as a 3-5 second bolus intravenous injection through a peripheral or central intravenous catheter followed by a flush with sodium chloride 9 mg/ml (0.9%) solution for injection. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Subcutaneous injection

         

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Bortezomib TBM is administered subcutaneously through the thighs (right or left) or abdomen (right or left). The solution should be injected subcutaneously, at a 45-90° angle. Injection sites should be rotated for successive injections.
If local injection site reactions occur following Bortezomib TBM subcutaneous injection, either a less concentrated Bortezomib TBM solution (Bortezomib TBM 3.5 mg to be reconstituted to 1 mg/ml instead of 2.5 mg/ml) may be administered subcutaneously or a switch to intravenous injection is recommended.

When Bortezomib TBM is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.

4.2.1 Important Dosing Guidelines

Bortezomib TBM is for intravenous or subcutaneous use only. Bortezomib TBM should not be administered by any other route.
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 TBM is 1.3 mg/m2. Bortezomib TBM may be administered intravenously at a concentration of 1 mg/mL, or subcutaneously at a concentration of 2.5 mg/mL.
Bortezomib TBM retreatment may be considered for patients with multiple myeloma who had previously responded to treatment with Bortezomib TBM and who have relapsed at least 6 months after completing prior Bortezomib TBM treatment. Treatment may be started at the last tolerated dose (see section 4.2).

When administered intravenously, Bortezomib TBM is administered as a 3 to 5 second bolus intravenous injection.

4.2.2 Dosage in Previously Untreated Multiple Myeloma

Bortezomib TBM 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, Bortezomib TBM is administered twice weekly (days 1, 4, 8, 11, 22, 25, 29 and 32). In Cycles 5-9, Bortezomib TBM is administered once weekly (days 1, 8, 22 and 29). At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Table 1: Dosage Regimen for Patients with Previously Untreated Multiple Myeloma Twice Weekly Bortezomib TBM (Cycles 1-4)

Week 1 2 3 4 5 6

            

Bortezomib TBM (1.3 mg/m2)

Day 1

--

--

Day 4

Day 8

Day 11

rest period

Day 22

Day 25

Day 29

Day 32

rest period

Melphalan (9 mg/m2) Prednisone (60 mg/m2)

Day 1

Day 2

Day 3

Day 4

--

--

rest period

--

--

--

--

rest period

Once Weekly Bortezomib TBM (Cycles 5-9 when used in combination with Melphalan and Prednisone)
Week 1 2 3 4 5 6

 

Bortezomib Day -- --

Day

rest

Day

Day rest

        

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TBM 1 8 period 22 29 period (1.3 mg/m2)

Day Day Day Day -- 1234

4.2.3 Dose Modification Guidelines for Bortezomib TBM when Given in Combination with Melphalan and Prednisone
Prior to initiating any cycle of therapy with Bortezomib TBM in combination with melphalan and prednisone:

 Platelet count should be at least 70 × 109 /L and the absolute neutrophil count (ANC) should be at least 1.0 × 109 /L
 Non-hematological toxicities should have resolved to Grade 1 or baseline

Table 2: Dose Modifications during Cycles of Combination Bortezomib TBM, Melphalan and Prednisone Therapy

Toxicity Dose modification or delay

      

Melphalan (9 mg/m2) Prednisone (60 mg/m2)

--

rest period

--

--

--

--

rest period

              

Hematological toxicity during a cycle: If prolonged Grade 4 neutropenia or thrombocytopenia, or thrombocytopenia with bleeding is observed in the previous cycle	Consider reduction of the melphalan dose by 25% in the next cycle
If platelet count is not above 30 × 109 /L or ANC is not above 0.75 × 109 /L on a Bortezomib TBM dosing day (other than day 1)	Withhold Bortezomib TBM dose
If several Bortezomib TBM doses in consecutive cycles are withheld due to toxicity	Reduce Bortezomib TBM dose by 1 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 TBM therapy until symptoms of toxicity have resolved to Grade 1 or baseline. Then, Bortezomib TBM 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 TBM-related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib TBM as outlined in Table 5.

For information concerning melphalan and prednisone, see the corresponding Summary of product characteristics.

 

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Bortezomib for injection 3.5mg/vial

Dose modifications guidelines for peripheral neuropathy are provided (see section 4.2).

4.2.4 Dosage in Previously Untreated Mantle Cell Lymphoma

Bortezomib TBM (1.3 mg/m2) is administered intravenously in combination with intravenous rituximab, cyclophosphamide, doxorubicin and oral prednisone (VcR-CAP) for six 3-week treatment cycles as shown in Table 3. Bortezomib TBM is administered first followed by rituximab. Bortezomib TBM is administered twice weekly for two weeks (Days 1, 4, 8, and 11) followed by a 10-day rest period on Days 12-21. For patients with a response first documented at cycle 6, two additional VcR-CAP cycles are recommended. At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Table 3: Dosage Regimen for Patients with Previously Untreated Mantle Cell Lymphoma Twice Weekly Bortezomib TBM (Six 3-Week Cycles) *

123

    

Bortezomib TBM (1.3 mg/m2)	Day 1	--	--	Day 4	--	Day 8	Day 11	rest period
Rituximab (375 mg/m2) Cyclophosphamide (750 mg/m2) Doxorubicin (50 mg/m2)	Day 1	--	--			--	--	rest period

Prednisone Day Day Day Day Day -- -- rest

(100 mg/m2) 1 2 3 4 5
*Dosing may continue for 2 more cycles (for a total of 8 cycles) if response is first seen at cycle 6.

4.2.5 Dose Modification Guidelines for Bortezomib TBM When Given in Combination with Rituximab, Cyclophosphamide, Doxorubicin and Prednisone
Prior to the first day of each cycle (other than Cycle 1):
 Platelet count should be at least 100 × 109/L and absolute neutrophil count (ANC) should be at least 1.5 × 109/L

 Hemoglobin should be at least 8 g/dL (at least 4.96 mmol/L)
 Non-hematologic toxicity should have recovered to Grade 1 or baseline
Interrupt Bortezomib TBM treatment at the onset of any Grade 3 hematologic or non-hematological toxicities, excluding neuropathy (see Table 5 and section 4.4) For dose adjustments, see Table 4 below.

Table 4: Dose Modifications on Days 4, 8, and 11 during Cycles of Combination Bortezomib TBM, Rituximab, Cyclophosphamide, Doxorubicin and Prednisone Therapy
Toxicity Dose modification or delay

Hematological toxicity

period

                 

Grade 3 or higher neutropenia, or a platelet count not at or above 25 × 109 /L

Withhold Bortezomib TBM therapy for up to 2 weeks until the patient has an ANC at or above 0.75 × 109/L and a platelet count at or above 25 × 109/L.  If, after Bortezomib TBM has been withheld, the toxicity does not resolve, discontinue Bortezomib TBM.  If toxicity resolves such that the patient has

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	an ANC at or above 0.75 × 109/L and a platelet count at or above 25 × 109 /L, Bortezomib TBM dose should be reduced by 1 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 TBM therapy until symptoms of the toxicity have resolved to Grade 2 or better. Then, Bortezomib TBM 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 TBM -related neuropathic pain and/or peripheral neuropathy, hold or modify Bortezomib TBM as outlined in Table 5.

For information concerning rituximab, cyclophosphamide, doxorubicin and prednisone, see the corresponding Summary of product characteristics.

4.2.6 Dosage and Dose Modifications for Relapsed Multiple Myeloma and Relapsed Mantle Cell Lymphoma
Bortezomib TBM (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 TBM 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). At least 72 hours should elapse between consecutive doses of Bortezomib TBM.

Patients with multiple myeloma who have previously responded to treatment with Bortezomib TBM (either alone or in combination) and who have relapsed at least 6 months after their prior Bortezomib TBM therapy may be started on Bortezomib TBM at the last tolerated dose. Retreated patients are administered Bortezomib TBM twice weekly (Days 1, 4, 8, and 11) every three weeks for a maximum of 8 cycles. At least 72 hours should elapse between consecutive doses of Bortezomib TBM. Bortezomib TBM may be administered either as a single agent or in combination with dexamethasone (see section 5).

Bortezomib TBM therapy should be withheld at the onset of any Grade 3 non-hematological or Grade 4 hematological toxicities excluding neuropathy as discussed below.(see section 4.4) Once the symptoms of the toxicity have resolved, Bortezomib TBM 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 the peripheral neuropathy see section 4.2.7

4.2.7 Dose Modifications for Peripheral Neuropathy

Starting Bortezomib TBM 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 TBM only after careful risk-benefit assessment.
Patients experiencing new or worsening peripheral neuropathy during Bortezomib TBM 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 TBM -related neuropathic pain and/or peripheral neuropathy see Table 5.

              

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Bortezomib for injection 3.5mg/vial

4.2.8 Dosage in Patients with Hepatic Impairment

Patients with mild hepatic impairment do not require a starting dose adjustment and should be treated per the recommended Bortezomib TBM dose. Patients with moderate or severe hepatic impairment should be started on Bortezomib TBM 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/m may be considered based on patient tolerance (see Table 6 and section 5).

Table 6: Recommended Starting Dose Modification for Bortezomib TBM in Patients with Hepatic Impairment

     

Bilirubin Level SGOT (AST) Levels

Mild Less than or equal More than ULN to 1.0x ULN

More than 1.0x–1.5x Any ULN

Modification of Starting Dose

None

None

Reduce Bortezomib TBM to 0.7 mg/m2 in the first 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.

       

Moderate More than 1.5x–3x ULN

Any

    

Severe

More than 3x ULN

Any

Abbreviations: SGOT = serum glutamic oxaloacetic transaminase;

AST = aspartate aminotransferase; ULN = upper limit of the normal range.

       

4.2.9 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 (see section 4.2). 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 TBM administration subcutaneously, a less concentrated Bortezomib TBM solution (1 mg/mL instead of 2.5 mg/mL) may be administered subcutaneously (see section 4.2). Alternatively, the intravenous route of administration should be considered (see section 4.2).

Bortezomib TBM is an antineoplastic. Procedures for proper handling and disposal should be considered.

Hypersensitivity to the active substance, to boron or to any of the excipients listed in section 6.1. Acute diffuse infiltrative pulmonary and pericardial disease. When Bortezomib TBM is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.Bortezomib TBM is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol. Reactions have included anaphylactic reactions (see section 4.8). Bortezomib TBM is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of Bortezomib TBM.

Peripheral Neuropathy

When bortezomib is given in combination with other medicinal products, the Summary of Product Characteristics of these other medicinal products must be consulted prior to initiation of treatment with Bortezomib TBM. When thalidomide is used, particular attention to pregnancy testing and prevention requirements is needed (see section 4.6).

Intrathecal administration
There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib TBM is for intravenous or subcutaneous use. Bortezomib should not be administered intrathecally.

Gastrointestinal toxicity
Gastrointestinal toxicity, including nausea, diarrhoea, vomiting and constipation are very common with bortezomib treatment. Cases of ileus have been uncommonly reported (see section 4.8). Therefore, patients who experience constipation should be closely monitored.

Haematological toxicity
Bortezomib treatment is very commonly associated with haematological toxicities (thrombocytopenia, neutropenia and anaemia). In studies in patients with relapsed multiple myeloma treated with bortezomib and in patients with previously untreated MCL treated with bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BzR- CAP), one of the most common haematologic toxicity was transient thrombocytopenia. Platelets were lowest at Day 11 of each cycle of bortezomib treatment and typically recovered to baseline by the next cycle. There was no evidence of cumulative thrombocytopenia. The mean platelet count nadir measured was approximately 40% of baseline in the single-agent multiple myeloma studies and 50% in the MCL study. In patients with advanced myeloma the severity of thrombocytopenia was related to pre-treatment platelet count: for baseline platelet counts < 75,000/μl, 90% of 21 patients had a count :5 25,000/μl during the study, including 14% < 10,000/μl; in contrast, with a baseline platelet count > 75,000/μl, only 14% of 309 patients had a count :5 25,000/μl during the study.
In patients with MCL (study LYM-3002), there was a higher incidence (56.7% versus 5.8%) of Grade ≥ 3 thrombocytopenia in the bortezomib treatment group (BzR-CAP) as compared to the non- bortezomib treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP]). The two treatment groups were similar with regard to the overall incidence of all-grade bleeding events (6.3% in the BzR-CAP group and 5.0% in the R- CHOP group) as well as Grade 3 and higher bleeding events (BzR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the BzR-CAP group, 22.5% of patients received platelet transfusions compared to 2.9% of patients in the R-CHOP group.
Gastrointestinal and intracerebral haemorrhage, have been reported in association with bortezomib treatment. Therefore, platelet counts should be monitored prior to each dose of bortezomib. Bortezomib therapy should be withheld when the platelet count is < 25,000/μl or, in the case of combination with melphalan and prednisone, when the platelet count is ≤30,000/μl (see section 4.2). Potential benefit of the treatment should be carefully weighed against the risks, particularly in case of moderate to severe thrombocytopenia and risk factors for bleeding.
Complete blood counts (CBC) with differential and including platelet counts should be frequently monitored throughout treatment with Bortezomib. Platelet transfusion should be considered when clinically appropriate (see section 4.2).
In patients with MCL, transient neutropenia that was reversible between cycles was observed, with no evidence of cumulative neutropenia. Neutrophils were lowest at Day 11 of each cycle of

          

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Bortezomib for injection 3.5mg/vial

Bortezomib treatment and typically recovered to baseline by the next cycle. In study LYM-3002, colony stimulating factor support was given to 78% of patients in the BzR-CAP arm and 61% of patients in the R-CHOP arm. Since patients with neutropenia are at increased risk of infections, they should be monitored for signs and symptoms of infection and treated promptly. 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 (see section 4.2).

Herpes zoster virus reactivation
Antiviral prophylaxis is recommended in patients being treated with Bortezomib.
In the Phase III study in patients with previously untreated multiple myeloma, the overall incidence of herpes zoster reactivation was more common in patients treated with Bortezomib+Melphalan+Prednisone compared with Melphalan+Prednisone (14% versus 4% respectively).
In patients with MCL (study LYM-3002), the incidence of herpes zoster infection was 6.7% in the BzR-CAP arm and 1.2% in the R-CHOP arm (see section 4.8).

Hepatitis B Virus (HBV) reactivation and infection
When rituximab is used in combination with Bortezomib, HBV screening must always be performed in patients at risk of infection with HBV before initiation of treatment. Carriers of hepatitis B and patients with a history of hepatitis B must be closely monitored for clinical and laboratory signs of active HBV infection during and following rituximab combination treatment with Bortezomib. Antiviral prophylaxis should be considered. Refer to the Summary of Product Characteristics of rituximab for more information.

Progressive multifocal leukoencephalopathy (PML)
Very rare cases with unknown causality of John Cunningham (JC) virus infection, resulting in PML and death, have been reported in patients treated with Bortezomib. Patients diagnosed with PML had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their first dose of Bortezomib. Patients should be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML as part of the differential diagnosis of CNS problems. If a diagnosis of PML is suspected, patients should be referred to a specialist in PML and appropriate diagnostic measures for PML should be initiated. Discontinue Bortezomib if PML is diagnosed.

Peripheral neuropathy
Treatment with Bortezomib is very commonly associated with peripheral neuropathy, which is predominantly sensory. However, cases of severe motor neuropathy with or without sensory peripheral neuropathy have been reported. The incidence of peripheral neuropathy increases early in the treatment and has been observed to peak during cycle 5.
It is recommended that patients be carefully monitored for symptoms of neuropathy such as a burning sensation, hyperesthesia, hypoesthesia, paraesthesia, discomfort, neuropathic pain or weakness.
In the Phase III study comparing Bortezomib administered intravenously versus subcutaneously, the incidence of Grade ≥2 peripheral neuropathy events was 24% for the subcutaneous injection group and 41% for the intravenous injection group (p=0.0124). Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 16% in the intravenous treatment group (p=0.0264). The incidence of all grade peripheral neuropathy with Bortezomib administered intravenously was lower in the historical studies with Bortezomib administered intravenously than in study MMY-3021.
Patients experiencing new or worsening peripheral neuropathy should undergo neurological evaluation and may require a change in the dose, schedule or route of administration to

            

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Pg. 15

Bortezomib for injection 3.5mg/vial

subcutaneous (see section 4.2). Neuropathy has been managed with supportive care and other therapies.
Early and regular monitoring for symptoms of treatment-emergent neuropathy with neurological evaluation should be considered in patients receiving Bortezomib in combination with medicinal products known to be associated with neuropathy (e.g. thalidomide) and appropriate dose reduction or treatment discontinuation should be considered.

In addition to peripheral neuropathy, there may be a contribution of autonomic neuropathy to some adverse reactions such as postural hypotension and severe constipation with ileus. Information on autonomic neuropathy and its contribution to these undesirable effects is limited.

Seizures
Seizures have been uncommonly reported in patients without previous history of seizures or epilepsy. Special care is required when treating patients with any risk factors for seizures.

Hypotension
Bortezomib treatment is commonly associated with orthostatic/postural hypotension. Most adverse reactions are mild to moderate in nature and are observed throughout treatment. Patients who developed orthostatic hypotension on Bortezomib (injected intravenously) did not have evidence of orthostatic hypotension prior to treatment with Bortezomib. Most patients required treatment for their orthostatic hypotension. A minority of patients with orthostatic hypotension experienced syncopal events. Orthostatic/postural hypotension was not acutely related to bolus infusion of Bortezomib. The mechanism of this event is unknown although a component may be due to autonomic neuropathy. Autonomic neuropathy may be related to bortezomib or bortezomib may aggravate an underlying condition such as diabetic or amyloidotic neuropathy. Caution is advised when treating patients with a history of syncope receiving medicinal products known to be associated with hypotension; or who are dehydrated due to recurrent diarrhoea or vomiting. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medicinal products, rehydration or administration of mineralocorticosteroids and/or sympathomimetics. Patients should be instructed to seek medical advice if they experience symptoms of dizziness, light-headedness or fainting spells.

Posterior Reversible Encephalopathy Syndrome (PRES)
There have been reports of PRES in patients receiving Bortezomib. PRES is a rare, often reversible, rapidly evolving neurological condition, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably Magnetic Resonance Imaging (MRI), is used to confirm the diagnosis. In patients developing PRES, Bortezomib should be discontinued.

Heart failure
Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported during bortezomib treatment. Fluid retention may be a predisposing factor for signs and symptoms of heart failure. Patients with risk factors for or existing heart disease should be closely monitored.

Electrocardiogram investigations
There have been isolated cases of QT-interval prolongation in clinical studies, causality has not been established.

Pulmonary disorders
There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown aetiology such as pneumonitis, interstitial pneumonia, lung infiltration, and acute respiratory distress syndrome (ARDS) in patients receiving Bortezomib (see section 4.8). Some of these events have

            

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Bortezomib for injection 3.5mg/vial

been fatal. A pre-treatment chest radiograph is recommended to serve as a baseline for potential post-treatment pulmonary changes.
In the event of new or worsening pulmonary symptoms (e.g., cough, dyspnoea), a prompt diagnostic evaluation should be performed and patients treated appropriately. The benefit/risk ratio should be considered prior to continuing Bortezomib therapy.

In a clinical trial, two patients (out of 2) given high-dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours with daunorubicin and Bortezomib for relapsed acute myelogenous leukaemia died of ARDS early in the course of therapy, and the study was terminated. Therefore, this specific regimen with concomitant administration with high-dose cytarabine (2 g/m2 per day) by continuous infusion over 24 hours is not recommended.

Renal impairment
Renal complications are frequent in patients with multiple myeloma. Patients with renal impairment should be monitored closely (see sections 4.2 and 5.2).

Hepatic impairment
Bortezomib is metabolised by liver enzymes. Bortezomib exposure is increased in patients with moderate or severe hepatic impairment; these patients should be treated with Bortezomib at reduced doses and closely monitored for toxicities (see sections 4.2 and 5.2).

Hepatic reactions
Rare cases of hepatic failure have been reported in patients receiving Bortezomib and concomitant medicinal products and with serious underlying medical conditions. Other reported hepatic reactions include increases in liver enzymes, hyperbilirubinaemia, and hepatitis. Such changes may be reversible upon discontinuation of bortezomib (see section 4.8).

Tumour lysis syndrome
Because bortezomib is a cytotoxic agent and can rapidly kill malignant plasma cells and MCL cells, the complications of tumour lysis syndrome may occur. The patients at risk of tumour lysis syndrome are those with high tumour burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Concomitant medicinal products
Patients should be closely monitored when given bortezomib in combination with potent CYP3A4- inhibitors. Caution should be exercised when bortezomib is combined with CYP3A4- or CYP2C19 substrates (see section 4.5).
Normal liver function should be confirmed and caution should be exercised in patients receiving oral hypoglycemics (see section 4.5).

Potentially immunocomplex-mediated reactions
Potentially immunocomplex-mediated reactions, such as serum-sickness-type reaction, polyarthritis with rash and proliferative glomerulonephritis have been reported uncommonly. Bortezomib should be discontinued if serious reactions occur.

In vitro studies indicate that bortezomib is a weak inhibitor of the cytochrome P450 (CYP) isozymes 1A2, 2C9, 2C19, 2D6 and 3A4. Based on the limited contribution (7%) of CYP2D6 to the metabolism of bortezomib, the CYP2D6 poor metaboliser phenotype is not expected to affect the overall disposition of bortezomib.

A drug-drug interaction study assessing the effect of ketoconazole, a potent CYP3A4 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 35% (CI90% [1.032 to 1.772]) based on data from 12 patients. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir).

In a drug-drug interaction study assessing the effect of omeprazole, a potent CYP2C19 inhibitor, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 17 patients.
A drug-drug interaction study assessing the effect of rifampicin, a potent CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC reduction of 45% based on data from 6 patients. Therefore, the concomitant use of bortezomib with strong CYP3A4 inducers (e.g., rifampicin, carbamazepine, phenytoin, phenobarbital and St. John's Wort) is not recommended, as efficacy may be reduced.

In the same drug-drug interaction study assessing the effect of dexamethasone, a weaker CYP3A4 inducer, on the pharmacokinetics of bortezomib (injected intravenously), there was no significant effect on the pharmacokinetics of bortezomib based on data from 7 patients.
A drug-drug interaction study assessing the effect of melphalan-prednisone on the pharmacokinetics of bortezomib (injected intravenously), showed a mean bortezomib AUC increase of 17% based on data from 21 patients. This is not considered clinically relevant.

During clinical trials, hypoglycemia and hyperglycemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic

Contraception in males and females
Male and female patients of childbearing potential must use effective contraceptive measures during and for 3 months following treatment.

No clinical data are available for bortezomib with regard to exposure during pregnancy. The teratogenic potential of bortezomib has not been fully investigated.
In non-clinical studies, bortezomib had no effects on embryonal/foetal development in rats and rabbits at the highest maternally tolerated doses. Animal studies to determine the effects of bortezomib on parturition and post-natal development were not conducted (see section 5.3). Bortezomib should not be used during pregnancy unless the clinical condition of the woman requires treatment with bortezomib.

If bortezomib is used during pregnancy, or if the patient becomes pregnant while receiving this medicinal product, the patient should be informed of potential for hazard to the foetus.
Thalidomide is a known human teratogenic active substance that causes severe life-threatening birth defects. Thalidomide is contraindicated during pregnancy and in women of childbearing potential unless all the conditions of the thalidomide pregnancy prevention programme are met. Patients receiving bortezomib in combination with thalidomide should adhere to the pregnancy prevention programme of thalidomide. Refer to the Summary of Product Characteristics of thalidomide for additional information.

 

 

Breast-feeding

It is not known whether bortezomib is excreted in human milk. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding should be discontinued during treatment with Bortezomib.

 

Fertility

Fertility studies were not conducted with Bortezomib (see section 5.3)

 

Bortezomib TBM may have a moderate influence on the ability to drive and use machines. Bortezomib may be associated with fatigue very commonly, dizziness commonly, syncope uncommonly and orthostatic/postural hypotension or blurred vision commonly. Therefore, patients must be cautious when driving or using machines and should be advised not to drive or operate machinery if they experience these symptoms (see section 4.8)

a. Summary of the safety profile
Serious adverse reactions uncommonly reported during treatment with Bortezomib Injection include Peripheral Neuropathy, Hypotension, Cardiac Toxicity, Pulmonary Toxicity, Posterior Reversible Encephalopathy Syndrome (PRES), Gastrointestinal Toxicity, Thrombocytopenia/Neutropenia, Tumor Lysis Syndrome, Hepatic Toxicity.

                         

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System Organ Class
Infections and infestations

Incidence

Common

Rare

Very Common Common Uncommon

Uncommon Rare

Uncommon

Adverse reaction

Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, Herpes simplex*, Fungal infection*

Meningitis (inc bacterial), Epstein-Barr virus infection, Genital herpes, Tonsillitis, Mastoiditis, Post viral fatigue syndrome

Thrombocytopenia*, Neutropenia*, Anaemia* Leukopenia*, Lymphopenia*
Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia#

Angioedema#, Hypersensitivity*
Anaphylactic shock, Amyloidosis, Type III immune complex mediated reaction
Cushing's syndrome*, Hyperthyroidism*, Inappropriate

Bortezomib for injection 3.5mg/vial

The most commonly reported adverse reactions during treatment with Bortezomib Injection are nausea, diarrhoea, constipation, vomiting, fatigue, pyrexia, thrombocytopenia, anaemia, neutropenia, peripheral neuropathy (including sensory), headache, paraesthesia, decreased appetite, dyspnoea, rash, herpes zoster and myalgia.

b. Tabulated summary of adverse reactions
Multiple Myeloma
Undesirable effects in Table 7 were considered by the investigators to have at least a possible or probable causal relationship to Bortezomib Injection. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with Bortezomib Injection at 1.3 mg/m2 and included in Table 87.
Overall, Bortezomib Injection was administered for the treatment of multiple myeloma in 3,974 patients.
Adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable

effects are presented in order of decreasing seriousness. Table 8 7has been generated using Version 14.1 of the MedDRA.
Post-marketing adverse reactions not seen in clinical trials are also included.

Table 87: Adverse reactions in patients with Multiple Myeloma treated with Bortezomib Injection as single agent or in combination

Uncommon

Infection*, Bacterial infections*, Viral infections*, Sepsis (inc septic shock)*, Bronchopneumonia, Herpes virus infection*, Meningoencephalitis herpetic#, Bacteraemia (inc staphylococcal), Hordeolum, Influenza, Cellulitis, Device related infection, Skin infection*, Ear infection*, Staphylococcal infection, Tooth infection*

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Rare

Neoplasm malignant, Leukaemia plasmacytic, Renal cell carcinoma, Mass, Mycosis fungoides, Neoplasm benign*

Blood and lymphatic system
disorders

Immune system disorders

Endocrine

 

Rare	Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombocytopenic purpura, Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration

   

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Pg. 23

System Organ Class
disorders

Metabolism and nutrition disorders

Incidence

Rare
Very Common Common

Adverse reaction

antidiuretic hormone secretion
Hypothyroidism
Decreased appetite
Dehydration, Hypokalaemia*, Hyponatraemia*, Blood glucose abnormal*, Hypocalcaemia*, Enzyme abnormality*

Mood disorders and disturbances*, Anxiety disorder*, Sleep disorders and disturbances*
Mental disorder*, Hallucination*, Psychotic disorder*, Confusion*, Restlessness

Suicidal ideation*, Adjustment disorder, Delirium, Libido decreased
Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*

Motor neuropathy*, Loss of consciousness (inc syncope), Dizziness*, Dysgeusia*, Lethargy, Headache*

Bortezomib for injection 3.5mg/vial

Uncommon	Tumour lysis syndrome, Failure to thrive*, Hypomagnesaemia*, Hypophosphataemia*, Hyperkalaemia*, Hypercalcaemia*, Hypernatraemia*, Uric acid abnormal*, Diabetes mellitus*, Fluid retention
Rare	Hypermagnesaemia*, Acidosis, Electrolyte imbalance*, Fluid overload, Hypochloraemia*, Hypovolaemia, Hyperchloraemia*, Hyperphosphataemia*, Metabolic Disorder, Vitamin B complex deficiency, Vitamin B12 deficiency, Gout, Increased appetite, Alcohol intolerance

 

Psychiatric disorders

Nervous disorders

Common Uncommon Rare
Very Common Common

 

system

Uncommon

Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*, Cerebellar coordination and balance disturbances*, Memoryloss (exc dementia)*, Encephalopathy*, Posterior Reversible Encephalopathy Syndrome#, Neurotoxicity, Seizure disorders*, Post herpetic neuralgia, Speech disorder*, Restless legs syndrome, Migraine, Sciatica, Disturbance in attention, Reflexes abnormal*, Parosmia

Rare

Cerebral haemorrhage*, Haemorrhage intracranial (inc subarachnoid) *, Brain oedema, Transient ischaemic attack, Coma, Autonomic nervous system imbalance, Autonomic neuropathy, Cranial palsy*, Paralysis*, Paresis*, Presyncope, Brain stem syndrome, Cerebrovascular disorder, Nerve root lesion, Psychomotor hyperactivity, Spinal cord compression, Cognitive disorder NOS, Motor dysfunction, Nervous system disorder NOS, Radiculitis, Drooling, Hypotonia

 

Eye disorders

Common Uncommon

Rare

Eye swelling*, Vision abnormal*, Conjunctivitis*
Eye haemorrhage*, Eyelid infection*, Eye inflammation*, Diplopia, Dry eye*, Eye irritation*, Eye pain, Lacrimation increased, Eye discharge
Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eye disorder (inc. eyelid) NOS, Dacryoadenitis acquired,

   

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Pg. 24

System Organ Class

Ear and labyrinth disorders

Incidence

Common Uncommon

Rare

Adverse reaction

Photophobia, Photopsia, Optic neuropathy#, Different degrees of visual impairment (up to blindness)*
Vertigo*
Dysacusis (inc tinnitus) *,Hearing impaired (up to and inc deafness), Ear discomfort*

Ear haemorrhage, Vestibular neuronitis, Ear disorder NOS

Bortezomib for injection 3.5mg/vial

 

Cardiac disorders	Uncommon	Cardiac tamponade#, Cardio-pulmonary arrest*, Cardiac fibrillation (inc atrial), Cardiac failure (inc left and right ventricular)*, Arrhythmia*, Tachycardia*, Palpitations, Angina pectoris, Pericarditis (inc pericardial effusion)*, Cardiomyopathy*, Ventricular dysfunction*, Bradycardia
	Rare	Atrial flutter, Myocardial infarction*, Atrioventricular block*, Cardiovascular disorder (inc cardiogenic shock), Torsade de pointes, Angina unstable, Cardiac valve disorders*, Coronary artery insufficiency, Sinus arrest

V ascular disorders

Respiratory, thoracic and mediastinal disorders

Common

Rare Common

Hypotension*, Orthostatic hypotension, Hypertension*

Peripheral embolism, Lymphoedema, Pallor, Erythromelalgia, Vasodilatation, Vein discolouration, Venous insufficiency
Dyspnoea*, Epistaxis, Upper/lower respiratory tract infection*, Cough*

Uncommon

Cerebrovascular accident#, Deep vein thrombosis*, Haemorrhage*, Thrombophlebitis (inc superficial), Circulatory collapse (inc hypovolaemic shock), Phlebitis, Flushing*, Haematoma (inc perirenal)*, Poor peripheral circulation*, Vasculitis, Hyperaemia (inc ocular)*

 

Uncommon

Pulmonary embolism, Pleural effusion, Pulmonary oedema (inc acute), Pulmonary alveolar haemorrhage#, Bronchospasm, Chronic obstructive pulmonary disease*, Hypoxaemia*, Respiratory tract congestion*, Hypoxia, Pleurisy*, Hiccups, Rhinorrhoea, Dysphonia, Wheezing

Rare

Respiratory failure, Acute respiratory distress syndrome, Apnoea, Pneumothorax, Atelectasis, Pulmonary hypertension, Haemoptysis, Hyperventilation, Orthopnoea, Pneumonitis, Respiratory alkalosis, Tachypnoea, Pulmonary fibrosis, Bronchial disorder*, Hypocapnia*, Interstitial lung disease, Lung infiltration, Throat tightness, Dry throat,Increased upper airway secretion, Throat irritation, Upper airway cough syndrome

 

Gastrointestinal disorders

Very Common

Uncommon

Nausea and vomiting symptoms*, Diarrhoea*, Constipation

Pancreatitis (inc chronic)*, Haematemesis, Lip swelling*, Gastrointestinal obstruction (inc small intestinal

Common

Gastrointestinal haemorrhage (inc mucosal)*, Dyspepsia, Stomatitis*, Abdominal distension, Oropharyngeal pain*, Abdominal pain (inc gastrointestinal and splenic pain)*, Oral disorder*, Flatulence

   

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Pg. 25

System Organ Class

Incidence

Adverse reaction

Bortezomib for injection 3.5mg/vial

		obstruction, ileus)*, Abdominal discomfort, Oral ulceration*, Enteritis*, Gastritis*, Gingival bleeding, Gastrooesophageal reflux disease*, Colitis (inc clostridium difficile)*, Colitis ischaemic#, Gastrointestinal inflammation*, Dysphagia, Irritable bowel syndrome, Gastrointestinal disorder NOS, Tongue coated, Gastrointestinal motility disorder*, Salivary gland disorder*
	Rare	Pancreatitis acute, Peritonitis*, Tongue oedema*, Ascites, Oesophagitis, Cheilitis, Faecal incontinence, Anal sphincter atony, Faecaloma*, Gastrointestinal ulceration and perforation*, Gingival hypertrophy, Megacolon, Rectal discharge, Oropharyngeal blistering*, Lip pain, Periodontitis, Anal fissure, Change of bowel habit, Proctalgia, Abnormal faeces

Hepatobiliary disorders

Skin subcutaneous tissue disorders

and

Common Uncommon Rare

Common

Hepatic enzyme abnormality*
Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis Hepatic failure, Hepatomegaly, Budd-Chiari syndrome, Cytomegalovirus hepatitis, Hepatic haemorrhage, Cholelithiasis
Rash*, Pruritus*, Erythema, Dry skin

 

Uncommon	Erythema multiforme, Urticaria, Acute febrile neutrophilic dermatosis, Toxic skin eruption, Toxic epidermal necrolysis#, Stevens-Johnson syndrome#, Dermatitis*, Hair disorder*, Petechiae, Ecchymosis, Skin lesion, Purpura, Skin mass*, Psoriasis, Hyperhidrosis, Night sweats, Decubitus ulcer#, Acne*, Blister*, Pigmentation disorder*
Rare	Skin reaction, Jessner's lymphocytic infiltration, Palmarplantar erythrodysaesthesia syndrome, Haemorrhage subcutaneous, Livedo reticularis, Skin induration, Papule, Photosensitivity reaction, Seborrhoea, Cold sweat, Skin disorder NOS, Erythrosis, Skin ulcer, Nail disorder

 

Musculoskeletal and connective tissue disorders

Renal and urinary disorders

Reproductive

Very Common Common Uncommon

Common

Rare Uncommon

Musculoskeletal pain*
Muscle spasms*, Pain in extremity, Muscular weakness Muscle twitching, Joint swelling, Arthritis*, Joint stiffness, Myopathies*,Sensation of heaviness

Renal impairment*

Bladder irritation
Vaginal haemorrhage, Genital pain*, Erectile dysfunction,

 

Rare	Rhabdomyolysis, Temporomandibular joint syndrome, Fistula, Joint effusion, Pain in jaw, Bone disorder, Musculoskeletal and connective tissue infections and inflammations*, Synovial cyst

Uncommon

Renal failure acute, Renal failure chronic*, Urinary tract infection*, Urinary tract signs and symptoms*, Haematuria*, Urinary retention, Micturition disorder*, Proteinuria, Azotaemia, Oliguria*, Pollakiuria

   

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Pg. 26

Bortezomib for injection 3.5mg/vial

System Organ Class
system and breast

disorders

General disorders and administration site conditions

Investigations

Injury, poisoning and procedural complications

Surgical and medical procedures

Incidence

Rare

Very Common Common

Adverse reaction

Testicular disorder*, Prostatitis, Breast disorder female, Epididymal tenderness, Epididymitis, Pelvic pain, Vulval ulceration

Pyrexia*, Fatigue, Asthenia
Oedema (inc peripheral), Chills, Pain*, Malaise*

Congenital, familial and genetic disorders

Rare

Aplasia, Gastrointestinal malformation, Ichthyosis

Uncommon	General physical health deterioration*, Face oedema*, Injection site reaction*, Mucosal disorder*, Chest pain, Gait disturbance, Feeling cold, Extravasation*, Catheter related complication*, Change in thirst*, Chest discomfort, Feeling of body temperature change*, Injection site pain*
Rare	Death (inc sudden), Multi-organ failure, Injection site haemorrhage*, Hernia(inc hiatus)*, Impaired healing*, Inflammation, Injection site phlebitis*, Tenderness, Ulcer, Irritability, Non-cardiac chest pain, Catheter site pain, Sensation of foreign body

 

Common Uncommon

Uncommon Rare

Rare

Weight decreased
Hyperbilirubinaemia*, Protein analyses abnormal*, Weight increased, Blood test abnormal*,C-reactive protein increased

Fall, Contusion
Transfusion reaction, Fractures*, Rigors*, Face injury, Joint injury*, Burns, Laceration, Procedural pain, Radiation injuries*
Macrophage activation

Rare	Blood gases abnormal*, Electrocardiogram abnormalities (inc QT prolongation)*, International normalised ratio abnormal*, Gastric pH decreased, Platelet aggregation increased, Troponin I increased, Virus identification and serology*, Urine analysis abnormal*

   

NOS=not otherwise specified
* Grouping of more than one MedDRA preferred term.
# Postmarketing adverse reaction
Mantle Cell Lymphoma (MCL)
The safety profile of Bortezomib Injection in 240 MCL patients treated with Bortezomib Injection at 1.3 mg/m2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BzR-CAP) versus 242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described below. Additional adverse drug reactions identified associated with the use of the combination therapy (BzR-CAP) were hepatitis B infection (< 1%) and myocardial ischaemia (1.3%). The similar incidences of these events in both treatment arms, indicated that these adverse drug reactions are not attributable to Bortezomib Injection alone. Notable differences in the MCL patient population as compared to patients in the multiple myeloma studies were a ≥ 5% higher incidence of the haematological adverse reactions (neutropenia,

sa-spc

Pg. 27

Bortezomib for injection 3.5mg/vial

thrombocytopenia, leukopenia, anemia, lymphopenia), peripheral sensory neuropathy, hypertension, pyrexia, pneumonia, stomatitis, and hair disorders.
Adverse drug reactions identified as those with a ≥ 1% incidence, similar or higher incidence in the BzR-CAP arm and with at least a possible or probable causal relationship to the components of the BzR-CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in the BzR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to Bortezomib Injection based on historical data in the multiple myeloma studies.

Adverse reactions are listed below by system organ class and frequency grouping. Frequencies are defined as: Very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Table 8 has been generated using Version 16 of the MedDRA.

Table 8 Adverse reactions in patients with Mantle Cell Lymphoma treated with BzR-CAP

System Organ Class

Infections and infestations

Blood and lymphatic system disorders

Immune system disorders

Metabolism and nutrition disorders

Psychiatric disorders Nervous system disorders

Eye disorders
Ear and labyrinth disorders

Cardiac disorders

Incidence

Very Common

Uncommon Very Common

Uncommon Common Uncommon Very Common Common

Uncommon Common
Very Common

Uncommon Common Common Uncommon

Adverse reaction

Pneumonia*

Hepatitis B, Infection*, Bronchopneumonia Thrombocytopenia*, Febrile neutropenia, Neutropenia*, Leukopenia*, Anaemia*, Lymphopenia*

Pancytopenia*
Hypersensitivity*
Anaphylactic reaction
Decreased appetite
Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*, Diabetes mellitus*, Fluid retention

Tumour lysis syndrome
Sleep disorders and disturbances*
Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*

Autonomic nervous system imbalance
Vision abnormal*
Dysacusis (inc tinnitus)*
Vertigo*, Hearing impaired (up to and inc deafness)

Common

Sepsis (inc septic shock)*, Herpes zoster (inc disseminated & ophthalmic), Herpes virus infection*, Bacterial infections*, Upper/lower respiratory tract infection*, Fungal infection*, Herpes simplex*

     

Common

Neuropathies*, Motor neuropathy*, Loss of consciousness (inc syncope), Encephalopathy*, Peripheral sensorimotor neuropathy, Dizziness*, Dysgeusia*, Autonomic neuropathy

  

Common

Cardiac fibrillation (inc atrial), Arrhythmia*, Cardiac failure (inc left and right ventricular)*, Myocardial ischaemia, V entricular dysfunction*

Uncommon

Cardiovascular disorder (inc cardiogenic

  

sa-spc

Pg. 28

Bortezomib for injection 3.5mg/vial

Vascular disorders

Respiratory, thoracic and mediastinal disorders

Gastrointestinal disorders

Hepatobiliary disorders

Skin and subcutaneous tissue
disorders
Musculoskeletal and connective

tissue disorders
Renal and urinary disorders General disorders and administration site conditions
Investigations

Common

Common Uncommon

Very Common

Uncommon Common Uncommon Very Common Common

Common

Common
Very Common Common

shock)
Hypertension*, Hypotension*, Orthostatic hypotension
Dyspnoea*, Cough*, Hiccups
Acute respiratory distress syndrome, Pulmonary embolism, Pneumonitis, Pulmonary hypertension, Pulmonary oedema (inc acute) Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*, Constipation

Colitis (inc clostridium difficile)* Hepatotoxicity (inc liver disorder) Hepatic failure
Hair disorder*

Pruritus*, Dermatitis*, Rash*

Muscle spasms*, Musculoskeletal pain*, Pain in extremity

Urinary tract infection*
Pyrexia*, Fatigue, Asthenia
Oedema (inc peripheral), Chills, Injection site reaction*, Malaise*
Hyperbilirubinaemia*, Protein analyses

 

Common

Gastrointestinal haemorrhage (inc mucosal)*, Abdominal distension, Dyspepsia, Oropharyngeal pain*, Gastritis*, Oral ulceration*, Abdominal discomfort, Dysphagia, Gastrointestinal inflammation*, Abdominal pain (inc gastrointestinal and splenic pain)*, Oral disorder*

    

Common
* Grouping of more than one MedDRA preferred term.

abnormal*, increased

Weight

decreased,

Weight

  

c. Description of selected adverse reactions
Herpes zoster virus reactivation
Multiple Myeloma
Antiviral prophylaxis was administered to 26% of the patients in the Bz+M+P arm. The incidence of herpes zoster among patients in the Bz+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis. Mantle cell lymphoma

Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the BzR-CAP arm. The incidence of herpes zoster among patients in the BzR-CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis (see section 4.4).

Hepatitis B Virus (HBV) reactivation and infection

Mantle cell lymphoma

HBV infection with fatal outcomes occurred in 0.8% (n=2) of patients in the non- Bortezomib Injection treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) and 0.4% (n=1) of patients receiving Bortezomib Injection in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (BzR-CAP). The overall incidence of

 

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Pg. 29

Bortezomib for injection 3.5mg/vial

hepatitis B infections was similar in patients treated with BzR-CAP or with R-CHOP (0.8% vs 1.2% respectively).

Peripheral neuropathy in combination regimens

Multiple Myeloma

In trials in which Bortezomib Injection was administered as induction treatment in combination with dexamethasone (study IFM- 2005-01), and dexamethasone-thalidomide (study MMY-3010), the incidence of peripheral neuropathy in the combination regimens is presented in the table 9 below:

Table 9: Incidence of peripheral neuropathy during induction treatment by toxicity and treatment discontinuation due to peripheral neuropathy

 

IFM-2005-01

MMY-3010

vincristine, doxorubicin, dexamethasone (N=239)

Bortezomib Injection, dexamethasone (N=239)

thalidomide, dexamethasone (N=126)

Bortezomib Injection, thalidomide, dexamethasone (N=130)

Incidence of PN (%)
All GradePN
≥ Grade 2 PN
≥ Grade 3 PN
Discontinuation <1 2 1 5 due to PN (%)

PN=peripheral neuropathy

Note: Peripheral neuropathy included the preferred terms: neuropathy peripheral, peripheral motor neuropathy, peripheral sensory neuropathy, and polyneuropathy.

Mantle cell lymphoma

In study LYM-3002 in which Bortezomib Injection was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in the table 10 below:
Table 10: Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatment discontinuation due to peripheral neuropathy

  

3 15

12 45 2 31 0 5

  

1 10 < 1 5

         

IFM-2005-01
Bortezomib Injection , rituximab, cyclophosphamide, doxorubicin, and prednisone,BzR-CAP (N=240)

MMY-3010
rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP (N=242)

29 9 4 <1

Incidence of PN (%) All GradePN
≥ Grade 2 PN
≥ Grade 3 PN Discontinuation

30 18 8 2

due to PN (%)
PN=peripheral neuropathy
Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

  

sa-spc

Pg. 30

Bortezomib for injection 3.5mg/vial

Elderly MCL patients

42.9% and 10.4% of patients in the BzR-CAP (Bortezomib Injection, rituximab, cyclophosphamide, doxorubicin, and prednisone) arm were in the range 65-74 years and ≥ 75 years of age, respectively. Although in patients aged ≥ 75 years, both BzR-CAP and R-CHOP were less tolerated, the serious adverse event rate in the BzR-CAP groups was 68%, compared to 42% in the R-CHOP group.

Notable differences in the safety profile of Bortezomib Injection administered subcutaneously versus intravenously as single agent
In the Phase III study patients who received Bortezomib Injection subcutaneously compared to intravenous administration had 13% lower overall incidence of treatment emergent adverse reactions that were Grade 3 or higher in toxicity, and a 5% lower incidence of discontinuation of Bortezomib Injection. The overall incidence of diarrhoea, gastrointestinal and abdominal pain, asthenic conditions, upper respiratory tract infections and peripheral neuropathies were 12%-15% lower in the subcutaneous group than in the intravenous group. In addition, the incidence of Grade 3 or higher peripheral neuropathies was 10% lower, and the discontinuation rate due to peripheral neuropathies 8% lower for the subcutaneous group as compared to the intravenous group.

Six percent of patients had an adverse local reaction to subcutaneous administration, mostly redness. Cases resolved in a median of 6 days, dose modification was required in two patients. Two (1%) of the patients had severe reactions; 1 case of pruritus and 1 case of redness.
The incidence of death on treatment was 5% in the subcutaneous treatment group and 7% in the intravenous treatment group. Incidence of death from “Progressive disease” was 18% in the subcutaneous group and 9% in the intravenous group.

Retreatment of patients with relapsed multiple myeloma

In a study in which Bortezomib Injection retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a Bortezomib Injection -containing regimen, the most common all-grade adverse events occurring in at least 25% of patients were thrombocytopenia (55%), neuropathy (40%), anaemia (37%), diarrhoea (35%), and constipation (28%). All grade peripheral neuropathy and grade ≥ 3 peripheral neuropathy were observed in 40% and 8.5% of patients, respectively.

 

To reports any side effect(s):
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to the competent authority in Saudi Arabia as per details below:

              

 The National Pharmacovigilance Centre (NPC)

• -  Fax: +966-11-205-7662

• -  Call NPC at +966-11-2038222, Ext 2317-2356-2340

• -  SFDA Call Centre: 19999

• -  E-mail: npc.drug@sfda.gov.sa

• -  Website: https://ade.sfda.gov.sa/

The National Pharmacovigilance and Drug Safety Centre (NPC) Fax: +966-11-205-7662

Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340. Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

         

In patients, overdose more than twice the recommended dose has been associated with the acute onset of symptomatic hypotension and thrombocytopenia with fatal outcomes. For preclinical cardiovascular safety pharmacology studies, see section 5.3.
There is no known specific antidote for bortezomib overdose. In the event of an overdose, the patient's vital signs should be monitored and appropriate supportive care given to maintain blood pressure (such as fluids, pressors, and/or inotropic agents) and body temperature (see sections 4.2 and 4.4).

Bortezomib is a proteasome inhibitor. It is specifically designed to inhibit the chymotrypsin-like activity of the 26S proteasome in mammalian cells. The 26S proteasome is a large protein complex that degrades ubiquitinated proteins. The ubiquitin-proteasome pathway plays an essential role in regulating the turnover of specific proteins, thereby maintaining homeostasis within cells. Inhibition of the 26S proteasome prevents this targeted proteolysis and affects multiple signalling cascades within the cell, ultimately resulting in cancer cell death.

Bortezomib is highly selective for the proteasome. At 10 μM concentrations, bortezomib does not inhibit any of a wide variety of receptors and proteases screened and is more than 1,500-fold more selective for the proteasome than for its next preferable enzyme. The kinetics of proteasome inhibition were evaluated in vitro, and bortezomib was shown to dissociate from the proteasome with a t% of 20 minutes, thus demonstrating that proteasome inhibition by bortezomib is reversible. Bortezomib mediated proteasome inhibition affects cancer cells in a number of ways, including, but not limited to, altering regulatory proteins, which control cell cycle progression and nuclear factor kappa B (NF-kB) activation. Inhibition of the proteasome results in cell cycle arrest and apoptosis. NF-kB is a transcription factor whose activation is required for many aspects of tumourigenesis, including cell growth and survival, angiogenesis, cell-cell interactions, and metastasis. In myeloma, bortezomib affects the ability of myeloma cells to interact with the bone marrow microenvironment. Experiments have demonstrated that bortezomib is cytotoxic to a variety of cancer cell types and that cancer cells are more sensitive to the pro-apoptotic effects of proteasome inhibition than normal cells. Bortezomib causes reduction of tumour growth in vivo in many preclinical tumour models, including multiple myeloma.

Data from in vitro, ex-vivo, and animal models with bortezomib suggest that it increases osteoblast differentiation and activity and inhibits osteoclast function. These effects have been observed in patients with multiple myeloma affected by an advanced osteolytic disease and treated with bortezomib.

 

 

Clinical efficacy in previously untreated multiple myeloma
A prospective Phase III, international, randomised (1:1), open-label clinical study (MMY-3002 VISTA) of 682 patients was conducted to determine whether Bortezomib (1.3 mg/ m2m2 injected intravenously) in combination with melphalan (9 mg/m2) and prednisone (60 mg/m2) resulted in improvement in time to progression (TTP) when compared to melphalan (9 mg/m2) and prednisone (60 mg/m2) in patients with previously untreated multiple myeloma. Treatment was administered for a maximum of 9 cycles (approximately 54 weeks) and was discontinued early for disease progression or unacceptable toxicity. The median age of the patients in the study was 71 years, 50% were male, 88% were Caucasian and the median Karnofsky performance status score for the patients was 80. Patients had IgG/IgA/Light chain myeloma in 63%/25%/8% instances, a median hemoglobin of 105 g/l, and a median platelet count of 221.5 x 109/l. Similar proportions of patients had creatinine clearance :5 30 ml/min (3% in each arm).
At the time of a pre-specified interim analysis, the primary endpoint, time to progression, was met and patients in the M+P arm were offered Bz+M+P treatment. Median follow-up was 16.3 months. The final survival update was performed with a median duration of follow-up of 60.1 months. A statistically significant survival benefit in favour of the Bz+M+P treatment group was observed (HR=0.695; p=0.00043) despite subsequent therapies including Bortezomib-based regimens. Median survival for the Bz+M+P treatment group was 56.4 months compared to 43.1 for the M+P treatment group. Efficacy results are presented in Table 11:

           

Table 11: Efficacy results following the final survival update to VISTA study

Efficacy endpoint Time to progression Events n (%)

Mediana (95% CI) Hazard ratiob (95% CI)

p-valuec
Progression-free survival Events n (%)

Mediana (95% CI) Hazard ratiob (95% CI)

p-value c
Overall survival* Events (deaths) n (%)

Mediana (95% CI) Hazard ratiob (95% CI)

Vc+M+P n=344

101 (29) 20.7 mo (17.6, 24,7)

135 (39) 18.3 mo (16.6, 21.7)

176 (51.2)
56.4 mo (52.8, 60.9)

M+P n=338

152 (45) 15.0 mo (14.1, 17.9)

0.54 (0.42, 0.70) 0.000002

190 (56) 14.0 mo (11.1, 15.0)

0.61 (0.49, 0.76) 0.00001

211 (62.4)
43.1 mo (35.3, 48.3)

0.695 (0.567, 0.852)

                                   

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Bortezomib for injection 3.5mg/vial

 

p-valuec Response rate

populatione n=668

CRf n (%)

PRf n (%) nCR n (%)

CR+PRf n (%) p-valued

Reduction in serum M-protein

populationg n=667
≥90% n (%)
Time to first response in CR + PR Median

Mediana response duration

CRf

CR+PRf

Time to next therapy

Events n (%)
Mediana (95% CI) Hazard ratiob (95% CI)

p-valuec

Clinical efficacy and safety

Multiple Myeloma

n=337

102 (30) 136 (40)

5 (1) 238 (71)

n=336

151 (45) 1.4 mo

24.0 mo 19.9 mo

224 (65.1)
27.0 mo (24.7, 31.1)

0.00043

< 10-10

n=331

12 (4) 103 (31)

0 115 (35)

n=331

                

34 (10) 4.2 mo

12.8 mo 13.1 mo

260 (76.9)
19.2 mo (17.0, 21.0)

                

0.557 (0.462, 0.671) < 0.000001

Absorption

Following intravenous bolus administration of a 1.0 mg/ m2 and 1.3 mg/ m2 dose to 11 patients with multiple myeloma and creatinine clearance values greater than 50 ml/min, the mean first-dose maximum plasma concentrations of bortezomib were 57 and 112 ng/ml, respectively. In subsequent doses, mean maximum observed plasma concentrations ranged from 67 to 106 ng/ml for the

1.0 mg/ m2 dose and 89 to 120 ng/ml for the 1.3 mg/ m2 dose.
Following an intravenous bolus or subcutaneous injection of a 1.3 mg/m2 dose to patients with multiple myeloma (n=14 in the intravenous group, n=17 in the subcutaneous group), the total systemic exposure after repeat dose administration (AUClast) was equivalent for subcutaneous and intravenous administrations. The Cmax after subcutaneous administration (20.4 ng/ml) was lower than intravenous (223 ng/ml). The AUClast geometric mean ratio was 0.99 and 90% confidence intervals were 80.18%-122.80%.

 

 

Metabolism

In vitro studies with human liver microsomes and human cDNA-expressed cytochrome P450 isozymes indicate that bortezomib is primarily oxidatively metabolised via cytochrome P450 enzymes, 3A4, 2C19, and 1A2. The major metabolic pathway is deboronation to form two deboronated metabolites that subsequently undergo hydroxylation to several metabolites. Deboronated-bortezomib metabolites are inactive as 26S proteasome inhibitors.

 

 

Elimination

The mean elimination half-life (t1/2) of bortezomib upon multiple dosing ranged from 40-193 hours. Bortezomib is eliminated more rapidly following the first dose compared to subsequent doses. Mean total body clearances were 102 and 112 l/h following the first dose for doses of 1.0 mg/ m2 and 1.3 mg/ m2, respectively, and ranged from 15 to 32 l/h and 18 to 32 l/h following subsequent doses for doses of 1.0 mg/ m2 and 1.3 mg/ m2, respectively.

Special populations

Hepatic impairment

The effect of hepatic impairment on the pharmacokinetics of bortezomib was assessed in a Phase I study during the first treatment cycle, including 61 patients primarily with solid tumors and varying degrees of hepatic impairment at bortezomib doses ranging from 0.5 to 1.3 mg/ m2.
When compared to patients with normal hepatic function, mild hepatic impairment did not alter dose-normalised bortezomib AUC. However, the dose-normalised mean AUC values were increased by approximately 60% in patients with moderate or severe hepatic impairment. A lower starting dose is recommended in patients with moderate or severe hepatic impairment, and those patients should be closely monitored (see section 4.2, Table 6).

Renal impairment

A pharmacokinetic study was conducted in patients with various degrees of renal impairment who were classified according to their creatinine clearance values (CrCL) into the following groups: Normal (CrCL ≥ 60 ml/min/1.73 m2, n=12), Mild (CrCL=40-59 ml/min/1.73 m2, n=10), Moderate (CrCL=20-39 ml/min/1.73 m2, n=9), and Severe (CrCL < 20 ml/min/1.73 m2, n=3). A group of dialysis patients who were dosed after dialysis was also included in the study (n=8).

Patients were administered intravenous doses of 0.7 to 1.3 mg/ m2 of Bortezomib twice weekly. Exposure of Bortezomib (dose-normalised AUC and Cmax) was comparable among all the groups (see section 4.2).

Age

The pharmacokinetics of bortezomib were characterized following twice weekly intravenous bolus administration of 1.3mg/m2 doses to 104 pediatric patients (2-16 years old) with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Based on a population pharmacokinetic analysis, clearance of bortezomib increased with increasing body surface area

                  

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Pg. 51

Bortezomib for injection 3.5mg/vial

(BSA). Geometric mean (%CV) clearance was 7.79 (25%) L/hr/ m2, volume of distribution at steadystate was 834 (39%) L/ m2, and the elimination half-life was 100 (44%) hours. After correcting for the BSA effect, other demographics such as age, body weight and sex did not have clinically significant effects on bortezomib clearance. BSA normalized clearance of bortezomib in pediatric patients was similar to that observed in adults.

Bortezomib was positive for clastogenic activity (structural chromosomal aberrations) in the in vitro chromosomal aberration assay using Chinese hamster ovary (CHO) cells at concentrations as low as 3.125 μg/ml, which was the lowest concentration evaluated. Bortezomib was not genotoxic when tested in the in vitro mutagenicity assay (Ames assay) and in vivo micronucleus assay in mice. Developmental toxicity studies in the rat and rabbit have shown embryo-fetal lethality at maternally toxic doses, but no direct embryo-foetal toxicity below maternally toxic doses. Fertility studies were not performed but evaluation of reproductive tissues has been performed in the general toxicity studies. In the 6-month rat study, degenerative effects in both the testes and the ovary have been observed. It is, therefore, likely that bortezomib could have a potential effect on either male or female fertility. Peri- and postnatal development studies were not conducted.

In multi-cycle general toxicity studies conducted in the rat and monkey, the principal target organs included the gastrointestinal tract, resulting in vomiting and/or diarrhoea; haematopoietic and lymphatic tissues, resulting in peripheral blood cytopenias, lymphoid tissue atrophy and haematopoietic bone marrow hypocellularity; peripheral neuropathy (observed in monkeys, mice and dogs) involving sensory nerve axons; and mild changes in the kidneys. All these target organs have shown partial to full recovery following discontinuation of treatment.

 

Based on animal studies, the penetration of bortezomib through the blood-brain barrier appears to be limited, if any and the relevance to humans is unknown.

Mannitol (PFG)

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

24 months

Store below 30°C

The product is packed in 10 mL USP Type -1 glass vial stoppered with 13 mm rubber stoppers and sealed with 13 mm aluminium seals.

Bortezomib is a cytotoxic agent. Therefore, caution should be used during handling and preparation of Bortezomib TBM. Use of gloves and other protective clothing to prevent skin contact is recommended.
Aseptic technique must be strictly observed throughout the handling of Bortezomib TBM, since it contains no preservative. There have been fatal cases of inadvertent intrathecal administration of bortezomib. Bortezomib TBM is for intravenous or subcutaneous use. Bortezomib TBM should not be administered intrathecally.

Instructions for reconstitution
Bortezomib TBM must be reconstituted by a healthcare professional.
Intravenous injection
Each 10 ml vial of Bortezomib TBM must be carefully reconstituted with 3.5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by using a syringe of the appropriate size, without removing the vial stopper. Dissolution of the lyophilized powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 1 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7.
The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.

Subcutaneous injection

Each 10 ml vial of Bortezomib TBM must be carefully reconstituted with 1.4 ml of sodium chloride 9 mg/ml (0.9%) solution for injection, by using a syringe of the appropriate size, without removing the vial stopper. Dissolution of the lyophilised powder is completed in less than 2 minutes.
After reconstitution, each ml solution contains 2.5 mg bortezomib. The reconstituted solution is clear and colourless, with a final pH of 4 to 7. The reconstituted solution must be inspected visually for particulate matter and discolouration prior to administration. If any discolouration or particulate matter is observed, the reconstituted solution must be discarded.

Disposal
Bortezomib TBM is for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements