VELCADE 3.5 mg powder for solution for injection

Each vial contains 3.5 mg bortezomib (as a mannitol boronic ester).

After reconstitution, 1 ml of solution for subcutaneous injection contains 2.5 mg bortezomib.

After reconstitution, 1 ml of solution for intravenous injection contains 1 mg bortezomib.

For the full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white cake or powder.

 

VELCADE 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.

VELCADE 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.

VELCADE 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.

VELCADE 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.

VELCADE treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients, however VELCADE may be administered by a healthcare professional experienced in use of chemotherapeutic agents. VELCADE 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

VELCADE 3.5 mg powder for solution for injection 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 VELCADE 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 VELCADE therapy. At least 72 hours should elapse between consecutive doses of VELCADE.

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

VELCADE 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, VELCADE 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 VELCADE 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 VELCADE only after careful risk/benefit assessment.

Table 1: Recommended* posology modifications for bortezomib-related neuropathy

Severity of neuropathy	Posology modification
Grade 1 (asymptomatic; loss of deep tendon reflexes or paresthesia) with no pain or loss of function	None
Grade 1 with pain or Grade 2 (moderate symptoms; limiting instrumental Activities of Daily Living (ADL)**)	Reduce VELCADE to 1.0 mg/m2 or Change VELCADE treatment schedule to 1.3 mg/m2 once per week
Grade 2 with pain or Grade 3 (severe symptoms; limiting self care ADL***)	Withhold VELCADE treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate VELCADE treatment and reduce dose to 0.7 mg/m2 once per week.
Grade 4 (life-threatening consequences; urgent intervention indicated) and/or severe autonomic neuropathy	Discontinue VELCADE

* 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 medicinal products, and not bedridden.

Combination therapy with pegylated liposomal doxorubicin

VELCADE 3.5 mg powder for solution for injection 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 VELCADE.

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

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.

Combination with dexamethasone

VELCADE 3.5 mg powder for solution for injection 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 VELCADE.

Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the VELCADE treatment cycle.

Patients achieving a response or a stable disease after 4 cycles of this combination therapy can continue to receive the same combination for a maximum of 4 additional cycles.

For additional information concerning dexamethasone, see the corresponding Summary of Product Characteristics.

Dose adjustments for combination therapy for patients with progressive multiple myeloma

For VELCADE 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

VELCADE 3.5 mg powder for solution for injection 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, VELCADE is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, VELCADE is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of VELCADE.

Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each VELCADE treatment cycle.

Nine treatment cycles of this combination therapy are administered.

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

Twice weekly VELCADE (cycles 1-4)
Week	1				2		3	4		5		6
Vc (1.3 mg/m2)	Day 1	--	--	Day 4	Day 8	Day 11	rest period	Day 22	Day 25	Day 29	Day 32	rest period
M (9 mg/m2) P (60 mg/m2)	Day 1	Day 2	Day 3	Day 4	--	--	rest period	--	--	--	--	rest period
Once weekly VELCADE (cycles 5-9)
Week	1				2		3	4		5		6
Vc (1.3 mg/m2)	Day 1	--	--	--	Day 8		rest period	Day 22		Day 29		rest period
M (9 mg/m2) P (60 mg/m2)	Day 1	Day 2	Day 3	Day 4	--		rest period	--				rest period

Vc=VELCADE; 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 VELCADE therapy in combination with melphalan and prednisone

Toxicity	Posology modification or delay
Haematological 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 counts ≤ 30 x 109/l or ANC ≤ 0.75 x 109/l on a VELCADE dosing day (other than day 1)	VELCADE therapy should be withheld
• If several VELCADE doses in a cycle are withheld (≥ 3 doses during twice weekly administration or ≥ 2 doses during weekly administration)	VELCADE 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 non-haematological toxicities	VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, VELCADE 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 VELCADE-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELCADE as outlined in Table 1.

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

VELCADE 3.5 mg powder for solution for injection 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 VELCADE.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE treatment cycle.

Four treatment cycles of this combination therapy are administered.

Combination therapy with dexamethasone and thalidomide

VELCADE 3.5 mg powder for solution for injection 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 VELCADE.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the VELCADE 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 VELCADE combination therapy for patients with previously untreated multiple myeloma eligible for haematopoietic stem cell transplantation

Vc+ Dx	Cycles 1 to 4
	Week	1		2		3
	Vc (1.3 mg/m2)	Day 1, 4		Day 8, 11		Rest Period
	Dx 40 mg	Day 1, 2, 3, 4		Day 8, 9, 10, 11		-
Vc+Dx+T	Cycle 1
	Week	1	2		3		4
	Vc (1.3 mg/m2)	Day 1, 4	Day 8, 11		Rest Period		Rest Period
	T 50 mg	Daily	Daily		-		-
	T 100 mga	-	-		Daily		Daily
	Dx 40 mg	Day 1, 2, 3, 4	Day 8, 9, 10, 11		-		-
	Cycles 2 to 4b
	Vc (1.3 mg/m2)	Day 1, 4	Day 8, 11		Rest Period		Rest Period
	T 200 mga	Daily	Daily		Daily		Daily
	Dx 40 mg	Day 1, 2, 3, 4	Day 8, 9, 10, 11		-		-

Vc=VELCADE; 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 VELCADE dosage adjustments, dose modification guidelines described for monotherapy should be followed.

In addition, when VELCADE 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 (VcR-CAP)

VELCADE 3.5 mg powder for solution for injection 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 VELCADE cycles are recommended, although for patients with a response first documented at cycle 6, two additional VELCADE cycles may be given. At least 72 hours should elapse between consecutive doses of VELCADE.

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

VELCADE treatment must be withheld at the onset of any ≥ Grade 3 VELCADE-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	Posology modification or delay
Haematological toxicity
•  ≥ Grade 3 neutropenia with fever, Grade 4 neutropenia lasting more than 7 days, a platelet count < 10,000 cells/μL	VELCADE 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 VELCADE has been held, the toxicity does not resolve, as defined above, then VELCADE must be discontinued. • If toxicity resolves i.e. patient has an ANC ≥ 750 cells/μL and a platelet count ≥ 25,000 cells/μL, VELCADE 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 VELCADE dosing day (other than Day 1 of each cycle)	VELCADE therapy should be withheld
Grade ≥ 3 non-haematological toxicities considered to be related to VELCADE	VELCADE therapy should be withheld until symptoms of the toxicity have resolved to Grade 2 or better. Then, VELCADE 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 VELCADE-related neuropathic pain and/or peripheral neuropathy, hold and/or modify VELCADE as outlined in Table 1.

In addition, when VELCADE 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 VELCADE 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 VELCADE were in the range 65-74 years and ≥ 75 years of age, respectively. In patients aged ≥ 75 years, both regimens, VcR-CAP as well as R-CHOP, were less tolerated (see section 4.8).

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 VELCADE 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 VELCADE in patients with hepatic impairment

Grade of hepatic impairment*	Bilirubin level	SGOT (AST) levels	Modification of starting dose
Mild	≤ 1.0 x ULN	> ULN	None
	> 1.0 x −1.5 x ULN	Any	None
Moderate	> 1.5 x −3 x ULN	Any	Reduce VELCADE to 0.7 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.
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, VELCADE should be administered after the dialysis procedure (see section 5.2).

Paediatric population

The safety and efficacy of VELCADE 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

VELCADE 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.

VELCADE 1 mg powder for solution for injection is available for intravenous administration only.

VELCADE should not be given by other routes. Intrathecal administration has resulted in death.

Intravenous injection

VELCADE 3.5 mg reconstituted solution 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 VELCADE.

Subcutaneous injection

VELCADE 3.5 mg reconstituted solution 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 VELCADE subcutaneous injection, either a less concentrated VELCADE solution (VELCADE 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 VELCADE is given in combination with other medicinal products, refer to the Summary of Product Characteristics of these products for instructions for administration.

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 VELCADE is given in combination with other medicinal products, refer to their Summaries of Product Characteristics for additional contraindications.