4.1. Therapeutic indications

Bortezomib 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 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 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 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.

4.2. Posology and method of administration

Bortezomib treatment must be initiated under supervision of a physician experienced in the treatment of cancer patients, however Bortezomib may be administered by a healthcare professional experienced in use of chemotherapeutic agents. Bortezomib 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 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 Bortezomib 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 therapy. At least 72 hours should elapse between consecutive doses of Bortezomib.

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

Bortezomib 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 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 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 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 Bortezomib to 1.0 mg/m2 Or Change bortezomib treatment schedule to 1.3 mg/m2 once per week

Grade 2 with pain or Grade 3 (severe symptoms; limiting self-care ADL***)

Withhold bortezomib treatment until symptoms of toxicity have resolved. When toxicity resolves re-initiate Bortezomib 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 bortezomib

* 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

Bortezomib 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 Bortezomib.

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

Bortezomib 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 Bortezomib.

Dexamethasone is administered orally at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 of the Bortezomib 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 Bortezomib 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 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, bortezomib is administered twice weekly on days 1, 4, 8, 11, 22, 25, 29 and 32. In Cycles 5-9, bortezomib is administered once weekly on days 1, 8, 22 and 29. At least 72 hours should elapse between consecutive doses of bortezomib. Melphalan and prednisone should both be given orally on days 1, 2, 3 and 4 of the first week of each bortezomib treatment cycle.

Nine treatment cycles of this combination therapy are administered.

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

Twice weekly Bortezomib (cycles 1-4)

week

1

2

3

4

5

6

Vc

(1.3 mg/m2)

Day1

--

--

Day4

Day 8

Day 11

Rest period

Day 22

Day 55

Day 29

Day 32

Rest period

M(9 mg/m2)

P(60mg/m2)

Day 1

Day 2

Day 3

Day 4

Rest period

-

-

-

-

Rest period

Once weekly Bortezomib (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(60mg/m2)

Day 1

Day 2

Day 3

Day 4

--

Rest period

--

Rest period

Vc=Bortezomib; 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 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 Bortezomib dosing day (other than day 1)

Bortezomib therapy should be withheld

• If several Bortezomib doses in a cycle are withheld (≥ 3 doses during twice weekly administration or ≥ 2 doses during weekly administration)

Bortezomib 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

Bortezomib therapy should be withheld until symptoms of the toxicity have resolved to Grade 1 or baseline. Then, Bortezomib may be reinitiated with one dose level reduction (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2). For Bortezomib-related neuropathic pain and/or peripheral neuropathy, hold and/or modify Bortezomib 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

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

Combination therapy with dexamethasone and thalidomide

Bortezomib 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 bortezomib.

Dexamethasone is administered orally at 40 mg on days 1, 2, 3, 4, 8, 9, 10 and 11 of the bortezomib 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 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 (1.3mg/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 mg

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 Bortezomib dosage adjustments, dose modification guidelines described for monotherapy should be followed. In addition, when Bortezomib 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)

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

The following medicinal products are administered on day 1 of each Bortezomib 3 week treatment cycle as intravenous infusions: rituximab at 375 mg/m2, cyclophosphamide at 750 mg/m2 and doxorubicin at 50 mg/m2. Prednisone is administered orally at 100 mg/m2 on days 1, 2, 3, 4 and 5 of each Bortezomib treatment cycle.

Dose adjustments during treatment for patients with previously untreated mantle cell lymphoma

Prior to initiating a new cycle of therapy:

• Platelet counts should be ≥ 100,000 cells/µL and the absolute neutrophils count (ANC) should be ≥ 1,500 cells/µL

• Platelet counts should be ≥ 75,000 cells/µL in patients with bone marrow infiltration or splenic sequestration

• Haemoglobin ≥ 8 g/dL

• Non-haematological toxicities should have resolved to Grade 1 or baseline.

Bortezomib treatment must be withheld at the onset of any ≥ Grade 3 Bortezomib-related non-haematological toxicities (excluding neuropathy) or ≥ Grade 3 haematological toxicities (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

Bortezomib therapy should be withheld for up to 2 weeks until the patient has an ANC

≥ 750 cells/µL and a platelet count ≥ 25,000 cells/µL.

• If, after Bortezomib has been held, the toxicity does not resolve, as defined above, then Bortezomib must be discontinued.

• If toxicity resolves i.e. patient has an ANC ≥ 750 cells/µL and a platelet count ≥ 25,000 cells/µL, Bortezomib may be reinitiated at a dose reduced by one dose level (from 1.3 mg/m2 to 1 mg/m2, or from 1 mg/m2 to 0.7 mg/m2).

• If platelet counts < 25,000 cells/µL. or ANC < 750 cells/µL on a Bortezomib dosing day (other than Day 1 of each cycle)

Bortezomib therapy should be withheld

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

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

In addition, when Bortezomib is given in combination with other chemotherapeutic medicinal products, appropriate dose reductions for these medicinal products should be considered in the event of toxicities, according to the recommendations in the respective Summary of Product Characteristics.

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 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 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 bortezomib 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 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 Bortezomib 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, Bortezomib 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 3.5 mg powder for solution for injection is available for intravenous or subcutaneous administration.

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

Intravenous injection

Bortezomib 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 bortezomib.

Subcutaneous injection

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

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. 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 3.5 mg powder for solution for injection 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 (VcR-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≤ 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 ≤ 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 (VcR-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 VcR-CAP group and 5.0% in the R-CHOP group) as well as Grade 3 and higher bleeding events (VcR-CAP: 4 patients [1.7%]; R-CHOP: 3 patients [1.2%]). In the VcR-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 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 VcR-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 VcR-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 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 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- orCYP2C19 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.

4.5. Interaction with other medicinal products and other forms of interaction

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 anti diabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

4.6. Fertility, pregnancy and lactation

Contraception in males and females

Due to the genotoxic potential of bortezomib (see section 5.3), women of childbearing potential must use effective contraceptive measures and avoid becoming pregnant while being treated with bortezomib and for 8 months following completion of treatment. Male patients should use effective contraceptive measures and be advised not to father a child while receiving bortezomib and for 5 months following completion of treatment (see section 5.3).

Pregnancy

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). Due to the genotoxic potential of bortezomib (see section 5.3), male patients should seek advice on conservation of sperm and women of childbearing potential should seek consultation regarding oocyte cryopreservation prior to initiation of treatment.

4.7. Effects on ability to drive and use machines

Bortezomib 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).

4.8. Undesirable effects

Summary of the safety profile

Serious adverse reactions uncommonly reported during treatment with bortezomib include cardiac failure, tumour lysis syndrome, pulmonary hypertension, posterior reversible encephalopathy syndrome, acute diffuse infiltrative pulmonary disorders and rarely autonomic neuropathy.

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

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. These adverse reactions are based on an integrated data set of 5,476 patients of whom 3,996 were treated with bortezomib at 1.3 mg/m2 and included in Table 7.Overall, bortezomib 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 7 has been generated using Version 14.1 of the MedDRA.

Post-marketing adverse reactions not seen in clinical trials are also included.

Table 7: Adverse reactions in patients with Multiple Myeloma treated with Bortezomib in clinical trials, and all post-marketing adverse reactions regardless of indication#

System Organ Class

Incidence

Adverse reaction

Infections and infestations

Common

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

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*

Rare

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

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

Very Common

Thrombocytopenia*, Neutropenia*, Anaemia*

Common

Leukopenia*, Lymphopenia*

Uncommon

Pancytopenia*, Febrile neutropenia, Coagulopathy*, Leukocytosis*, Lymphadenopathy, Haemolytic anaemia#

Rare

Disseminated intravascular coagulation, Thrombocytosis*, Hyperviscosity syndrome, Platelet disorder NOS, Thrombotic microangiopathy (inc thrombocytopenic purpura) #, Blood disorder NOS, Haemorrhagic diathesis, Lymphocytic infiltration

Immune system disorders

Uncommon

Angioedema#, Hypersensitivity*

Rare

Anaphylactic shock, Amyloidosis, Type III immune complex mediated reaction

Endocrine disorders

Uncommon

Cushing's syndrome*, Hyperthyroidism*, Inappropriate antidiuretic hormone secretion

Rare

Hypothyroidism

Metabolism and nutrition disorders

Very Common

Decreased appetite

Common

Dehydration, Hypokalaemia*, Hyponatraemia*, Blood glucose abnormal*, Hypocalcaemia*, Enzyme abnormality*

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

Common

Mood disorders and disturbances*, Anxiety disorder*, Sleep disorders and disturbances*

Uncommon

Mental disorder*, Hallucination*, Psychotic disorder*, Confusion*, Restlessness

Rare

Suicidal ideation*, Adjustment disorder, Delirium, Libido decreased

Nervous system disorders

Very Common

Neuropathies*, Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*

Common

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

Uncommon

Tremor, Peripheral sensorimotor neuropathy, Dyskinesia*, Cerebellar coordination and balance disturbances*, Memory loss (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, Guillain-Barré syndrome#, Demyelinating polyneuropathy#

Eye disorders

Common

Eye swelling*, Vision abnormal*, Conjunctivitis*

Uncommon

Eye haemorrhage*, Eyelid infection*, Chalazion#, Blepharitis#, Eye inflammation*, Diplopia, Dry eye*, Eye irritation*, Eye pain, Lacrimation increased, Eye discharge

Rare

Corneal lesion*, Exophthalmos, Retinitis, Scotoma, Eye disorder (inc. eyelid) NOS, Dacryoadenitis acquired, Photophobia, Photopsia, Optic neuropathy#, Different degrees of visual impairment (up to blindness)*

Ear and labyrinth disorders

Common

Vertigo*

Uncommon

Dysacusis (inc tinnitus)*,Hearing impaired (up to and inc deafness), Ear discomfort*

Rare

Ear haemorrhage, Vestibular neuronitis, Ear disorder NOS

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

Vascular disorders

Common

Hypotension*, Orthostatic hypotension, Hypertension*

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)*

Rare

Peripheral embolism, Lymphoedema, Pallor, Erythromelalgia, Vasodilatation, Vein discolouration, Venous insufficiency

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea*, Epistaxis, Upper/lower respiratory tract infection*, Cough*

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

Nausea and vomiting symptoms*, Diarrhoea*, Constipation

Common

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

Uncommon

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

Common

Hepatic enzyme abnormality*

Uncommon

Hepatotoxicity (inc liver disorder), Hepatitis*, Cholestasis

Rare

Hepatic failure, Hepatomegaly, Budd-Chiari syndrome, Cytomegalovirus hepatitis, Hepatic haemorrhage, Cholelithiasis

Skin and subcutaneous tissue disorders

Common

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, Palmar-plantar 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

Very Common

Musculoskeletal pain*

Common

Muscle spasms*, Pain in extremity, Muscular weakness

Uncommon

Muscle twitching, Joint swelling, Arthritis*, Joint stiffness, Myopathies*,Sensation of heaviness

Rare

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

Renal and urinary disorders

Common

Renal impairment*

Uncommon

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

Rare

Bladder irritation

Reproductive system and breast disorders

Uncommon

Vaginal haemorrhage, Genital pain*, Erectile dysfunction,

Rare

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

Congenital, familial and genetic disorders

Rare

Aplasia, Gastrointestinal malformation, Ichthyosis

General disorders and administration site conditions

Very Common

Pyrexia*, Fatigue, Asthenia

Common

Oedema (inc peripheral), Chills, Pain*, Malaise*

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

Investigations

Common

Weight decreased

Uncommon

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

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*

Injury, poisoning and procedural complications

Uncommon

Fall, Contusion

Rare

Transfusion reaction, Fractures*, Rigors*, Face injury, Joint injury*, Burns, Laceration, Procedural pain, Radiation injuries*

Surgical and medical procedures

Rare

Macrophage activation

NOS=not otherwise specified

* Grouping of more than one MedDRA preferred term.

# Post-marketing adverse reaction regardless of indication

Mantle Cell Lymphoma (MCL)

The safety profile of bortezomib in 240 MCL patients treated with bortezomib at 1.3 mg/m2 in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-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 (VcR-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 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, 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 VcR-CAP arm and with at least a possible or probable causal relationship to the components of the VcR-CAP arm, are listed in Table 8 below. Also included are adverse drug reactions identified in the VcR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib 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 VcR-CAP

System Organ Class

Incidence

Adverse reaction

Infections and infestations

Very Common

Pneumonia*

Common

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

Uncommon

Hepatitis B, Infection*, Bronchopneumonia

Blood and lymphatic system disorders

Very Common

Thrombocytopenia*, Febrile neutropenia, Neutropenia*, Leukopenia*, Anaemia*, Lymphopenia*

Uncommon

Pancytopenia*

Immune system disorders

Common

Hypersensitivity*

Uncommon

Anaphylactic reaction

Metabolism and nutrition disorders

Very Common

Decreased appetite

Common

Hypokalaemia*, Blood glucose abnormal*, Hyponatraemia*, Diabetes mellitus*, Fluid retention

Uncommon

Tumour lysis syndrome

Psychiatric disorders

Common

Sleep disorders and disturbances*

Nervous system disorders

Very Common

Peripheral sensory neuropathy, Dysaesthesia*, Neuralgia*

Common

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

Uncommon

Autonomic nervous system imbalance

Eye disorders

Common

Vision abnormal*

Ear and labyrinth disorders

Common

Dysacusis (inc tinnitus)*

Uncommon

Vertigo*, Hearing impaired (up to and inc deafness)

Cardiac disorders

Common

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

Uncommon

Cardiovascular disorder (inc cardiogenic shock)

Vascular disorders

Common

Hypertension*, Hypotension*, Orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Common

Dyspnoea*, Cough*, Hiccups

Uncommon

Acute respiratory distress syndrome, Pulmonary embolism, Pneumonitis, Pulmonary hypertension, Pulmonary oedema (inc acute)

Gastrointestinal disorders

Very Common

Nausea and vomiting symptoms*, Diarrhoea*, Stomatitis*, Constipation

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*

Uncommon

Colitis (inc clostridium difficile)*

Hepatobiliary disorders

Common

Hepatotoxicity (inc liver disorder)

Uncommon

Hepatic failure

Skin and subcutaneous tissue disorders

Very Common

Hair disorder*

Common

Pruritus*, Dermatitis*, Rash*

Musculoskeletal and connective tissue disorders

Common

Muscle spasms*, Musculoskeletal pain*, Pain in extremity

Renal and urinary disorders

Common

Urinary tract infection*

General disorders and administration site conditions

Very Common

Pyrexia*, Fatigue, Asthenia

Common

Oedema (inc peripheral), Chills, Injection site reaction*, Malaise*

Investigations

Common

Hyperbilirubinaemia*, Protein analyses abnormal*, Weight decreased, Weight increased

* Grouping of more than one MedDRA preferred term.

Description of selected adverse reactions

Herpes zoster virus reactivation

Multiple Myeloma

Antiviral prophylaxis was administered to 26% of the patients in the Vc+M+P arm. The incidence of herpes zoster among patients in the Vc+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 VcR-CAP arm. The incidence of herpes zoster among patients in the VcR-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 treatment group (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) and 0.4% (n=1) of patients receiving bortezomib in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (VcR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with VcR-CAP or with R-CHOP (0.8% vs 1.2% respectively).

Peripheral neuropathy in combination regimens

Multiple Myeloma

In trials in which bortezomib 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 below:

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

IFM-2005-01

MMY-3010

VDDx

(N=239)

VcDx

(N=239)

TDx

(N=126)

VcTDx

(N=130)

Incidence of PN (%)

All GradePN

3

15

12

45

≥ Grade 2 PN

1

10

2

31

≥ Grade 3 PN

< 1

5

0

5

Discontinuation due to PN (%)

< 1

2

1

5

VDDx=vincristine, doxorubicin, dexamethasone; VcDx= bortezomib, dexamethasone; TDx=thalidomide, dexamethasone;

VcTDx= bortezomib, thalidomide, dexamethasone; 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 was administered with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CAP), the incidence of peripheral neuropathy in the combination regimens is presented in the table below:

Table 10: Incidence of peripheral neuropathy in study LYM-3002 by toxicity and treatment discontinuation due to peripheral neuropathy

VcR-CAP

(N=240)

R-CHOP

(N=242)

Incidence of PN (%)

All GradePN

30

29

≥ Grade 2 PN

18

9

≥ Grade 3 PN

8

4

Discontinuation due to PN (%)

2

< 1

VcR-CAP= Bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone; R-CHOP= rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; PN=peripheral neuropathy

Peripheral neuropathy included the preferred terms: peripheral sensory neuropathy, neuropathy peripheral, peripheral motor neuropathy, and peripheral sensorimotor neuropathy

Elderly MCL patients

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

Notable differences in the safety profile of bortezomib administered subcutaneously versus intravenously as single agent

In the Phase III study patients who received bortezomib 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. 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 retreatment was administered in 130 patients with relapsed multiple myeloma, who previously had at least partial response on a bortezomib -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.

Reporting of suspected adverse reactions

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 via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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)