Bortezomib Accord · 4.5 Interaction with other medicinal products and other forms of interaction · 2

HOS-097419 · has-adverse-reaction-information · PDF-Seite 14

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 list 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 studies are also included. Table 7:Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical studies, and all post-marketing adverse reactions regardless of indication# System Organ Class Incidence Adverse reaction Infections and Common Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, infestations 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

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HOS-097425 · has-adverse-reaction-information · PDF-Seite 47

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 list 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 studies are also included. Table 7:Adverse reactions in patients with multiple myeloma treated with bortezomib in clinical studies, and all post-marketing adverse reactions regardless of indication# System Organ Class Incidence Adverse reaction Infections and Common Herpes zoster (inc disseminated & ophthalmic), Pneumonia*, infestations 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 rela

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HOS-097415 · has-contraindication-information · PDF-Seite 9

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

HOS-097421 · has-contraindication-information · PDF-Seite 42

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

HOS-097414 · has-indication-information · PDF-Seite 2

Bortezomib Accord 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 Accord 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 Accord 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 Accord 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.

HOS-097420 · has-indication-information · PDF-Seite 35

Bortezomib Accord 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 Accord 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 Accord 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 Accord 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.

HOS-097423 · has-interaction-information · PDF-Seite 45

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). 45 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 studies, hypoglycaemia and hyperglycaemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

HOS-097417 · has-interaction-information · PDF-Seite 12

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). 12 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 studies, hypoglycaemia and hyperglycaemia were uncommonly and commonly reported in diabetic patients receiving oral hypoglycaemics. Patients on oral antidiabetic agents receiving bortezomib treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetics.

HOS-097424 · has-pregnancy-information · PDF-Seite 46

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 Accord 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 Accord 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. 46 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.

HOS-097418 · has-pregnancy-information · PDF-Seite 13

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 Accord 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 Accord 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. 13 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.

HOS-097422 · has-warning-information · PDF-Seite 42

When Bortezomib Accord 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 Accord. 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 Accord 1 mg powder for solution for injection is for intravenous use only, while Bortezomib Accord 3.5 mg powder for solution for injection is for intravenous or subcutaneous use. Bortezomib Accord 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/l, 90% of 21 patients had a count ≤ 25,000/l during the study, including 14% < 10,000/l; in contrast, with a baseline platelet count > 75,000/l, only 14% of 309 patients had a count ≤ 25,000/l 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 re

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HOS-097416 · has-warning-information · PDF-Seite 9

When Bortezomib Accord 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 Accord. 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 Accord 2.5 mg/mL 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 (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/l, 90% of 21 patients had a count ≤ 25,000/l during the study, including 14% < 10,000/l; in contrast, with a baseline platelet count > 75,000/l, only 14% of 309 patients had a count ≤ 25,000/l 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-CAPgroup and 5.0% in the R-CHOP

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