Zomod 1/Zomod 3.5 Adverse Reactions

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.
Zomod 1: Tabulated list of adverse reactions: Multiple myeloma: Undesirable effects in Table 15 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 15.
Overall, bortezomib was administered for the treatment of multiple myeloma in 3,974 patients.
Adverse reactions are listed as follows 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 15 has been generated using Version 14.1 of the MedDRA. Post-marketing adverse reactions not seen in clinical trials are also included. (See Tables 15a and 15b.)

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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 (BzR-CAP) versus 242 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] was relatively consistent to that observed in patients with multiple myeloma with main differences described as follows. Additional adverse drug reactions identified associated with the use of the combination therapy (BzR-CAP) were hepatitis B infection (<1%) and myocardial ischemia (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 BzR-CAP arm and with at least a possible or probable causal relationship to the components of the BzR-CAP arm, are listed in Table 16 as follows. Also included are adverse drug reactions identified in the BzR-CAP arm that were considered by investigators to have at least a possible or probable causal relationship to bortezomib based on historical data in the multiple myeloma studies.
Adverse reactions are listed as follows 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 16 has been generated using Version 16 of the MedDRA. (See Table 16.)

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Description of selected adverse reactions: Herpes zoster virus reactivation: Multiple Myeloma: Antiviral prophylaxis was administered to 26% of the patients in the Bz+M+P arm. The incidence of herpes zoster among patients in the Bz+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
Mantle cell lymphoma: Antiviral prophylaxis was administered to 137 of 240 patients (57%) in the BzR-CAP arm. The incidence of herpes zoster among patients in the BzR-CAP arm was 10.7% for patients not administered antiviral prophylaxis compared to 3.6% for patients administered antiviral prophylaxis (see Precautions).
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 (BzR-CAP). The overall incidence of hepatitis B infections was similar in patients treated with BzR-CAP or with R-CHOP (0.8% vs 1.2% respectively).
Peripheral neuropathy in combination regimens: Multiple Myeloma: In trials in which Bortezomib 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 Table 17 as follows: See Table 17.

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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 as follows: See Table 18.

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Elderly MCL patients: 42.9% and 10.4% of patients in the BzR-CAP arm were in the range 65-74 years and ≥ 75 years of age, respectively. Although in patients aged ≥ 75 years, both BzR-CAP and R-CHOP were less tolerated, the serious adverse event rate in the BzR-CAP groups was 68%, compared to 42% in the R-CHOP group.
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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Zomod 3.5: Tabulated summary of adverse reactions: Undesirable effects in Table 19 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 19.
Overall, Bortezomib was administered for the treatment of multiple myeloma in 3,974 patients.
Adverse reactions are listed as follows 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 19 has been generated using Version 14.1 of the MedDRA. Post-marketing adverse reactions not seen in clinical trials are also included. (See Tables 19a and 19b.)

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Description of selected adverse reactions: Herpes zoster virus reactivation: Antiviral prophylaxis was administered to 26% of the patients in the Bz+M+P arm. The incidence of herpes zoster among patients in the Bz+M+P treatment group was 17% for patients not administered antiviral prophylaxis compared to 3% for patients administered antiviral prophylaxis.
Peripheral neuropathy in combination regimens: 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 as follows: See Table 20.

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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 authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.