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.
Tabulated summary of adverse reactions: Undesirable effects in Table 11 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 11.
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 11 has been generated using Version 14.1 of the MedDRA.
Post-marketing adverse reactions not seen in clinical trials are also included. (See Table 11.)

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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 Table 12 as follows: See Table 12.

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