"The U.S. Food and Drug Administration yesterday approved Ruconest, the first recombinant C1-Esterase Inhibitor product for the treatment of acute attacks in adult and adolescent patients with hereditary angioedema (HAE).
The following adverse reactions are also discussed in other sections of the labeling:
- Concurrent active serious infections [see WARNINGS AND PRECAUTIONS]
- Infusion-related reactions and hypersensitivity [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The most common adverse reactions ( > 10% compared to placebo) during treatment with SYLVANT in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.
The data presented below in Table 3 were collected from Study 1. Study 1, in MCD, was an international, multicenter, randomized phase 2 study of every 3 week infusions comparing SYLVANT and best supportive care (BSC) to placebo and BSC. There were 53 patients randomized to the SYLVANT arm at a dose of 11 mg/kg and 26 patients randomized to the placebo arm. Of the 26 placebo-treated patients, 13 patients subsequently crossed-over to receive SYLVANT. The median age was 48 years (range 20 to 78), 66% male, 48% Asian, 39% White, 4% Black or African American, 7% other. The patients randomized to SYLVANT received a median of 19 infusions (range 1 to 50) compared to patients randomized to placebo who received a median of 8 infusions (range 2 to 32). To control for disparate exposure between arms, Table 3 reports the per patient incidence of adverse reactions that occurred during the first 8 infusions. Adverse reactions that occurred > 3% in the SYLVANT arm are presented.
Table 3: Per Patient Incidence of Common Adverse
Reactions in Study 1 During Initial 8 Infusions
|All Grades||Grades 3-4||All Grades||Grades 3-4|
|Rash (rash, rash generalized, rash maculo-papular, rash popular and rash pruritic)||15 (28%)||1 (2%)||3 (12%)||0|
|Pruritis||15 (28%)||0||2 (8%)||0|
|Skin hyperpigmentation||2 (4%)||0||0||0|
|Dry skin||2 (4%)||0||0||0|
|Lower respiratory tract||4 (8%)||2 (4%)||1 (4%)||1 (4%)|
|Upper respiratory tract||14 (26%)||1 (2%)||4 (15%)||1 (4%)|
|Blood and lymphatic system disorders|
|Thrombocytopenia||5 (9%)||2 (4%)||1 (4%)||1 (4%)|
|Edema(general and localized)||14 (26%)||4 (8%)||7 (27%)||0|
|Constipation||4 (8%)||0||1 (4%)||0|
|Hyperuricemia||6 (11%)||1 (2%)||0||0|
|Respiratory, thoracic and mediastinal disorders|
|Oropharyngeal pain||4 (8%)||0||1 (4%)||0|
|Renal and Urinary disorders|
|Renal impairment||4 (8%)||0||0||0|
|Nervous system disorders|
|Headache||4 (8%)||0||1 (4%)||0|
|Weight increased||10 (19%)||1 (2%)||0||0|
|Hypotension||2 (4%)||1 (2%)b||0||0|
|a Best Supportive Care
SYLVANT was also evaluated as a single agent in another hematologic disease in Study 2. Study 2 was an international, multicenter, randomized phase 2 study of every 4 week infusions comparing SYLVANT and BSC to placebo and BSC. There were 50 patients randomized to the SYLVANT arm at a dose of 15 mg/kg (unapproved dose) and 26 patients randomized to the placebo arm. The median age was 72 years (range 50 to 85), 58% male, 96% White, 1% Asian, 1% Black, 1% other. The median number of infusions in both arms was 3 (range 1 to 4). The study was stopped early due to a lack of efficacy. Adverse reactions that occurred > 3% in the SYLVANT arm are presented in Table 4.
Table 4: Per Patient
Incidence of Common Adverse Reactions in Study 2
|All Grades||Grades 3-4||All Grades||Grades 3-4|
|Lower respiratory tract||4 (8%)||4 (8%)||0||0|
|Edema(peripheral)||8 (16%)||0||2 (8%)||0|
|Abdominal pain/abdominal distension||6 (12%)||0||0||0|
|Decreased appetite||2 (4%)||0||0||0|
|Dehydration||2 (4%)||1 (2%)||0||0|
Long Term Exposure
The safety of long term administration of SYLVANT to patients with MCD was evaluated in Study 3. Study 3 enrolled patients from the initial dose finding study of SYLVANT with MCD who were benefiting from chronic SYLVANT therapy. SYLVANT was administered at a dose of 11 mg/kg every 3 to 6 weeks. At the time of data cut off 19 patients were enrolled. The median age was 44 years (range 18 - 76), 63% male, 84% Caucasian, 11% Asian, and 5% Black. The median exposure to SYLVANT for these 19 patients was 5.1 years (range 3.4 to 7.2). The most common adverse reaction ( > 20%) reported by subjects receiving SYLVANT in this study was upper respiratory tract infection (63%); diarrhea (32%); pain in extremities, arthralgia and fatigue (21%, each). No patient was removed from therapy for any reason. There were no deaths. There were no cumulative toxicities identified with prolonged treatment with SYLVANT.
Anaphylaxis and Infusion Related Reactions
Approximately 750 patients have been treated with SYLVANT. Of these, one patient experienced an anaphylactic reaction. Data from 249 patients treated with SYLVANT monotherapy forms the basis of the safety evaluation of infusion related reactions. Infusion related reactions were reported in 4.8% of these patients. Symptoms of infusion reactions consisted of back pain, chest pain or discomfort, nausea and vomiting, flushing, erythema, and palpitations.
Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to SYLVANT with the incidence of antibodies to other products may be misleading. The clinical significance of anti-siltuximab antibodies following treatment with SYLVANT is not known.
The immunogenicity of siltuximab has been evaluated using antigen-bridging enzyme immunoassay (EIA) and electrochemiluminescence-based immunoassay (ECLIA) methods. A total of 411 patients across the clinical trials were evaluated at multiple time points for anti-therapeutic antibody (ATA) responses to siltuximab after treatment with SYLVANT. Following SYLVANT dosing, 0.2% (1/411) of patients tested positive for anti-siltuximab antibodies. Further immunogenicity analyses of the single positive sample revealed a low titer of antisiltuximab antibodies with non-neutralizing capabilities.
No evidence of altered toxicity profile was identified in the patient who developed antibodies to siltuximab.
Read the Sylvant (siltuximab injection, for intravenous infusion) Side Effects Center for a complete guide to possible side effects
No in vitro or in vivo drug-drug interaction studies have been conducted with SYLVANT.
Cytochrome P450 Substrates
Cytochrome P450s in the liver are down regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in patients treated with SYLVANT may restore CYP450 activities to higher levels leading to increased metabolism of drugs that are CYP450 substrates compared to metabolism prior to treatment with SYLVANT.
Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with a narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. The effect of SYLVANT on CYP450 enzyme activity can persist for several weeks after stopping therapy. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).
Last reviewed on RxList: 5/12/2014
This monograph has been modified to include the generic and brand name in many instances.
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