Ecallantide

Pregnancy Category C.

There are no adequate and well-controlled trials of ecallantide in pregnant women. Ecallantide has been shown to cause developmental toxicity in rats, but not rabbits. Because animal reproductive studies are not always predictive of human response, ecallantide should be used during pregnancy only if clearly needed.

In rats, intravenous ecallantide at an intravenous dose approximately 13 times the maximum recommended human dose (MRHD) (on a mg/kg basis at a maternal dose of 15 mg/kg/day in rats) caused increased numbers of early resorptions and percentages of resorbed conceptuses per litter in the presence of mild maternal toxicity. No development toxicity was observed in rats that received an intravenous dose approximately 8 times the MRHD (on a mg/kg basis at a maternal dose of 10 mg/kg/day in rats). There were no adverse effects of ecallantide on embryofetal development in rats that received subcutaneous doses up to approximately 2.4 times the MRHD (on an AUC basis at a maternal dose of 20 mg/kg/day in rats), and in rabbits that received intravenous doses up to approximately 6 times the MRHD (on an AUC basis at a maternal dose of 5 mg/kg/day in rabbits).

It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman.

A two-year study was conducted in rats to assess the carcinogenic potential of ecallantide. No evidence of tumorigenicity was observed in rats at ecallantide doses up to 10 mg/kg administered subcutaneously every three days (approximately 2-fold greater than the MRHD on an AUC basis).

Ecallantide had no effects on fertility and reproductive performance in rats at subcutaneous doses up to 25 mg/kg/day (approximately 21 times the MRHD on a mg/kg basis).

Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with ecallantide.

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 practice.

The safety data described below reflect exposure to ecallantide in 255 patients with HAE treated with either intravenous or subcutaneous ecallantide. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with ecallantide were between the ages of 10 and 78 years.

Overall, the most common adverse reactions in 255 patients with HAE were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), injection site reactions (7%), nasopharyngitis (6%), vomiting (6%), pruritus (5%), upper abdominal pain (5%), and pyrexia (5%).

Anaphylaxis was reported in 4% of patients with HAE. Injection site reactions were characterized by local pruritus, erythema, pain, irritation, urticaria, and/or bruising.

The incidence of adverse reactions below is based upon 2 placebo-controlled, clinical trials (EDEMA3 and EDEMA4) in a total of 143 unique patients with HAE. Patients were treated with ecallantide 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to ecallantide was attributed to treatment with ecallantide, and safety data collected during exposure to placebo was attributed to treatment with placebo. Table 1 shows adverse reactions occurring in ≥3% of ecallantide-treated patients that also occurred at a higher rate than in the placebo-treated patients in the two controlled trials (EDEMA3 and EDEMA4) of the 30 mg subcutaneous dose.

Table 1. Adverse Reactions Occurring at ≥3% and Higher than Placebo in 2 Placebo Controlled Clinical Trials in Patients with HAE Treated with ecallantide:

* Patients experiencing more than 1 event with the same preferred term are counted only once for that preferred term.

Some patients in EDEMA3 and EDEMA4 received a second, open-label 30 mg subcutaneous dose of ecallantide within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of ecallantide were consistent with those reported in the patients receiving a single dose.

Immunogenicity

In the ecallantide HAE program, patients developed antibodies to ecallantide. Rates of seroconversion increased with exposure to ecallantide over time. Overall, 20.2% of patients seroconverted to anti-ecallantide antibodies. Neutralizing antibodies to ecallantide were determined in vitro to be present in 8.8% of patients and were not associated with loss of efficacy.

Anti-ecallantide IgE antibodies were detected at a rate of 4.7% for tested patients, and anti-P. pastoris IgE antibodies were also detected at a rate of 20.2%. Patients who seroconvert may be at a higher risk of a hypersensitivity reaction. The long-term effects of antibodies to ecallantide are not known.

The test results for the ecallantide program were determined using one of two assay formats: ELISA and bridging electrochemiluminescence (ECL). As with all therapeutic proteins, there is a potential for immunogenicity with the use of ecallantide. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to ecallantide with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

Similar adverse reactions have been observed postmarketing as described for clinical trial experience. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or to establish a causal relationship with drug exposure.