KALBITOR Solution for injection Ref.[10232] Active ingredients: Ecallantide

5.1 Hypersensitivity Reactions, Including Anaphylaxis

Potentially serious hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR. In 255 HAE patients treated with intravenous or subcutaneous KALBITOR in clinical studies, 10 patients (4%) experienced anaphylaxis. For the subgroup of 187 patients treated with subcutaneous KALBITOR, 5 patients (3%) experienced anaphylaxis. Symptoms associated with these reactions have included chest discomfort, flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. These reactions occurred within the first hour after dosing.

Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%).

Patients should be observed for an appropriate period of time after administration of KALBITOR, taking into account the time to onset of anaphylaxis seen in clinical trials. Given the similarity in hypersensitivity symptoms and acute HAE symptoms, patients should be monitored closely in the event of a hypersensitivity reaction.

KALBITOR should not be administered to any patients with known clinical hypersensitivity to KALBITOR [see Contraindications (4)].

Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [see Contraindications (4) and Warnings and Precautions (5.1)].

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 KALBITOR in 255 patients with HAE treated with either intravenous or subcutaneous KALBITOR. Of the 255 patients, 66% of patients were female and 86% were Caucasian. Patients treated with KALBITOR 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 KALBITOR 30 mg subcutaneous or placebo. Patients were permitted to participate sequentially in both placebo-controlled trials; safety data collected during exposure to KALBITOR was attributed to treatment with KALBITOR, and safety data collected during exposure to placebo was attributed to treatment with placebo. Table 1 shows adverse reactions occurring in ≥3% of KALBITOR-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 KALBITOR:

* 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 KALBITOR within 24 hours following the initial dose. Adverse reactions reported by these patients who received the additional 30 mg subcutaneous dose of KALBITOR were consistent with those reported in the patients receiving a single dose.

In the KALBITOR HAE program, patients developed antibodies to KALBITOR. Rates of seroconversion increased with exposure to KALBITOR 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 KALBITOR 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 KALBITOR. 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 KALBITOR with the incidence of antibodies to other products may be misleading.

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.

No formal drug interactions studies were performed. No in vitro metabolism studies were performed.

Pregnancy Category C.

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

In rats, intravenous KALBITOR 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 KALBITOR 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).

No information is available on the effects of KALBITOR during labor and delivery.

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

The safety and effectiveness of KALBITOR have been established in patients 12 to 17 years of age. The efficacy of KALBITOR in the 12-15 year age group is extrapolated from efficacy in patients 16 years of age and older with support from population pharmacokinetic analyses showing similar drug exposure levels in adults and adolescents [see Clinical Pharmacology (12.3) and Clinical Studies (14)]. The safety profile observed in pediatric patients 12-17 years of age was similar to the adverse reactions observed in the overall clinical trial population [see Adverse Reactions (6.1)].

Safety and effectiveness of KALBITOR in patients less than 12 years of age have not been established.

Clinical trials of KALBITOR did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.