|indication=acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older
|indication=acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older
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<!--Contraindications-->
<!--Contraindications-->
|contraindications=* Condition1
|contraindications=* Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.
<!--Warnings-->
<!--Warnings-->
|warnings=* Description
|warnings=* 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.
====Precautions====
Other adverse reactions indicative of hypersensitivity reactions included the following: pruritus (5%), rash (3%), and urticaria (2%).
* Description
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
<!--Adverse Reactions-->
<!--Adverse Reactions-->
<!--Clinical Trials Experience-->
<!--Clinical Trials Experience-->
|clinicalTrials=There is limited information regarding <i>Clinical Trial Experience</i> of {{PAGENAME}} in the drug label.
|clinicalTrials=Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [see Contraindications (4) and Warnings and Precautions (5.1)].
=====Body as a Whole=====
6.1 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 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.
=====Cardiovascular=====
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.
: [[File:Ecallantide Adv Eff.png|none|500px]]
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.
6.2 Immunogenicity
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.
=====Digestive=====
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.
|postmarketing=* 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.
|drugInteractions=* No formal drug interactions studies were performed. No in vitro metabolism studies were performed.
<!--Use in Specific Populations-->
|FDAPregCat=C
|useInPregnancyFDA=* 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).
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Postmarketing Experience-->
|postmarketing=There is limited information regarding <i>Postmarketing Experience</i> of {{PAGENAME}} in the drug label.
=====Body as a Whole=====
=====Cardiovascular=====
=====Digestive=====
=====Endocrine=====
=====Hematologic and Lymphatic=====
=====Metabolic and Nutritional=====
=====Musculoskeletal=====
=====Neurologic=====
=====Respiratory=====
=====Skin and Hypersensitivy Reactions=====
=====Special Senses=====
=====Urogenital=====
=====Miscellaneous=====
<!--Drug Interactions-->
|drugInteractions=* Drug
:* Description
<!--Use in Specific Populations-->
|useInPregnancyFDA=* '''Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
|useInPregnancyAUS=* '''Australian Drug Evaluation Committee (ADEC) Pregnancy Category'''
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of {{PAGENAME}} in women who are pregnant.
|useInLaborDelivery=There is no FDA guidance on use of {{PAGENAME}} during labor and delivery.
|useInLaborDelivery=* No information is available on the effects of KALBITOR during labor and delivery.
|useInNursing=There is no FDA guidance on the use of {{PAGENAME}} with respect to nursing mothers.
|useInNursing=* It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman.
|useInPed=There is no FDA guidance on the use of {{PAGENAME}} with respect to pediatric patients.
|useInPed=* 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)].
|useInGeri=There is no FDA guidance on the use of {{PAGENAME}} with respect to geriatric patients.
Safety and effectiveness of KALBITOR in patients less than 12 years of age have not been established.
|useInGeri=* 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.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInGender=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific gender populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
|useInRace=There is no FDA guidance on the use of {{PAGENAME}} with respect to specific racial populations.
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<!--Overdosage-->
<!--Overdosage-->
|overdose====Acute Overdose===
|overdose=* There have been no reports of overdose with KALBITOR. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.
====Signs and Symptoms====
* Description
====Management====
* Description
===Chronic Overdose===
There is limited information regarding <i>Chronic Overdose</i> of {{PAGENAME}} in the drug label.
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Black Box Warning
ANAPHYLAXIS:
See full prescribing information for complete Boxed Warning.
ANAPHYLAXIS:
Anaphylaxis has been reported after administration of KALBITOR. Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR.
Overview
Ecallantide is a Immune Modulator that is FDA approved for the treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, nausea, diarrhea, pyrexia, injection site reactions, and nasopharyngitis.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
KALBITOR® (ecallantide) is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
Dosage
The recommended dose of KALBITOR is 30 mg (3 mL), administered subcutaneously in three 10 mg (1 mL) injections. If the attack persists, an additional dose of 30 mg may be administered within a 24 hour period.
3 DOSAGE FORMS AND STRENGTHS
KALBITOR is a clear, colorless liquid free of preservatives. Each vial of KALBITOR contains ecallantide at a concentration of 10 mg/mL.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Indications
KALBITOR® (ecallantide) is indicated for treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Ecallantide in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Ecallantide in pediatric patients.
Contraindications
Do not administer KALBITOR to a patient who has known clinical hypersensitivity to KALBITOR.
Warnings
ANAPHYLAXIS:
See full prescribing information for complete Boxed Warning.
ANAPHYLAXIS:
Anaphylaxis has been reported after administration of KALBITOR. Because of the risk of anaphylaxis, KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema. Healthcare professionals should be aware of the similarity of symptoms between hypersensitivity reactions and hereditary angioedema and patients should be monitored closely. Do not administer KALBITOR to patients with known clinical hypersensitivity to KALBITOR.
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
Adverse Reactions
Clinical Trials Experience
Hypersensitivity reactions, including anaphylaxis, have occurred in patients treated with KALBITOR [see Contraindications (4) and Warnings and Precautions (5.1)].
6.1 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 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.
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.
6.2 Immunogenicity
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.
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.
Drug Interactions
No formal drug interactions studies were performed. No in vitro metabolism studies were performed.
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).
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Ecallantide in women who are pregnant.
Labor and Delivery
No information is available on the effects of KALBITOR during labor and delivery.
Nursing Mothers
It is not known whether ecallantide is excreted in human milk. Caution should be exercised when ecallantide is administered to a nursing woman.
Pediatric Use
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.
Geriatic Use
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.
Gender
There is no FDA guidance on the use of Ecallantide with respect to specific gender populations.
Race
There is no FDA guidance on the use of Ecallantide with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Ecallantide in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Ecallantide in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Ecallantide in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Ecallantide in patients who are immunocompromised.
Administration and Monitoring
Administration
Subcutaneous
Administration Instructions
KALBITOR should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
KALBITOR should be refrigerated and protected from the light. KALBITOR is a clear, colorless liquid; visually inspect each vial for particulate matter and discoloration prior to administration. If there is particulate matter or discoloration, the vial should not be used.
Using aseptic technique, withdraw 1 mL (10 mg) of KALBITOR from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection. The recommended needle size is 27 gauge. Inject KALBITOR into the skin of the abdomen, thigh, or upper arm. Repeat the procedure for each of the 3 vials comprising the KALBITOR dose. The injection site for each of the injections may be in the same or in different anatomic locations (abdomen, thigh, upper arm). There is no need for site rotation. Injection sites should be separated by at least 2 inches (5 cm) and away from the anatomical site of attack.
The same instructions apply to an additional dose administered within 24 hours. Different injection sites or the same anatomical location (as used for the first administration) may be used.
Monitoring
There is limited information regarding Monitoring of Ecallantide in the drug label.
Description
IV Compatibility
There is limited information regarding IV Compatibility of Ecallantide in the drug label.
Overdosage
There have been no reports of overdose with KALBITOR. HAE patients have received single doses up to 90 mg intravenously without evidence of dose-related toxicity.
Pharmacology
There is limited information regarding Ecallantide Pharmacology in the drug label.
