Ecallantide (Kalbitor, DX-88) is a kallikrein inhibitor used for the treatment of acute hereditary angioedema (HAE) attacks and is under investigation for the reduction of blood loss during cardiothoracic surgery. It is a 60-amino acid recombinant protein produced in Pichia pastoris yeast cells. Hereditary angioedema is a rare, genetic syndrome that causes nonpitting, nonpruritic edema in most parts of the body, although attacks are most common in the face, limbs, genitalia, and gastrointestinal mucosa. If an HAE attack involves the larynx or oropharynx, the attack can be life-threatening and ventilatory support of the patient may be needed. During clinical trials, ecallantide has demonstrated an improved extent of and time to resolution of HAE symptoms during an attack. If symptoms persist or relapse after the initial ecallantide dose, a second dose may be administered within 24 hours. Although responses have been reported after the second ecallantide dose, efficacy of the second dose was not systematically assessed in the initial clinical trials. Enrollment in two phase II trials investigating the use of ecallantide for the reduction of blood loss during cardiothoracic surgery was temporarily suspended in December 2009 after a data safety monitoring board found a higher incidence of death in the ecallantide treated patients. It should be noted that overall mortality appeared to be consistent with the expected outcomes for the patient population. In December 2009, ecallantide received FDA approval for the treatment of acute attacks of hereditary angioedema in patients 16 years of age and older; the indication was expanded to include pediatric patients as young as 12 years in March 2014.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Ecallantide should only be administered by a health care professional with appropriate medical support to manage anaphylaxis and hereditary angioedema.
Route-Specific Administration
Injectable Administration
Subcutaneous Administration
-Using aseptic technique, withdraw 1 mL (10 mg) of ecallantide from the vial using a large bore needle. Change the needle on the syringe to a needle suitable for subcutaneous injection (27 gauge recommended).
-Inject ecallantide into the skin of the abdomen, thigh, or upper arm.
-Repeat the procedure for each of the three vials of ecallantide (30 mg total dose). The injection site for each of the three injections may be in the same or different anatomic location (abdomen, thigh, or upper arm). There is no need for site rotation. Individual injections should be separated by at least 2 inches and away from the anatomical site of attack.
-The same directions for administration apply if an additional dose of ecallantide is required within 24 hours. Different injection sites or the same anatomical location as used for the first dose may be used.
-Ecallantide is a clear, colorless solution. Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. If there is particulate matter or discoloration, the vial should not be used.
In clinical trials, patients who received an additional 30 mg subcutaneous dose of ecallantide presented with adverse reactions consistent with that reported in patients receiving a single dose.
Potentially serious hypersensitivity reactions or anaphylaxis may occur as a result of treatment with ecallantide. In clinical trials, 255 patients received ecallantide either intravenously or subcutaneously. Anaphylaxis occurred in 4% of patients. Symptoms related to anaphylactic reactions may include chest pain (unspecified), flushing, pharyngeal edema, pruritus, rhinorrhea, sneezing, nasal congestion, throat irritation, urticaria, wheezing, and hypotension. Reactions occurred within the first hour after dosing. In addition, pruritus (5%), rash (3%), and urticaria (2%) have occurred and are indicative of a hypersensitivity reaction. Furthermore, an injection site reaction (7%) may occur after ecallantide injection. Injection site reactions were characterized by pruritis, erythema, pain and/or irritation at the site of injection, urticaria, and/or bruising. Patients should be monitored for an appropriate time after administration of ecallantide to allow for the onset of hypersensitivity reactions. Careful monitoring is required, as the symptoms associated with hereditary angioedema and hypersensitivity reactions may be similar.
Patients administered ecallantide may experience antibody formation to ecallantide. In the ecallantide hereditary angioedema program, 20.2% of patients seroconverted to anti-ecallantide antibodies. Rates of conversion increase with exposure to ecallantide over time. In vitro, 8.8% of patients displayed neutralizing antibodies to ecallantide; these antibodies were not associated with a loss of efficacy. Anti-ecallantide IgE antibodies and anti-P. pastoris IgE antibodies were also detected in 4.7% and 20.2% of patients, respectively. Patients who seroconvert to anti-ecallantide antibodies may be at a higher risk of a hypersensitivity reaction. The long term impact of anti-ecallantide antibodies is not known.
In clinical trials of ecallantide, the most common adverse events were headache (16%), nausea (13%), fatigue (12%), diarrhea (11%), upper respiratory tract infection (8%), naso-pharyngitis (6%), vomiting (6%), upper abdominal pain (5%), and fever (5%).
Do not administer ecallantide to a patient who has known ecallantide hypersensitivity. Potentially serious hypersensitivity reactions or anaphylaxis have occurred. Observe patients for an appropriate period of time after administration. During clinical trials, hypersensitivity reactions occurred within the first hour after dosing. Given the similarity in hypersensitivity symptoms and acute hereditary angioedema symptoms, monitor patients closely if a hypersensitivity reaction occurs. Ecallantide administration requires an experienced clinician with appropriate medical support to manage anaphylaxis and hereditary angioedema. Patients administered ecallantide may develop antibodies to ecallantide. Patients who seroconvert to anti-ecallantide antibodies may be at a higher risk of a hypersensitivity reaction.
In general, ecallantide dose selection for a geriatric 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.
The available data from the pharmacovigilance database for ecallantide have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes with use during pregnancy. In an animal reproductive study, increased early fetal deaths resulting in decreased live fetuses were observed after treatment during the period of organogenesis at an intravenous dose approximately 1.6 times the maximum recommended human dose (MRHD) in the presence of maternal toxicity. There were no effects on embryofetal survival or structural abnormalities in other animal studies after treatment during the period of organogenesis with intravenous doses up to approximately 1.1 and 6 times the MRHD or with subcutaneous doses up to 2.4 times the MRHD. In a pre- and post-natal development animal study, there were no effects on pup survival and development with subcutaneous doses up to approximately 2.7 times the MRHD.
There are no data on the presence of ecallantide in human breast milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for ecallantide and any potential adverse effects on the breast-fed child from ecallantide or the underlying maternal condition.
For the treatment of acute attacks of hereditary angioedema (HAE):
Subcutaneous dosage:
Adults, Adolescents, and Children >= 12 years: 30 mg subcutaneously administered as three 10-mg (1 mL) injections. If the attack persists, an additional 30 mg dose may be administered within a 24-hour period. The efficacy of ecallantide in children and adolescents 12 to 15 years of age is extrapolated from efficacy in patients 16 years of age or older and from pharmacokinetic data demonstrating similar drug exposure in adolescents and adults.
Maximum Dosage Limits:
-Adults
30 mg/dose subcutaneously. May repeat once within 24 hour period.
-Geriatric
30 mg/dose subcutaneously. May repeat once within 24 hour period.
-Adolescents
30 mg/dose subcutaneously. May repeat once within 24 hour period.
-Children
12 years: 30 mg/dose subcutaneously. May repeat once within 24 hour period.
< 12 years: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
*non-FDA-approved indication
There are no drug interactions associated with Ecallantide products.
Ecallantide is a potent, selective, reversible inhibitor of kallikrein that blocks the production of kallikrein, a precursor to bradykinin. Ecallantide binds to the protease plasma kallikrein and blocks its binding site, preventing the conversion of high molecular weight kininogen to bradykinin. People with hereditary angioedema (HAE) have mutations to C1-esterase inhibitor (C1-INH) located on chromosome 11q. C1-INH, a serine protease, is the primary regulator of the kallikrein-kinin cascade, but is also involved in complement and intrinsic coagulation, fibrinolysis, hypotension, and pain and inflammation pathways. A deficiency in C1-INH causes an increase in the production of kallikrein, and thus, bradykinin. The edema and swelling of HAE attacks are thought to be due to the excessive production of bradykinin. Because ecallantide is selective for the kallikrein-kinin pathway, ecallantide should not affect other pathways regulated by C1-INH.
In regard to the investigational use of ecallantide for the prevention of blood loss during cardiothoracic surgery, ecallantide's inhibition of kallikrein production may be very beneficial. Kallikrein liberates bradykinin, which causes local leakage of fluid from the blood vessels into the tissues. Ecallantide helps reduce bradykinin liberation and may reduce both blood transfusions associated with on-pump cardiothoracic surgery and systemic inflammatory effects. Contact activation of the inflammatory cascade is one of the inherent risks of on-pump cardiothoracic surgery. Blood loss and the systemic inflammatory response syndrome may occur when the patient's blood comes into contact with the artificial surface of the cardiopulmonary bypass machine and tubing.
Ecallantide is administered subcutaneously. After administration, the mean elimination half-life of ecallantide was approximately 2 hours. Plasma clearance was 153 +/- 20 mL/min and the volume of distribution was 26.4 +/- 7.8 L. Ecallantide is a small protein with a molecular weight of 7054 Da. Renal elimination of ecallantide has been observed in treated subjects.
-Route-Specific Pharmacokinetics
Subcutaneous Route
After the subcutaneous administration of a single 30 mg dose of ecallantide to healthy subjects, the maximum plasma concentration, 586 +/- 106 ng/mL, was observed 2-3 hours after the dose.
-Special Populations
Hepatic Impairment
No pharmacokinetic data are available in patients with hepatic impairment.
Renal Impairment
No pharmacokinetic data are available in patients with renal impairment.
Geriatric
In a population pharmacokinetic analysis, age did not have a significant impact on systemic ecallantide exposure.
Gender Differences
In a population pharmacokinetic analysis, gender did not have a significant impact on systemic ecallantide exposure.
Obesity
In a population pharmacokinetic analysis, body weight did not have a significant impact on systemic ecallantide exposure.