` ---------------------DOSAGE FORMS AND STRENGTHS---------------------­
`
`
` •
` Single use glass vial containing 10 mg/mL of ecallantide as a solution
`
` for injection (3)
`
`
`
`
`-------------------------------CONTRAINDICATIONS-----------------------------­
`
`
`
`
`
`
`
`
` Do not administer KALBITOR to a patient who has known clinical
` •
` hypersensitivity to KALBITOR (4)
`
`
`
`
`
`
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`
`
`
`
` Hypersensitivity Reactions Including Anaphylaxis: Anaphylaxis has
` •
` occurred in 4% of treated patients Administer KALBITOR in a setting
`
`
`
`
`
`
`equipped to manage anaphylaxis and hereditary angioedema Given the
`
`
`
`similarity in hypersensitivity symptoms and acute HAE symptoms,
`
`
`monitor patients closely for hypersensitivity reactions (5)
`
`
`
`
`
`
`
`------------------------------ADVERSE REACTIONS------------------------------­
`•
`The most common adverse reactions occurring in ≥3% of KALBITOR-
`
`
`
`
`treated patients and greater than placebo are headache, nausea, diarrhea,
`
`
`
`
`pyrexia, injection site reactions, and nasopharyngitis (6)
`
`
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Dyax Corp. at
`
`1-888-452-5248 or FDA at 1-800-FDA-1088 or
`
`
`
`www.fda.gov/medwatch
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`
`
`
`
`
`
`
`
`
`Revised: 09/2014
`
`
`
`
`
`
`
`
`
`
`
`
`10
`
`11
`
`12
`
`
`13
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`KALBITOR® safely and effectively. See full prescribing information for
`KALBITOR.
`
`KALBITOR (ecallantide) injection, for subcutaneous use
`Initial U.S. Approval: 2009
`
`
`WARNING: ANAPHYLAXIS
`See full prescribing information for complete boxed warning
`
`
`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 [see Contraindications (4),
`Warnings and Precautions (5.1), and Adverse Reactions (6)].
`
`----------------------------RECENT MAJOR CHANGES-------------------------­
`Indications and Usage (1) -----------------------------------------------------3/2014
`
`----------------------------INDICATIONS AND USAGE--------------------------­
`•
`KALBITOR is a plasma kallikrein inhibitor indicated for treatment of
`acute attacks of hereditary angioedema (HAE) in patients 12 years of
`age and older (1)
`
`•
`
`
`----------------------DOSAGE AND ADMINISTRATION-----------------------­
`•
`30 mg (3 mL), administered subcutaneously in three 10 mg ( 1 mL)
`injections If an attack persists, an additional dose of 30 mg may be
`administered within a 24 hour period (2 1)
`KALBITOR should only be administered by a healthcare professional
`with appropriate medical support to manage anaphylaxis and hereditary
`angioedema (2 2)
`
`3
`
`4
`
`5
`
`
`6
`
`
`7
`
`8
`
`
`
`
`
`
`
`_______________________________________________________________________________________________________________________________________
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: ANAPHYLAXIS
`
`INDICATIONS AND USAGE
`1
`
`
`2
`DOSAGE AND ADMINISTRATION
`
`
`2 1
`Recommended Dosing
`
`
`2 2
`Administration Instructions
`
`
`DOSAGE FORMS AND STRENGTHS
`
`CONTRAINDICATIONS
`
`WARNINGS AND PRECAUTIONS
`
`Hypersensitivity Reactions, Including Anaphylaxis
`5 1
`
`
`
`
`ADVERSE REACTIONS
`
`Clinical Trials Experience
`6 1
`
`
`6 2
`Immunogenicity
`
`
`6 3
`Postmarketing Experience
`
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`8 1
`Pregnancy
`
`
`8 2
`Labor and Delivery
`
`
`8 3
`Nursing Mothers
`
`
`8 4
`Pediatric Use
`
`
`8 5
`Geriatric Use
`
`
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`12 1 Mechanism of Action
`
`
`12 2
`Pharmacodynamics
`
`
`12 3
`Pharmacokinetics
`
`
`NONCLINICAL TOXICOLOGY
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`13 1
`
`
`
`CLINICAL STUDIES
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`PATIENT COUNSELING INFORMATION
`
`
`14
`
`16
`
`17
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`
`
`
`
`listed
`
`
`
`
`
`
`
`
`Reference ID: 3623294
`
`
`
` 1
`
`
`
`Page 1 of 13
`
`CSL EXHIBIT 1017
`
`

`

`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
`
` 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. [see Contraindications (4),
`
`
`
`
`Warnings and Precautions (5.1), and Adverse Reactions (6)]
`
`
`
`
` INDICATIONS AND USAGE
` 1
`
`
`
`
` KALBITOR® (ecallantide) is indicated for treatment of acute attacks of hereditary
` angioedema (HAE) in patients 12 years of age and older.
`
`
`
`
`
`
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
` 2.1 Recommended Dosing
`
`
`
`
` 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.
`
`
`
`
`
` 2.2 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.
`
`
`
`Reference ID: 3623294
`
`
`2
`
`
`
`Page 2 of 13
`
`

`

`
`
` 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.
`
`
`
`
`
` 4 CONTRAINDICATIONS
`
`
`
`
`
`
` Do not administer KALBITOR to a patient who has known clinical hypersensitivity to
`
` KALBITOR. [see Warnings and Precautions (5.1)].
`
`
`
`
`
`
`
`
`
` 5 WARNINGS AND PRECAUTIONS
`
` 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)].
`
`
`
` 6 ADVERSE REACTIONS
`
`
`
`
` 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,
`
`
`
`
`
`
`
`
`
`Reference ID: 3623294
`
`
`3
`
`
`
`Page 3 of 13
`
`

`

`
`
`
`
` 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
` KALBITOR
` Placebo
`
`
`
`
` N=100
` N=81
`
` n (%) a
`
` n (%)a
` Adverse Reactions
`
`
`
`
`
` 8 (8%)
` 6 (7%)
` Headache
`
` 1 (1%)
`
` 5 (5%)
`
` Nausea
`
` 4 (4%)
`
` 3 (4%)
` Diarrhea
`
` 4 (4%)
`
`
` Pyrexia
` 0
`
`
` 3 (3%)
` 1 (1%)
` Injection site reactions
`
` 3 (3%)
`
`
` Nasopharyngitis
` 0
` a 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.
`
`
`
` Immunogenicity
` 6.2
`
`
` 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.
`
`
`
`
`
`
`
`Reference ID: 3623294
`
`
`4
`
`
`
`Page 4 of 13
`
`

`

`
`
`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.
`
`
`
`
` 6.3 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.
`
` 7 DRUG INTERACTIONS
`
`
` No formal drug interactions studies were performed. No in vitro metabolism studies
`
` were performed.
`
`
`
`
`
`
`
`
`
`
`
`
` 8 USE IN SPECIFIC POPULATIONS
` 8.1 Pregnancy
`
`
` 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
`
`
`
`Reference ID: 3623294
`
`
`5
`
`
`
`Page 5 of 13
`
`

`

`
`
`
`
`
`
`
`
`intravenous doses up to approximately 6 times the MRHD (on an AUC basis at a
`
`maternal dose of 5 mg/kg/day in rabbits).
`
` 8.2 Labor and Delivery
`
`
`
` No information is available on the effects of KALBITOR during labor and delivery.
`
`
`
`
`
`
` 8.3 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.
`
`
`
`
`
` 8.4 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.
`
`
`
`
`
`
`
`
`
`
`
` 8.5 Geriatric 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.
`
`
`
`
` 10 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.
`
`
`
` 11 DESCRIPTION
`
`
` KALBITOR (ecallantide) is a human plasma kallikrein inhibitor for injection for
`
`
`
`
`
` subcutaneous use. Ecallantide is a 60-amino-acid protein produced in Pichia pastoris
` yeast cells by recombinant DNA technology.
`
`
`
`
` KALBITOR is a clear and colorless, sterile, and nonpyrogenic solution. Each vial
`
`
`
`
`
` contains 10 mg ecallantide as the active ingredient, and the following inactive ingredients:
` 0.76 mg disodium hydrogen orthophosphate (dihydrate), 0.2 mg monopotassium
`
`
`
` phosphate, 0.2 mg potassium chloride, and 8 mg sodium chloride in water for injection,
`
`
`
`
`
`Reference ID: 3623294
`
`
`6
`
`
`
`Page 6 of 13
`
`

`

`
`
`
`
`
`
`
`
`
`
`USP. KALBITOR is preservative free, with a pH of approximately 7.0. A 30 mg dose is
`
`
`
`
`supplied as 3 vials each containing 1 mL of 10 mg/mL KALBITOR. Vials are intended
`
`for single use.
`
`
`
`
` 12 CLINICAL PHARMACOLOGY
` 12.1 Mechanism of Action
`
`
`
` Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations to
`
`
`
`C1-esterase-inhibitor (C1-INH) located on Chromosome 11q and inherited as an
`autosomal dominant trait. HAE is characterized by low levels of C1-INH activity and
`
`
`
`low levels of C4. C1-INH functions to regulate the activation of the complement and
`
`
`
`intrinsic coagulation (contact system pathway) and is a major endogenous inhibitor of
`
`
`
`
`plasma kallikrein. The kallikrein-kinin system is a complex proteolytic cascade involved
`
`
`in the initiation of both inflammatory and coagulation pathways. One critical aspect of
`
`
`this pathway is the conversion of High Molecular Weight (HMW) kininogen to
`
`
`bradykinin by the protease plasma kallikrein. In HAE, normal regulation of plasma
`
`
`kallikrein activity and the classical complement cascade is therefore not present. During
`
`
`
`
`attacks, unregulated activity of plasma kallikrein results in excessive bradykinin
`
`
`
`generation. Bradykinin is a vasodilator which is thought by some to be responsible for
`
`
`the characteristic HAE symptoms of localized swelling, inflammation, and pain.
`
`
`
`
`KALBITOR is a potent (Ki = 25 pM), selective, reversible inhibitor of plasma kallikrein.
`
`
`
`
`KALBITOR binds to plasma kallikrein and blocks its binding site, inhibiting the
`
`conversion of HMW kininogen to bradykinin. By directly inhibiting plasma kallikrein,
`
`
`
`KALBITOR reduces the conversion of HMW kininogen to bradykinin and thereby treats
`
`
`
`
`symptoms of the disease during acute episodic attacks of HAE.
`
`
`
`
`
`
`
` 12.2 Pharmacodynamics
`
`
`
`
` No exposure-response relationships for KALBITOR to components of the complement or
` kallikrein-kinin pathways have been established.
`
`
`
`
`
`
`
`
` The effect of KALBITOR on activated partial thromboplastin time (aPTT) was measured
`
`
`
`
`
` because of potential effect on the intrinsic coagulation pathway. Prolongation of aPTT
` has been observed following intravenous dosing of KALBITOR at doses ≥20 mg/m2 . At
`
`
`
`
`
`
`80 mg administered intravenously in healthy subjects, aPTT values were prolonged
`
`
`
`approximately two-fold over baseline values and returned to normal by 4 hours post-
`
`
`
`
`
`dose.
`
`
`
`
`
`
`For patients taking KALBITOR, no significant QT prolongation has been seen. In a
`
`
`
`
`
`randomized, placebo-controlled trial (EDEMA4) studying the 30 mg subcutaneous dose
`
`
`
`
`
`
`versus placebo, 12-lead ECGs were obtained at baseline, 2 hours and 4 hours post-dose
`
`
`
`
`
`
`(covering the time of expected Cmax), and at follow-up (day 7). ECGs were evaluated for
`
`
`
`
`
`
`
`PR interval, QRS complex, and QTc interval. KALBITOR had no significant effect on
`
`
`the QTc interval, heart rate, or any other components of the ECG.
`
`
`
`
`
`
`Reference ID: 3623294
`
`
`7
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`Page 7 of 13
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` 12.3 Pharmacokinetics
`
`
`
`
`
` Following the administration of a single 30 mg subcutaneous dose of KALBITOR to
`
` healthy subjects, a mean (± standard deviation) maximum plasma concentration of
`
`
` 586 ± 106 ng/mL was observed approximately 2 to 3 hours post-dose. The mean area
`
`
`
`
` under the concentration-time curve was 3017 ± 402 ng*hr/mL. Following
`
`
`
`
`
`administration, plasma concentration declined with a mean elimination half-life of
`2.0 ± 0.5 hours. Plasma clearance was 153 ± 20 mL/min and the volume of distribution
`
`
`
`
`
`
`
`was 26.4 ± 7.8 L. Based on a population pharmacokinetic analysis, body weight, age,
`
`
`
`and gender were not found to affect KALBITOR exposure significantly. Ecallantide is a
`
`
`
`
`
`
`
`
`small protein (7054 Da) and renal elimination in the urine of treated subjects has been
`
`
`demonstrated.
`
`
`
`
`No pharmacokinetic data are available in patients or subjects with hepatic or renal
`
`
`impairment.
`
`
`
`
` 13 NONCLINICAL TOXICOLOGY
`
` 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`
` A two-year study was conducted in rats to assess the carcinogenic potential of
` KALBITOR. 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).
`
`
` KALBITOR 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).
`
`
`
` 14 CLINICAL STUDIES
`
`
` The safety and efficacy of KALBITOR to treat acute attacks of hereditary angioedema in
`
`
`
`
`
`
`
`
`
`
` adolescents and adults were evaluated in 2 randomized, double-blind, placebo-controlled
` trials (EDEMA4 and EDEMA3) in 168 patients with HAE. Patients having an attack of
`
`
`
`
`
`
`
`
`
`
` hereditary angioedema, at any anatomic location, with at least 1 moderate or severe
` symptom, were treated with 30 mg subcutaneous KALBITOR or placebo. Because
`
`
`
`
`
` patients could participate in both trials, a total of 143 unique patients participated. Of the
`
`
` 143 patients, 94 were female, 123 were Caucasian, and the mean age was 36 years (range
`
`
`
`
`
` 11-77). There were 64 patients with abdominal attacks, 55 with peripheral attacks, and
`
`
`
`
`24 with laryngeal attacks.
`
`
` In both trials, the effects of KALBITOR were evaluated using the Mean Symptom
`
`
`
`
`
`
`
` Complex Severity (MSCS) score and the Treatment Outcome Score (TOS). These
`
` endpoints evaluated attack severity (MSCS) and patient response to treatment (TOS) for
`
`
`
` an acute HAE attack.
`
`
`
`
`
`
`Reference ID: 3623294
`
`
`8
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`Page 8 of 13
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`

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`
` MSCS score is a point-in-time measure of symptom severity. At baseline, and post-
` dosing at 4 hours and 24 hours, patients rated the severity of each affected symptom on a
`
`
`
`
`
`
` categorical scale (0 = normal, 1 = mild, 2 = moderate, 3 = severe). Patient-reported
`
`
`
`
`
` severity was based on each patient’s assessment of symptom impact on their ability to
`
` perform routine activities. Ratings were averaged to obtain the MSCS score. The
`
`
`
`
`
` endpoint was reported as the change in MSCS score from baseline. A decrease in MSCS
` score reflected an improvement in symptom severity; the maximum possible change
`
`
`
`
` toward improvement was -3.
`
`
`
`
`
`
`
`
`
`
`
`
` TOS is a measure of symptom response to treatment. At 4 hours and 24 hours post-
`
` dosing, patient assessment of response for each anatomic site of attack involvement was
`
`
`
` recorded on a categorical scale (significant improvement [100], improvement [50], same
`
` [0], worsening [-50], significant worsening [-100]). The response at each anatomic site
`
`
`
`
`
` was weighted by baseline severity and then the weighted scores across all involved sites
`
`
`
`
` were averaged to calculate the TOS. A TOS value >0 reflected an improvement in
`
`
`
` symptoms from baseline. The maximum possible score was +100.
`
`
`
`
`
`
`
` EDEMA4
`
`
`
`
`
` EDEMA4 was a randomized, double-blind, placebo-controlled trial in which 96 patients
` were randomized 1:1 to receive KALBITOR 30 mg subcutaneous or placebo for acute
`
`
`
`
`
`
`
`
`
`
` attacks of HAE. The primary endpoint was the change from baseline in MSCS score at
` 4 hours, and the TOS at 4 hours was a key secondary endpoint. Patients treated with
`
`
`
`
` KALBITOR demonstrated a greater decrease from baseline in the MSCS than placebo
`
`
`
` and a greater TOS than patients with placebo and the results were statistically significant
` (Table 2). At 24 hours, patients treated with KALBITOR also demonstrated a greater
`
`
`
`
` decrease from baseline in the MSCS than placebo (-1.5 vs. -1.1; p = 0.04) and a greater
`
` TOS (89 vs. 55, p = 0.03).
`
`
`
`
`
`
`
`
`
` Table 2:
`
`
`
`
` Placebo
`
` (N=48)
`
` 42
`
`
` -0.4
` -0.6, -0.1
`
`
`
` 42
`
` 8
` -12, 28
`
`
`
`
`
`
` 0.010
`
`
`
`
` 47
`
` 53
` 39, 68
`
`
`
` Change in MSCS Score and TOS at 4 Hours
` EDEMA4
`
`
` KALBITOR
`
` (N=48)
` Change in MSCS Score at 4 Hours
`
`
`
` n
` 47
` Mean
` -0.8
`
`
` -1.0, -0.6
`
` 95% CI
`
`
` P-value
` TOS at 4 Hours
`
`
` n
` Mean
`
`
` 95% CI
` 0.003
`
`
` P-value
`
` MSCS: Mean Symptom Complex Severity
`
` TOS: Treatment Outcome Score
`
`
` CI: confidence interval
`
`
`
`
`
`
`
` EDEMA3
`
` KALBITOR
`
` (N=36)
`
` 34
`
`
` -1.1
` -1.4, -0.8,
`
`
`
` 34
`
` 63
` 49, 76
`
`
`
`
` 0.041
`
`
`
` 0.045
`
`
` Placebo
`
` (N=36)
`
` 35
`
`
` -0.6
` -0.8, -0.4
`
`
`
` 35
`
` 36
` 17, 54
`
`
`
`
`Reference ID: 3623294
`
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`9
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`Page 9 of 13
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`More patients in the placebo group (24/48, 50%) required medical intervention to treat
`
`
`
`
`unresolved symptoms within 24 hours compared to the KALBITOR-treated group
`
`(16/48, 33%).
`
`
`
`Some patients reported improvement following a second 30 mg subcutaneous dose of
`
`KALBITOR, administered within 24 hours following the initial dose for symptom
`
`
`persistence or relapse, but efficacy was not systematically assessed for the second dose.
`
`
`EDEMA3
`
`
`
`
`
`
`
`EDEMA3 was a randomized, double-blind, placebo-controlled trial in which 72 patients
`
`
`were randomized 1:1 to receive KALBITOR or placebo for acute attacks of HAE.
`
`EDEMA3 was similar in design to EDEMA4 with the exception of the order of the
`
`
`prespecified efficacy endpoints. In EDEMA3, the primary endpoint was the TOS at
`
`
`
`4 hours, and the key secondary efficacy endpoint was the change from baseline in MSCS
`
`
`at 4 hours. As in EDEMA4, patients treated with KALBITOR demonstrated a greater
`
`
`decrease from baseline in the MSCS than placebo and a greater TOS than patients treated
`
`
`with placebo and the results were statistically significant (Table 2).
`
`
`In addition, more patients in the placebo group (13/36, 36%) required medical
`
`intervention to treat unresolved symptoms within 24 hours compared to the
`
`KALBITOR-treated group (5/36, 14%).
`
` 16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`
` KALBITOR (ecallantide) is supplied as three 10 mg/mL single-use vials packaged in a
`
`
`
` carton. Each vial contains 10 mg of ecallantide. Each vial contains a slight overfill.
`
`
`
` • NDC (47783-101-01): 3 single-use vials in 1 carton
`
`
`
`
` KALBITOR should be kept refrigerated (2ºC to 8ºC/36ºF to 46ºF). Vials removed from
`
`
`
`
`
` refrigeration should be stored below 86ºF/30ºC and used within 14 days or returned to
`
` refrigeration until use.
`
`
`
`
`
`
`
`
`
` Protect vials from light until use.
`
`
`
`
`
` Do not use beyond the expiration date.
`
`
`
`See FDA-approved patient labeling (Medication Guide)
`
`
`
` 17 PATIENT COUNSELING INFORMATION
`
`
`
`• Advise patients that KALBITOR may cause anaphylaxis and other hypersensitivity
`
`
`
`
`
`reactions. Advise patients that KALBITOR should be administered by a healthcare
`
`
`
`professional with appropriate medical support to manage anaphylaxis and hereditary
`
`angioedema. Instruct patients who have known clinical hypersensitivity to
`
`
`
`
`Reference ID: 3623294
`
`
`10
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`Page 10 of 13
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`

`
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`KALBITOR not to receive additional doses of KALBITOR. [see Boxed Warning,
`
`
`Contraindications (4), and Warnings and Precautions (5.1)]
`
`
`
`• Advise patients to consult the Medication Guide for additional information
`
`
`
`regarding the risk of anaphylaxis and other hypersensitivity reactions.
`
`
`
`
`
`Reference ID: 3623294
`
`
`11
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`Page 11 of 13
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`

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`
`
`
`
`
`
`
`
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`
`
`
`
`
`
` Medication Guide
` KALBITOR® (KAL-bi-tor)
`
`(ecallantide)
`
`
`
` Read this Medication Guide before you start receiving KALBITOR and before each
` treatment. There may be new information. This Medication Guide does not take the
`
`
`
` place of talking to your doctor about your medical condition or your treatment.
`
`
`
`
` What is the most important information that I should know about KALBITOR?
`
`
`
`
`
`
` Serious allergic reactions may happen in some people who receive KALBITOR. These
` allergic reactions can be life-threatening and usually happen within 1 hour after receiving
`
`
`
`
`
`KALBITOR.
`
` • KALBITOR should be given to you by a doctor or nurse in a healthcare setting
`
`
`
`
`
`
` where serious allergic reactions and hereditary angioedema (HAE) can be treated.
`
` • Symptoms of a serious allergic reaction to KALBITOR can be similar to the
`
`
`
`
`
` symptoms of HAE, the condition that you are being treated for. Your doctor or
`
`
`
` nurse should watch you for any signs of a serious allergic reaction after treatment
`
`
` with KALBITOR.
`
` • Tell your doctor or nurse right away if you have any of these symptoms of a
`
` serious allergic reaction during or after treatment with KALBITOR:
`
`  wheezing, shortness of breath, cough, chest tightness, or trouble
`
`
`
` breathing
` dizziness, fainting, fast or weak heartbeat, or feeling nervous
`
`
`
` reddening of the face, itching, hives, or feeling warm
` swelling of the throat or tongue, throat tightness, hoarse voice, or
`
` trouble swallowing
` runny nose, nasal congestion, or sneezing
`
`
`
`
`
`
`
`
`
`
`
` What is KALBITOR?
`
` KALBITOR is a prescription medicine used to treat sudden attacks of hereditary
`
`
`
`
` angioedema (HAE) in people 12 years of age and older.
`
` KALBITOR is not a cure for HAE.
`
`
` It is not known if KALBITOR is safe and effective in children under 12 years of age.
`
`
` Who should not receive KALBITOR?
`
`
`
`
`
`
`
`
` Do not receive KALBITOR if you are allergic to KALBITOR.
`
`
`
` What should I tell my doctor before I receive KALBITOR?
` Before receiving KALBITOR, tell your doctor if you:
`
`
`
` • have ever had an allergic reaction to KALBITOR. See “Who should not receive
`
`
`
`
`
` KALBITOR?”
`
`
` • are pregnant or plan to become pregnant. It is not known if KALBITOR will harm
`
`
` your unborn baby.
`
`
` • are breast-feeding or plan to breast-feed. It is not known if KALBITOR passes into
`
`
` your breast milk.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3623294
`
`1
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`Page 12 of 13
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`Tell your doctor about all the medicines you take, including prescription and over-the­
`
`
`
`counter medicines, vitamins, and herbal supplements.
`
`
`
`Know the medicines you take. Keep a list of them to show to your doctor and pharmacist
`
`
`
`when you get a new medicine.
`
`
`
`
`
`How wi