Firazyr - Product Information
|Manufacture:||Shire US, Inc.|
|Class:||Cardiovascular agents, Miscellaneous cardiovascular agents|
|Form:||Liquid solution, Subcutaneous (SC)|
|Ingredients:||icatibant acetate, sodium hydroxide, acetic acid, sodium chloride, water|
Summary Product Information
|Dosage Form /|
|Clinically Relevant Nonmedicinal|
|subcutaneous||Solution /10 mg/mL||none|
For a complete listing see Dosage Forms,
Composition and Packaging section.
Indications and Clinical Use
FIRAZYR (icatibant acetate) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults with C1-esterase inhibitor deficiency.
Patients or a caregiver should be trained in subcutaneous injection techniques under the guidance of a healthcare professional before they can administer FIRAZYR (see Dosage and Administration).
Geriatrics (> 65 years of age)
Limited information is available regarding the use of FIRAZYR in patients older than 65 years of age (see Warnings and Precautions and Action and Clinical Pharmacology,Pharmacokinetics).
Pediatrics (<18 years of age)
There are no data to support the use of FIRAZYR in children and adolescents. Repeat administration of icatibant reversibly delayed sexual maturation in rats and dogs (see Toxicology).
Patients who are hypersensitive to icatibant acetate or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging.
Warnings and Precautions
Patients or a caregiver should be trained in subcutaneous injection techniques under the guidance of a healthcare professional before they can administer FIRAZYR. The first administration of FIRAZYR should be performed under the guidance of a healthcare professional before beginning the self-administration of FIRAZYR (see Dosage and Administration).
Patients with laryngeal symptoms or any swelling causing breathing difficulties should seek medical attention immediately after administration of FIRAZYR (see Dosage and Administration).
Ischemic Heart Disease
Icatibant has been shown to aggravate induced cardiac ischemia in several animal models by antagonising the cardioprotective effects of bradykinin (see Detailed Pharmacology). Use of icatibant acetate in patients with acute ischemic heart disease or unstable angina pectoris could theoretically lead to a decrease in coronary blood flow and a deterioration in cardiac function.
Use of icatibant acetate in the weeks following a stroke could theoretically attenuate the positive late phase neuroprotective effects of bradykinin.
No formal studies of the use of FIRAZYR in pregnant women have been conducted. FIRAZYR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Animal studies showed that icatibant had effects in late stage pregnancy where icatibant exhibited a tocolytic effect resulting in delayed parturition and fetal death at 0.5 and 2-fold the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively). Increased fetal distress and perinatal death were observed at high doses (at 7-fold the MRHD, on an AUC basis at a maternal daily dose of 10 mg/kg/day). The potential risk for humans is unknown (see Toxicology).
Animal studies showed that icatibant is excreted in the milk of lactating rats at concentrations similar to those in maternal blood (see Detailed Pharmacology). It is unknown whether icatibant is excreted in human breast milk. Many drugs are excreted in human milk, therefore caution should be exercised.
Pediatrics (< 18 years of age)
The safety and efficacy of FIRAZYR in children and adolescents have not been evaluated. Repeat administration of icatibant reversibly delayed sexual maturation in rats and dogs (see Toxicology).
Geriatrics (> 65 years of age)
Limited information is available for FIRAZYR in patients older than 65 years of age. Studies demonstrated that the total exposure to icatibant in geriatric patients was higher than in young adults (see Action and Clinical Pharmacology, Pharmacokinetics).
Data from subjects with a wide range of hepatic insufficiency suggest that icatibant exposure is not influenced by hepatic impairment. No dosage adjustment is required in patients with hepatic impairment.
Limited data from subjects with renal insufficiency suggest that icatibant exposure is not influenced by renal impairment. No dosage adjustment is required in patients with renal impairment.
Adverse Drug Reaction Overview
Almost all patients (97%) who were treated with subcutaneous (SC) FIRAZYR in clinical trials developed reactions at the site of injection including erythema, swelling, warm sensation, burning, itching and /or cutaneous pain. These reactions were generally mild to moderate in severity, transient, and the majority (62%) resolved without intervention within 4 hours of FIRAZYR dosing. Other adverse reactions reported by patients treated with FIRAZYR (≥1% to <10% of patients) were dizziness, headache, nausea, rash, erythema, pruritus, pyrexia, and increased transaminase (ALT and AST).
The overall incidence of serious adverse events (SAEs) was low in the clinical development program. In the Phase I and II studies, only 2 SAEs were reported within 14 days of FIRAZYR treatment (manic episode, HAE); these were judged as not related/probably not related to treatment. In the controlled part of the three Phase III studies, only one SAE (cystitis) was reported within 14 days of dosing with FIRAZYR. This event was judged as not related to treatment. In the repeated treatment part of the Phase III studies, safety was evaluated for up to 15 FIRAZYR-treated attacks for patients. Sixteen patients experienced a total of 22 SAEs that occurred within 14 days of FIRAZYR administration. The only SAE that occurred in more than one patient was worsening or recurrence of HAE. Two SAEs were considered by the investigator as related to FIRAZYR treatment (events of arrhythmia and noncardiac chest pain).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
In all clinical studies, a total of 1,411 HAE attacks have been treated with 30 mg FIRAZYR administered SC.
The safety of FIRAZYR was evaluated in three controlled Phase III trials that included 223 patients who received subcutaneous injection of FIRAZYR 30 mg (n=113), placebo (n=75), or tranexamic acid (n=38), administered by healthcare professionals. Study drug treatment occurred within 6 hours of the attack becoming at least moderate in severity for abdominal or cutaneous attacks. The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were Caucasian. Patients were excluded if they were receiving treatment with an angiotensin converting enzyme inhibitor; had evidence of coronary artery disease based on medical history (e.g., unstable angina pectoris, severe coronary heart disease or congestive heart failure [New York Heart Association class 3 and 4]) that in the investigator's judgment would be a contraindication for participation in the trial; or were pregnant or breastfeeding.
The safety data described below represent adverse reactions observed from the two placebocontrolled Phase III trials, consisting of 77 patients who were randomized to receive FIRAZYR at a dose of 30 mg SC, and 75 who were randomized to receive placebo. The safety data represent events occurring within 14 days of treatment of the patient's first attack. The most frequently reported adverse reactions occurring in greater than 2% of FIRAZYR-treated patients (2 or more patients), and at a higher frequency with FIRAZYR compared to placebo, are shown in Table 1. The severity of adverse reactions was assessed by the investigator based on the following definitions: mild - no limitation of usual activities; moderate - some limitation of usual activities; and severe – inability to carry out usual activities. The majority of adverse reactions reported following FIRAZYR treatment were judged to be mild or moderate in severity.
(N = 77) (%)
(N = 75) (%)
|Abdominal distension||2 (3)||0 (0)|
|Abdominal pain||2 (3)||0 (0)|
|Diarrhea||2 (3)||0 (0)|
|General disorders and|
administration site conditions
|Injection site reactionb||75 (97)||25 (33)|
|Pyrexia||3 (4)||0 (0)|
|Infections and infestations|
|Nasopharyngitis||2 (3)||0 (0)|
|Sinusitis||2 (3)||1 (1)|
|Urinary tract infection||2 (3)||1 (1)|
|Transaminase increased c||3 (4)||0 (0)|
|Nervous System Disorders|
|Dizziness||2 (3)||1 (1)|
|Respiratory, thoracic and|
|Nasal congestion||2 (3)||0 (0)|
a Events occurring within 14 days of study drug administration. Five patients who experienced laryngeal attacks (mild to moderate in severity) were randomized in Study 1 and are included in this table (3 in the FIRAZYR group and 2 in the placebo group); patients with laryngeal attacks were not randomized in Studies 2 and 3 and are excluded from this table.
b Injection site reactions include any of the following: injection site burning, injection site erythema, injection site swelling, injection site pain, injection site pruritus, and injection site warmth.
c Alanine aminotransferase (ALT), Aspartate minotransferase (AST)
The third Phase III trial was active-controlled and was comprised of 36 patients who received a single subcutaneous injection of FIRAZYR 30 mg and 38 patients who received the comparator, tranexamic acid. Adverse reactions for FIRAZYR were similar in nature and frequency to those reported in Table 1.
In all three Phase III trials, patients were eligible for FIRAZYR treatment of subsequent attacks in an open-label extension. Patients were treated with FIRAZYR 30 mg and could receive up to 3 doses of FIRAZYR 30 mg administered SC at least 6 hours apart for each attack. Across the controlled and open-label phases of the studies, a total of 237 patients were treated with FIRAZYR for at least one acute attack of HAE and 68 were treated for at least 5 attacks. A Page 8 of 32 limited number of patients experienced up to 15 FIRAZYR-treated attacks. Adverse reactions similar in nature and frequency to those seen in the controlled phase of the trials were observed. Other adverse reactions reported (<5% incidence) included worsening or recurrence of HAE, headache, rash and nausea.
No anaphylactic reactions were reported with FIRAZYR. One patient experienced non-serious adverse reactions of generalized pruritus (moderate in severity) and generalized cutaneous burning sensation approximately 5 hours after injection with FIRAZYR during the patient's eighth treated attack. An antihistamine was administered and the symptoms resolved later that same day. There was no associated rash, no respiratory symptoms or compromise, and no abnormalities in vital signs. There were no similar symptoms or other symptoms related to hypersensitivity during the patient's ninth FIRAZYR-treated attack. At the tenth treated attack, the patient experienced mild generalized pruritus following FIRAZYR administration, which resolved the same day.
In an open-label study, the safety profile of FIRAZYR in patients who self-administered FIRAZYR was similar to that of patients whose therapy was administered by healthcare professionals.
Abnormal Hematologic and Clinical Chemistry Findings
Serum chemistry and hematology parameters were measured at baseline and then at day 2 and day 14 post-treatment during the controlled part of the Phase III studies, and at day 14 posttreatment during the open-label extension phases of these studies.
Liver enzyme tests
Transaminase levels (ALT, AST) were increased in 4% of patients treated with FIRAZYR. See Table 1.
Post-Market Adverse Drug Reactions
The following adverse reactions have been identified during post-marketing experience with icatibant. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Acute myocardial infarction, chest pain.
One case of serious AST/ALT increase was reported in a patient with multiorgan failure due to sepsis.
Formal drug-drug interaction studies have not been conducted with icatibant acetate. Pharmacokinetic drug interactions involving CYP450 are not expected (see Action and Clinical Pharmacology, Metabolism). The treatment with FIRAZYR may interfere with the mode of action of angiotensin converting enzyme inhibitor (ACE-I) products.
enzyme inhibitor (ACE-I)
|T||Co-administration of FIRAZYR|
and ACE-I is not expected to lead
to changes in blood or tissue
levels of either medicinal product.
A theoretical mode of action for
ACE-I in treatment of cardiac
indications is the increase of
systemic bradykinin. Thus,
treatment with FIRAZYR may
interfere with the mode of action
of ACE-I products by blocking
the bradykinin 2 receptor.
FIRAZYR has been reported to
attenuate the blood pressurelowering
effects of ACE-I in
normotensive and hypertensive
|Caution is recommended if|
FIRAZYR is administered
concomitantly with ACE-I products.
Legend: T = Theoretical
Interactions with food have not been established.
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established
FIRAZYR may have an influence on the ability to drive or use machines. Fatigue, lethargy, tiredness, somnolence, and dizziness have been reported following the use of FIRAZYR. These symptoms may occur as a result of an attack of HAE. Patients should be advised not to drive or use machines if they feel tired or dizzy.
Dosage and Administration
Recommended Dose and Dosage Adjustment
The recommended dose of FIRAZYR is 30 mg administered by slow subcutaneous injection in the abdominal area. Additional doses may be administered at intervals of at least 6 hours if response is inadequate or if symptoms recur. No more than 3 doses may be administered in any 24 hour period. The safety of more than 8 injections in a month has not been investigated in clinical trials.
FIRAZYR is supplied as a single-dose pre-filled syringe that delivers 3 mL of solution, equivalent to a 30 mg icatibant acetate dose. Each syringe and needle are for single-use only and should be discarded in a sharps container after use.
FIRAZYR is not to be injected if the patient has only pre-attack symptoms (e.g. paresthesia or erythema).
FIRAZYR should be inspected visually for particulate matter and discoloration prior to administration. The drug solution should be clear and colorless. Do not administer if the product contains particulates or is discolored.
Attach the provided 25 gauge needle to the syringe hub and screw on securely. Do not use a different needle. Disinfect the injection site and administer FIRAZYR by subcutaneous injection in the abdominal area over at least 30 seconds.
Patients (or their caregivers) may self-administer FIRAZYR upon recognition of symptoms of an HAE attack. They should be trained in subcutaneous injection techniques by a healthcare professional before they can administer FIRAZYR. The first administration of FIRAZYR should be performed under the guidance of a healthcare professional before beginning the selfadministration of FIRAZYR.
Self-administration training is also available to patients directly through Shire's HAE Patient Support Program.
Patients with laryngeal symptoms or any swelling causing breathing difficulties should seek medical attention immediately after administration of FIRAZYR and need to be managed in an appropriate medical institution after injection until the physician considers discharge to be safe.
The safety and efficacy of FIRAZYR in children 0-18 years of age have not been established.
Patients >65 years of age are likely to have increased systemic exposure to FIRAZYR compared to younger patients. The magnitude of these differences is not expected to be clinically relevant for safety or efficacy, and therefore no dose adjustment is necessary for elderly patients.
Patients with Hepatic Impairment
No dosage adjustment is required.
Patients with Renal Impairment
No dosage adjustment is required.
In a clinical study evaluating a 90 mg dose (30 mg in each of 3 subcutaneous sites), the adverse event profile was similar to that seen with 30 mg administered in a single subcutaneous site.
In another clinical study, a dose of 3.2 mg/kg intravenously (approximately 8 times the therapeutic dose) caused transient erythema, itching or hypotension in healthy subjects. No therapeutic intervention was necessary.
|For management of a suspected drug overdose, contact your regional Poison Control Centre.|
Action and Clinical Pharmacology
Mechanism of Action
Hereditary angioedema (HAE) types I and II is an autosomal dominant disease. It is caused by absence or dysfunction of C1-esterase-inhibitor, a key regulator of the Factor XII/kallikrein proteolytic cascade, that leads to bradykinin production. Bradykinin is a vasodilator which is the key mediator of the characteristic HAE symptoms of localized swelling, inflammation and pain. An HAE attack usually lasts between 2 to 5 days.
Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin and thereby treats the clinical symptoms of an acute, episodic attack of HAE (see Detailed Pharmacology).
Following bradykinin challenge, development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia was prevented in healthy young subjects who received doses of 0.8 mg/kg over 4 hours, 1.5 mg/kg/day or 0.15 mg/kg/day for 3 days. Icatibant was shown to be a competitive antagonist when the bradykinin challenge dose was increased 4-fold. Doses of 0.4 and 0.8 mg/kg inhibited response to challenge with bradykinin for 6 to 12 hours after the infusion was initiated.
In a randomized, placebo- and positive-controlled, crossover ECG assessment study in healthy subjects (N=70), single subcutaneous doses of icatibant 30 mg (therapeutic dose) and 90 mg (3X supratherapeutic dose) were not associated with effects on the QTc interval, the QRS duration, the PR interval, or heart rate.
| ||Cmax||tВЅ (h)||AUC0-4||Clearance||Volume of|
|974 В± 280|
|2165 В± 568|
|245 В± 58 mL/min||29.0 В± 8.7 L|
Following subcutaneous administration of a single 30 mg dose of FIRAZYR to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (Cmax) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the plasma concentration-time curve (AUC0−∞) after a single 30 mg dose was 2165 ± 568 ng·hr/mL, with no evidence of accumulation of icatibant following three 30 mg doses administered 6 hours apart.
Following subcutaneous administration of a single 30 mg dose the volume of distribution at steady state (Vss) was 29.0 ± 8.7 L.
Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites. Icatibant is not degraded by oxidative metabolic pathways, is not an inhibitor of major cytochrome P450 (CYP) isoenzymes (CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4) and is not an inducer of CYP 1A2 and 3A4.
Following subcutaneous administration of a 30 mg dose, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours.
Inactive metabolites are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug.
Special Populations and Conditions
The plasma clearance was higher in patients with increased body weight.
Elderly patients (>65 years of age) have been shown to have increased systemic exposure to icatibant.
Hepatic and Renal Insufficiency
Clinical pharmacokinetic studies demonstrate that for mild to moderate impairment of renal or hepatic function, no dose adjustment is necessary. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of icatibant was not dependent on renal function. Icatibant clearance in subjects with a wide range of hepatic impairment (Child-Pugh score ≥ 7 and ≤ 15) was similar to that of healthy subjects.
There are no pharmacokinetic data in children.
Storage and Stability
Store at 2-25° C; do not freeze.
Special Handling Instructions
The solution should be clear and colorless and free from visible particles. Pre-filled syringes are for single use only. Any unused product or waste materials should be disposed of in accordance with local requirements.
Dosage Forms, Composition and Packaging
FIRAZYR is supplied as a sterile solution for subcutaneous injection in a single use pre-filled syringe. The solution is clear and colorless.
Each pre-filled syringe delivers 3 mL containing icatibant acetate equivalent to 30 mg icatibant. Each mL of the solution contains 10 mg of icatibant. Each mL of solution contains the nonmedicinal ingredients acetic acid glacial, sodium chloride, sodium hydroxide, and water for injection.
3 mL of solution is supplied in a 3 mL pre-filled syringe (clear type I glass) with grey plunger stopper (bromobutyl coated with fluorocarbon polymer), a Luer-lock with a screw tip cap, and a white polypropylene backstop. A hypodermic needle (25 G; 16 mm) is included in the pack.
Pack includes one pre-filled syringe with one needle.
A patient self-administration kit, containing a travel case, needle protection devices and alcohol wipes can also be obtained through Shire's HAE patient support program.