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治疗遗传性血管水肿抗药艾替班特预填充注射剂获欧盟批准上市

2012-12-26 16:34:58 作者：新特药房来源：互联网浏览次数：81 文字大小：【大】【中】【小】

简介： 欧盟批准德国Jerini公司的主导药物缓激肽拮抗药艾替班特预填充注射剂（Icatibant，Firazyr）上市，用于治疗遗传性血管水肿（HAE）急性发作。HAE是退行性病变有可能威胁生命的遗传性疾病，特征是自发和复 ...

关键字：艾替班特预填充注射剂 Firazyr 缓激肽拮抗药复发性水肿

欧盟批准德国Jerini公司的主导药物缓激肽拮抗药艾替班特预填充注射剂（Icatibant，Firazyr）上市，用于治疗遗传性血管水肿（HAE）急性发作。HAE是退行性病变有可能威胁生命的遗传性疾病，特征是自发和复发性水肿。

2001年开始研发的本品是该类新化合物中的第1个，作为肽类激素缓激肽的拮抗剂通过阻断B2受体发挥作用。HAE患者体内的缓激肽浓度升高，HAE发作时形成水肿。欧洲药品管理局（EMEA）和美国FDA已批准艾替班特作为罕用药物对症治疗血管水肿的急性发作，并分别给予10年和7年的市场专卖权。本品迄今在临床研究中显示对患者治疗安全有效。本品皮下注射，以预填充注射器包装，室温稳定。

本品对皮肤和腹部血管水肿患者进行了2项重要的临床研究。第1项研究纳入74例患者，比较本品与另1种治疗此种疾病的氨甲环酸的作用；第2项研究56例患者，比较本品与安慰剂的作用。结果表明，本品控制症状较氨甲环酸和安慰剂有效。在这2项研究中，本品组改善患者症状的时间较氨甲环酸组和安慰剂组缩短，分别为2.0～2.5小时、12.0小时和4.6小时。

本品最常见的不良反应是红肿，温热感，灼热，瘙痒，疼痛。

本品推荐剂量为一次性注射，若症状持续或复发，可在用药后6小时第2次注射。按需，可再过6小时第3次注射，但24小时内不可多于3剂。

Angioedema is a well-demarcated, localized oedema of the skin and suncutaeeous tissues (urticaria oedema involves dermis alone). There is local venodilation and perivenular infiltrates of lymphocytes, eosinophils, and neutrophils.
Introduction
■Type 1 - 85% deficiency of C1E - INH
■Type 2 - 15% enzyme normal C1E - INH dysfunctional
■75% have family history (25% speontaneous gene mutation)
■C1E-INH is a serine protease inhibitor. It is the major inhibitor of both factors 12A and kallikrein and the only known inhibitor of activation of C1 from complement pathway
■C1E-INH regulates the activity of two plasma cascade systems. Responsible for vasodilation and vasopermeability
■HAE patients have reduced or abnormal C1E-INH causing uncontrolled activation of complement and coagulation cascade, particularly in increasing bradykinin resulting in angio-oedema
■Acute attacks are precipitated by trauma (dental), anxiety and stress
■Occasionally triggered by malignancy, glomerulonephritis, rheumatoid arthritis, thyroiditis, Sjogren's syndrome, and pernicious anaemia
■ACE inhibitors can also cause particularly in healthy people.
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Firazyr
Generic Name: icatibant acetate
Dosage Form: injection, solution

Indications and Usage for Firazyr
Firazyr® (icatibant) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.

Firazyr® (icatibant) is indicated for the treatment of acute attacks of hereditary angioedema (HAE) in adults 18 years of age and older.

Firazyr Dosage and Administration
Recommended Dosing
The recommended dose of Firazyr is 30 mg administered by subcutaneous (SC) 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.

Administration Instructions
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 over at least 30 seconds.

Patients may self-administer Firazyr upon recognition of symptoms of an HAE attack after training under the guidance of a healthcare professional [see Patient Counseling Information (17)].

Dosage Forms and Strengths
Firazyr injection is supplied in a prefilled syringe delivering 30 mg icatibant. Each syringe delivers 3 mL solution with a concentration of 10 mg per mL.

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Contraindications
None.
Warnings and Precautions
Laryngeal Attacks
Given the potential for airway obstruction during acute laryngeal HAE attacks, patients should be advised to seek medical attention in an appropriate healthcare facility immediately in addition to treatment with Firazyr.

Adverse Reactions
Clinical Trials Experience
The safety of icatibant was evaluated in three controlled trials that included 223 patients who received Firazyr 30 mg (n=113), placebo (n=75), or comparator (n=38). The mean age at study entry was 38 years (range 18 to 83 years), 64% were female, and 95% were white. The data described below represent adverse reactions observed from the two placebo-controlled trials, consisting of 77 patients who received Firazyr at a dose of 30 mg SC, and 75 who received placebo.

The most frequently reported adverse reactions (occurring in greater than 1% of patients and at a higher rate with Firazyr versus placebo) are shown in Table 1.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Table 1 Adverse reactions observed in >1% of patients with acute attacks of HAE and at a higher rate with Firazyr versus placebo in the placebo-controlled trials*

Firazyr
(N =77) Placebo
(N = 75)

System Organ Class
Preferred Term
Subjects (%)
Subjects (%)

Events occurring within 14 days of study drug administration

Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injection site hypoesthesia, Injection site irritation, Injection site numbness, Injection site edema, Injection site pain, Injection site pressure sensation, Injection site pruritus, Injection site swelling, Injection site urticaria, and Injection site warmth

General disorders and administration site conditions

  Injection site reaction † 75 (97) 25 (33)

  Pyrexia 3 (4) 0

Investigations

Transaminase increased 3 (4) 0

Nervous system disorders

  Dizziness 2 (3) 1 (1)

Events occurring within 14 days of study drug administration
Injection site bruising, Injection site hematoma, Injection site burning, Injection site erythema, Injection site hypoesthesia, Injection site irritation, Injection site numbness, Injection site edema, Injection site pain, Injection site pressure sensation, Injection site pruritus, Injection site swelling, Injection site urticaria, and Injection site warmth

The third trial was active-controlled and was comprised of 35 patients who received Firazyr 30 mg and 38 patients who received the comparator. Adverse reactions for Firazyr were similar in nature and frequency to those reported in Table 1.

In all three controlled trials, patients were eligible for 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 at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg Firazyr for 987 attacks of acute HAE. Adverse reactions similar in nature and frequency were observed to those seen in the controlled phase of the trials. Other adverse reactions reported included rash, nausea, and headache in patients exposed to Firazyr.

The safety of self-administration was evaluated in a separate, open-label trial in 56 patients with HAE. In this trial, the safety profile of Firazyr in patients who self-administered Firazyr was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals.

Immunogenicity

Across repeated treatment in the controlled trials, 4 patients tested positive for anti-icatibant antibodies. Three of these patients had subsequent tests which were negative. No hypersensitivity or anaphylactic reactions were reported with Firazyr. No association between anti-icatibant antibodies and efficacy was observed.

Postmarketing experience

Similar adverse reactions have been observed in postmarketing use as compared to the clinical trials. Because these events 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.

Drug Interactions

ACE Inhibitors

Firazyr is a bradykinin B2 receptor antagonist and thereby has the potential to have a pharmacodynamic interaction with ACE inhibitors where Firazyr may attenuate the antihypertensive effect of ACE inhibitors. Clinical trials to date have excluded subjects taking ACE inhibitors.

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Icatibant was not teratogenic in rats or rabbits; however, it caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits. Firazyr should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Delayed parturition and fetal death in rats occurred at 0.5 and 2-fold, respectively, the maximum recommended human dose (MRHD) (on an AUC basis at maternal doses of 1 and 3 mg/kg, respectively). Increased pre-implantation loss in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg). In rabbits, premature birth and abortion rates increased at a dose that was less than 1/40th the MRHD (on a mg/m2 basis at a maternal dose of 0.1 mg/kg). Studies in rabbits also indicated that pre-implantation loss and increased fetal deaths occurred at 13-fold greater than the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

Nonteratogenic effects: Impairment of pup air-righting reflex and decreased pup hair growth in rats occurred at 7-fold the MRHD (on an AUC basis at a maternal dose of 10 mg/kg).

Labor and Delivery

There are no human studies that have investigated the effects of Firazyr on preterm labor or labor at term; however, animal studies showed that icatibant causes delayed parturition and associated fetal death in rats and premature birth and abortion in rabbits. Delayed parturition occurred in rats at 0.5-fold times the MRHD (on an AUC basis at a maternal dose of 1 mg/kg).

Nursing Mothers

Because many drugs are excreted in human milk, caution should be exercised when Firazyr is administered to a nursing woman. Icatibant is excreted into the milk of lactating rats.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 18 years have not been established.

Geriatric Use

Clinical studies of Firazyr did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Elderly patients are likely to have increased systemic exposure to Firazyr compared to younger (18-45 years) patients [see Clinical Pharmacology (12.3)]. Since other reported clinical experience has not identified differences in efficacy and safety between elderly and younger patients, no dose adjustment is recommended.

Hepatic Impairment

Firazyr was studied in patients with mild to moderate (Child Pugh scores of 5 to 8) hepatic impairment. No change in systemic exposure is noted in these patient populations. No dose adjustment is required in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Renal Impairment

Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with Firazyr had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min. Firazyr is cleared non-renally and hence it is not expected to show any change in systemic exposure in patients with impaired renal function. No dose adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3)].

Overdosage

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 administered intravenously (approximately 8 times the therapeutic dose for HAE) caused erythema, itching and hypotension in healthy subjects. No therapeutic intervention was necessary.

Firazyr Description

Firazyr (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acids. The chemical structure of icatibant acetate is presented in Figure 1.

Figure 1 Chemical Structure

Chemical name: D - Arginyl - L - arginyl - L - prolyl - L[(4R) - 4 - hydroxyprolyl] - glycyl - L[3 - (2 - thienyl)alanyl] - L - seryl - D - (1,2,3,4 - tetrahydroisoquinolin - 3 - ylcarbonyl) - L[(3aS,7aS) - octahydroindol - 2 - ylcarbonyl] - L - arginine, acetate salt

Firazyr is provided as a sterile, isotonic, and buffered solution of icatibant acetate in a single-use, prefilled syringe for subcutaneous administration. Each mL of the solution contains 10 mg of icatibant (free base). Each prefilled syringe delivers 3 mL of solution equivalent to a 30 mg icatibant dose. The solution is clear and colorless.

The solution also contains sodium chloride, glacial acetic acid, sodium hydroxide and water for injection with a pH of approximately 5.5. The solution does not contain preservatives.

Pharmacological class: Icatibant is a bradykinin B2 receptor antagonist.

Firazyr - Clinical Pharmacology

Mechanism of Action

Icatibant is a competitive antagonist selective for the bradykinin B2 receptor, with an affinity similar to bradykinin. Hereditary angioedema is caused by an 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 thought to be responsible for the characteristic HAE symptoms of localized swelling, inflammation, and pain. Icatibant inhibits bradykinin from binding the B2 receptor and thereby treats the clinical symptoms of an acute, episodic attack of HAE.

Pharmacodynamics

Following bradykinin challenge, intravenous administration of Firazyr caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. Firazyr intravenous doses of 0.4 and 0.8 mg/kg infused over 4 hours inhibited response to bradykinin challenge for 6 to 8 hours following completion of the infusion. Based on exposure-response analysis, a subcutaneous dose of 30 mg Firazyr is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown.

The effect of Firazyr 30 and 90 mg following a single subcutaneous injection on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 72 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on individual correction method (QTcI) was below 10 ms, the threshold for regulatory concern. The dose of 90 mg is adequate to represent the high exposure clinical scenario.

Pharmacokinetics

The pharmacokinetics of Firazyr has been characterized in studies using both intravenous and subcutaneous administration to healthy subjects and patients. The pharmacokinetic profile of Firazyr in patients with HAE is similar to that in healthy subjects.

The absolute bioavailability of Firazyr following a 30 mg subcutaneous dose is approximately 97%. 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 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, plasma clearance was 245 ± 58 mL/min with a mean elimination half-life of 1.4 ± 0.4 hours and volume of distribution at steady state (Vss) of 29.0 ± 8.7 L.

Icatibant is extensively metabolized by proteolytic enzymes to inactive metabolites that are primarily excreted in the urine, with less than 10% of the dose eliminated as unchanged drug. 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.

Special populations

Hepatic Impairment

The pharmacokinetic parameters of Firazyr were found to be generally comparable between healthy subjects (n=8) and mild to moderate (Child Pugh scores of 5 to 8) hepatic impaired patients (n=8) following a dose of 0.15 mg/kg/day as continuous intravenous infusion over 3 days. In a separate study, Firazyr clearance in subjects with a wide range of hepatic impairment (Child-Pugh scores of 7 to 15) was similar to that in healthy subjects. No dose adjustment is necessary for patients with impairment of hepatic function [see Use in Specific Populations (8.6)].

Renal Impairment

Since renal clearance of icatibant is a minor eliminating pathway, renal impairment is not expected to affect the pharmacokinetics of Firazyr and hence a formal renal impairment study was not conducted for Firazyr. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of Firazyr was not dependent on renal function and therefore, did not show any observable differences in the plasma levels of icatibant or its metabolites compared to subjects with normal renal function. No dose adjustment is necessary for patients with impairment of renal function [see Use in Specific Populations (8.7)].

Age and Gender

Three 30 mg subcutaneous doses of Firazyr administered every 6 hours were studied in young (18 to 45 years of age) and elderly (over 65 years of age) healthy male and female subjects. Following single-dose administration of 30 mg subcutaneous Firazyr, elderly males and females showed approximately 2-fold higher AUC compared to young males and females, respectively. However, only minor differences (~12-14%) between Cmax of gender–matched elderly and young subjects were observed. Older subjects tend to exhibit lower clearance compared to younger subjects and therefore higher systemic exposure. Gender effect on Firazyr pharmacokinetics was also observed in addition to age effect. Clearance of Firazyr is significantly correlated with bodyweight with lower clearance values noted for lower bodyweights. Hence, females with typically lower body weights compared to males exhibit lower clearance values, resulting in approximately 2-fold higher systemic exposure (both AUC and Cmax) compared to males. Differences in efficacy and safety between elderly and younger patients and male and female patients have not been identified. Dose adjustment based on age and gender is not warranted.

Drug Interactions

Formal drug-drug interaction studies were not conducted with Firazyr. Icatibant metabolism is not mediated by CYP450 enzymes. In vitro study did not show any significant inhibition and/or induction of drug metabolizing CYP450 enzymes; therefore, metabolic drug interactions between Firazyr and CYP450 substrates, inhibitors and inducers are not expected.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term studies to determine the carcinogenic potential of icatibant have not been conducted.

Icatibant tested negative for genotoxicity in the in vitro Ames bacterial reverse mutation test, in vitro Chinese hamster bone marrow chromosome aberration assay, and in vivo mouse micronucleus test.

Daily subcutaneous administration of icatibant to rats and dogs caused ovarian, uterine, and testicular atrophy/degeneration and adverse effects on the mammary and prostate glands. In rats, testicular atrophy, reduced prostate gland secretion, decreased testosterone levels and degenerate corpora lutea occurred at doses greater than or equal to 3 mg/kg (approximately 5-fold greater than the MRHD in males and 2-fold greater than the MRHD in females on an AUC basis) and a decrease in developing ovarian follicles, mammary gland masculinization, and uterine atrophy occurred at doses greater than or equal to 10 mg/kg (approximately 6-fold greater than MRHD in females on an AUC basis). In dogs, reduced sperm counts and uterine atrophy occurred at doses greater than or equal to 1 mg/kg (approximately 2-fold greater than the MRHD on an AUC basis). Atrophy of the testes and prostate with decreased testosterone levels, decreased ovary size and decreased number of developing follicles occurred at a dose of 10 mg/kg (approximately 30-fold greater than the MRHD in males and 15-fold greater than at the MRHD in females on an AUC basis).

In contrast to the effects of daily icatibant administration, toxicity to the ovary, uterus, testis, mammary gland, and prostate did not occur in dogs treated twice a week for 9 months. AUC exposures from a dose of 3 mg/kg in these dogs were 5- and 3-fold the MRHD exposures in men and women, respectively. Sperm counts and testosterone remained unaffected over the course of the study in male dogs dosed twice a week.

Reproduction studies in male mice and rats with daily administration of icatibant found no effects on fertility or reproductive performance with intravenous doses up 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively.

Animal Toxicology and/or Pharmacology

The B2 receptor has been implicated in the cardioprotective effects of bradykinin and antagonism of this receptor could potentially have negative cardiovascular effects during reperfusion after acute ischemia. Icatibant decreased coronary blood flow in the isolated guinea pig heart and aggravated the duration of post-ischemic reperfusion arrhythmias in the isolated rat heart. Intracoronary infusion of icatibant in an anesthetized myocardial infarction dog model increased mortality rate 2-fold over saline ischemia. There is limited human experience in acute ischemia. Firazyr should be used during acute coronary ischemia, unstable angina pectoris, or in the weeks following a stroke only if the benefit exceeds the theoretical risk to the patient.

Clinical Studies

The efficacy and safety of Firazyr for the treatment of acute attacks of HAE in adults were studied in three controlled clinical trials. Among the 223 patients in these studies, the mean age was 38 years, 64% were female, and 95% were white. Approximately 57% of patients reported use of attenuated androgens, antifibrinolytic agents, or C1 inhibitors. Response to therapy was primarily assessed using visual analog scores on a 100 mm scale and patient- and physician-reported symptom scores for abdominal and cutaneous pain and swelling.

Trial 1 was a randomized, placebo-controlled, double-blind, parallel-group study of 98 adult patients with a median age of 36 years. Patients who had developed moderate to severe cutaneous or abdominal or mild to moderate laryngeal attacks of HAE were randomized to receive either Firazyr 30 mg or placebo by subcutaneous injection. Patients with severe laryngeal attacks of HAE received open-label Firazyr 30 mg. The primary endpoint was assessed using a 3-item composite visual analog score (VAS), comprised of averaged assessments of skin swelling, skin pain, and abdominal pain. Response was defined as at least a 50% reduction from the pretreatment composite 3-itemVAS score (Figure 2). The median time to 50% reduction in symptoms for patients with cutaneous or abdominal attacks treated with Firazyr (n=43) compared to placebo (n=45) was 2.0 hours [95% CI 1.5, 3.0] versus 19.8 hours [95% CI 6.1, 26.3], respectively (p<0.001).

Other evaluated endpoints included time to almost complete symptom relief (VAS<10 mm) and rescue medication use. In Trial 1, the median times to almost complete symptom relief were 8.0 versus 36.0 hours for Firazyr and placebo, respectively. In terms of rescue medication use, 3/43 (7%) patients treated with Firazyr used additional rescue medication in comparison to 18/45 (40%) patients treated with placebo.

In a second placebo-controlled trial and an active-controlled trial, a total of 26 and 35 patients, respectively, received Firazyr 30 mg for the treatment of an acute HAE attack. Across the three trials, Firazyr had a median time to 50% reduction from baseline symptoms ranging from 2.0 to 2.3 hours.

Recurrent attacks

In all three controlled trials, patients were eligible for 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 at least 6 hours apart for each attack. A total of 225 patients were treated with 1,076 doses of 30 mg Firazyr for 987 attacks of acute HAE in these trials. In an assessment of the first 5 Firazyr-treated attacks (621 doses for 582 attacks), the median times to a 50% reduction from the pretreatment composite 3-itemVAS score were similar across attacks (2.0, 2.0, 2.4, 2.0, 1.5 hours). The majority (93%) of these attacks of HAE were treated with a single dose of Firazyr.

Laryngeal attacks

A total of 60 patients with laryngeal attacks were treated with Firazyr in the controlled trials. Efficacy results were similar to those observed for non-laryngeal (cutaneous and abdominal) sites of attack.

Self-administration

Self-administration of Firazyr by 56 patients was assessed in an open label trial. Patients who administered Firazyr during an acute attack of HAE had a median time to 50% reduction from the pretreatment composite 3-itemVAS score of 2.6 hours.

How Supplied/Storage and Handling

How Supplied

Firazyr is supplied as a single-use, prefilled syringe for subcutaneous administration. Each syringe delivers 3 mL of a sterile solution of icatibant 30 mg (as icatibant acetate). Each glass syringe has a bromobutyl plunger stopper, which is not made of latex natural rubber.

Firazyr is available in cartons containing one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-02.

Firazyr is also available in a pack containing 3 cartons; each carton contains one single-use, prefilled syringe and one 25 G Luer lock needle. NDC 54092-702-03.

Storage and Handling

Keep out of the reach of children.

Store between 2 - 25° C (36 - 77° F).