Firazyr - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Firazyr - Scientific Information

Manufacture: Shire US, Inc.
Country: Canada
Condition: Hereditary Angioedema
Class: Cardiovascular agents, Miscellaneous cardiovascular agents
Form: Liquid solution, Subcutaneous (SC)
Ingredients: icatibant acetate, sodium hydroxide, acetic acid, sodium chloride, water

Pharmaceutical Information

Drug Substance

Common name:icatibant acetate
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)-
octahydrindol-2-ylcarbonyl]-L-arginine, acetate salt
Molecular formula and molecular mass:C59H89N19O13S (net), 1304.55 g/mol (average,net)
Structural formula:

Physicochemical properties: FIRAZYR (icatibant) is a synthetic decapeptide with five non-proteinogenic amino acids.

Solubility properties: Icatibant acetate is soluble in water, isotonic saline, phosphatebuffer (pH 7.4), acetate buffer (pH 3.5), Tris buffer, ethanol,and methanol.

Clinical Trials

Study Demographics and Trial Design

Table 1 - Summary of patient demographics for clinical trials in HAE
Study #Trial designDosage, route of
administration and
duration
Study subjects
(n=number)
Mean age
(Range)
Gender
Study 1
(FAST 3, HGTFIR-
054)
Randomized,
placebo-controlled,
parallel-group:
Patients with
moderate to severe
cutaneous or
abdominal attacks
or mild to
moderately severe
laryngeal attacks
FIRAZYR
30mg/3mL SC x 1
dose
or
placebo 3mL SC x 1
dose.
9336.8 years
(18 to 83)
34 male;
59 female
Open-label:
Patients with
severe laryngeal
attack
FIRAZYR
30mg/3mL SC x 1
dose.
541.6 years
(29 to 59)
3 male;
2 female
Open-label
extension:
Patients with
subsequent attacks
FIRAZYR 30mg/3
mL SC for up to 3
doses at least 6
hours apart.
8237.2 years
(18 to 83)
27 male;
55 female
Entire Study9837.0 years
(18 to 83)
37 male;
61 female
Study 2
(FAST 1, JE049
#2103)
Randomized,
double-blind,
placebo-controlled:
Patients with
moderate to severe
abdominal or
cutaneous attacks
FIRAZYR
30mg/3mL SC x 1
dose.
or
placebo 3mL SC x 1
dose.
5634.9 years
(18 to 58)
19 male;
37 female
Open-label:
Patients with any
laryngeal attack
FIRAZYR
30mg/3mL SC x 1
dose.
847.1 years
(25 to 61)
3 male;
5 female
Open-label
extension:
Patients with
subsequent attacks
FIRAZYR
30mg/3mL SC for
up to 3 doses at least
6 hours apart.
7235.5 years
(18 to 65)
23 male;
49 female
Entire Study8436.6 years
(18 to 65)
27 male;
57 female
Study 3
(FAST 2, JE049
#2102)
Randomized,
double-blind,
active- controlled:
Patients with
moderate to severe
abdominal or
cutaneous attacks
FIRAZYR
30mg/3mL SC x 1
dose or tranexamic
acid PO TID for 2
days plus a placebo
matched to the
alternate therapy.
7441.1 years
(19 to 68)
27 male;
47 female
Open-label:
Patients with any
laryngeal attack
FIRAZYR
30mg/3mL SC x 1
dose.
335.0 years
(27 to 48)
2 male;
1 female
Open-label
extension:
Patients with
subsequent attacks
FIRAZYR
30mg/3mL SC for
up to 3 doses at least
6 hours apart.
5442.3 years
(22 to 70)
19 male;
35 female
Entire Study8540.9 years
(19 to 70)
30 male;
55 female
Study 4
(JE049-3101)
Open-label,
uncontrolled
FIRAZYR
30mg/3mL SC x 1
dose.
10441.6 years
(18 to76)
36 male;
68 female
HCP
Administration:
Any attack severe
enough to warrant
treatment.
2344.0 years
(19 to 76)
8 male;
15 female
Selfadministration:
Any attack severe
enough to warrant
treatment
9840.8 years
(18 to 76)
33 male;
65 female

SC=subcutaneous; HCP=Healthcare professional

The efficacy and safety of FIRAZYR for the treatment of acute attacks of HAE in adults was established by three controlled Phase III clinical trials (designated Study 1, 2, and 3). In these studies, patients were enrolled if their attack involved the cutaneous, abdominal and/or laryngeal areas; the cutaneous or abdominal attacks were at least moderate in severity and the laryngeal attacks were at least mild in severity, as determined by the investigator; and study drug could be administered within 6 hours of the attack severity becoming at least mild (laryngeal) or moderate (non-laryngeal), but not more than 12 hours after the onset of the attack.

The phase III clinical trials used endpoints that were specifically developed to assess the response to therapy in patients with acute HAE attacks. The effect of therapy on HAE-specific symptoms was recorded by the patients using a visual analog scale (VAS) during pretreatment and at predetermined time points after administration of therapy. The symptoms assessed by the patient using the VAS were skin swelling, skin pain, and abdominal pain. Patients with laryngeal attacks also assessed difficulty swallowing and voice change.

Study 1was a randomized, double-blind, placebo-controlled study of 98 adult HAE type I or II patients with a mean age of 37.0 years (88.8% white; 86.7% HAE type I; 3.1% >65 years of age) who had developed moderate to very severe cutaneous or abdominal, or mild to moderately severe laryngeal attacks of HAE. These patients were randomized to receive a single dose of either FIRAZYR 30 mg or placebo by SC injection. Patients with severe laryngeal attacks of HAE were not randomized and received open-label FIRAZYR 30 mg SC. In the open-label extension phase of the study, patients were eligible for treatment of subsequent attacks with FIRAZYR 30 mg SC and could receive up to 3 doses at least 6 hours apart for each attack.

The primary endpoint of Study 1 was the Time to Onset of Symptom Relief (TOSR), assessed using a 3-item composite visual analog scale score (VAS-3) consisting of assessments of skin swelling, skin pain and abdominal pain. The non-laryngeal ITT population was used for the primary efficacy analysis. The onset of symptom relief was defined as a 50% reduction from pretreatment in the composite VAS score. The time of onset of symptom relief was determined retrospectively as the earliest of 3 consecutive non-missing measurements for which there was at least a 50% reduction in the pretreatment composite VAS score.

Studies 2 and 3 were randomized, double-blind, controlled trials and had identical designs except for the comparator. In Study 2 an attack of HAE was treated with a single dose of either FIRAZYR 30 mg, or placebo administered by SC injection. Study 3 was designed as a doubleblind, double-dummy trial with tranexamic acid as an active comparator. Tranexamic acid tablets were encapsulated and oral placebo consisted of capsules of identical size, shape and color. Initial treatment of the attack in the double-blind phase consisted of 1 SC injection of FIRAZYR administered with 2 capsules of placebo (oral) or 1 SC injection of placebo administered with 2 capsules of tranexamic acid (oral). Subsequent study drug treatment consisted of tranexamic acid or matching placebo administered orally (3 times per day) for 2 days.

In Studies 2 and 3, patients who developed moderate to very severe cutaneous or abdominal attacks of HAE were eligible for randomization to study drug treatment; patients with laryngeal symptoms were not randomized and were treated with open-label FIRAZYR 30 mg SC. Similar to Study 1, both studies had open-label extension phases in which patients were eligible for treatment of subsequent attacks with FIRAZYR (30 mg SC for up to 3 doses administered at least 6 hours apart).

The primary efficacy endpoint for Studies 2 and 3 was the Time to Onset of Primary Symptom Relief based on a pre-specified reduction from the pretreatment VAS score for a single identified primary symptom. The primary symptom was identified based on the type of attack. For abdominal attacks, the single primary symptom was based on the VAS for "abdominal pain." For cutaneous attacks, the single primary symptom was based on the most severe VAS for "skin swelling" or "skin pain." If both were equally severe, the VAS for "skin pain" was used. This endpoint was defined as the key secondary efficacy endpoint for Study 1. The non-laryngeal ITT population was used for the primary efficacy analyses of both studies.

Study 2 enrolled 84 adult HAE type I or II patients with a mean age of 36.6 years (95.2% white; 84.5% HAE type I; 0% >65 years of age). Study 3 enrolled 85 adult HAE type I or II patients with a mean age of 40.9 years (100% white; 91.8% HAE type I; 4.7% >65 years of age).

Study Results

Double-blind, Controlled Trials

Efficacy results are shown in Figure 1 and Table 2 below.


Table 2 - Results of studies 1, 2, and 3 in the non-laryngeal ITT population
Study 1StatisticFIRAZYR
(n = 43)
Placebo
(n = 45)
Primary Endpoint
Time to Onset of Symptom
Relief (hours) a
Median
p-value
2.0
< 0.001
19.8
Other Endpoints
Time to Onset of Primary
Symptom Relief (hours) b
Median
p-value
1.5
< 0.001
18.5
Time to Onset of Symptom
Relief (hours) for the
Individual VAS score of c
Skin SwellingMedian
p-value
3.0
<0.001
22.3
Skin PainMedian
p-value
2.0
0.013
8.0
Abdominal PainMedian
p-value
1.8
0.007
3.5
Change in Composite VAS
Score at 2 hours After
Treatment
Mean
p-value
-19.74
<0.001
-7.49
Time to Almost Complete
Symptom Relief (hours) d
Median
p-value
8.0
0.012
36.0
Patients who use Rescue
Medication Prior to Onset of
Symptom Relief
Number (%)
p-value
0/43 (0%)
<0.001
16/45 (35.6%)
Study 2StatisticFIRAZYR
(n = 27)
Placebo
(n = 29)
Primary Endpoint
Time to Onset of Primary
Symptom Relief (hours) b
Median
p-value
2.5
0.142
4.6
Other Endpoints
Time to Onset of Symptom
Relief (hours) a, e
Median
p-value
2.3
0.014
7.9
Time to Almost Complete
Symptom Relief (hours)d
Median
p-value
8.5
0.079
19.4
Patients who used Rescue
Medication Prior to Onset of
Symptom Relief e, f
Number (%)
p-value
1/26 (3.8)
0.005
10/27 (37.0)
Study 3StatisticFIRAZYR
(n = 36)
Tranexamic Acid
(n=38)
Primary Endpoint
Time to Onset of Primary
Symptom Relief (hours)b
Median
p-value
2.0
< 0.001
12.0
Other Endpoints
Time to Onset of Symptom
Relief (hours)a e
Median
p-value
2.0
< 0.001
12.0
Time to Almost Complete
Symptom Relief (hours) d
Median
p-value
10.0
<0.001
51.0
Patients who used Rescue
Medication Prior to Onset of
Symptom Relief e, f
Number (%)
p-value
0/33 (0)
0.002
9/34 (26.5)

aOnset ofsymptom relief was defined as the earliest of 3 consecutive non-missing measurements for which there was at least a 50% reduction from pretreatment composite 3-item (skin swelling, skin pain, and abdominal pain) VAS score.
b Primary symptom relief was defined as a reduction from pretreatment in the score of a single primary VAS Symptom. Onset of symptom relief was defined as the earliest of 3 consecutive non-missing measurements for which there was any reduction below (6/7) pre-treatment value – 16 for pretreatment VAS ≥30mm. For a pre-treatment VAS < 30mm, symptom relief was defined as a 68% reduction from pre-treatment.
c Onset of symptom relief (hours) for the individual VAS scores was defined as the earliest of 3 consecutive non-missing measurements for which there was at least a 50% reduction from the pretreatment VAS score for each of the individualsymptoms.
dAlmost complete symptom relief (hours) was defined as the earliest of 3 consecutive non-missing measurements for which allVAS scores were less than 10 mm.
e Post-hoc analysis
f Analysis includes only those subjects who achieved onset of symptom relief; Study 2: FIRAZYR n=26, Placebo n=27; Study 3: FIRAZYR n= 33, Tranexamic Acid n=34.

Response was also consistent across repeated attacks in the controlled Phase III trials. A total of 237 patients were treated with 1,383 doses of 30 mg FIRAZYR for 1,278 attacks of acute HAE in these Phase III clinical trials. Ninety-one and one-half percent (91.5%) of attacks of HAE that were eligible for 3 injections (1149) were treated with a single dose of FIRAZYR. In the first 15 FIRAZYR treated attacks (1,114 doses for 1,030 attacks), the median times to onset of symptom relief were similar across attacks (2.0 to 2.5 hours).

Patients with laryngeal attacks were treated during the open-label phases of the studies, therefore comparisons of the efficacy of FIRAZYR with a control arm are not available for most of the patients with laryngeal attacks. In study 1, 27 patients completed laryngeal symptom assessments using a 5-item composite visual analog score (VAS-5). Post-hoc analyses of these efficacy data are shown in Table 3 below. The median time to onset of symptom relief (2.0 hours) was similar to those observed for the non-laryngeal attacks in studies 1, 2 and 3 (2.0 to 2.3 hours). This was reflected by similar median times to onset of symptom relief for the individual laryngeal symptoms of difficulty swallowing (1.8 hours) and voice change (1.7 hours). No formal studies have been conducted to determine if Firazyr treatment can reduce the risk of suffocation and mortality in HAE patients with laryngeal attacks.

Table 3 - Results of Study 1 in the laryngeal treated population (post-hoc analysis)
EndpointsStatisticFIRAZYR
(n = 27)
Time to onset of symptom relief
(hours) a
Median
(95% CI)
2.0
(1.5, 3.5)
Time to Onset of Primary Symptom
Relief (hours) b
Median
(95% CI)
2.0
(1.5. 2.5)
Time to Onset of Symptom Relief
(hours) for the Individual VAS
score of c
Difficulty SwallowingMedian
(95% CI)
1.8
(1.3, 2.5)
Voice ChangeMedian
(95% CI)
1.7
(1.5, 2.5)
Skin SwellingMedian
(95% CI)
1.8
(1.3, 5.0)
Skin PainMedian
(95% CI)
1.8
(1.3, 3.5)
Abdominal PainMedian
(95% CI)
2.2
(1.0, 48.4)
Time to Almost Complete Symptom
Relief (hours) d
Median
(95% CI)
6.4
(3.1, 24.3)

a Onset of symptom relief was defined as the earliest of 3 consecutive non-missing measurements for which there was at least a 50% reduction from pretreatment composite 5-item (difficulty swallowing, voice change, skin swelling, skin pain, and abdominal pain) VAS score.
b Primary symptom relief was defined as a reduction from pretreatment in the score of a single primary VAS Symptom. Onset of symptom relief was classified as the ealiest of 3 consecutive non-missing measurements for which there was any reduction below (6/7) pre-treatment value – 16 for pretreatment VAS ≥30mm. For a pretreatment VAS < 30mm, symptom relief was defined as a 68% reduction from pre-treatment. For the laryngeal attacks, the single primary symptom was based on the more severe pretreatment VAS score of either difficulty swallowing or voice change. If both were equally severe at pretreatment, then the VAS score for difficulty swallowing was used as the single primary symptom.
c Onset of symptom relief (hours) for the individual VAS scores was defined as the earliest of 3 consecutive non-missing measurements for which there was at least a 50% reduction from the pretreatment VAS score for each of the individual symptoms.
dAlmost complete symptom relief (hours): was defined as the earliest of 3 consecutive non-missing measurements for which all VAS scores were less than 10 mm.

Open-label, Uncontrolled Study

Self-administration of FIRAZYR by patients who experienced acute attacks of HAE was assessed in the open-label uncontrolled Study 4. Patients who self-administered FIRAZYR during an acute attack of HAE had results similar to those seen after administration by a healthcare professional in the controlled Phase III studies.

Detailed Pharmacology

Icatibant is a potent antagonist of the bradykinin (B2) receptors with an affinity similar to bradykinin itself. Receptor binding of icatibant has been demonstrated in various tissues and cells in vitro, including guinea pig ileum and tracheal epithelial cells, human synovial cells and human recombinant CHO cells.

In bradykinin type-1 (B1) receptor binding assays in vitro using human recombinant CHO cells, the half-maximal inhibitory concentration (IC50) of icatibant was determined to be 6 μM, with an inhibition constant (Ki) of 1.2 μM. In binding to the B2 receptor, the IC50 of icatibant was 4.3 nM, and the Ki was 2.0 nM. Selectivity for the B2 receptor was also demonstrated in vitro by the inability of icatibant to inhibit contractions of rabbit aorta, which contains the B1 receptor, induced by the B1 agonist, des-Arg10-kallidin.

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 infusion. Icatibant does not cause cardiac conduction changes in vitro using the Xenopus oocyte model, nor does it have significant effects on HERGmediated outward current in CHO cells at concentrations up to 300 μM. Icatibant did not elicit any cardiac conduction changes or in vivo in normal dogs or in various dog models (ventricular pacing, physical exertion and coronary ligation) where no associated hemodynamic changes were observed.

Based on animal data there is a theoretical potential that antagonism of the B2 receptor can lead to myocardial ischemia. Myocardial ischemic events have been reported infrequently in postmarketing experience with Firazyr but there is no clear evidence that such events were related to product use. Overall, there is limited human experience in acute ischemia. Prescribers should consider benefits and risks of therapy.

Absorption, distribution, metabolism, and excretion studies have been performed in mice, rats, and dogs. Two inactive metabolites, M1 and M2, have been isolated, identified, and found to be similar across species. Excretion of radioactivity was mainly renal, regardless of species and route of administration. Based on the pharmacokinetic data generated in these studies, including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), the absolute bioavailability of icatibant following SC administration is high (approximately 100%). Subcutaneous administration studies indicated a biphasic decline of radioactivity in blood, initially rapid (1 to 2 hours post-dose), followed by a second phase lasting days.

Icatibant and its metabolites M1 and M2 were tested for in vitro metabolic stability in the presence of human liver microsomes and (for icatibant only) in the presence of dog liver microsomes as well as dog and human S9-fractions. In vitro studies investigating effects on human cytochrome P450 (CYP) enzymes did not show any induction or inhibition. The data from these studies showed that the metabolism of icatibant, M1, and M2 is CYP-independent.

Icatibant is excreted in the milk of lactating rats at concentrations similar to those in maternal blood.

Symptoms consistent with histamine release have been observed in dogs after IV administration of icatibant, where the ears and muzzle became swollen. These nonclinical study data help explain the mechanisms underlying the adverse localized cutaneous reactions observed at injection sites in humans.

Broad receptor binding, using standard agonists, has been investigated for icatibant and its two major metabolites (M1 and M2). Inhibition by icatibant was detected for the following humanized receptors: B2 (percent of control specific binding 98%), M3 (52%), M4 (16%), NK2 (96%), opiate (19%), EP1 (13%), VIP1 (56%), VIP2 (41%), and V1a (66%) receptor. The IC50 value of icatibant for the binding at NK2 receptors was 420 nM, which is approximately 100-fold higher than the IC50 value for the B2 receptor. Partial inhibition of control specific binding was observed for M2 at the B2 (62%) receptor only, at concentrations of 10 μM-approximately 10 times the Cmax in human following SC administration of icatibant with no inhibition observed with M1.

Toxicology

Long-term Multidose (Repeat dose) Studies

Repeated-dose studies have been conducted in rats and dogs for durations of 6 and 9 months, respectively. In both rats and dogs, there was a dose-related reduction in circulating sex hormone levels.

In the mature rat, ovary weights were increased in females and prostate weights decreased in males. With the exception of the spleen weights (increased), these changes in organ weights were completely or partially reversed following the dose-free recovery period. Histopathological changes of the reproductive organs in the males included minimal to severe bilateral hypospermia and minimal or slight intratubular degenerate spermatozoa/spermatids in the epididymides, minimal or moderate reduction in secretion in the prostate gland and seminal vesicles, minimal to marked bilateral germinal epithelial degeneration in the testes in males. In the females, changes included masculinization of the mammary glands, increased numbers of corpora lutea and decreased developing follicles in the ovaries, minimal to marked uterine atrophy and mucification and/or atrophy of the vaginal mucosa. Microscopic findings in reproductive organs of male and female animals included severe bilateral tubular atrophy of the testes, atrophy and inactivation of the mammary glands, severe atrophy of the prostate gland, slight to moderate uterine atrophy, no corpora lutea or developing follicles in the ovaries and absence of spermatozoa in the epididymal tubules. Following the 4-week recovery period, most findings showed evidence of at least partial recovery.

In the mature dog, testosterone levels in males were lowered in the majority of animals. FSH levels (both sexes) showed a trend toward decrease. These findings were reversible following the 4 week treatment-free period.

Repeat use of icatibant reversibly delayed sexual maturation of juvenile rats and dogs. Sexually immature rats were treated daily with 3 mg/kg for 7 weeks. Macroscopic observations in the male rats included atrophy of testes and epididymides. Microscopic findings of tubular cell vacuolation and germ cell degeneration in the testes were observed. In the males treated with 9.0 and 25 mg/kg/day, there was statistically significant delays in physical maturation, lowered prostate and testes weights, tubular cell vacuolation and germ cell degeneration. Decreased sperm count, motility, and velocity were observed when males were treated with the dose of 25 mg/kg/day. Consequently, decreased fertility was observed in untreated females paired with males treated with an icatibant dose of 25 mg/kg/day. All microscopic and organ weight findings were either completely or partially reversible following the treatment-free period. In the females, there was reduced uterine weight.

Sexually immature dogs were treated with icatibant for 13-weeks. The observations in the male dogs included lower testicular volume, lower testosterone, LH (males) and FSH levels. In the female dogs, the FSH levels were lower. These effects showed partial reversibility during the treatment-free period. Macroscopic observations included decreased testes, epididymides, prostate, uterus, vagina and ovaries. Immaturity of the genital organs was observed in all males at all dose levels as well as in the females, which also demonstrated lack of glandular portion of the mammary glands. During the treatment-free period, progressive development and maturation of the male and female reproductive organs was considered to be consistent with the normal maturation process and recovery.

The observations regarding the reproductive organs in the sexually immature animals are similar to the effects of icatibant on reproductive tissues in sexually mature rats and dogs (see above). Icatibant has a reversible effect on the gonadotrophins.

Bradykinin, acting through the B2 receptor, is recognized to have a role in the control of hormone secretion within the hypothalamus. Therefore, these effects on hormone secretion, with consequent effects on sexual organs, are not unexpected. The daily dosing regimen utilized in the nonclinical studies is an exaggeration of the clinical treatment conditions. Adult patients treated with icatibant are unlikely to experience adverse reactions affecting sexual organs, given the intermittent nature of HAE attacks and use of icatibant.

In a clinical setting, 39 healthy adult men and women were treated with a single SC 30 mg injection every 6 hours for 3 doses every 3 days for a total of 9 doses. There were no clinically significant changes from baseline in basal and GnRH-stimulated concentrations of reproductive hormones (estradiol, progesterone, prolactin, DHEA, DHEAS, SHBG, FSH, and LH) in females and (testosterone, DHEA, DHEA-S, SHBG, FSH, LH, and Inhibin-B) in males. There were no significant effects of icatibant on the concentration of luteal phase progesterone and luteal function, or on menstrual cycle length in females, and there were no significant effects of icatibant on sperm count, motility and morphology in males. The dosing regimen used for this study is very unlikely to be sustained in the clinical setting.

Carcinogenicity

A two-year study was conducted in rats to assess the carcinogenic potential of icatibant. No evidence of tumorigenicity was observed in rats at icatibant subcutaneous doses up to 6 mg/kg/day (approximately 6-fold greater than the Maximum Recommended Human Dose on an AUC basis).

Genotoxiciy

In a standard battery of in vitro and in vivo tests, icatibant was not genotoxic.

Developmental and Reproductive Studies

Icatibant was not teratogenic when administered by subcutaneous injection during early embryonic and fetal development in rat (25 mg/kg/day) and rabbit (10 mg/kg/day). In animal studies, icatibant caused delayed parturition, fetal death, and pre-implantation loss in rats and premature birth, abortion, fetal death, and pre-implantation loss in rabbits. 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 daily dose of 10 mg/kg). The mean number of pups born per female was lower than for the controls and pup survival rate (10 mg/kg/day) was 25% between day 1 and day 4 post-partum. After day 4 post-partum, pup survival was 100%.

Studies in rabbits 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). Icatibant is a potent antagonist of bradykinin and therefore, at high dose levels, treatment can have effects on the uterine implantation process and subsequent uterine stability in early pregnancy. These uterine effects also manifest in late stage pregnancy where icatibant exhibits a tocolytic effect resulting in delayed parturition in the rat, with increased fetal distress and perinatal death at high doses (10 mg/kg/day).

Following a single SC dose (1 mg/kg) to pregnant rats, no effects were detected in the post-natal development of rat pups.