CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

12.1 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.

12.2 Pharmacodynamics

Following bradykinin challenge, intravenous administration of icatibant injection caused dose and time-dependent inhibition of development of bradykinin-induced hypotension, vasodilation, and reflex tachycardia in healthy young subjects. Icatibant injection 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 icatibant injection is predicted to be effective against bradykinin challenge for at least 6 hours. The clinical significance of these findings is unknown.

The effect of icatibant injection 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.

12.3 Pharmacokinetics

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

The absolute bioavailability of icatibant injection following a 30 mg subcutaneous dose is approximately 97%. Following subcutaneous administration of a single 30 mg dose of icatibant injection to healthy subjects (N=96), a mean (± standard deviation) maximum plasma concentration (C max ) of 974 ± 280 ng/mL was observed after approximately 0.75 hours. The mean area under the concentration-time curve (AUC 0-∞ ) 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 (V ss ) 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 icatibant injection 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, icatibant injection 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 icatibant injection and hence a formal renal impairment study was not conducted for icatibant injection. In 10 patients with hepatorenal syndrome (GFR 30-60 mL/min), clearance of icatibant injection 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 icatibant injection 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 icatibant injection, elderly males and females showed approximately 2-fold higher AUC compared to young males and females, respectively. However, only minor differences (~12-14%) between C max 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 icatibant injection pharmacokinetics was also observed in addition to age effect. Clearance of icatibant injection 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 C max ) 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 icatibant injection. 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 icatibant injection and CYP450 substrates, inhibitors and inducers are not expected.

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INDICATIONS & USAGE SECTION

1 INDICATIONS AND USAGE

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

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CONTRAINDICATIONS SECTION

4 CONTRAINDICATIONS

None.

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ADVERSE REACTIONS SECTION

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

The safety of icatibant was evaluated in three controlled trials that included 223 patients who received icatibant injection 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 icatibant injection 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 icatibant injection 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 icatibant injection versus placebo in the placebo-controlled trials****a**

The third trial was active-controlled and was comprised of 35 patients who received icatibant injection 30 mg and 38 patients who received the comparator. Adverse reactions for icatibant injection 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 icatibant injection 30 mg and could receive up to 3 doses of icatibant injection 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 icatibant injection 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 icatibant injection.

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 icatibant injection in patients who self-administered icatibant injection was similar in nature and frequency to that of patients whose therapy was administered by healthcare professionals.

6.2 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 icatibant injection. No association between anti-icatibant antibodies and efficacy was observed.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post approval use of icatibant injection: urticaria. 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.

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NONCLINICAL TOXICOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year studies were conducted in CD1 mice and Wistar rats to assess the carcinogenic potential of icatibant injection. No evidence of tumorigenicity was observed in mice and rats at icatibant subcutaneous doses up to 15 mg/kg/day (twice per week) and 6 mg/kg/day (daily), respectively (approximately 10-fold and 6-fold greater than the MRHD on an AUC basis, respectively).

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 degenenerate 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 to 81 mg/kg (approximately 5-fold greater than the MRHD on a mg/m 2 basis) or subcutaneous doses up to 10 mg/kg (approximately 11-fold greater than the MRHD on an AUC basis), respectively.

13.2 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. Icatibant injection 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.

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