SAJAZIR (Page 2 of 4)

8.2 Lactation

Risk Summary

There are no data on the presence of icatibant in human milk, the effects on the breastfed infant, or the effects on milk production. Icatibant and the M2 metabolite were found in rat milk following subcutaneous administration of icatibant (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. However, systemic absorption of icatibant in infants is not expected after oral exposure through breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for icatibant and any potential adverse effects on the breastfed child from icatibant or from the underlying maternal condition.

Data

Animal Data

Icatibant is excreted into the milk of lactating rats at concentrations that sometimes slightly exceeded those measured in the maternal plasma.

8.4 Pediatric Use

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

Juvenile Toxicity Data

Subcutaneous daily administration of icatibant to young rats during the juvenile period of development (postnatal days 22-70) delayed the sexual maturation of male reproductive tissues (atrophy of testes and epididymides) at exposures approximating one-third or greater the MRHD on a mg/m2 basis. Impaired fertility and reproductive performance were also observed in male rats at the end of the postnatal treatment period at exposures approximating the MRHD or greater on a mg/m2 basis. No effects were observed in females at exposures approximating 3-fold the MRHD on a mg/m2 basis. The observed tissue findings in males were consistent with those seen in sexually mature rats and dogs and are attributed to antagonism of the bradykinin B2 receptor and subsequent effects on gonadotropins. The observed effects may be a consequence of daily icatibant administration. Toxicity to the testis did not occur in dogs treated twice a week for 9 months [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

8.5 Geriatric Use

Clinical studies of icatibant injection 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 icatibant injection 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.

8.6 Hepatic Impairment

Icatibant injection 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)].

8.7 Renal Impairment

Although a formal renal impairment study has not been conducted, 10 of 37 patients treated with icatibant injection had hepatorenal syndrome with glomerular filtration rate (GFR) below 60 mL/min. Icatibant injection 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)].

10 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.

11 DESCRIPTION

SAJAZIR (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

Image
(click image for full-size original)

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

SAJAZIR (icatibant) injection 30 mg/3ml (10 mg/mL) 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.

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 (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 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 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 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 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 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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