Curosurf (Page 2 of 3)

6.2 Immunogenicity

Immunological studies have not demonstrated differences in levels of surfactant-anti-surfactant immune complexes and anti-CUROSURF antibodies between patients treated with CUROSURF and patients who received control treatment.

6.3 Postmarketing Experience

Pulmonary hemorrhage, a known complication of premature birth and very low birth-weight, has been reported both in clinical trials with CUROSURF and in postmarketing adverse event reports in infants who had received CUROSURF.

8 USE IN SPECIFIC POPULATIONS

8.4 Pediatric Use

The safety and effectiveness of CUROSURF for the rescue treatment, including the reduction of mortality and pneumothoraces, of Respiratory Distress Syndrome (RDS) have been established in premature infants and the information on this use is discussed throughout the labeling.

The safety and effectiveness of CUROSURF in the treatment of full term infants or older pediatric patients with respiratory failure has not been established.

10 OVERDOSAGE

There have been no reports of overdosage following the administration of CUROSURF.

In the event of accidental overdosage, and if there are clear clinical effects on the infant’s respiration, ventilation, or oxygenation, aspirate as much of the suspension as possible and provide the infant with supportive treatment, with particular attention to fluid and electrolyte balance.

11 DESCRIPTION

Poractant alfa is an extract of natural porcine lung (pulmonary) surfactant consisting of 99% polar lipids (mainly phospholipids) and 1% hydrophobic low molecular weight surfactant associated proteins (SP). The molecular weight of SP-B is 8.7 KDa and the molecular weight of SP-C is 3.7 KDa.

CUROSURF (poractant alfa) intratracheal suspension is a sterile, white to creamy white suspension provided in a single-dose vial for intratracheal use. Each milliliter of suspension contains 80 mg of poractant alfa (surfactant extract) that includes 76 mg of phospholipids and 1 mg of SP of which 0.45 mg is SP-B, a 79-amino acid protein and 0.59 mg is SP-C, a 35-amino acid peptide . The amount of phospholipids is calculated from the content of phosphorus and contains 55 mg of phosphatidylcholine of which 30 mg is dipalmitoylphosphatidylcholine. It is suspended in 0.9% sodium chloride solution. The pH is adjusted with sodium bicarbonate to a pH of 6.2 (5.5 to 6.5).

Curosurf contains no preservatives.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Endogenous pulmonary surfactant reduces surface tension at the air-liquid interface of the alveoli during ventilation and stabilizes the alveoli against collapse at resting transpulmonary pressures. A deficiency of pulmonary surfactant in preterm infants results in Respiratory Distress Syndrome (RDS) characterized by poor lung expansion, inadequate gas exchange, and a gradual collapse of the lungs (atelectasis).

CUROSURF compensates for the deficiency of surfactant and restores surface activity to the lungs of these infants.

12.2 Pharmacodynamics

In vitro — CUROSURF lowers minimum surface tension to ≤ 4mN/m as measured by the Wilhelmy Balance System.

12.3 Pharmacokinetics

CUROSURF is administered directly to the lung, where biophysical effects occur at the alveolar surface. No human pharmacokinetic studies have been performed to characterize the absorption, biotransformation, or elimination of CUROSURF.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess potential carcinogenic effects of CUROSURF have not been conducted.

Poractant alfa was negative for genotoxicity in the following assays: bacterial reverse mutation assay (Ames test), gene mutation assay in Chinese hamster V79 cells, chromosomal aberration assay in Chinese hamster ovary cells, unscheduled DNA synthesis in HELA S3 cells, and in vivo mouse micronucleus assay.

No studies to assess reproductive effects of CUROSURF have been performed.

14 CLINICAL STUDIES

14.1 Rescue Treatment of Respiratory Distress Syndrome

The clinical efficacy of CUROSURF in the treatment of established Respiratory Distress Syndrome (RDS) in premature infants was demonstrated in one single-dose study (Study 1) and one multiple-dose study (Study 2) involving approximately 500 infants. Each study was randomized, multicenter, and controlled.

In study 1, premature infants 700 to 2000 grams birth weight with RDS requiring mechanical ventilation and a FiO2 ≥ 0.60 were enrolled. CUROSURF 2.5 mL/kg single dose (200 mg/kg) or control (disconnection from the ventilator and manual ventilation for 2 minutes) was administered after RDS developed and before 15 hours of age. The results from Study 1 are shown below in Table 2.

Table 2: Study 1 Results in Premature Infants with Respiratory Distress Syndrome

Efficacy Parameter

Single Dose

CUROSURF

n=78

Control

n=67

p-Value

Mortality at 28 Days (All Causes)

31%

48%

≤0.05

Bronchopulmonary Dysplasia*

18%

22%

N.S.

Pneumothorax

21%

36%

≤0.05

Pulmonary Interstitial Emphysema

21%

38%

≤0.05

*Bronchopulmonary dysplasia (BPD) diagnosed by positive x-ray and supplemental oxygen dependence at 28 days of life.

N.S.: not statistically significant

In Study 2, premature infants 700 to 2000 g birth weight with RDS requiring mechanical ventilation and a FiO2 ≥ 0.60 were enrolled. In this two-arm trial, CUROSURF was administered after RDS developed and before 15 hours of age, as a single-dose or as multiple doses. In the single-dose arm, infants received CUROSURF 2.5 mL/kg (200 mg/kg). In the multiple-dose arm, the initial dose of CUROSURF was 2.5 mL/kg followed by up to two 1.25 mL/kg (100 mg/kg) doses of CUROSURF. The results from Study 2 are shown below in Table 3.

Table 3: Study 2 Results in Premature Infants with Respiratory Distress Syndrome

Efficacy Parameter

Single Dose

CUROSURF

n=184

Rate (%)

Multiple Dose

CUROSURF

n=173

Rate (%)

p-Value

Mortality at 28 Days (All Causes)

21

13

0.048

Bronchopulmonary Dysplasia*

18

18

N.S.

Pneumothorax

17

9

0.03

Pulmonary Interstitial Emphysema

27

22

N.S.

*Bronchopulmonary dysplasia (BPD) diagnosed by positive x-ray and supplemental oxygen dependence at 28 days of life.

N.S.: not statistically significant

There is no controlled experience on the effects of administering initial doses of CUROSURF other than 2.5 mL/kg (200 mg/kg), subsequent doses other than 1.25 mL/kg (100 mg/kg), administration of more than three total doses, dosing more frequently than every 12 hours, or initiating therapy with CUROSURF more than 15 hours after diagnosing RDS. Adequate data are not available on the use of CUROSURF in conjunction with experimental therapies of RDS, e.g., high-frequency ventilation or extracorporeal membrane oxygenation.

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