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Curosurf

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Curosurf

CLINICAL PHARMACOLOGY

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 preterminfants results in Respiratory Distress Syndrome (RDS) characterized by poor lung expansion, inadequate gas exchange, and a gradual cöllapse of the lungs (atelectasis).

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

Activity

In vitro - CUROSURF (poractant alfa) lowers minimum surface tension to ≤ 4mN/m as measured by the Wilhelmy Balance System.

In vivo - In several pharmacodynamic studies, CUROSURF (poractant alfa) improved lung compliance, pulmonary gas exchange, or survival in premature rabbits.

Pharmacokinetics

CUROSURF (poractant alfa) is administered directly to the target organ, the lung, where biophysical effects occur at the alveolar surface.

No human pharmacokinetic studies to characterize the absorption, biotransformation, or excretion of CUROSURF (poractant alfa) have been performed. Non-clinical studies have been performed to evaluate the disposition of phospholipids present in CUROSURF (poractant alfa) .

Animal Metabolism

In both adult and newborn rabbits, approximately 50% of the radiolabeled component was rapidly removed from the alveoli in the first three hours after single intratracheal administration of CUROSURF (poractant alfa) -14C-DPPC (dipalmitoylphosphatidylcholine).

Over a 24-hour period, approximately 45% of the labeled DPPC was cleared from the lungs of adult rabbits compared to approximately 20% in newborn rabbits.

In newborn rabbits, CUROSURF (poractant alfa) -14C-DPPC passed from the alveolar space into the lung parenchyma and then was secreted again into the alveoli, whereas in adult rabbits, most of the DPPC was not recycled. The half-life in the lung appeared to be about 25 hours in adult rabbits and 67 hours in newborn rabbits.

The Concentration of 14C-DPPC in alveolor macrophages was ≤ 2% of that in the lung in newborn and adult rabbits. Of the total 14C-DPPC recovered in newborn rabbits, < 0.6% was found in the serum, liver, kidneys, and brain, respectively, at 48 hours.

No information is available about the metabolic rate of the surfactant-associated proteins in CUROSURF (poractant alfa) .

Clinical Studies

The clinical efficacy of CUROSURF (poractant alfa) was demonstrated in one single-dose study (Study 1) and one multiple-dose study (Study 2) in the treatment of established neonatal RDS involving approximately 500 infants. Each study was randomized, multicenter, and controlled. In Study 1, infants 700-2000g birth weight with RDS requiring mechanical ventilation and a Fi02 ≥ 0.60 were enrolled.

CUROSURF (poractant alfa) 2.5 mL/kg single dose (200 mg/kg) or control (disconnection from the ventilator and manual ventiation for 2 minutes) was administered after RDS developed and before 15 hours of age.

The results from Study 1 are shown below in Table 1.

TABLE 1

EFFICACY PARAMETER SINGLE DOSE CUROSURF (poractant alfa)
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
N.S.: not statistically significant
* Bronchopulmonary dysplasia (BPD) diagnosed by positive x-ray and supplemental oxygen dependence at 28 days of life.

In Study 2, infants 700-2000g birth weight with RDS requiring mechanical ventilation and a Fi02 ≥ 0.60 were enrolled.

In this two-arm trial, CUROSURF (poractant alfa) 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 (poractant alfa) 2.5mL/kg (200mg/kg). In the multiple-dose arm, the initial dose of CUROSURF (poractant alfa) was 2.5mL/kg (200mg/kg) and subsequent doses of CUROSURF (poractant alfa) were 1.25mL/kg (100mg/kg). The results from Study 2 are shown below in Table 2.

TABLE 2

EFFICACY PARAMETER SINGLE-DOSE CUROSURF (poractant alfa)
n=184
%
MUL TIPLE-DOSE CUROSURF (poractant alfa)
n= 173
%
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.
N.S.: not statistically significant

Acute Clinical Effects

As with Qther surfactants, marked improvements in oxygenation may occur within minutes of the administration of CUROSURF (poractant alfa) .

Last reviewed on RxList: 12/4/2008
This monograph has been modified to include the generic and brand name in many instances.

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