Curosurf intratracheal suspension

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.

Activity

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

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

CUROSURF 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 have been performed. Non-clinical studies have been performed to evaluate the disposition of phospholipids present in CUROSURF.

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- 14 C-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- 14 C-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 14 C-DPPC in alveolar macrophages was </=2% of that in the lung in newborn and adult rabbits. Of the total 14 C-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.

General

Correction of acidosis, hypotension, anemia, hypoglycemia, and hypothermia is recommended prior to CUROSURF administration.

Surfactant administration can be expected to reduce the severity of RDS but will not eliminate the mortality and morbidity associated with other complications of prematurity.

Sufficient information is not available 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies to assess potential carcinogenic and reproductive effects of CUROSURF, or other surfactants, have not been conducted.

Mutagenicity studies of CUROSURF, which included the Ames test, gene mutation assay in Chinese hamster V79 cells, chromosomal aberration assay in Chinese hamster ovarian cells, unscheduled DNA synthesis in HELA S3 cells, and in vivo mouse nuclear test, were negative.

Transient adverse effects seen with the administration of CUROSURF include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation.

The rates of common complications of prematurity observed in Study 1 are shown below in Table 3.

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.

FOLLOW-UP EVALUATIONS

Seventy-six infants (45 treated with CUROSURF) were evaluated at 1 year of age and 73 infants (44 treated with CUROSURF) at 2 years of age. Data from follow-up evaluations for weight and length, persistent respiratory symptoms, incidence of cerebral palsy, visual impairment, or auditory impairment was similar between treatment groups. In 16 patients (10 treated with CUROSURF and 6 controls) evaluated at 5.5 years of age, the developmental quotient, derived using the Griffiths Mental Developmental Scales, was similar between groups.

CUROSURF (poractant alfa) Intratracheal Suspension (NDC Numbers: 49502-180-01 [1.5 mL]; 49502-180-03 [3 mL]) is available in sterile, ready-to-use rubber-stoppered clear glass vials containing 1.5 mL [120 mg phospholipids (extract)] or 3 mL [240 mg phospholipids (extract)] of suspension. One vial per carton.

Store CUROSURF Intratracheal Suspension in a refrigerator at +2 to +8°C (36-46°F). Unopened vials of CUROSURF may be warmed to room temperature for up to 24 hours prior to use. CUROSURF should not be warmed to room temperature and returned to the refrigerator more than once. PROTECT FROM LIGHT. Do not shake. Vials are for single use only. After opening the vial discard the unused portion of the drug.

Rx only.

DEY

Manufactured for:

DEY, Napa, CA 94558

Manufactured by and licensed from:

chiesi

Chiesi Farmaceutici, S.p.A.

Parma, Italy 43100

05/200403-572-03A

           82W03.04/01

PRODUCT PHOTO(S):