Drug Criteria & Outcomes

Poractant alfa (Curosurf) Formulary Evaluation

By Penny Jones, PharmD candidate
Harrison School of Pharmacy
Auburn (AL) University

Background

Respiratory Distress Syndrome (RDS), also known as hyaline membrane disease, is one of the leading causes of infant mortality in the United States. The incidence of RDS is approximately 1% of live births. Between 60,000 and 80,000 infants in the United States are diagnosed with the syndrome each year, the majority of whom are born prematurely. Approximately 60%-80% of infants born at fewer than 28 weeks develop RDS, compared to only 5% of infants born between 37 weeks and full-term.

RDS is caused by a deficiency in pulmonary surfactant that results in poor lung compliance and an increased effort to breathe. Surfactant reduces surface tension and stabilizes alveoli at low lung volumes, allowing alveoli of all sizes to inflate. Premature infants often produce insufficient surfactant, resulting in the collapse of alveoli (atelectasis), decreased functional residual capacity, and increased dead space within the lungs. This review will compare poractant alfa (Curosurf) are calfactant (Infasurf).

Similar drugs in class

Drugs that are similar to poractant alfa are calfactant, beractant (Survanta), and colfosceril palmitate (Exosurf). Curosurf is manufactured sby DEY. Infasurf is manufactured by Forest Pharmaceuticals.

Description

Poractant alfa is an extract of natural porcine lung surfactant consisting of 99% polar lipids (primarily phospholipids) and 1% hydrophobic low molecular weight proteins (surfactant-associated proteins SP-B and SP-C). It is suspended in 0.9% sodium chloride solution and the pH is adjusted as required with sodium bicarbonate to a pH of 6.2 (5.5-6.5). It is sterile, nonpyrogenic, and contains no preservatives. Each milliliter of poractant alfa contains 80 mg of total phospholipids (including 54 mg phosphatidylcholine, of which 30.5 mg is dipalmitoylphosphatidylcholine) and 1 mg protein, including 0.3 mg SP-B.

Calfactant is a sterile, nonpyrogenic lung surfactant that is an extract of natural surfactant from calf lungs, which includes phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C. It contains no preservatives. It is suspended in 0.9% sodium chloride and the pH is 5.7 (5.0-6.2). Each milliliter contains 35 mg total phospholipids (including 26 mg phosphatidylcholine, of which 16 mg is disaturated phosphatidylcholine) and 0.65 mg proteins, including 0.26 mg of SP-B.

Strengths/dosage forms available

Poractant alfa is available in sterile, ready-to-use rubber-stoppered clear glass vials containing 1.5 mL (120 mg phospholipids) or 3 mL (240 mg phospholipids) of suspension. Calfactant is available in sterile, ready-to-use rubber-stoppered clear glass vials containing 3 mL (105 mg phospholipids) and 6 mL (210 mg phospholipids) of suspension.

Mechanism of action

Poractant alfa and calfactant have the same mechanism of action. As endogenous pulmonary surfactants, they reduce surface tension at the air-liquid interface of the alveoli during ventilation and stabilize the alveoli against collapse at resting transpulmonary pressure.

Indications

Poractant alfa is indicated for the treatment (rescue) of RDS in premature infants. Calfactant is indicated for the treatment of RDS in neonates < 72 hours of age and for prophylaxis of premature infants < 29 weeks gestational age at significant risk for RDS.

Off-label uses

No off-label uses are known at this time.

Storage

Poractant alfa should be refrigerated at 2°-8° C. Unopened vials may be warmed to room temperature for up to 24 hours prior to use. It should not be warmed to room temperature and returned to the refrigerator more than once. It should be protected from light and should not be shaken. Vials are for single use only and any unused portion after opening should be discarded.

Calfactant should be refrigerated at 2°-8° C and protected from light. Vials are for single use only and any unused portion after opening should be discarded. The 3 mL vial should be stored upright. It is not necessary to warm the vial prior to use. It should not be shaken and unopened, unused vials that have been warmed to room temperature can be returned to refrigerated storage once within 24 hours for future use.

Pharmacokinetics

Poractant alfa has an initial response that usually is seen within 3-6 hours, and effects may persist for up to 48 hours. It is administered intratracheally 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 have been performed, due to the medical fragility of premature infants, which prohibits the use of some techniques of clinical pharmacologic investigation. Nonclinical studies have been performed to evaluate the disposition of phospholipids present in poractant alfa.

Calfactant has an initial response that usually is seen within one to four hours, and effects may persist for 24-72 hours. It is administered intratracheally directly to the target organ, the lung, where biophysical effects occur at the alveolar surface. It is extensively and uniformly distributed in the lung. Metabolism occurs in the lungs as well.

Dosage/administration

Poractant alfa has an initial dose of 2.5 mL/kg birth weight (200 mg/kg). Up to two subsequent doses of 1.25 mL/kg birth weight (100 mg/kg) can be administered at 12-hour intervals if needed. It is administered intratracheally by instillation through a 5 French end-hole catheter (cut to a standard length of 8 cm) inserted into the infant’s endotracheal tube. The dose should be administered in two equal aliquots of 1.25 mL/kg (100 mg/kg) each. The infant’s ventilator settings should be changed before administration to a rate of 40-60 breaths/min, inspiratory time 0.5 seconds, and supplemental oxygen sufficient to maintain oxygen saturation (SaO2) > 92%.

Briefly disconnect the endotracheal tube from the ventilator. Insert the pre-cut 5 French catheter into the endotracheal tube and instill the first aliquot. After each aliquot is instilled, the infant should be positioned on either the right or the left side, allowing gravity to help distribute the drug. Administration is made while ventilation is continued over 20-30 breaths for each aliquot, with small bursts timed only during the inspiratory cycles. A pause followed by evaluation of the respiratory status and repositioning should separate the two aliquots. Repeat dosing is by the same procedures but at 1.25 mL/kg (100 mg/kg). Maximum total dose administration is 5 mL/kg (400 mg/kg).

Calfactant has an initial dose of 3 mL per kg birth weight (100 mg/kg). Up to three subsequent doses can be administered at 12-hour intervals if needed. It is administered intratracheally through a side port adaptor of the endotracheal tube. The dose should be administered in two equal aliquots of 1.5 mL/kg (50 mg/kg) each. After each aliquot is instilled, the infant should be positioned on either the right or the left side, allowing gravity to help distribute the drug. Administration is made while ventilation is continued over 20-30 breaths for each aliquot, with small bursts timed only during the inspiratory cycles. A pause followed by evaluation of the respiratory status and repositioning should separate the two aliquots. Repeat dosing is by the same procedures.

Special populations

No special populations have been identified.

Adverse reactions

Poractant alfa adverse reactions include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. Calfactant adverse reactions include cyanosis, airway obstruction, bradycardia, reflux of surfactant into the endotracheal tube, requirement for mechanical ventilation, and reintubation.

Warnings/precautions

Poractant alfa should be administered intratracheally only; administration of exogenous surfactants can rapidly affect oxygenation and lung compliance. Poractant alfa should be used with caution in the following situations: infants born after more than three weeks of ruptured membranes (to avoid cases of pulmonary hypoplasia), intraventricular hemorrhage of Grade III or IV, and major congenital malformations.

Calfactant should be administered intratracheally only; administration of exogenous surfactants can rapidly affect oxygenation and lung compliance. Calfactant should be used with caution in the following situations: infants born after more than three weeks of ruptured membranes (to avoid cases of pulmonary hypoplasia), intraventricular hemorrhage of Grade III or IV, and major congenital malformations.

Potential for medication errors

If both drugs are stocked, the nurse could mix up dosages or products. Infasurf also is a look-alike/sound-alike to Exosurf.

Drug-drug interactions

No identified interactions.

Drug-food

No identified interactions.

Cost

The cost of poractant alfa is $225.00 for a 1.5 mL vial and $450 for a 3.0 mL vial. The cost of calfactant is $245.60 for a 3.0 mL vial and $440 for a 6.0 mL vial. Based on a 200 mg/kg initial dose for a 1 kg infant, the cost of poractant alfa would be $376. Based on a 100 mg/kg initial dose for a 1 kg infant, the cost of calfactant would be $234.

Poractant alfa currently does not have any patient assistance programs, but calfactant does have them available. Last year, $173,000 was spent on 454-6 mL vials of calfactant of which 60 vials were returned, making the total cost of 394-6 mL vials of calfactant $150,140 for one year. Comparing this to poractant alfa, 394-3 mL vials would have cost $177,300 for the same one-year supply. Poractant alfa would have cost an extra $27,160.

Pregnancy/lactation information

No information identified.

Overdose

There have been no reports of overdosage following the administration of poractant alfa. In the event of accidental overdosage (and only if there are clear clinical effects on the infant’s respiration, ventilation, or oxygenation), the suspension should be aspirated as much as possible. The infant should be managed with supportive treatment, with particular attention to fluid and electrolyte balance.

There have been no reports of overdosage following the administration of calfactant. Although there are no known adverse effects of excess surfactant, overdosage would result in overloading the lungs with an isotonic solution. Ventilation should be supported until clearance of the liquid is accomplished.

Patient education (special)

No information identified.

Staff education (special)

Staff should be educated on administration requirements. See dosage/administration, p. 2.

Clinical trial summary

Trial 1: Ramanathan R, Rasmussen M, Gerstmann D, et al., and The North American Study Group. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) vs. beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol 2004;21:109-119.

Objective

To evaluate the effectiveness of a 100 mg/kg initial dose of poractant alfa, by comparing its onset of clinical response to that of a 200 mg/kg initial dose of poractant alfa or a 100 mg/kg initial dose of beractant, for treatment of RDS in infants weighing 750-1750 g.

Study design

Prospective, randomized, masked trial conducted from January 2000 to May 2001 at 20 centers in the United States.

Inclusion criteria

  • Birth weight 750 to 1750 g.
  • Gestational age < 35 weeks.
  • Clinical or radiographic evidence of RDS.
  • Intubated and receiving conventional mechanical ventilation.
  • Fraction of inspired oxygen (FIO2) > 0.30 to maintain oxygen saturation by pulse oximeter of 88% to 96% or an arterial to alveolar PaO2 (oxygen pressure) ratio (a/A ratio) of < 0.33.
  • Age 6 hours or younger at the time of randomization.
  • Signed informed consent by a parent or legal guardian.

Exclusion criteria

  • Respiratory failure not due to RDS.
  • Proven fetal lung maturity profile from amniocentesis prior to delivery.
  • Suspected lung hypoplasia.
  • Prior treatment with an exogenous surfactant.
  • Apgar score < 3 at 5 minutes.
  • One or more major congenital anomalies considered to be life-threatening.
  • Prolonged rupture of membranes, defined as > three weeks in duration.
  • Untreated pneumothorax, hypotension, or hypoglycemia.
  • Use of high-frequency ventilation prior to first dose of surfactant.
  • Severe grades of intraventricular hemorrhage (Grades III or IV) by cranial ultrasound.
  • Any condition believed by the investigator to place the subject at undue risk.
  • Participation in another clinical trial.

Patient population

  • Three hundred and one infants were enrolled in the study.
  • Ninety-six infants received low-dose poractant alfa, 99 infants received high-dose poractant alfa, and 98 patients received beractant.
  • Birth weight, gestational age, gender, race, baseline FIO2, and mean airway pressure were similar among all three groups.
  • More male infants were treated overall, but there were no differences among the treatment groups.

Outcomes

Primary:

Area of FIO2 under the curve during the six-hour period (FIO2 AUC0-6) after the first dose of poractant alfa or beractant.

Secondary:

Mean FIO2, mean airway pressure (MAP), total number of doses, median durations of oxygen dependence and mechanical ventilation, and complications of prematurity.

Treatment regimen

  • Ninety-six infants received poractant alfa 100 mg/kg.
  • Ninety-nine infants received poractant alfa 200 mg/kg.
  • Ninety-eight infants received beractant 100 mg/kg.
  • All repeat dosing was given at 100 mg/kg.

Statistical analysis

  • Kruskal-Wallis test.
  • Nonparametric rank tests.
  • Kaplan-Meier.
  • 95% confidence intervals.
  • Chi-square test.

Results

  • FIO2 AUC0-6 was significantly lower for both poractant alfa 100 mg/kg (P < 0.001) and poractant alfa 200 mg/kg (P < 0.005) compared with the beractant group.
  • Mean FIO2 for 100 and 200 mg/kg poractant alfa groups were significantly lower than that for the beractant group at all time points until six hours (P < 0.05).
  • No significant difference between the mean FIO2 in infants treated with 100 or 200 mg/kg of poractant alfa.
  • FIO2 AUC0-6 was significantly lower in infants treated with either initial dose of poractant alfa within 2.5 hours of birth compared with beractant (P < 0.02).
  • Seventy-three percent of infants were successfully treated with only one dose of 200 mg/kg poractant alfa compared with 59% in the poractant alfa 100 mg/kg group and 51% in the beractant group (P < 0.002).
  • Thirty-six percent of infants received two or more doses of surfactant in the poractant alfa 200 mg/kg group compared with 68% in the beractant group (P = 0.002).
  • There was no difference in changes in MAP during the six hours after the first dose of surfactant in the three groups.
  • Neonatal mortality rate at 28 days was not significant between the three groups.
  • Mortality at 36 weeks postconceptional age for infants born < 32 weeks gestation was 3% in the 200 mg/kg poractant alfa group, compared with 11% each in the 100 mg/kg poractant alfa-treated (P = 0.046) and beractant-treated (P = 0.034) infants.

Strengths

  • Randomized.
  • Comparative.
  • Appropriate study population.

Weaknesses

  • Repeat doses not masked.
  • Surfactant preparations not well-blinded.
  • Onset of clinical response only assessed for the first dose.
  • Three participants violated entry criteria (one born at 36 weeks gestational age, one had an Apgar score < 3 at 5 minutes, and one was ventilated with high frequency prior to treatment) but their results were included in the analysis.
  • Mortality reasons not specified.

Authors’ conclusion

Infants < 35 weeks gestation treated with an initial dose of 200 mg/kg poractant alfa are weaned from supplemental oxygen more rapidly during the first six hours after dosing; significantly fewer infants require additional doses if the 200 mg/kg initial dose of poractant alfa is used; and infants < 32 weeks treated with an initial dose of 200 mg/kg poractant alfa have a survival advantage.

Trial 2: Bloom B, Kattwinkel J, Hall R, et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997;100:31-38.

Objective

To compare the relative safety and efficacy of calfactant vs. beractant in reducing the acute severity of RDS when given at birth and to infants with established RDS.

Study design

Prospective, randomized, double-blind, multicenter clinical trial.

Inclusion criteria

  • Infants < 2,000 g birth weight and < 48 hours of age.
  • Radiographically confirmed RDS.
  • Intubation.
  • FIO2 > 0.4 with a PaO2 < 80 Torr or an a/A oxygen ratio of < 0.22.
  • Mothers who presented in labor or were expected to deliver before 30 weeks gestation (no minimum) were asked to enroll their infants in the prevention arm.

Exclusion criteria

  • Infant birth weight > 1,250 g birth weight.
  • Greater than 15 minutes old before resuscitation was successful.
  • Major anomaly that interfered with lung development of function.
  • More than one type of surfactant used during retreatment process.
  • A dosage error of greater than 50% occurred.
  • Major malformation recognized after study entry.
  • Diagnosed congenital sepsis or pneumonia.

Patient population

No differences in birth weight, gestational age, sex, racial distribution, maternal conditions, prenatal, intrapartum, and delivery room variables including Apgar scores.

Age and respiratory status were similar at study entry.

Outcomes

  • Twenty-five percent reduction between groups in the need for a third dose of surfactant for infants with established RDS.
  • Twenty-five percent reduction in the need for a second dose of surfactant for infants who received prophylactic surfactant.

Treatment regimen

The treatment arm enrolled infants of < 2,000 g birth weight with established RDS, and the prevention arm enrolled infants of < 29 weeks gestation with birth weights < 1,250 g.

Three hundred and three infants received calfactant at the recommended dosage of 100 mg/kg along with 180 infants in the prevention arm but in a special 25 mg/mL formulation to provide masking.

Three hundred and five infants received beractant at a dosage of 100 mg/kg in the treatment arm along with 194 infants in the prevention arm, also in a 25 mg/mL formulation.

Statistical analysis

  • ANOVA.
  • Mann-Whitney U test.
  • Cochran-Mantel-Haenszel chi square test.
  • Intention-to-treat.

Results

In the treatment arm, there was no difference between groups in the number of infants requiring more than two doses of surfactant.

The interval between doses was significantly longer for calfactant, suggesting an increased duration of treatment effect. The inspired oxygen concentration and mean airway pressure were lower in the calfactant infants during the first 48 hours in the treatment arm. There were no significant differences noted in the incidence of mortality, chronic lung disease, dosing re-evaluated events, or complications of prematurity.

In the prevention arm, there were no differences with respect to the number of surfactant doses. The dosing intervals were longer for calfactant infants after the second dose. No difference in inspired oxygen or mean airway pressure was noted during the first 72 hours.

Strengths

  • Randomized.
  • Double-blinded.
  • Appropriate dosages.
  • Appropriate study population.
  • Comparative.

Weaknesses

Mortality reasons not specified.

Authors’ conclusion

Infants treated with calfactant have a modest benefit in the acute phase of RDS. Calfactant seems to produce a longer duration of effect than beractant.

Recommendation

With the current information available, poractant alfa and calfactant appear to have comparable efficacy and safety except for a faster onset of action and longer duration of action for calfactant. Poractant alfa claims to have advantages over other surfactants such as less volume administered and higher phospholipid content; however, these proposed advantages have not been completely studied in clinical trials.

The cost of comparable doses of poractant alfa and calfactant show that calfactant is less expensive than poractant alfa for most situations. Based on comparable one-year cost evaluations and usage figures, poractant alfa would cost the hospital an additional $28,000 with no apparent additional clinical benefit to justify the increased cost. Calfactant has been supplied as both a 3 mL and 6 mL vial, and this availability has contributed to decreasing wastage.

It is recommended that only one neonatal surfactant product by used in the neonatal intensive care unit to minimize confusion among the products and reduce medication error potential. Therefore, it is recommended that calfactant remain the formulary agent instead of changing the formulary agent to poractant alfa.

References

  • Bloom B, Kattwinkel J, Hall R, et al. Comparison of Infasurf (calf lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997;100:31-38.
  • DEY. Curosurf [package insert]. Napa, CA; February 2002.
  • Forest Pharmaceuticals. Infasurf [package insert]. St. Louis; June 2003.
  • MICROMEDEX Healthcare Series. Greenwood Village, CO: MICROMEDEX; (edition expires March 2005).
  • Ramanathan R, Rasmussen M, Gerstmann D, et al. A randomized, multicenter masked comparison trial of poractant alfa (Curosurf) versus beractant (Survanta) in the treatment of respiratory distress syndrome in preterm infants. Am J Perinatol 2004;21:109-119.