Drug Criteria & Outcomes: Calfactant (Infasurf)for respiratory distress
Drug Criteria & Outcomes
Calfactant (Infasurf)for respiratory distress
By Monica L. Burleson, PharmD
Pharmacy Practice Drug Information Resident
Medical University of South Carolina
Charleston
Indications:
Calfactant (Infasurf), manufactured by Forest Pharmaceuticals, is indicated for the prevention of respiratory distress syndrome (RDS) in premature infants (less than 29 weeks gestational age) that are at high risk for developing RDS, and for the treatment of premature infants (72 hours of age) who develop RDS and require endotracheal (ET) intubation.1,2
Pharmacology:
Calfactant is a calf-lung surfactant that contains phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C (SP-B and SP-C).1,2 It rapidly adsorbs to the surface of the air:liquid interface resulting in decreased surface tension and stabilization of the alveoli, thereby increasing lung compliance and decreasing the work of breathing.1,2
Pharmacokinetics:
Absorption and metabolism of calfactant in humans is unknown, because pharmacokinetic studies have not been performed. In one study, radiolabeled calfactant was administered to adult rabbits. After 24 hours, 50% of the radioactivity persisted in the lung alveolar lining, 25% persisted in the lung tissue, and less than 5% was found in other organs.1
Selected clinical trials:
Bloom and colleagues3 conducted a randomized, double-blind clinical trial comparing the safety and efficacy of calfactant and beractant in the prevention and treatment of RDS. The prevention arm enrolled 374 patients (calfactant, n = 180; beractant, n = 194) less than 29 weeks gestation with birth weights less than 1,250 g. The treatment arm enrolled 608 patients (calfactant, n = 303; beractant, n = 305) who were less than 2,000 g birth weight with established RDS. The primary endpoints were a 25% reduction in the need for a second dose in the prevention arm and a 25% reduction in the need for a third dose in the treatment arm. Secondary endpoints included severity of RDS, number of air leaks, complications of surfactant administration, and survival to 36 weeks postmenstrual age without oxygen requirement.3
Infants in both arms were randomized to receive either calfactant 4 mL/kg via ET tube or beractant 4 mL/kg via ET tube.3 Administration of surfactant occurred within 15 minutes of birth in the prevention arm and within two hours of meeting criteria in the treatment arm. In the prevention arm, the patients were stratified into two gestational age groups (less than 27 weeks and 27 to 29 weeks). In the treatment arm, stratification was according to birth weight (less than 750, 751 to 1,250, and 1,251 to 2,000 g). In order to maintain blinding, both the initial and subsequent doses were administered according to the beractant dosing protocol (100 mg/kg of phospholipid). In the first 96 hours, three repeat treatments at least six hours apart were scheduled only if the infant remained intubated for RDS and required at least 30% oxygen.3
Comparing doses
The primary endpoint of the number of doses required did not reach statistical significance in the prophylaxis arm.3 In the treatment arm, the number of patients requiring four or more doses was significantly lower in the calfactant group than in the beractant group (67 vs. 101, respectively). The number of hours between doses reached statistical significance after dose two in the prophylactic arm, and was significantly longer between all doses in the treatment arm.3
The secondary endpoints of total number of deaths and deaths related to RDS were statistically significant in the prophylaxis arm.3 There were 40 total deaths in the calfactant arm and 26 total deaths in the beractant arm (p = 0.03). There were 25 RDS-related deaths in the calfactant arm and nine RDS-related deaths in the beractant arm (p = 0.005). This was an unexpected finding and is explained by examining the birth-weight subgroups. The calfactant arm had 63% mortality for infants weighing less than 600 g, a rate that would be expected in such low-weight infants. The beractant arm had an unusually low mortality (26%) in this same weight group. The investigators do not have an explanation for this occurrence, and these results have not been seen in other studies.3
In the treatment arm, significant reductions in the time-weighted average (0 to 72 hours) for supplemental oxygen and mean airway pressure requirements were seen in the calfactant arm.3 There was no statistically significant difference in any other secondary endpoints in the prophylaxis or treatment arms.3
The authors concluded that a modest improvement in mean airway pressure, need for supplemental oxygen, and duration of surfactant effect can be achieved when calfactant is administered to infants of less than 2,000 g birth weight with established RDS.3 The lengthening of the duration of surfactant effect is also seen when calfactant is administered to infants less than 29 weeks gestation with birth weights less than 1,250 g.3
Adverse reactions:
The most common adverse reactions seen in clinical trials were cyanosis (65%), airway obstruction (39%), bradycardia (34%), reflux of calfactant into the endotracheal tube (21%), manual ventilation (16%), and reintubation (3%). In general, these events were transient and did not result in serious complications or death.1,2
Pregnancy/lactation:
Calfactant has not been assigned a Food and Drug Administration pregnancy category since studies assessing the effect of calfactant in pregnancy have not been performed.1,2,4 Lung surfactants are sometimes used in the treatment of acute respiratory distress syndrome in adults. If this agent were to be considered for use during pregnancy, the benefit to the mother would need to outweigh the possible risk to the fetus, since studies in women or animals are not available.1
Contraindications:
There are no contraindications stated in the product labeling for this agent.1,2
Warnings:
The administration of exogenous surfactants rapidly improves oxygenation and lung compliance. Patients should be carefully monitored to allow for modification of oxygen therapy and ventilatory support in response to respiratory status changes.1 If cyanosis, bradycardia, airway obstruction, or reflux of calfactant into the endotracheal tube occur, therapy should be discontinued, followed by appropriate management of these complications. After resolution of complications, therapy may be reinitiated with appropriate monitoring.1 There is a theoretical risk of immunologic or allergic reactions due to the foreign proteins in calfactant; however, no cases have been described in humans.1,2
Dosage and administration:
Calfactant is intended for intratracheal administration only. The usual dose is 3 mL/kg body weight at birth instilled via an endotracheal tube.1,2 It may be administered every 12 hours for a total of three doses. The product may settle during storage and should be gently swirled before administration; however, it should not be shaken. It does not require reconstitution or dilution. Calfactant should be refrigerated. Warming prior to administration is not necessary.1,2
Drug interactions:
There are no documented drug interactions.1
Drug-food interactions:
No drug-food interactions have been reported.1
Dosage forms available:
Calfactant is available as a sterile 35 mg/mL suspension for intratracheal use.1,5
Samples status:
Inpatient samples of calfactant should not be allowed.
Potential for medication errors:
A medication error could potentially occur with beractant since the name sounds similar and it is used for the same indication.
Filtration requirement:
Since calfactant is not an intravenous preparation, filtration is not required.
Discussion:
Calfactant is a calf-lung surfactant that contains phospholipids, neutral lipids, and hydrophobic surfactant-associated proteins B and C (SP-B and SP-C).1,2 It is indicated for the prevention of RDS in premature infants (less than 29 weeks gestational age) who are at high risk for developing RDS, and for the treatment of premature infants (72 hours of age) who develop RDS and require endotracheal intubation.1,2
Common adverse reactions seen with calfactant therapy are cyanosis, airway obstruction, bradycardia, reflux of calfactant into the endotracheal tube, need for manual ventilation, and reintubation.1 Due to the rapid improvement in oxygenation that occurs following administration of calfactant, this agent should not be used in situations where rapid modifications of oxygen therapy and ventilatory support cannot be made (i.e., transport).
The two major categories of exogenous surfactant preparations are synthetic and natural preparations. Many trials have compared natural vs. synthetic surfactants. In general, natural surfactant preparations have a more rapid onset of action and a longer duration of action than the synthetic surfactant preparations.6
In a trial conducted by Bloom and colleagues comparing calfactant to beractant, a modest improvement in mean airway pressure, a decreased need for supplemental oxygen, and a longer duration of surfactant effect was seen with calfactant.3 There was also a statistically significant difference in the number of infants requiring a fourth dose of surfactant therapy (67 vs. 101, respectively).3 This is approximately a 10% reduction in the need for a fourth dose. Due to the high cost of these agents, the ability to use fewer doses without compromising efficacy should be an important consideration when choosing between surfactant preparations.
|
Pulmonary Surfactant |
| Is a phospholipid bound to a protein |
| Is secreted by type II alveolar cells |
| Lowers surface tension of the water layer at the alveolar surface, which increases lung compliance (i.e., it makes it easier for the lungs to expand) |
| Its concentration decreases when lung volume is small and constant |
| Is replenished when type II alveolar cells are stimulated by a deep breath |
|
From Vander AJ, Sherman JH, Luciano DS, eds. Human Physiology. 5th ed. New York, NY: McGraw-Hill Publishing Co.; 1990. |
References
1. Infasurf package insert.: Forest Pharmaceuticals Inc., St. Louis; 1998 July.
2. DRUGDEX Editorial Staff. Calfactant. In: Gelman CR, Rumack BH, Hutchison TA, eds. DRUGDEX System. MICROMEDEX Inc.: Englewood, CO; Edition expires December 2000.
3. Bloom BT, Kattwinkel J, Hall RT, et al. Comparison of Infasurf (calf-lung surfactant extract) to Survanta (beractant) in the treatment and prevention of respiratory distress syndrome. Pediatrics 1997; 100(1):31-8.
4. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. 5th ed. Baltimore: Williams & Wilkins; 1998.
5. Cardinale V, ed. 2000 Drug Topics Red Book. 104th ed. Montvale, NJ: Medical Economics Co.; 2000.
6. Halliday HL. Natural vs. synthetic surfactant in neonatal respiratory distress syndrome. Drugs 1996; 51(2):226-37.
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