Calfactant (Infasurf®): A Comprehensive Monograph on its Pharmacology, Clinical Efficacy, and Safety in Neonatal Respiratory Distress Syndrome

Executive Summary

Calfactant, marketed under the brand name Infasurf®, is a sterile, non-pyrogenic, natural pulmonary surfactant of bovine origin. It is a cornerstone therapy in neonatal intensive care for the prevention and treatment of Neonatal Respiratory Distress Syndrome (RDS) in premature infants. Extracted from calf lungs using a distinct lung lavage method, Calfactant is a complex mixture of phospholipids, neutral lipids, and the critical hydrophobic surfactant-associated proteins B (SP-B) and C (SP-C). Its mechanism of action is to replace deficient or dysfunctional endogenous surfactant, rapidly adsorbing to the alveolar air-liquid interface to reduce surface tension. This biophysical action stabilizes the alveoli, prevents end-expiratory collapse (atelectasis), improves lung compliance, and facilitates effective gas exchange.

Clinical evidence has robustly demonstrated Calfactant's efficacy in decreasing the incidence of RDS, associated air leaks, and mortality due to RDS. Comparative trials have established its superiority over first-generation, protein-free synthetic surfactants and have shown it to be at least as effective as other natural surfactants, such as beractant, with potential advantages in duration of effect and speed of weaning from mechanical ventilation. Administration is exclusively intratracheal, requiring a highly controlled clinical setting and personnel experienced in the ventilatory management of premature neonates. The drug's potent and rapid pharmacodynamic effects necessitate immediate and frequent adjustments to ventilator support to prevent iatrogenic lung injury.

The safety profile of Calfactant is characterized primarily by transient, administration-related adverse events, including cyanosis, bradycardia, and airway obstruction. The high incidence of serious morbidities reported in clinical trials, such as intracranial hemorrhage and necrotizing enterocolitis, largely reflects the profound systemic immaturity of the patient population rather than direct drug toxicity. Calfactant was approved by the U.S. Food and Drug Administration (FDA) in 1998 and remains a vital tool in neonatology. Future developments are focused on less invasive administration methods, such as aerosolization, to extend the benefits of surfactant therapy while avoiding the risks associated with endotracheal intubation.

Historical Context and Development

The development of Calfactant is a culmination of nearly a century of scientific inquiry into the fundamental mechanics of respiration, representing a landmark achievement in neonatal medicine. Its story is interwoven with the broader history of surfactant discovery and the dedicated effort to combat RDS, once a leading cause of death in premature infants.

The Scientific Genesis of Surfactant Therapy

The conceptual framework for surfactant therapy began long before the substance itself was identified. In 1929, Swiss physiologist Kurt von Neergaard conducted experiments demonstrating that a force greater than tissue elasticity—surface tension—was responsible for a significant portion of the lung's recoil. He correctly hypothesized the existence of a substance lining the alveoli that reduced this tension, but his work was largely overlooked for over two decades.[1]

The field was reignited in the 1950s through disparate lines of research. In Britain, Richard Pattle, studying the effects of nerve gas, observed remarkable stability in foam expressed from mammalian lungs, leading him to deduce the presence of a surface-active lining.[2] Concurrently, in the United States, John Clements quantified the physical properties of this lining, solidifying the physiological role of pulmonary surfactant.[1] The pivotal clinical connection was made in 1959 by Mary Ellen Avery and Jere Mead, who published a seminal paper demonstrating that the lungs of premature infants dying from "hyaline membrane disease" were critically deficient in this surface-active material. This discovery fundamentally redefined the condition as Respiratory Distress Syndrome (RDS), shifting its etiology from a pathological membrane formation to a specific biochemical deficiency.[2]

Public and scientific momentum for developing a treatment surged dramatically after the death of President John F. Kennedy's premature son, Patrick Bouvier Kennedy, from RDS in 1963.[1] This tragic event galvanized research efforts and led to the first clinical trials. However, these initial attempts in the 1960s, using nebulized, protein-free synthetic surfactants, were unsuccessful.[1] This failure, while a setback, provided a crucial piece of the puzzle. It suggested that the phospholipid components alone were insufficient for therapeutic effect. Subsequent research in the 1970s by investigators like Goran Enhorning, Bengt Robertson, and Forrest Adams using animal models demonstrated that

natural surfactants, which contained proteins, were highly effective.[1] This work underscored the indispensable role of surfactant-associated proteins (SP-B and SP-C) for the proper biophysical function and rapid spreading of the surfactant film. The entire field was thus guided away from simple phospholipid mixtures and toward more complex, protein-containing formulations.

This foundational research culminated in 1980 when Tetsuro Fujiwara, who had worked with Adams, published a landmark study detailing the successful treatment of 10 premature infants with RDS using a modified bovine surfactant extract. This was the first successful demonstration of surfactant replacement therapy in humans, heralding a new era in neonatology.[2]

Development of Infasurf® (Calfactant)

Building on this scientific legacy, Calfactant was developed by a team of researchers at the University at Buffalo, led by Dr. Edmund A. Egan and Dr. Bruce A. Holm.[4] In 1985, they co-founded ONY Inc. (later ONY Biotech) with the specific mission of developing a superior natural lung surfactant replacement therapy.[7]

A key differentiator in their approach was the method of extraction. While early natural surfactants like beractant (Survanta®) were derived from minced lung tissue, the ONY team developed a calf lung lavage method.[8] This process involves washing the lungs to collect the surfactant from the alveolar surface, a gentler technique intended to yield a product that more closely mirrors the composition and activity of native surfactant.[9] This distinction in manufacturing is significant, as it results in a final product with a different biochemical profile. Specifically, Calfactant contains a notably higher concentration of the vital SP-B protein compared to minced lung extracts.[8] Given the critical role of SP-B in accelerating the adsorption of phospholipids to the air-liquid interface, this compositional difference provides a strong mechanistic basis for some of the clinical advantages later observed with Calfactant, such as a longer duration of effect.[10]

The development timeline proceeded steadily through the late 1980s and 1990s. Pivotal clinical trials required for regulatory submission were conducted between 1991 and 1993, followed by direct comparative trials against the synthetic surfactant Exosurf® and the natural surfactant Survanta® in 1994.[7] After a thorough review of the extensive clinical data, the U.S. Food and Drug Administration (FDA) granted marketing approval for Infasurf® (calfactant) on July 1, 1998.[7] Since its introduction, it has become an established therapy in neonatal intensive care units (NICUs) across the United States and, since 2002, in international markets.[6]

Physicochemical Properties and Formulation

Calfactant is a biological extract, and its therapeutic activity is derived from its complex, multicomponent composition, which is formulated as a sterile suspension for direct administration to the lungs.

Chemical Identification

• Generic Name: Calfactant [15]
• DrugBank ID: DB06415 [15]
• CAS Number: 183325-78-2 [17]
• Type: Small Molecule (DrugBank classification), though more accurately described as a biological complex.[15]
• Synonyms and Other Identifiers: Infasurf, Calf lung surfactant extract (CLSE), Bovactant, Alveofact, AeroFact, UNII Q4K217VGA9, ChEMBL1201447.[15]

Composition and Formulation

Infasurf® is supplied as a sterile, non-pyrogenic intratracheal suspension. It is not a chemically synthesized product but rather a purified extract of natural surfactant obtained from the lung lavage of calves.[9]

• Source and Key Components: The extract contains a mixture of phospholipids, neutral lipids, and the hydrophobic surfactant-associated proteins B (SP-B) and C (SP-C), which are essential for its surface-active properties.[19] The formulation contains no preservatives.[19]
• Concentration: Each milliliter (mL) of Infasurf® suspension contains a precise concentration of active components suspended in 0.9% aqueous sodium chloride solution [15]:
• Total Phospholipids: 35 mg
• Phosphatidylcholine: 26 mg (a major component)
• Disaturated Phosphatidylcholine (DPPC): 16 mg (the primary surface tension-reducing phospholipid)
• Total Proteins: 0.65 mg - 0.7 mg
• Surfactant Protein B (SP-B): 0.26 mg

Physical Characteristics and Storage

• Appearance: The product is an off-white suspension. During storage, the active components may settle, which is normal. Visible flecks within the suspension and some foaming at the surface after agitation are also characteristic and do not indicate degradation.[19]
• pH: The pH of the suspension is maintained between 5.0 and 6.2.[19]
• Storage and Handling: Proper storage is critical to maintain the integrity of the product. Vials must be stored under refrigeration at 2°C to 8°C (36°F to 46°F) and protected from light.[23] The 3 mL vial should be stored in an upright position.[23] Before use, the vial requires gentle swirling or agitation to create a uniform suspension; vigorous shaking must be avoided as it can denature the essential proteins.[24] Warming the vial prior to administration is not necessary. If an unopened vial is warmed to room temperature, it can be returned to the refrigerator one time if done within 24 hours.[23] Each vial is intended for single use only, and any unused portion must be discarded after initial entry.[25]

Table 1: Calfactant (Infasurf®) Drug Profile Summary

Property	Description
Generic Name	Calfactant
Brand Name(s)	Infasurf®
Manufacturer	ONY Biotech Inc.
DrugBank ID	DB06415
CAS Number	183325-78-2
Source	Natural extract from calf lung lavage
Formulation	Sterile, non-pyrogenic intratracheal suspension in 0.9% NaCl
Key Components & Concentration (per mL)	- Total Phospholipids: 35 mg - Phosphatidylcholine: 26 mg - Disaturated Phosphatidylcholine: 16 mg - Proteins (SP-B, SP-C): ~0.7 mg
Appearance	Off-white suspension; visible flecks and foaming are normal
Storage Conditions	Refrigerate at 2°C to 8°C (36°F to 46°F); protect from light

Data compiled from sources: [7]

Clinical Pharmacology

The therapeutic utility of Calfactant is rooted in its ability to mimic the physiological function of endogenous pulmonary surfactant, thereby correcting the core pathophysiological defect in RDS. Its pharmacological profile is characterized by a localized mechanism of action, rapid and profound pharmacodynamic effects, and minimal systemic exposure.

Mechanism of Action

Endogenous pulmonary surfactant is a complex lipoprotein mixture produced by Type II alveolar cells that is essential for normal respiration. Its primary function is to modify the surface tension at the air-liquid interface of the alveoli, which stabilizes them and prevents them from collapsing at the end of expiration.[23] Neonatal RDS is caused by a developmental deficiency of this surfactant, leading to high alveolar surface tension, widespread atelectasis, decreased lung compliance, and severe respiratory failure.[15]

Calfactant acts as an exogenous surfactant replacement.[17] When administered via intratracheal instillation, it is delivered directly to its site of action in the lung lumen.[15] The mixture of phospholipids and surfactant proteins (SP-B and SP-C) rapidly adsorbs to the alveolar surface.[19] This process effectively restores surface activity, dramatically lowering surface tension to a minimum of

≤3 mN/m.[15] By reducing surface tension, Calfactant prevents alveolar collapse, stabilizes the terminal airspaces, and reduces the work of breathing required to inflate the lungs.[20]

Pharmacodynamics

The administration of Calfactant produces rapid and marked physiological changes in pulmonary function.[19] The primary pharmacodynamic effects are:

• Improved Lung Compliance: The lungs become less stiff and expand more easily with each ventilated breath, which is reflected by a decrease in the ventilator pressure required to achieve adequate tidal volumes.[19]
• Enhanced Gas Exchange: The stabilization of alveoli increases the functional residual capacity and the surface area available for gas exchange. This leads to a swift improvement in oxygenation, clinically measured by a reduction in the fraction of inspired oxygen (FiO2​) needed to maintain adequate arterial oxygen saturation, and more efficient clearance of carbon dioxide.[19]

These potent effects are both the therapeutic goal and a significant clinical challenge. The rapidity with which a neonate's respiratory status can improve—often within minutes of administration—necessitates constant, vigilant monitoring by an experienced clinical team.[19] Failure to promptly and appropriately wean ventilator settings (e.g., peak inspiratory pressure,

FiO2​) in response to these changes can expose the fragile premature lung to iatrogenic injury, including barotrauma, volutrauma, and oxygen toxicity. Therefore, the safe use of Calfactant is inextricably linked to the availability of a highly skilled team and the resources of a NICU capable of managing dynamic ventilatory changes.[25] This drug-environment interaction is a critical determinant of patient outcomes.

Preclinical studies support these observations, with ex vivo data showing that Calfactant restores normal pressure-volume mechanics in surfactant-deficient rat lungs, and in vivo studies demonstrating improved lung compliance, gas exchange, and survival in a preterm lamb model of severe RDS.[19]

Pharmacokinetics (ADME Profile)

Formal human pharmacokinetic studies of Calfactant have not been conducted, as its action is local within the lungs and systemic exposure is not intended or expected.[15] The ADME profile is inferred from its route of administration and animal data.

• Absorption: Calfactant is administered directly to the lung surface and is not systemically absorbed in any significant amount. Its effects are confined to the pulmonary compartment.[15]
• Distribution: Following instillation, the drug distributes across the alveolar surfaces. An animal study using radiolabeled Calfactant in adult rabbits confirmed this localized distribution. After 24 hours, 75% of the radioactivity remained within the lungs (50% in the alveolar lining and 25% in lung tissue), while less than 5% was detected in other organs.[21]
• Metabolism: Calfactant is presumed to be metabolized by the same pathways as endogenous surfactant. This involves a local recycling process where surfactant components are taken up by Type II alveolar cells, reprocessed, and re-secreted.[15]
• Excretion: Clearance is a local pulmonary process. Data from a study in normal rabbits reported a clearance half-time from the lung lumen of approximately 12 hours.[15]

Clinical Application and Efficacy

Calfactant is a critical intervention for a well-defined population of premature neonates. Its efficacy has been established in large-scale clinical trials, demonstrating significant benefits in reducing the morbidity and mortality associated with RDS.

Approved Clinical Indications

The U.S. FDA has approved Infasurf® for two primary indications in the management of RDS [15]:

1. Prophylaxis: For the prevention of RDS in premature infants at high risk. This indication is specifically for neonates with a gestational age of less than 29 weeks. To be effective, prophylactic therapy should be administered as soon as possible after birth, with a target of within 30 minutes.[16]
2. Rescue Treatment: For the treatment of premature infants who have already developed established RDS. This indication is for neonates who are 72 hours of age or younger, have a confirmed diagnosis of RDS based on clinical and radiological findings, and require endotracheal intubation for respiratory support.[27]

The overarching therapeutic goal for both indications is to decrease the incidence of RDS, reduce mortality directly attributable to RDS, and lower the rate of air leak syndromes (e.g., pneumothorax, pulmonary interstitial emphysema) associated with the disease and its treatment with positive pressure ventilation.[15]

It is important to note that while prophylaxis is an approved indication, clinical practice has evolved. Many current neonatal care guidelines now recommend an initial approach of non-invasive continuous positive airway pressure (CPAP) for at-risk infants, with subsequent selective surfactant administration only for those who demonstrate progressive respiratory failure. This shift away from routine prophylaxis reflects efforts to minimize invasive procedures in this vulnerable population.[29]

Evidence from Clinical Trials

The clinical efficacy of Calfactant is supported by a robust body of evidence from multiple controlled trials.

• Pivotal Trials vs. Colfosceril Palmitate (Exosurf Neonatal®): The initial approval of Calfactant was based on two large, multi-dose, randomized, controlled trials that compared it to colfosceril palmitate, a first-generation, protein-free synthetic surfactant.[19] Across approximately 2,000 infants, these trials consistently showed that Calfactant was superior. For both prophylaxis and rescue use, Calfactant led to a greater reduction in RDS severity and mortality rates compared to colfosceril.[11] Furthermore, Calfactant was associated with a significantly lower incidence of pulmonary air leaks (12% vs. 22%) and produced more rapid improvements in oxygenation ( FiO2​) and mean airway pressure (MAP) within the first 48 hours of treatment.[11]
• Comparative Trials vs. Beractant (Survanta®): Calfactant has also been compared to beractant, another widely used natural surfactant derived from minced bovine lung. In rescue treatment trials, Calfactant demonstrated a greater reduction in RDS severity, although a significant difference in mortality rates was not observed.[11] A key finding from these comparisons was the apparently longer duration of clinical effect with Calfactant, which translated into a reduced need for repeat doses.[11] While most studies found similar efficacy for major outcomes like mortality and chronic lung disease, one prophylaxis trial reported an unexpected increase in mortality in the Calfactant arm. This was determined to be driven by an anomalously low mortality rate in the beractant group among the smallest infants (<600g), a finding that may not be generalizable.[11]

In summary, the clinical evidence confirms that Calfactant is a highly effective and well-tolerated therapy for RDS in premature infants. It is clearly superior to older synthetic surfactants and demonstrates comparable, if not slightly advantageous, efficacy compared to other contemporary natural surfactants.

Table 2: Summary of Key Comparative Clinical Trials for Calfactant

Trial/Reference	Comparator Drug	Study Design & Population	Key Efficacy Endpoints & Results
Pivotal Prophylaxis & Treatment Trials 11	Colfosceril Palmitate (Exosurf Neonatal®)	Multiple-dose, randomized, double-blind trials (~2,000 infants). Prophylaxis: Infants <29 weeks gestation. Treatment: Infants ≤72 hours old with established RDS.	- RDS Severity & Mortality: Calfactant reduced RDS severity and mortality to a greater extent than colfosceril. - Air Leaks: Lower incidence of pulmonary air leaks with Calfactant (12% vs. 22%). - Oxygenation: Significant improvements in FiO2​ and MAP within 24-48 hours with Calfactant.
Comparative Trials 11	Beractant (Survanta®)	Randomized, double-blind, multicenter trials. Prophylaxis & Treatment: Preterm infants with or at risk for RDS.	- RDS Severity: Calfactant reduced RDS severity more than beractant in rescue treatment. - Mortality: No significant difference in overall mortality rates. - Duration of Effect: Calfactant demonstrated a longer duration of effect and a reduced need for redosing compared to beractant.
Korean Cohort Study 35	Surfactant-TA, Poractant alfa	Retrospective cohort study (332 infants, 24-31 weeks gestation) with RDS.	- Primary Outcomes: No significant differences between Calfactant, Surfactant-TA, and Poractant alfa in rates of redosing, air leaks, duration of ventilation, high-grade IVH, or mortality. - Conclusion: Calfactant was found to be equally as effective as the other two natural surfactants in this cohort.

Dosage and Administration

The safe and effective use of Calfactant requires strict adherence to established dosing regimens and a meticulous administration protocol performed by trained personnel in a specialized setting.

Recommended Dosing Regimens

• Standard Dose: The recommended dose of Calfactant is 3 mL/kg based on the infant's birth weight.[19] This volume delivers a phospholipid dose of approximately 105 mg/kg.[11] This dose is consistent for both prophylactic and rescue treatment strategies.
• Repeat Dosing: Up to two additional doses of 3 mL/kg each may be administered if the infant continues to show evidence of respiratory distress and remains on endotracheal intubation. The standard interval between doses is 12 hours.[16] While some clinical studies have used intervals as short as 6 hours, a 12-hour interval is generally considered sufficient unless there is clinical evidence of surfactant inactivation, which can occur in the presence of infection, meconium, or pulmonary hemorrhage.[23] A maximum of three total doses is typically administered.[34]

Administration Protocol

The administration of Calfactant is a specialized medical procedure that must be performed with precision to ensure efficacy and safety.

• Route of Administration: Calfactant is for intratracheal administration only.[19]
• Clinical Setting and Personnel: Administration is restricted to a highly supervised clinical setting, such as a NICU, with immediate access to clinicians experienced in the intubation, resuscitation, and ventilatory management of premature infants.[25]
• Preparation of Dose:

1. The vial should be gently swirled or agitated to ensure a uniform suspension. Do not shake, as this can damage the surfactant proteins.[24]
2. Warming the vial is not necessary.[23]
3. Using a sterile technique, the calculated dose should be drawn into a syringe with a 20-gauge or larger needle to minimize foaming.[24]

• Instillation Procedure: The technique of instillation is a critical variable for efficacy, designed to achieve the most uniform distribution of the drug throughout the lungs. Uneven delivery could lead to under-recruited lung regions coexisting with over-distended areas, undermining the therapeutic goal and potentially causing harm.

1. The total dose is divided into two or four equal aliquots.[19]
2. The infant should be appropriately positioned. The aliquots are instilled into the proximal end of the endotracheal tube (ETT), either through a side-port adapter on the ETT connector or via a 5 French feeding catheter passed just beyond the ETT tip.[19]
3. Between the administration of each aliquot, the infant's position is changed (e.g., from right side down to left side down) to use gravity to facilitate distribution into different lung lobes.[20]
4. During the procedure, mechanical ventilation is continued. Each aliquot is instilled in small bursts over 20-30 inspiratory cycles. After each aliquot, ventilation is maintained for at least 30 seconds to 2 minutes to help drive the surfactant distally into the airways before the next aliquot is given.[19]

Essential Monitoring During and After Administration

• Immediate Monitoring: Continuous monitoring of heart rate, respiratory status, and transcutaneous oxygen saturation is mandatory throughout the administration procedure.[23]
• Post-Administration Monitoring: Due to the rapid improvement in lung function, frequent monitoring of arterial blood gases (ABGs) is essential after dosing. This allows for timely adjustments to ventilator settings to prevent the complications of hyperoxia and hypocarbia.[23]

Safety and Tolerability Profile

The safety profile of Calfactant must be interpreted within the context of its use in an extremely vulnerable patient population. Many of the serious adverse events observed during clinical trials are known complications of extreme prematurity itself. It is crucial to distinguish between transient events directly related to the administration procedure and the background morbidities of the treated infants.

Adverse Events

• Administration-Related Adverse Events: The most frequently reported adverse reactions are those that occur during or immediately following the instillation procedure. These events are typically transient and resolve after pausing the administration and providing supportive measures.[11]
• Very Common (>10%): Cyanosis (65%), airway obstruction (39%), bradycardia (34%), and reflux of surfactant into the endotracheal tube (21%).[23]
• Other Procedural Events: Requirement for manual ventilation (16%) and reintubation (3%) have also been reported.[33]
• Post-Administration Complications and Morbidities of Prematurity: The high incidence rates of the following serious conditions reported in clinical trials reflect the severe underlying illness and multi-system immaturity of infants with RDS, not necessarily a direct causal effect of the drug. Comparative data across different surfactants show similar rates for these complications, suggesting they represent the baseline risk in this population.[38]
• Respiratory: Apnea (76%), pulmonary air leaks (15%), pulmonary interstitial emphysema (10%), and pulmonary hemorrhage (7%).[33]
• Neurological: Intracranial hemorrhage (ICH) (36%), including severe grade ICH (12%), and periventricular leukomalacia (PVL) (7%).[33]
• Cardiovascular: Patent ductus arteriosus (PDA) (45%).[33]
• Gastrointestinal: Necrotizing enterocolitis (NEC) (17%).[33]
• Infectious: Sepsis (28%).[33]

Interpreting this safety data requires careful consideration. Calfactant is a life-saving therapy for a single-organ failure (respiratory) in a patient population at profound risk for multi-organ dysfunction. The "adverse event" list is therefore more a characterization of the natural history of extreme prematurity than a list of drug-induced toxicities. This distinction is fundamental to an accurate risk-benefit assessment in the NICU.

Table 3: Incidence of Adverse Events Associated with Calfactant in Clinical Trials

Category	Adverse Event	Incidence Rate (%)
Administration-Related (Transient) Events	Cyanosis	65%
	Airway Obstruction	39%
	Bradycardia	34%
	Reflux into Endotracheal Tube	21%
	Requirement for Manual Ventilation	16%
	Reintubation	3%
Post-Administration Complications (Common Morbidities of Prematurity)	Apnea	76%
	Patent Ductus Arteriosus (PDA)	45%
	Intracranial Hemorrhage (ICH)	36%
	Sepsis	28%
	Necrotizing Enterocolitis (NEC)	17%
	Pulmonary Air Leaks	15%
	Severe Intracranial Hemorrhage	12%
	Pulmonary Interstitial Emphysema	10%
	Periventricular Leukomalacia (PVL)	7%
	Pulmonary Hemorrhage	7%

Data compiled from source: [33]

Contraindications, Warnings, and Precautions

• Contraindications: There are no absolute contraindications listed by the manufacturer for the use of Calfactant.[21]
• Black Box Warnings: Calfactant does not have a black box warning in its labeling.
• Warnings and Precautions: The product labeling contains several important warnings:
• Rapid Physiological Changes: The most critical warning emphasizes that administration can lead to rapid improvements in oxygenation and lung compliance. This necessitates careful and continuous monitoring so that ventilator support can be modified promptly to avoid lung injury.[19]
• Administration Complications: Clinicians should be prepared to manage transient episodes of bradycardia, oxygen desaturation, airway obstruction, and reflux during the dosing procedure. If these occur, the instillation should be stopped until the infant is stable.[29]
• Intratracheal Use Only: The product is strictly for administration into the trachea.[19]
• Allergic Reactions: While no cases have been reported in humans, a theoretical risk of immunologic or allergic reactions exists due to the presence of bovine proteins.[21]

Drug Interactions

Due to its local administration within the lungs and negligible systemic absorption, clinically significant pharmacokinetic drug-drug interactions with Calfactant are not expected.[16] However, a potential pharmacodynamic interaction exists with other medications that cause bradycardia. The transient bradycardia sometimes seen during Calfactant administration may be enhanced by concomitant use of other bradycardia-causing agents. Close monitoring of heart rate is advised if such combinations are used.[15]

Regulatory Status and Future Directions

Calfactant has a well-established regulatory and commercial history in the United States and is part of an evolving field of therapy focused on improving outcomes through less invasive techniques.

Global Regulatory Approvals

• United States (FDA): Calfactant was granted Orphan Drug Designation by the FDA on June 7, 1985, for its intended use in treating and preventing respiratory failure due to surfactant deficiency in preterm infants.[13] Following extensive clinical trials, it received full marketing approval on July 1, 1998, under New Drug Application (NDA) 20-521.[7]
• Australia (TGA): A review of the Therapeutic Goods Administration (TGA) public database and related materials indicates that Calfactant (Infasurf®) is not currently registered on the Australian Register of Therapeutic Goods (ARTG). Therefore, it is not approved for general marketing and supply in Australia.[39]
• Other Regions: Calfactant is approved and marketed in various other countries. Its international expansion began in 2002, with specific approvals noted in regions such as South America (e.g., Colombia) and Korea, and distribution partnerships established for areas including the Middle East.[3]

Commercial Information

• Manufacturer: Calfactant is manufactured by ONY Biotech Inc., a company headquartered in Amherst, New York, that specializes in neonatal therapies.[7]
• Brand Name: The sole brand name for Calfactant is Infasurf®.[8]

Innovations and Future Directions

The primary focus of current research and development in surfactant therapy is to overcome the main limitation of existing treatments: the need for endotracheal intubation and mechanical ventilation for administration. This invasive procedure carries its own risks and can contribute to the development of bronchopulmonary dysplasia (BPD), a form of chronic lung disease in premature infants. The future of the field, including the development pathway for Calfactant, is clearly aimed at less invasive strategies.

This shift represents a significant evolution in neonatal care philosophy. The goal is no longer just to rescue infants with severe, established RDS, but to intervene earlier and more gently. By decoupling the drug from the invasive procedure, it may become possible to treat infants with milder RDS who are on non-invasive support like CPAP, potentially preventing progression to respiratory failure and avoiding intubation altogether. This could significantly improve long-term pulmonary outcomes for a larger population of premature infants.

Key areas of innovation include:

• Aerosolized Delivery: ONY Biotech has actively pursued the development of an aerosolized form of Calfactant, known as InfasurfAero™. Clinical trials are investigating its delivery via a specialized nebulizer connected to a pacifier adapter, allowing spontaneously breathing infants to inhale the surfactant.[7] A completed trial showed that this method reduced the need for subsequent intubation and liquid surfactant instillation by nearly 50% in newborns with mild to moderate RDS, demonstrating the promise of this approach.[42]
• Minimally Invasive Surfactant Therapy (MIST/LISA): The technique of Less Invasive Surfactant Administration (LISA), where surfactant is instilled through a thin, soft catheter placed temporarily in the trachea while the infant continues to breathe spontaneously on CPAP, is a major area of clinical research. While this is not yet an FDA-approved administration method for Infasurf®, it is a leading strategy being explored globally.[28]
• Novel Delivery Devices: A pilot study is planned to assess the administration of Calfactant through a new supraglottic airway device. Like aerosolization, this method aims to deliver surfactant to the lungs while completely avoiding the need for direct tracheal intubation.[44]

Conclusion

Calfactant (Infasurf®) is a highly effective, natural bovine-derived surfactant that has been instrumental in reducing the morbidity and mortality of Neonatal Respiratory Distress Syndrome for over two decades. Its development was a direct result of foundational scientific discoveries that identified surfactant deficiency as the cause of RDS and recognized the critical role of surfactant-associated proteins for therapeutic efficacy. Its unique calf lung lavage extraction method yields a product rich in SP-B, which may contribute to its robust clinical performance.

The pharmacological profile of Calfactant is defined by its rapid and potent ability to restore pulmonary function, a characteristic that demands expert clinical management in a NICU setting. While its safety profile includes transient administration-related events, the more severe complications observed in clinical trials are largely attributable to the profound immaturity of the patient population it is designed to treat.

As a well-established therapy, Calfactant has a proven track record of saving lives. The future of its application, and of surfactant therapy in general, lies in the development of less invasive delivery systems. Ongoing research into aerosolized and other non-invasive administration techniques promises to further improve outcomes for premature infants by extending the benefits of this life-saving drug while minimizing the risks associated with traditional, invasive respiratory support.

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