PORACTANT ALFA: 564 Adverse Event Reports & Safety Profile

Poractant alfa is an extract of natural porcine lung (pulmonary) surfactant consisting of 99% polar lipids (mainly phospholipids) and 1% hydrophobic low molecular weight surfactant associated proteins (SP). The molecular weight of SP-B is

8.7 KDa and the molecular weight of SP-C is

3.7 KDa. CUROSURF (poractant alfa) intratracheal suspension is a sterile, white to creamy white suspension provided in a single-dose vial for intratracheal use. Each milliliter of suspension contains 80 mg of poractant alfa (surfactant extract) that includes 76 mg of phospholipids and 1 mg of SP of which 0.45 mg is SP-B, a 79-amino acid protein and 0.59 mg is SP-C, a 35-amino acid peptide . The amount of phospholipids is calculated from the content of phosphorus and contains 55 mg of phosphatidylcholine of which 30 mg is dipalmitoylphosphatidylcholine. It is suspended in 0.9% sodium chloride solution. The pH is adjusted with sodium bicarbonate to a pH of 6.2 (5.5 to 6.5). Curosurf contains no preservatives.

AND USAGE CUROSURF ® (poractant alfa)

Intratracheal

Suspension is indicated for the rescue treatment of Respiratory Distress Syndrome (RDS) in premature infants. CUROSURF reduces mortality and pneumothoraces associated with RDS. CUROSURF is a surfactant indicated for the rescue treatment, including the reduction of mortality and pneumothoraces, of Respiratory Distress Syndrome (RDS) in premature infants. ( 1 )

AND ADMINISTRATION Before administering CUROSURF, assure proper placement and patency of endotracheal tube ( 2.1 ) Administer intratracheally either in ( 2.1 ): Two divided aliquots through a 5 French end-hole catheter; or A single bolus through secondary lumen of a dual lumen endotracheal tube without interrupting mechanical ventilation Initial recommended dose is 2.5 mL/kg birth weight ( 2.2 ) Up to two repeat doses of 1.25 mL/kg birth weight may be administered at approximately 12-hour intervals ( 2.2 ) Maximum total dose (initial plus repeat doses) is 5 mL/kg ( 2.2 )

See Full Prescribing

Information for instructions on preparation and administration of the CUROSURF suspension ( 2.3 , 2.4 )

2.1 Important Administration Instructions For intratracheal administration only. CUROSURF should be administered by, or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants. Before administering CUROSURF, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering CUROSURF. Allow the infant to stabilize before proceeding with dosing. Administer CUROSURF either: Intratracheally by instillation in two divided aliquots through a 5 French end-hole catheter or Intratracheally in a single bolus through the secondary lumen of a dual lumen endotracheal tube without interrupting mechanical ventilation.

2.2 Recommended Dosage The initial recommended dose is 2.5 mL/kg birth weight, administered as one or two aliquots depending upon the instillation procedure <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. Up to two repeat doses of 1.25 mL/kg birth weight each may be administered at approximately 12-hour intervals in infants in whom RDS is considered responsible for their persisting or deteriorating respiratory status. The maximum recommended total dosage (sum of the initial and up to two repeat doses) is 5 mL/kg.

2.3 Preparation of the CUROSURF Suspension Remove the vial of CUROSURF suspension from a refrigerator at +2°C to +8°C (36°F to 46°F) and slowly warm the vial to room temperature before use. Visually inspect the CUROSURF suspension for discoloration prior to administration. The color of the CUROSURF suspension should be white to creamy white. Discard the CUROSURF vial if the suspension is discolored. Gently turn the vial upside-down, in order to obtain a uniform suspension. DO NOT SHAKE. Locate the notch (FLIP UP) on the colored plastic cap and lift the notch and pull upwards. Pull the plastic cap with the aluminum portion downwards. Remove the whole ring by pulling off the aluminum wrapper. Remove the rubber cap to extract content. Unopened, unused vials of CUROSURF suspension that have warmed to room temperature can be returned to refrigerated storage within 24 hours for future use. Do not warm to room temperature and return to refrigerated storage more than once. Protect from light.

2.4 Administration For endotracheal tube instillation using a 5 French end-hole catheter Slowly withdraw the entire contents of the vial of CUROSURF suspension into a 3 or 5 mL plastic syringe through a large-gauge needle (e.g., at least 20 gauge). Enter each single-use vial only once. Attach the 5 French end-hole catheter of appropriate length to position the catheter tip proximal to the distal portion of the endotracheal tube, to the syringe. Fill the catheter with CUROSURF suspension. Discard excess CUROSURF through the catheter so that only the dose to be given remains in the syringe. For the first dose: 1.25 mL/kg (birth weight) per aliquot For each repeated dose: 0.625 mL/kg (birth weight) per aliquot First aliquot of CUROSURF suspension: Position the infant in a neutral position (head and body in alignment without inclination), with either the right or left side dependent. Immediately before CUROSURF administration, ventilate the infant with supplemental oxygen sufficient to maintain SaO 2 &gt; 92%. Insert the catheter into the endotracheal tube and instill the first aliquot of CUROSURF suspension. After the first aliquot is instilled, remove the catheter from the endotracheal tube and manually ventilate with supplemental oxygen until clinically stable. Second aliquot of CUROSURF suspension: When the infant is stable, reposition the infant such that the other side is dependent. Administer the remaining aliquot using the same procedures as the first aliquot. After completion of the dosing procedure, do not suction airways for 1 hour after surfactant instillation unless signs of significant airway obstruction occur <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> . For endotracheal tube instillation using the secondary lumen of a dual lumen endotracheal tube Slowly withdraw the entire contents of the vial of CUROSURF suspension into a 3 or 5 mL plastic syringe through a large-gauge needle (e.g., at least 20 gauge). Do not attach 5 French end-hole catheter. Remove the needle and discard excess CUROSURF so that only the dose to be given remains in the syringe. Keep the infant in a neutral position (head and body in alignment without inclination). Administer CUROSURF suspension through the proximal end of the secondary lumen of the endotracheal tube as a single dose, given over 1 minute, and without interrupting mechanical ventilation. After completion of this dosing procedure, ventilator management may require transient increases in FiO 2 , ventilator rate, or PIP. Do not suction airways for 1 hour after surfactant instillation unless signs of significant airway obstruction occur.

2.1 Important Administration Instructions For intratracheal administration only. CUROSURF should be administered by, or under the supervision of clinicians experienced in intubation, ventilator management, and general care of premature infants. Before administering CUROSURF, assure proper placement and patency of the endotracheal tube. At the discretion of the clinician, the endotracheal tube may be suctioned before administering CUROSURF. Allow the infant to stabilize before proceeding with dosing. Administer CUROSURF either: Intratracheally by instillation in two divided aliquots through a 5 French end-hole catheter or Intratracheally in a single bolus through the secondary lumen of a dual lumen endotracheal tube without interrupting mechanical ventilation.

2.2 Recommended Dosage The initial recommended dose is 2.5 mL/kg birth weight, administered as one or two aliquots depending upon the instillation procedure <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 )]</span>. Up to two repeat doses of 1.25 mL/kg birth weight each may be administered at approximately 12-hour intervals in infants in whom RDS is considered responsible for their persisting or deteriorating respiratory status. The maximum recommended total dosage (sum of the initial and up to two repeat doses) is 5 mL/kg.

2.3 Preparation of the CUROSURF Suspension Remove the vial of CUROSURF suspension from a refrigerator at +2°C to +8°C (36°F to 46°F) and slowly warm the vial to room temperature before use. Visually inspect the CUROSURF suspension for discoloration prior to administration. The color of the CUROSURF suspension should be white to creamy white. Discard the CUROSURF vial if the suspension is discolored. Gently turn the vial upside-down, in order to obtain a uniform suspension. DO NOT SHAKE. Locate the notch (FLIP UP) on the colored plastic cap and lift the notch and pull upwards. Pull the plastic cap with the aluminum portion downwards. Remove the whole ring by pulling off the aluminum wrapper. Remove the rubber cap to extract content. Unopened, unused vials of CUROSURF suspension that have warmed to room temperature can be returned to refrigerated storage within 24 hours for future use. Do not warm to room temperature and return to refrigerated storage more than once. Protect from light.

None. None.

REACTIONS Common adverse reactions associated with the administration of CUROSURF include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse

Reactions in Studies in Premature Infants with Respiratory Distress Syndrome The safety data described below reflect exposure to CUROSURF at a single dose of 2.5 mL/kg (200 mg/kg), in 78 infants of 700-2000 grams birth weight with RDS requiring mechanical ventilation and a FiO 2 ≥ 0.60 (Study 1) [see Clinical Studies ( 14.1 )]. A total of 144 infants were studied after RDS developed and before 15 hours of age; 78 infants received CUROSURF 2.5 mL/kg single dose (200 mg/kg), and 66 infants received control treatment (disconnection from the ventilator and manual ventilation for 2 minutes). Transient adverse reactions seen with the administration of CUROSURF included bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. The rates of the most common serious complications associated with prematurity and RDS observed in Study 1 are shown in Table 1.

Table

1: Most Common Serious Complications Associated with Prematurity and RDS in Study 1 CUROSURF 2.5 mL/kgn=78 CONTROL*n=66 Acquired Pneumonia 17% 21% Acquired Septicemia 14% 18% Bronchopulmonary Dysplasia 18% 22% Intracranial Hemorrhage 51% 64% Patent Ductus Arteriosus 60% 48% Pneumothorax 21% 36% Pulmonary Interstitial Emphysema 21% 38% *Control patients were disconnected from the ventilator and manually ventilated for 2 minutes. No surfactant was instilled. Seventy-six infants (45 treated with CUROSURF) from study 1 were evaluated at 1 year of age and 73 infants (44 treated with CUROSURF) were evaluated at 2 years of age to assess for potential long-term adverse reactions. 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.

6.2 Immunogenicity 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.

6.3 Postmarketing Experience Pulmonary hemorrhage, a known complication of premature birth and very low birth-weight, has been reported both in clinical trials with CUROSURF and in postmarketing adverse event reports in infants who had received CUROSURF.

6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adverse

Reactions in Studies in Premature Infants with Respiratory Distress Syndrome The safety data described below reflect exposure to CUROSURF at a single dose of 2.5 mL/kg (200 mg/kg), in 78 infants of 700-2000 grams birth weight with RDS requiring mechanical ventilation and a FiO 2 ≥ 0.60 (Study 1) [see Clinical Studies ( 14.1 )]. A total of 144 infants were studied after RDS developed and before 15 hours of age; 78 infants received CUROSURF 2.5 mL/kg single dose (200 mg/kg), and 66 infants received control treatment (disconnection from the ventilator and manual ventilation for 2 minutes). Transient adverse reactions seen with the administration of CUROSURF included bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. The rates of the most common serious complications associated with prematurity and RDS observed in Study 1 are shown in Table 1.

Table

1: Most Common Serious Complications Associated with Prematurity and RDS in Study 1 CUROSURF 2.5 mL/kgn=78 CONTROL*n=66 Acquired Pneumonia 17% 21% Acquired Septicemia 14% 18% Bronchopulmonary Dysplasia 18% 22% Intracranial Hemorrhage 51% 64% Patent Ductus Arteriosus 60% 48% Pneumothorax 21% 36% Pulmonary Interstitial Emphysema 21% 38% *Control patients were disconnected from the ventilator and manually ventilated for 2 minutes. No surfactant was instilled. Seventy-six infants (45 treated with CUROSURF) from study 1 were evaluated at 1 year of age and 73 infants (44 treated with CUROSURF) were evaluated at 2 years of age to assess for potential long-term adverse reactions. 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.

6.2 Immunogenicity 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.

6.3 Postmarketing Experience Pulmonary hemorrhage, a known complication of premature birth and very low birth-weight, has been reported both in clinical trials with CUROSURF and in postmarketing adverse event reports in infants who had received CUROSURF.

AND PRECAUTIONS Acute Changes in Lung Compliance : Frequently assess need to modify oxygen and ventilatory support to respiratory changes ( 5.1 ) Administration-Related Adverse Reactions : Transient adverse effects include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. These events require stopping CUROSURF administration and taking appropriate measures to alleviate the condition ( 5.2 )

5.1 Acute Changes in Oxygenation and Lung Compliance The administration of exogenous surfactants, including CUROSURF, can rapidly affect oxygenation and lung compliance. Therefore, infants receiving CUROSURF should receive frequent clinical and laboratory assessments so that oxygen and ventilatory support can be modified to respond to respiratory changes. CUROSURF should only be administered by those trained and experienced in the care, resuscitation, and stabilization of pre-term infants.

5.2 Administration-Related Adverse Reactions Transient adverse reactions associated with administration of CUROSURF include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. These events require stopping CUROSURF administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing may proceed with appropriate monitoring.

5.1 Acute Changes in Oxygenation and Lung Compliance The administration of exogenous surfactants, including CUROSURF, can rapidly affect oxygenation and lung compliance. Therefore, infants receiving CUROSURF should receive frequent clinical and laboratory assessments so that oxygen and ventilatory support can be modified to respond to respiratory changes. CUROSURF should only be administered by those trained and experienced in the care, resuscitation, and stabilization of pre-term infants.

5.2 Administration-Related Adverse Reactions Transient adverse reactions associated with administration of CUROSURF include bradycardia, hypotension, endotracheal tube blockage, and oxygen desaturation. These events require stopping CUROSURF administration and taking appropriate measures to alleviate the condition. After the patient is stable, dosing may proceed with appropriate monitoring.