BLES® is indicated for rescue treatment of Neonatal Respiratory Distress Syndrome (NRDS/Hyaline Membrane Disease). For infants with NRDS confirmed by X-ray, with arterial to alveolar oxygen ratio (PaO2/PAO2) <0.22, BLES® is to be given as soon as possible after the oxygenation criteria are met.
The use of BLES® in infants less than 380 g or greater than 4460 g birth weight has not been evaluated in controlled trials.

BLES® is intended for intratracheal instillation only.

The recommended dosage of BLES® is 5 mL/kg at 27 mg of phospholipids/mL, which equals 135 mg phospholipid/kg. As many as 3 subsequent doses of BLES® can be given within the first 5 days of life. See Repeat Doses for details. Table 1 below suggests the total dosage for a range of birth weights.

Table 1
Weight (grams)
Total Dose
(mL)
Weight
(grams)
Total Dose
(mL)
600-650
3.2
1301-1350
6.8
651-700
3.5
1351-1400
7.0
701-750
3.8
1401-1450
7.2
751-800
4.0
1451-1500
7.5
801-850
4.2
1501-1550
7.8
851-900
4.5
1551-1600
8.0
901-950
4.8
1601-1650
8.2
951-1000
5.0
1651-1700
8.5
1001-1050
5.2
1701-1750
8.8
1051-1100
5.5
1751-1800
9.0
1101-1150
5.8
1801-1850
9.2
1151-1200
6.0
1851-1900
9.5
1201-1250
6.2
1901-1950
9.8
1251-1300
6.5
1951-2000
10.0

Dosing Considerations:
BLES® does not require reconstitution or filtering before use. Vials are for single use only, to ensure sterility. Once at room temperature, gently invert the vial to suspend the lipid and disperse any agglomerates. Inspect the vial for homogeneity. It is normal for warmed vials to have an even dispersion of fine but visible flecks of lipid. Contents should appear as an off-white to light yellow suspension. If contents are a darker color or will not disperse evenly, discard the vial. Report this and the lot number to the manufacturer.
BLES® should be warmed to at least room temperature, but no higher than body temperature before being administered. Warming can be accomplished in the following ways (times are approximate):

Table 2
Method of Warming
Refrigerated Vials
Frozen Vials
In the hand
5 min.
10 to 15 min.
On the counter
20 min.
60 min.
In a 37°C water bath
2 min.
5 min.

Method of Administration:
The infant should be suctioned and allowed to recover before commencing the procedure.
INSURE (INtubate-SURfactant-Extubate) Procedure: Ensure proper placement of the endotracheal tube (ETT) via chest auscultation and radiograph, if available (1-2 cm below the vocal cords, 1-2 cm above the carina). Do not instill BLES® down the right mainstream bronchus.
Draw the full dose into a syringe with a beveled large gauge (e.g. at least 20-gauge) needle, and fit the syringe with a sterile #5 Fr feeding tube which has been cut to an appropriate length so that it will reach the distal tip of the ETT. If product is not administered to the patient immediately, invert the prepared syringe before instillation to resuspend any lipid agglomerates. Briefly disconnect the infant from the ventilator so that the feeding tube may be threaded into the ETT. Alternately, to allow simultaneous mechanical ventilation or hand bagging, pass the feeding tube through the suction valve of a closed suctioning adaptor attached to the ETT.
Instill as a single bolus dose or up to three aliquots, as tolerated, with the infant supine for each aliquot. Instill each aliquot or dose over a period of 2 to 3 seconds. After each aliquot is instilled, the infant should be ventilated manually for 30 seconds, using pressures sufficient to achieve good chest expansion before returning the infant to the ventilator. If the infant remains on mechanical ventilation during dosing, raise the pressure by 1 to 2 cm H2O, if necessary, to assist with emptying the ETT. Allow approximately 1 – 2 minutes recovery time after each aliquot. Ensure oxygen saturation readings are about 95% before commencing the next aliquot.
The volume of surfactant will rise in the ETT during administration. If the surfactant is slow to subside, interrupt administration and hand ventilate until the ETT is clear before continuing. If the surfactant fails to subside, investigate the possibility of a mucous plug. Small aliquots or a slow drip are not recommended, as this may lead to poor surfactant distribution and uneven lung compliance.

MIST (Minimally Invasive Surfactant Therapy) Procedure:
Note: Variations of the MIST procedure detailed below have been described in the literature. A common variation is the LISA (less invasive surfactant administration) procedure that uses Magill forceps for placement. Thin catheter placement should be performed according to established protocols of the healthcare centre.
BLES® may also be administered as per MIST techniques. It is recommended that for MIST delivery the neonate is ≥ 28 weeks and / or ≥ 1000 grams, does not require intubation / mechanical ventilation and meets the criteria for surfactant administration (i.e. oxygenation requirement met). Neonates should be kept on nasal continuous positive airway pressure (NCPAP) or non-invasive positive-pressure ventilation (NIPPV) using nasal prongs or masks for the entire procedure.
To administer the dose via the MIST technique, guide a thin catheter (e.g. #5 Fr multi-access catheter) across the vocal cords to a depth of 6 cm + birth weight in kilograms as measured from the lip. This should ensure proper placement of the tip of the catheter mid-way between the vocal cords and carina. After catheter placement, keep the neonate’s mouth closed for NCPAP / NIPPV delivery. Synchronize surfactant instillation with the neonate’s inspiration using micro- boluses, over a period of 1 to 3 minutes. If unable to deliver the dose successfully using this technique in no more than three attempts, administer the dose via the INSURE method described above.

Monitoring after administration:
Once instillation is complete, new mechanical ventilatory parameters need to be established according to the TcPO2/TcPCO2 readings, the oxygen saturation monitor and chest expansion. TcPO2/TcPCO2 readings are preferred in infants of lower gestation (less than 32 weeks), and oxygen saturation readings preferred with older infants. Monitor tidal volume closely, as sudden lung compliance may occur without much chest movement. Start at pre-instillation settings and wean the pressures (PIP/PEEP), FiO2 and the ventilator rate, as indicated by the infant’s status. Follow-up blood gases one hour after dosing is a standard procedure for any infant who has received BLES® (PaO2 should be between 60-70 torr, PaCO2 should be kept between 35-45 torr, and pH between 7.35 – 7.45). Avoid suctioning for 2 hours post-BLES®, unless absolutely necessary. Due to the immediate effect of BLES® on lung compliance and oxygenation (usually within 5 to 30 minutes), FiO2 should be decreased accordingly, to prevent hyperoxia. Chest expansion should be observed closely and ventilatory pressures (PIP/PEEP) decreased accordingly. High oxygen saturation levels (>95%) or high TcPO2/TcPCO2 readings (as confirmed by comparison to blood gas measurements) indicate the infant should be weaned off FiO2, ventilator rates and pressures. Blood gas readings should be 60 – 70 torr for PaO2 and 35 – 45 torr for PaCO2. Failure to wean appropriately may result in a pneumothorax.
Infants whose ventilation becomes markedly impaired during or shortly after dosing may have mucous plugging of the ETT, particularly if pulmonary secretions were prominent prior to drug administration. In addition, surfactant may promote the movement of resident mucus. If suctioning is unsuccessful in removing the obstruction, the blocked ETT should be replaced immediately.

Repeat Doses:
Neonates can receive up to 3 additional doses of BLES® within the first 5 days of life. The criteria for an additional dose are:
• a positive response to the previous dose, and
• an increase in respiratory support as signalled by a gradual increase in FiO2. This increase must be at least 10% greater than the FiO2 required after the initial response to the previous dose of BLES®.
All infants exhibiting respiratory deterioration should be evaluated for a patent ductus arteriosus (PDA), pneumothorax and pulmonary haemorrhage before retreatment with BLES®. The regimen for repeat doses is the same as for the initial dose

• Administer in a highly supervised clinical setting with immediate availability of experienced neonatologists and other clinicians experienced with intubation, ventilator management, and general care of premature infants.
• BLES® can affect oxygenation and lung compliance rapidly. In some infants, hyperoxia may occur within minutes of administration. If hyperoxia develops and oxygen saturation is in excess of 95%, FiO2 should be reduced until saturation is 90 to 95%, to decrease the risk of retinopathy of prematurity.
• Transient episodes of bradycardia and decreased oxygen saturation may occur during dosing. If these occur, the dosing procedure should be stopped and appropriate measures to alleviate the condition initiated. After stabilization, the dosing procedure can be resumed.
• Administration techniques used with other surfactant products, such as slow administration or the use of small test aliquots, are not recommended with BLES®. Unlike other products that require a slow drip to prevent reflux, BLES® has a much lower viscosity and a higher protein content that promote a more rapid distribution. Slow administration may lead to uneven distribution, resulting in uneven lung compliance. If the dose fails to subside in the endotracheal tube with additional pressures recommended in Section 4.2, consider the possibility of a mucous plug.
Mucous Plugs: Infants whose ventilation becomes markedly impaired during or shortly after dosing, may have mucous plugging of the endotracheal tube, particularly if pulmonary secretions were prominent prior to drug administration. Suctioning of all infants prior to dosing may lessen the chance of mucous plugs obstructing the endotracheal tube. After dosing, exogenous surfactant may encourage the transport of resident mucus. If endotracheal tube obstruction from such plugs is suspected, and suctioning is unsuccessful in removing the obstruction, the blocked endotracheal tube should be replaced immediately.
A higher rate of sepsis has been described in those infants treated with BLES® than those in the control arm. Health professionals caring for these infants should be aware of this increased risk, take appropriate precautionary measures and be vigilant for any signs and symptoms of sepsis.
In 2018, two international studies reported an out-of-trend number of cases of pulmonary haemorrhage, including death; notwithstanding, the incidence remains below that seen in the clinical trial for patients treated with BLES® (8%) (see Post-Market Adverse Drug Reactions in Section 4.8).

There are no known drug interactions between BLES® and other substances. BLES® is not known to interfere with laboratory results.
Clinical experience with BLES® has shown it to be safe and effective when used with nitric oxide therapy, high frequency oscillation and extracorporeal membranous oxygenation.

Not applicable.

Not applicable.

Summary of the Safety Profile
Very common adverse events in clinical trials occurring in ≥1/10 of infants who received BLES® in descending order of frequency, were patent ductus arteriosus, decreased post-dose pulmonary function values, intraventricular haemorrhage of all grades, sepsis, retinopathy of prematurity, bradycardia and severe intraventricular haemorrhage.
Common adverse events occurring in ≥1/100 to < 1/10 of infants who received BLES®, in descending order of frequency, were pulmonary interstitial emphysema, periventricular leukomalacia, pneumothorax, pulmonary haemorrhage, endotracheal tube complications, necrotizing enterocolitis, respiratory acidosis, convulsions, hypotension, apnea, hydrocephalus and pneumonia.

Due to the rapid effect of BLES® on lung compliance and oxygenation, infants should be monitored for respiratory parameters and any of the common adverse events.

Tabulated List of Adverse Reactions
The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. As there are no rare, very rare, or not known adverse reactions, these groupings are not represented in Table 3.

Table 3
System Organ Class
Frequency of adverse reactions
Very common
Common
Uncommon
Infections and Infestation
• Sepsis
• Miscellaneous infections other than pneumonia
Blood and lymphatic system disorders
• Neonatal coagulation disorder
• Neonatal jaundice
• Thrombocytopenia
Endocrine disorders
• Hypercalcemia
• Hypoglycemia
Metabolism and nutrition disorders
• Acidosis
• Hyperkalemia
Nervous system
disorders
• Intraventricular hemorrhage of all grades
• Severe intraventricular hemorrhage
• Periventricular leukomalacia
• Convulsions
• Hydrocephalus
• Abnormal electro-encephalogram
• Cerebral infarction
• Encephalopathy
• Ependymitis
• Meningitis
Eye disorders
• Retinopathy of prematurity
Cardiac disorders
• Patent ductus arteriosus
• Bradycardia
• Cardiac arrest
• Cardiomegaly
• Cor-pulmonale
• Hypertrophic
cardiomyopathy
• Pneumopericardium
• Pulmonary edema
• Pulmonary valve stenosis
• Supraventricular tachycardia
Vascular disorders
• Hypotension
• Hemorrhage
• Hypertension
Respiratory, thoracic and mediastinal disorders
• Pulmonary interstitial emphysema
• Pneumothorax
• Pulmonary hemorrhage
• Endotracheal tube complications
• Asphyxia
• Bronchopulmonary dysplasia
• Hypoxia
• Pulmonary hypertension
Page 7 of 11
• Respiratory acidosis
• Apnea
• Pneumonia
Gastrointestinal disorders
• Necrotizing enterocolitis
• Enteritis
• Gastrointestinal hemorrhage
• Gastrointestinal reflux
• Ileus
• Intestinal perforation
• Pneumoperitoneum
Hepatobiliary disorders
• Hepatomegaly
Skin and subcutaneous tissue disorders
• Cellulitis
Renal and urinary disorders
• Anuria
• Hydronephrosis
• Hydroureter
• Nephrocalcinosis
General disorders and administration site conditions
• Growth retardation
• Neonatal hypothermia
Investigations
• Decreased post-dose pulmonary function values*
* The term “decreased pulmonary function” covered incidences of a fall in saturation or oxygenation, or an increase in CO2 values.

Comparative Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials are useful for identifying drug-related adverse events and for approximating rates.
In a double-blinded, comparative, multicenter clinical trial comparing the safety and efficacy of BLES® and Exosurf® Neonatal (colfosceril palmitate; Glaxo Wellcome), 568 infants received BLES® and 565 received Exosurf® for rescue treatment of NRDS. The most frequent events reported (in ≥ 1% of infants) to occur in either treatment group were patent ductus arteriosus in almost half of the infants, and decreased pulmonary function (defined as incidences of a fall in saturation or oxygenation, or an increase in CO2 values after dosing) in approximately one third of infants. These events occurred with similar frequency in either treatment group and are anticipated complications when infants in distress are handled.
Sepsis and pneumonia occurred significantly more frequently in BLES®-treated infants than in those who received Exosurf® (28% versus 23% for sepsis; 1% versus < 1% for pneumonia;
p < 0.05). Notwithstanding this higher incidence of sepsis, death due to infections was comparable between the two arms of the study.
Although the incidence of pulmonary hemorrhage was low (< 1%) within the first two hours after dosing, it was observed to increase to 8% before discharge from intensive care. This was not significantly different from the incidence of pulmonary hemorrhage with Exosurf®. For the 750-1250 grams birth weight group receiving BLES®, 7 of 32 deaths (22%) were attributed to pulmonary hemorrhage.

There was a significantly greater incidence of respiratory acidosis following treatment with BLES®. All incidences of respiratory acidosis occurred within two hours of dosing, and almost all incidences following either surfactant occurred at one study center, perhaps due to too rapid weaning of the ventilatory pressure and rate with decreased minute ventilation.
Significantly fewer infants who received BLES® developed pulmonary interstitial emphysema or pneumothorax than did those who were treated with Exosurf®. This may reflect the increased ventilatory requirements of infants who received Exosurf®. Thus, a reduction in ventilatory pressure following treatment with BLES® may protect infants from pulmonary air leaks.
Decreased pulmonary function (reported incidences of a fall in saturation or oxygenation, or an increase in CO2 values), bradycardia and endotracheal tube complications occurred with the same frequency in each treatment group and are commonly associated with handling and treatment of premature infants. As discussed above, respiratory acidosis occurred, for the most part, at one site and may have been due to inadequate monitoring of lung compliance at that site.
Other adverse events that were reported to occur within two hours after administration of BLES®, but at a frequency of < 1% were: acidosis; hypertension; hypotension; hypoxia; patent ductus arteriosus; pneumonia; pneumothorax; and pulmonary hemorrhage.
 

Post-Market Adverse Drug Reactions
In 2018, two international studies reported an out-of-trend number of cases of pulmonary haemorrhage, including death; notwithstanding, the incidence remains below that seen in the clinical trial for patients treated with BLES® (8%).
Three infants at one site, who were administered very small aliquots of 1 mL at a time, developed pulmonary haemorrhage, intraventricular haemorrhage and/or periventricular leukomalacia, and died. The very small doses may have led to uneven surfactant distribution and uneven lung compliance. As noted in Section 4.4, small aliquot or slow-drip methods are not appropriate for the administration of BLES®.

To report any side effect(s):
• Saudi Arabia:
- The National Pharmacovigilance and Drug Safety Centre (NPC):
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2340
o SFDA call center: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
- Please contact the relevant competent authority.

No evidence of human overdose with BLES® has been documented. Based on animal data, overdosage may result in acute airway obstruction.

Pharmacotherapeutic group: Lung surfactants
ATC Code: R07AA02
Mechanism of Action
BLES® restores surfactant activity in neonates with respiratory distress syndrome (NRDS), thereby improving gaseous exchange by decreasing alveolar surface tension and promoting lung compliance in the infant with NRDS.
BLES® is an extract of natural bovine surfactant which contains numerous phospholipids, with dipalmitoylphosphatidylcholine (DPPC) being the most abundant. It also includes hydrophobic surfactant-associated proteins SP-B and SP-C, which facilitate their dispersion. When administered intratracheally, BLES® is rapidly adsorbed, forming an active phospholipid monolayer at the air-fluid interface.
Pharmacodynamics
BLES® can have an immediate effect on lung compliance, usually within 5 to 30 minutes after treatment with a single dose. Clinical experience with BLES® has shown that BLES® significantly improved gas exchange and lung compliance by the 4-hour time-point. Fraction of inspired oxygen (FiO2) and ventilatory requirements were significantly decreased, and there was a reduction in the severity of NRDS and its associated complications

Surfactants act locally and are recycled within the lung tissue. The metabolic fate of BLES® has not been investigated.

Repeat-dose toxicity
Non-clinical data reveal no special hazard for humans based on a conventional study of repeated dose toxicity.
In a 17-day toxicity study, lambs were administered 10 mL/kg of BLES® or vehicle control by intratracheal instillation every other day for a total of 5 doses. A control group received no treatment. Dyspnea was commonly observed during dosing with both the vehicle control and BLES®. Two animals given BLES® died during the second dosing from apparent volume overload (drowning). Further doses of BLES® were administered in smaller aliquots. No other consistent adverse pharmacologic, toxicologic or behavioural clinical signs were noted from treatment with BLES® or vehicle control.

Genotoxicity
The genotoxic potential of BLES® has not been evaluated.
Carcinogenicity
The carcinogenic potential of BLES® has not been evaluated.
Reproductive and developmental toxicity
Impairment to reproductive potential has not been evaluated for BLES®.

Calcium chloride, saline for irrigation, sterile water for irrigation. BLES® contains no preservatives.

Clinical experience with BLES® has shown it to be safe and effective when used with nitric oxide therapy, high frequency oscillation and extracorporeal membranous oxygenation.

• Do not use past expiry date on label.
• Store frozen vials in cartons until ready for use. Frozen product may have two excursions to 2°–8°C for a combined maximum of two weeks.
• BLES® vials may be stored refrigerated (2°– 8°C) upon receipt, for up to 10 months. In the space provided on the vial labelling, record the new expiry date of up to 10 months from the day it is received. Refrigerated vials should not be returned to the freezer.
• An unopened vial warmed to room temperature for less than 6 hours, may be returned to its previous storage condition a maximum of 2 times. In the space provided on the vial labelling, record the number of times the vial has been warmed and returned to storage.

BLES® is available in 3 mL and 5 mL sterile, single use clear Type I glass vials, packaged individually or in cartons of 10 vials.

Not applicable.