Phospholipid fraction from bovine lung (surfactant).
1 vial with 54 mg contains 50.76 to 60.00 mg of a phospholipid fraction from bovine lung (powder), equivalent to a content of 66 µmol or 54 mg total phospholipids as freeze-dried powder.
Excipients/Inactive Ingredients: 1 pre-filled syringe of solvent of 1.2 ml contains: sodium chloride, sodium hydrogen carbonate, water for injections.
Pharmacotherapeutic Group: Bounding surface active phospholipids (natural surfactant). ATC Code: R07AA02.
Pharmacology: Pharmacodynamics: Alveofact effects a dose-dependent improvement in the pulmonary mechanisms and gas exchange in immature rabbit and lamb foetuses.
Endotracheal instillation of Alveofact in animals with mature lungs causes reversible impairment of respiratory function. Which will return to normal within a period of one week.
A favorable effect on pulmonary compliance and gas exchange can be expected from opening and stabilising the alveoli in immature, premature neonates with respiratory disorders.
Pharmacokinetics: After endotracheal instillation of radio active marked Alveofact (14-C lecithin) and distribution over the surface of the alveols maximum values of radioactivity has been found in the blood (2.5-5% of the total dose) of adult rabbits after 7-24 hours.
With adult rats as well as rabbits radioactivity could be proven over the whole body with accumulation in the liver, the kidneys and adrenal glands. The half time in the blood was calculated to be 70 hours. The most part of radioactivity could be detected 7 hours after application in the lung (rat), but also traces in the liver, the kidneys and the adrenal glands. Radioactivity could also be found in the lung after 7 days. The half time of phosphatide glycerol could be estimated with 43 ± 11 hours in premature infants treated with Alveofact.
Toxicology: Preclinical Safety Data: In animals with mature lungs, repeat endotracheal instillation of Alveofact leads to an increase and enlargement of the alveolar macrophages which are to some extent accumulated focally. Rounded atelectasis thereby forms. Such findings are not fully reversed within 14 days.
The potential risk of development of rounded atelectasis depends on the total lipid load of the lungs. With a view to the therapeutic benefit, the clinically recommended total dose of 4 x 54 mg total phospholipids per kg body weight with the first 2 days of life is justifiable.
Specific antibodies against Alveofact were found in 12 of 641 tested patients (2%) four weeks after administration. In four of those patients antibody detection was positive prior to Alveofact administration. The patients in whom the antibodies were found had a mean birth weight which was somewhat higher than in the entire population studied.
The clinical significance of these findings is not currently clear.
A sensitive preclinical test design demonstrated that Alveofact may trigger the development of specific antibodies. The antigenic potential from endotracheal administration is low, however.
Pre-existing antibodies could not be detected in the sera of healthy adult probands. It is essential to avoid a booster regimen, unless the absence of a humoral or local immune response can be proven.
Alveofact is indicated for treatment of respiratory distress syndrome (RDS) in neonates.
Alveofact is also indicated for the preventive use in premature neonates with a high risk of respiratory distress syndrome (RDS).
Each dose of Alveofact is 54 mg of total phospholipids per kg body weight (1.2 ml per kg body weight).
Prevention: A single dose of Alveofact and application within the first hour after birth are recommended.
Treatment: Alveofact should be administered early in the course of RDS i.e preferably less than 6 hours of age.
Treatment with Alveofact is given only by endotracheopulmonary instillation. A ready prepared catheter (e.g. umbilical catheter or gastric tube) is inserted through the positioned tracheal tube and the catheter opening positioned at the level of the tip of the tube. Using a syringe, the single dose of 1.2 ml Alveofact per kg body weight (corresponding to 54 mg total phospholipids per kg body weight) is administered as an intratracheal bolus via this catheter.
Additional injections of air are used to help ensure that instillation is complete. Upon removal of the catheter, the patient is reconnected to the respirator. To promote the equal distribution of Alveofact, the patient may be gently turned from side to side every few seconds.
Duration of treatment: Depending on the need for ventilation and on the initial dose, the following dosing scheme should be applied: Initial dose 54 mg: up to three subsequent applications of 54 mg.
Initial dose 108 mg: up to one dose of 108 mg or up to two doses of 54 mg.
The total dose should not exceed 216 mg total phospholipids per kg body weight within the first 2 days of life.
Administration: Alveofact should be administered by or under the supervision of clinicians experienced in intubation, ventilator management and general care of premature infants.
It is unlikely that premature neonates are already sensitive (hypersensitivity) to protein from bovine lung, but such a condition may cause anaphylactoid reactions which require the usual emergency treatment.
Overdose has not yet been reported. In the unlikely event of inadvertent overdose, it is recommended to aspirate the applied quantity of liquid applied as much as possible if there is a clinical deterioration. Symptomatic therapy should be given where necessary.
If an excessively large dose of Alveofact is given, observe the infant for signs of acute airway obstruction.
Hypersensitivity to the phospholipid fraction from bovine lung or any of the other ingredient.
No substance-related contraindications are known so far.
Caution: The benefits and risks of Alveofact therapy for congenital infections in premature neonates have not yet been adequately elucidated. The acute effect may be reduced if connatal pneumonia is suspected.
Pulmonary function may also deteriorate in the event of concomitant under development of the lung (prolonged deficiency of amniotic fluid due to ruptured membranes or congenital renal function impairment).
Preclinical studies demonstrate that the granulocytic defence cells (macrophages, leukocytes) phagocyte lipid emulsions. This process may be impaired by Alveofact in the presence of pneumonia and/or sepsis. Alveofact may only be used if adequate facilities for ventilation and monitoring of premature neonates with respiratory distress syndromes are available. There have been singular case reports of obstruction of the tracheal tube by viscous material. The origin and composition of this material is unknown. Although a certain causal connection between the use of Alveofact and such a life-threatening event has not been proven, it is important to heed the given instructions for use and storage (refer to Special instruction for use under Cautions for Usage and Storage). If obstruction of the tracheal tube is suspected, it is advised to aspirate the ventilation tubing and change the ventilation tube, respectively.
Following Alveofact administration, monitoring of the arterial blood gases, the fraction of inspired oxygen and ventilatory change is required to ensure appropriate adjustments.
If during the dosing procedure, episodes of bradycardia and decreased oxygen saturation occur, stop the dosing procedure and initiate appropriate measure to alleviate the condition. After stabilization, the dosing procedure should be resumed.
The pre-filled syringe with 1.2 ml solvent contains 0.078 mmol (=1.8 mg) sodium, thus less than 1 mmol (23 mg) sodium per pre-filled syringe (=single dose), i.e. almost free from sodium.
Effects on Ability to Drive and Use Machines: Not appliable.
The following frequencies are used as the basis for assessment of the undesirable effects: 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 or unknown); Not Known (frequency cannot be estimated from the available data) (refer also to Dosage & Administration, Precautions and Overdosage).
No substance-related side effects are to be expected when using as directed. Due to the quantity of fluid, brief obstruction of the upper airways may occur immediately after application of Alveofact, which can be remedied by increasing the respiratory pressure for 30 to 60 seconds.
Caution: There have been single reports of obstruction of the tracheal by viscous material. A causal connection to the use of Alveofact has not been proven. Cerebral and pulmonary haemorrhage has been described. Their frequency correlates roughly to declarations in the literature for this patient population.
No substance-related interactions are known so far.
Instruction for reconstitution of the powder: There are two options: Option 1- with vial adapter. Option 2- with cannula.
Option 1-with vial adapter: Caution: The syringe and vial adapter remain connected to the vial during the entire reconstitution procedure and are also used for removal of the reconstituted suspension.
Open the top of the vial adapter pack. Position the cone of the syringe on the vial adapter.
Push the tip of the vial adapter firmly into the rubber stopper until it is in place.
Add the solvent to the vial. Then shake immediately for 5 seconds.
With the suspension inverted, withdraw it into the syringe and then inject it back into the vial. Repeat 5 times.
Wait about one minute until the foam and suspension have separated. Recommendation: Use the holder enclosed in the pack.
With the suspension inverted, withdraw it into the syringe and remove the syringe ready for administration. Residual foam will be left in the vial.
Option 2-with cannula: Caution: The syringe with cannula remains connected to the vial during the entire reconstitution procedure and is also used for removal of the reconstituted suspension.
Open the top of the cannula pack. Place the core of the syringe on the cannula.
Insert the cannula into the vial through the rubber stopper.
Inject the solvent into the vial. Then shake immediately for 5 seconds.
Holding the suspension at an angle, withdraw it into the syringe and then inject it back into the vial. Repeat this procedure a total of 5 times. Then remove the cannula from the suspension (but not from the vial) in order to prevent the suspension from rising into the syringe.
Wait about one minute until the foam and suspension have separated. Recommendation: Use the holder enclosed in the pack.
The suspension can be removed by slow withdrawal. Residual foam will remain in the vial.
Special instruction for use: Check that the application catheter is positioned correctly in the tracheal tube prior to the administration of Alveofact.
The pCO2 values can change rapidly within the first hour of administration of Alveofact. It is therefore advisable, by means of continual transcutaneous pCO2 and pO2 measurements or by means of repeat capillary blood gas analysis, to ensure that pronounced changes in the CO2 partial pressure through the adjustment of the respiratory parameters (peak inspiratory pressure, respiratory frequency) are avoided.
Care must also be taken that through the adjustment of the inspiratory oxygen concentration, arterial pO2 does not exceed the desired limits so as to ensure that the risk of retinopathy of prematurity is not increased.
When using high-frequency mechanical ventilation (respiratory frequency above 60 per minute, expiratory time less than 0.6 seconds) it is essential to ensure that the expiratory period following Alveofact administration is sufficiently long.
If ventilation is not adapted in such a way following Alveofact therapy, the risk of slowly increasing hyperdistension of the lung from "inadvertent or auto-PEEP".
If passive expiration is incomplete, the intrapulmonary end-expiratory pressure will be higher than the setting on the respirator. A pathologically high functional residual capacity can thus develop. The peak inspiratory pressures required for ventilation must then be inappropriately increased, thereby increasing the risk of barotraumatic pulmonary injury.
Until Alveofact has been fully distributed in the lungs, coarse inspiratory rhonchi can be auscultated from the thorax in the first few minutes after administration. They are not an indication for tracheal aspiration, which otherwise may be done at any time.
If the need for oxygen with normoventilation exceeds level of 40%, up to three follow-up applications of 1.2 ml Alveofact per kg body weight (corresponding to 54 mg total phospholipids per kg body weight) may be given at intervals of 12 to 24 hours. If the response to the initial dose is inadequate, a prompt second dose (30 to 60 minutes after initial administration) of 1.2 ml Alveofact per kg body weight (corresponding to 54 mg total phospholipids per kg body weight) is recommended.
Through tracheal aspiration is required prior to each application in order to prevent impaired proliferation and foaming of Alveofact, caused by the mucosa.
If the oxygenation is acutely deteriorated (rise in pCO2 and drop in pO2), it is recommended to check the correct positioning and patency of the ventilation tube.
Metabolic or respiratory acidosis should be corrected prior to administration of Alveofact, since preclinial findings suggest that the efficacy of the preparation can thereby be impaired.
When using a double-lumen-tube or "side port connector" to administer Alveofact without interrupting ventilation, the respiratory parameters must be adjusted with particular care.
Special Precautions for Disposal: No special requirements.
Incompatibilities: No incompatibilities are known so far.
Do not store the powder and the solvent at temperatures above 30°C.
Do not freeze the powder, the solvent or the reconstituted suspension.
Shelf-Life: 36 months.
Storage conditions for the reconstituted medicinal product: The reconstituted suspension can be kept for up to six hours at temperatures up to 25°C or 24 hours at 2-8°C (refrigerated). In such a case the vial and the pre-filled syringe, respectively, need to be lightly agitated once prior to use.
R07AA02 - natural phospholipids ; Belongs to the class of lung surfactants. Used in the treatment of respiratory diseases.
Endotracheopulmonary instillation (vial + solvent) 45 mg/mL x 1's.