Source: Health Products Regulatory Authority (IE) Revision Year: 2018 Publisher: SOL S.p.A., Via Borgazzi 27, 20900 Monza, Italy
Neophyr, in conjunction with ventilatory support and other appropriate active substances, is indicated:
Prescription of nitric oxide should be supervised by a physician experienced in neonatal intensive care.
Prescription should be limited to those neonatal units that have received adequate training in the use of a nitric oxide delivery system. Neophyr should only be delivered according to a neonatologist’s prescription.
Neophyr should be used in ventilated newborn infants expected to require support >24 hours. Neophyr should be used only after respiratory support has been optimised. This includes optimising tidal volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end expiratory pressure).
Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anaesthesia & intensive care. Prescription should be limited to those cardio-thoracic units that have received adequate training in the use of a nitric oxide delivery system. Neophyr should only be delivered according to an anaesthetist’s or intensive care physician’s prescription.
The posology will be determined in accordance with the medical condition of the patient.
Due to the potential risk of NO2 formation, continuous monitoring of NO2 must be performed.
The maximum recommended dose of Neophyr is 20 ppm and this dose should not be exceeded. Starting as soon as possible, and in the first 4-24 hours of therapy, the dosage must be reduced gradually to 5 ppm or less, titrating it to the needs of the individual patient, as long as the clinical parameters (oxygenation, arterial pulmonary pressure) are within the desired limits. Inhaled nitric oxide therapy must be maintained at 5 ppm until an improvement in the oxygenation is observed in the newborn in such as way that the fraction of inhaled oxygen is diminished to below 60% (FiO2 <0.60).
The treatment can be pursued up to 96 hours or until the oxygen de-saturation is resolved and the patient is ready for gradual withdrawal from Neophyr treatment. The duration of the treatment should be limited to be as short as possible. The duration is variable, but typically, less than 4 days. If there is no response to the inhaled nitric oxide, consult section 4.4.
Attempts to wean Neophyr should be made after the ventilator support is substantially decreased or after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation during administration of Neophyr at 1 ppm, the FiO2 should be increased by 10%, the Neophyr is discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20%, Neophyr therapy should be resumed at 5 ppm and discontinuation of Neophyr therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off Neophyr by 4 days should undergo careful diagnostic work-up for other diseases.
Neophyr should be used only after conservative support has been optimised. Neophyr should be administered under close monitoring of hemodynamics and oxygenation.
The starting dose of inhaled nitric oxide is 10 ppm(parts per million) of inhaled gas. The dose may be increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.
Clinical data supporting the suggested dose in the age range 12-17 years is limited.
The starting dose of inhaled nitric oxide is 20 ppm (parts per million) of inhaled gas. The dose may be increased up to 40 ppm if the lower dose has not provided sufficient clinical effect. The lowest effective dose should be administered and the dose should be weaned down to 5 ppm provided that the pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.
The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after a minimum of 10 minutes.
Consideration should be given to discontinuation of treatment if no beneficial physiological effects are apparent after a 30-minute trial of therapy.
Treatment may be initiated at any time point in the perioperative course to lower pulmonary pressure.
In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass.
Inhaled NO has been given for time periods up to 7 days in the perioperative setting, but common treatment times are 24-48 hours.
Attempts to wean Neophyr should be commenced as soon as the hemodynamics have stabilised in conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide therapy should be performed in a stepwise manner.
The dose should be incrementally reduced to 1 ppm for 30 minutes with close observation of systemic and central pressure, and then turned off. Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of Neophyr.
Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability.
No relevant information for dosage adjustment recommendation on special populations, such as renal/hepatic impairment or geriatric, has been found. Therefore caution is recommended in these populations.
The safety and efficacy of inhaled nitric oxide in premature infants less than 34 weeks of gestation has not yet been established, no recommendation or posology can be made.
For inhalation use.
Modalities of administration of Neophyr can modify the toxicity profile of the drug. Administration recommendations have to be followed.
Nitric oxide is normally administered by inhalation in patients via mechanical ventilation after it has been diluted with a mix of oxygen/air using a nitric oxide administration device that has been approved for clinical use as per the European Community standards (CE marked). Direct endotracheal administration without dilution is contra-indicated due to the risk of local lesion of the mucous membrane when it comes into contact with the gas.
NO must correctly mix with other gases in the ventilator circuit. It is advisable to ensure the least amount of contact time possible between the nitric oxide and the oxygen in the inspiratory circuit in order to limit the risk of the formation of toxic oxidation derivatives in the inhaled gas. It is therefore recommended dilution of nitric oxide is administered in the inspiratory branch of the ventilation circuit and after the humidifier.
The administration system should supply a constant concentration of inhaled Neophyr, notwithstanding the ventilation equipment and ventilation modality utilised.
In order to avoid errors in the dosage, the concentration of Neophyr inhaled must be continually regulated in the inhalation branch of the circuit close to the patient, and near the tip of the endotracheal tube. The concentration of nitrogen dioxide (NO2) and FiO2 must also be regulated in the same place using a calibrated and EC-approved monitoring apparatus.
The concentration of NO2 in the inhaled mix must be as low as possible. If the concentration of NO2 exceeds 1 ppm, the dose of Neophyr and/or FiO2 must be reduced, ruling out any possible malfunction in the administration system.
For the safety of the patient, appropriate alarms must be configured for Neophyr (± 2 ppm of the prescribed dose), NO2 (maximum 1 ppm) and FiO2 (± 0.05).
If an unexpected change in the concentration of Neophyr is produced, the administration system will have to be checked for defects and the analyser will have to be calibrated again.
The pressure of the Neophyr gas cylinder must be monitored in order to allow the gas cylinder to be changed without interruptions or changes to the treatment. There must also be a reserve supply of gas cylinders to allow changes at the appropriate moment.
In case of failure of the system or a cut in the electricity supply, there must be an emergency battery electricity supply and a back-up system for the administration of the nitric oxide. The electricity supply of the monitoring equipment must be independent of the function of the administration device.
Neophyr therapy must be available for mechanical and manual ventilation, during transportation of the patient and during resuscitation. The doctor must have access near the head of the patient to place a reserve nitric oxide administration system.
Nitrogen dioxide (NO2) forms rapidly in gaseous mixtures that contain nitric oxide and O2. Nitric oxide, in reaction with oxygen, will produce nitrogen dioxide (NO2) in variable quantities depending on the NO and O2 concentrations. NO2 is a toxic gas that can provoke an inflammatory reaction in the respiratory tract; it is for this reason that its production must be closely monitored.
Immediately before starting the treatment on each patient, it is necessary to apply the appropriate procedures to purge the system of NO2.
The NO2 concentration must be kept as low as possible and always <0,5 ppm. If NO2 is >0,5 ppm, the administration system must be checked for defects, the NO2 analyser must be recalibrated and, if possible, the levels of Neophyr and/or FiO2 must be reduced.
If there is an unexpected change in Neophyr concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated.
Following its inhalation, the terminal compounds of nitric oxide that arrive in the systemic circulation are primarily methaemoglobin and nitrate. The nitrate is fundamentally excreted through the urinary system and the methaemoglobin is reduced by the methaemoglobin reductase.
Newborns and infants have diminished levels of MetHb reductase activity compared to adults; therefore the methaemoglobin concentrations in the blood must be monitored. The level of MetHb must be measured within 1 hour of the start of Neophyr therapy using an analyser that correctly distinguishes the fetal hemoglobin from the MetHb. If the MetHb is >2.5%, the dose of Neophyr will have to be reduced and the necessity for the administration of reducing agents such as methylene blue will be assessed. Although considerable increases in the level of MetHb are infrequent, since the level is low during the first determination, it is advisable to repeat the MetHb measurements every 12-24 hours thereafter.
In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the initiation of Neophyr therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the Neophyr dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered.
The maximum exposure limit (average exposure) of hospital personnel to nitric oxide has been determined by labour legislation and is 25 ppm over a period of 8 hours (30 mg/m³) and the corresponding limit for NO2 is 2-3 ppm (4-6 mg/m³) in the majority of European countries. Extrapolating these limits to intensive care units where the inhalation of NO can be administered for a period of 24 hours, it would be prudent to keep the atmospheric levels of NO2 below 1.5 ppm. Continuous monitoring of atmospheric levels of NO2 is mandatory.
The key elements that need to be covered in training hospital personnel are as follows.
Correct set-up and connections:
Operation:
Overdose with Neophyr will be manifest by elevations in methaemoglobin and NO2. Elevated NO2 may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels >3 ppm or methaemoglobin levels >7% were treated by reducing the dose of, or discontinuing, iNO.
Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.
3 years.
All regulations concerning handling of pressurised cylinders must be followed. Storage is supervised by the specialists at the hospital. Cylinders are to be stored in well-ventilated rooms or in ventilated sheds where they are protected from rain and direct sunlight.
The cylinders must be stored at a temperature between -10 and +50°C.
Protect the cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition.
The gas cylinders should be kept in a place designated exclusively for medicinal gas storage that is well ventilated, clean and under lock and key. This place should house a separate, special facility for the storage of nitric oxide gas cylinders.
The cylinder should be placed in an area with appropriate equipment to ensure that the cylinder is held vertically.
The gas cylinders should be transported with appropriate material in order to protect them from the risk of shocks and falls.During inter- or within-hospital transfers of patients treated with Neophyr, the gas cylinders should be securely stowed away in order to hold the gas cylinders vertically and to avoid the risk of falls or untimely modifying output. Particular attention should be also turned to the fastening of the pressure regulator so as to avoid the risk of accidental failures.
Do not use Neophyr after the expiry date which is stated on the gas cylinder label. The expiry date refers to the last day of that month.
Gas cylinders with a capacity of 10l.
A 10-liter gas cylinder filled to 150 bar contains about 1.77 kg of gas. Aluminum alloy cylinders have a white painted body and a turquoise-painted shoulder.
They are equipped with a stainless steel residual pressure valve with a specific ISO 5145 (2004) type outlet connector.
All equipment, including connectors, tubing and circuits, used in the delivery of nitric oxide must be made of materials compatible with the gas. From a corrosion point of view the supply system can be divided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From the humidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures can be used with most materials. However, the presence of nitrogen dioxide and moisture creates an aggressive atmosphere. Among metallic construction materials, only stainless steel can be recommended. Tested polymers which can be used in nitric oxide administration systems include polyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not be used.
Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylene have been used extensively with pure nitric oxide and other corrosive gases. They were considered so inert that testing was not required.
To avoid any incidents, the following instructions must be strictly adhered to:
When the cylinder is empty, do not dispose of it. Empty cylinders will be collected by the supplier.
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