Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Linde Healthcare AB, SE-181 81 Lidingö, Sweden
INOmax, 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. INOmax should only be delivered according to a neonatologist’s prescription.
INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmax 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. INOmax should only be delivered according to an anaesthetist’s or intensive care physician’s prescription.
The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In the pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) <0.60.
Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, but typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4.
Attempts to wean INOmax 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 INOmax at 1 ppm, the FiO2 should be increased by 10%, the INOmax is discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20%, INOmax therapy should be resumed at 5 ppm and discontinuation of INOmax therapy should be reconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days should undergo careful diagnostic work-up for other diseases.
INOmax should be used only after conservative support has been optimised. In clinical trials INOmax has been given in addition to other standard treatment regimes in the peri-operative setting, including inotropic and vasoactive medicinal products. INOmax should be administered under close monitoring of haemodynamics and oxygenation.
The starting dose of inhaled nitric oxide is 10 ppm(part 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 (part per million) of inhaled gas. The dose may be increased up to 40 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.
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 peri-operative 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 peri-operative setting, but common treatment times are 24-48 hours.
Attempts to wean INOmax should be commenced as soon as the haemodynamics 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 INOmax.
Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in pulmonary artery pressure with subsequent circulatory instability.
The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yet been established. Currently available data are described in section 5.1 but no recommendation or posology can be made.
For endotracheopulmonary use.
Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, during set-up, secure that the device setting is in agreement with the cylinder gas concentration.
The delivery system must provide a constant inhaled INOmax concentration irrespective of the ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of INOmax into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration.
The inspired INOmax concentration must be measured continuously in the inspiratory limb of the circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, appropriate alarms must be set for INOmax (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 (± 0.05). The INOmax gas cylinder pressure must be displayed to allow timely gas cylinder replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide timely replacement. INOmax therapy must be available for manual ventilation such as suctioning, patient transport, and resuscitation.
In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric oxide delivery system should be available. The power supply for the monitoring equipment should be independent of the delivery device function.
The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker’s legislation is 25 ppm for 8 hours (30 mg/m³) in most countries and the corresponding limit for NO2 is 2-3 ppm (4-6 mg/m³).
The key elements that need to be covered in training hospital personnel are as follows.
Correct set-up and connections:
Operation:
Neonates and infants are known to have diminished MetHb reductase activity compared to adults. Methaemoglobin level should be measured within one hour after initiation of INOmax therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is >2.5%, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements every one to two days.
In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the initiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the INOmax dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered.
Immediately prior to each patient initiation, proper procedure must be applied to purge the system of NO2. The NO2 concentration should be maintained as low as possible and always <0.5 ppm. If the NO2 is >0.5 ppm, the delivery system should be assessed for malfunction, the NO2 analyser should be recalibrated, and the INOmax and/or FiO2 should be reduced if possible. If there is an unexpected change in INOmax concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated.
Overdose with INOmax 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, INOmax.
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.
Shelf life: 3 years.
All regulations concerning handling of pressure vessels must be followed.
Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are protected from rain and direct sunlight.
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition.
The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas cylinders.
The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas cylinder vertically.
The gas cylinders should be transported with appropriate material in order to protect them from risks of shocks and falls.
During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should be fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or untimely modifying output. A particular attention should be also turned to the fastening of the pressure regulator so as to avoid the risks of accidental failures.
Pack sizes:
A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel.
A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel.
A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a standard valve hand-wheel.
A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific outlet connection and a INOmeter device equipped valve hand-wheel.
When connecting an INOmax cylinder to the delivery system, always secure that the cylinder concentration is of the same concentration for which the system is configured.
In order to avoid all incidents, the following instructions should be absolutely respected.
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.
The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed network and terminal units is forbidden.
There is in general no need for scavenging of excess gas, the work place ambient air quality should however be considered and trace concentrations of NO or NO2/NOx must not exceed set national occupational exposure limits. Accidental exposure to INOmax in hospital staff has been associated with adverse events (see section 4.8).
Cylinders equipped with a standard valve hand-wheel cannot be used with the INOmax DSIR delivery system.
When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by the supplier.
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