Noxap 800 Ppm Mol/Mol Medicinal Gas Compressed
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
NOXAP 800 ppm mol/mol, medicinal gas, compressed
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Nitric oxide (NO) 800 ppm mol/mol
Nitric oxide (NO) 0.8 ml in Nitrogen (N2) 999.2 ml
A 2 litre cylinder filled at 200 bar contains 400 litres (=0.400m3)of gas under pressure at 1 bar and 15°C
A 5 litre cylinder filled at 200 bar contains 945 litres (=0.945m3)of gas under pressure at 1 bar and 15°C
A 10 litre cylinder filled at 200 bar contains 1890 litres (=1.890m3)of gas under pressure at 1 bar and 15°C
A 20 litre cylinder filled at 200 bar contains 3780 litres (=3.780m3)of gas under pressure at 1 bar and 15°C
A 40 litre cylinder filled at 200 bar contains 7560 litres (=7.560m3)of gas under pressure at 1 bar and 15°C
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Medicinal gas, compressed.
Odourless and colourless gas.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of newborns > 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and reduce the need for extracorporeal membrane oxygenation .
Treatment of peri- and post-operative pulmonary hypertension in association with heart surgery in adults, children and newborns, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation.
4.2 Posology and method of administration
Treatment of Persistent Pulmonary Hypertension of the Newborn (PPHN)
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. NOXAP should only be delivered according to the prescription of the supervising physician.
NOXAP should be used only after respiratory support is optimal. NOXAP should be used in ventilated infants expected to require ventillatory support for >24 hours.
For an optimal response to NOXAP in hypoxic respiratory failure, it is required that there is optimal alveolar recruitment by adjusting the tidal pressure and volume, using surfactants, high frequency ventilation and ventilation with positive pressure at the end of exhalation, according to patient’s need.
Treatment of Pulmonary Hypertension associated to cardiac surgery
Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracic anaesthesia & intensive care and limited to those cardio-thoracic units that have received adequate training in the use of a nitric oxide delivery system. NOXAP should only be delivered according to an anaesthetist’s or intensive care physician’s prescription.
Posology
Persistent Pulmonary Hypertension in the Newborn (PPHN)
Newborns of >34 weeks gestation: The maximum recommended dose of NOXAP is 20 ppm and should not be exceeded. As soon as possible after starting treatment and within the initial 4-24 hours of treatment, the dosage must be gradually reduced to 5 ppm or less, as long as the clinical parameters of oxygenation and pulmonary arterial pressure are within the desired limits, and so titrating the dose to the individual patient’s needs. The NOXAP treatment must be maintained until there is an observed improvement in oxygenation of the newborn, such that the fraction of inhaled oxygen is reduced to below 60% (FiO2 < 0.60).
The NOXAP treatment may continue until the oxygen de-saturation is resolved and the patient is ready for gradual treatment withdrawal. The required duration of the NOXAP treatment varies but should be as brief as possible, and is typically <4 days. If there is no response to the inhaled nitric oxide, consult section 4.4.
Weaning
Because of the risk of a ‘rebound’ effect, the administration of NOXAP must not be interrupted suddenly. The NOXAP treatment should only be stopped once the target clinical parameters are stabilised to within satisfactory limits or, in cases of hypoxic respiratory insufficiency, when the required assisted ventilation (FiO2 and PEEP) are substantially reduced or after 96 hours of treatment.
After deciding to interrupt the NOXAP treatment, the concentration of inhaled nitric oxide must be reduced to 1 ppm over a period of 30 minutes to one hour.
In cases of hypoxic respiratory failure, if oxygenation is stable during the administration of NOXAP at 1 ppm, the FiO2 should be increased by 10-20% and then NOXAP treatment can be stopped. The patient will need to be carefully monitored for any signs of hypoxemia and, if oxygenation falls by >20%, NOXAP treatment needs to be resumed at 5 ppm and subsequently interrupted only after a further 12 to 24 hours of treatment and after assessing the level of oxygenation. If the criteria for stopping NOXAP treatment are not met after 4 days of treatment, the newborn will need to be submitted to an extensive diagnostic assessment for possible concomitant illnesses.
Pulmonary hypertension associated with heart surgery
NOXAP treatment should be used only after conservative ventilatory support has been optimized. In clinical trials, inhaled nitric oxide has been given in addition to other standard treatment regimens in the peri-operative setting, including inotropic and vasoactive medicinal products. NOXAP treatment should be accompanied by close monitoring of hemodynamics and oxygenation.The dose should be appropriate for the patient's clinical condition (severity of pulmonary arterial hypertension) and age group (neonate, child or adult). The recommended starting dose is 20 ppm. The dose should be titered to the minimum effective dose and, only exceptionally, increased above 20 ppm to a maximum of 40 ppm.
The effects of inhaled nitric oxide are rapid, with a decrease in pulmonary arterial pressure and improved oxygenation seen within 5-20 minutes. In case of an insufficient response, the dose may be titrated after a minimum of 10 minutes. Discontinuation of treatment should be considered if, after 30 min of initial treatment, there are no beneficial effects on the target hemodynamic and oxygenation parameters.
Treatment may be initiated at any time point during the peri-operative period in order to improve pulmonary hemodynamics and oxygenation. In clinical studies treatment was often initiated before separation from cardio pulmonary bypass. Inhaled nitric oxide treatment has been given for periods of up to 7 days in the peri-operative setting but 24-48 hours of treatment are most common.
Due to the possible formation, during inhaled NO, of toxic levels of NO2, the level of NO2 in the inhaled gas mixture must be continually monitored.
The required duration of NOXAP treatment will depend on the patients' pathology and response to inhaled NO. Weaning from the NOXAP treatment should be attempted at interval untils the pulmonary hemodynamics are stable.
Weaning
Attempts to wean patient off NOXAP treatment should be begin as soon as the hemodynamics have become stable while also reducing ventilator and inotropic support. The withdrawal of inhaled nitric oxide treatment should be step-wise, reducing to 1 ppm over 30 min while closely observing systemic and central hemodynamics, before stopping treatment. Weaning the patient from treatment should be attempted at least every 12 hours if the patient’s hemodynamics and oxygenation are stable at a low dose of NOXAP. If weaning from inhaled nitric oxide is too rapid, there is the risk of a rebound increase in pulmonary artery pressure with subsequent circulatory instability.
Additional information on special populations
No relevant information for any dosage adjustment recommendation for special patient populations, such as patients with renal/hepatic impairment or who are geriatric, are available. Therefore, caution is recommended when considering NOXAP treatment in such patient populations.
Method of administration
Different means of NOXAP administration affect the toxicity profile of the drug and recommendations for the method of administration need to be followed.
• Use with mechanical ventilation
Inhalation of nitric oxide is normally via the patient’s mechanical ventilator and involves dilution of the gas with a mixture of oxygen/air using a specific nitric oxide administration device that has been approved for clinical use in accordance with European Community standards (CE marked). Direct endotracheal administration without dilution is contra-indicated due to the risk of local lesion of the mucous membrane after contact with high concentrations of nitric oxide. The administration system must supply a constant concentration of inhaled NOXAP, irrespective of the type of ventilation equipment used.
NOXAP can be administered via continuous or intermittent flow ventilation through theinhalation branch of the ventilator circuit.
In the case of patients on intermittent flow ventilation, the use of continuous flows of NO can generate greater concentrations of NO2, as well as the accumulation of a small quantity of NO in the inspiratory branch of the circuit during the exhalation of the patient, as it is a source of a greater concentration of NO and a lower concentration of FiO2. In order to avoid this, the administration system of nitric oxide in the intermittent flow ventilation system will have to avoid these concentration peaks. Synchronised sequential administration in the inspiratory phase is recommended.
• Use with Anaesthesia machines
The administration of NOXAP via a Y-piece on the inspiratory branch of anaesthesia machine and close to the patient is a mode of administration that requires special care to remove any expired nitric oxide and NO2. This is because the anaesthesia machine is a semi-closed system and there is increased accumulation of expired nitric oxide and nitrogen dioxide. There needs to be appropriately placed filters to remove the expired nitric oxide and nitrogen dioxide in order to help prevent extreme fluctuations of inspired nitric oxide and toxic levels of NO2 being reached.
• Monitoring of NOXAP administration
Nitric oxide 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 that nitric oxide is administered via the inspiratory branch of the ventilation circuit or above the Y piece. This should be at least 15 cm from the patient’s mouth to allow sufficient space for a homogeneous mix to occur with the gas from the ventilator.
In order to avoid errors in the dosing, the concentration of inhaled NOXAP must be continuously monitored and accordingly 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 the FiO2 must also be monitored at the same location in the circuit using a fully-calibrated and EC-approved monitoring apparatus. The concentration of nitrogen dioxide in the inhaled mix must be as low as possible and if it exceeds 0.5 ppm and malfunction of the administration system is not the cause, the dose of NOXAP and/or the FiO2 must be reduced.
It is also vital for the safety of the patient that appropriate alarms are installed and configured for nitric oxide (± 2 ppm of the prescribed dose), NO2 (maximum 0.5 ppm) and FiO2 (± 0.05). If an unexpected change in the concentration of NOXAP is produced, the administration system will have to be checked for defects and the analyser will have to be re-calibrated. Also the pressure of the NOXAP gas cylinder must be monitored in order to allow the gas cylinder to be changed without interrupting or changing the treatment. There also needs to be a reserve supply of gas cylinders to allow cyclinder replacement as required. An emergency battery is needed in case of a cut in the electricity supply.
NOXAP treatment must be available for both mechanical and manual ventilation in order to continue treatment during possible transportation of the patient or during resuscitation. The physician must have easy access to the head of the patient in order to administer any required reserve supply of nitric oxide.
Exposure limits for hospital personnel
In most countries, the legal upper limit of mean exposure of personnel to nitric oxide is 25 ppm for 8 hours (30 mg/m3) and to nitrogen dioxide is 2-3 ppm (4-6 mg/m3). On extrapolation, these limits mean that for intensive care units where inhaled nitric oxide may be administered for a period of 24 hours, it is recommended to maintain the ambient atmospheric levels of NO2 at <1.5 ppm and continuous monitoring of the ambient atmospheric levels of NO2 is mandatory.
Monitoring of the formation of Nitrogen Dioxide
Nitrogen dioxide forms rapidly in gaseous mixtures that contain nitric oxide and oxygen and in amounts that depend on the NO and O2 concentrations. NO2 is a toxic gas that can provoke an inflammatory reaction in the respiratory tracts and, for this reason, its formation must be closely monitored.
Immediately before starting treatment, 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 the NO2 is >0.5 ppm, the administration system must be checked for defects, the NO2 analyser must be recalibrated and, if possible, the concentration of NOXAP and/or the FiO2 reduced.
Monitoring the formation of methemoglobin (MetHb)
Following inhalation, nitric oxide is rapidly processed and generates primarily methemoglobin and nitrate that reach the systemic circulation, where nitrate is excreted by the kidney and methemoglobin is reduced by the methemoglobin reductase. Newborns possess low levels of the enzyme MetHb-reductase compared to adults and, therefore, require particularly careful monitoring of serum methemoglobin concentrations in the blood must be monitored. The level of MetHb must be measured within 4 hours of the start of NOXAP therapy using an analyser that correctly distinguishes the fetal hemoglobin from the MetHb. If the MetHb is > 2.5%, the dose of NOXAP must be reduced. If it is > 5%, NOXAP treatment must be suspended and need for administration of reducing agents, such as methylene blue, must be assessed. Even though clinically significant increases in the level of MetHb are infrequent and initial measurements indicate low levels, it is advised to repeat the MetHb measurements every 12-24 hours.
4.3 Contraindications
- New-borns with known dependency to right-left blood shunt or newborns with significant left-right shunt.
- Patients with congenital or acquired deficiency of methemoglobin reductase (MetHb reductase) or glucose 6 phosphate dehydrogenase (G6PD).
- Hypersensitivity to the active substance or any of the excipients
4.4 Special warnings and precautions for use
Precautions to avoid exposures during inhaled NOXAP therapy
- Follow Standard Operating Procedures when preparing and using NOXAP
- Install scavenging systems on ventilators to capture the patient’s exhaled breath
- Take air samples when training therapists on how to use the iNO treatment.
- Portable personal alarm devices, which warn staff if environmental levels of NO or NO2 rise above occupational safety limits, can be provided.
Precautions to avoid accidental emptying of a gas cylinder and further actions
A spontaneous leak of nitric oxide from a gas cylinder is very rare due the exhaustive controls in the filling areas. Accidental release can happen if the cylinder falls heavily such that the valve is damaged and release occurs. This would be an exceptional case because gas cylinders and valve packages must comply with EN 962 Cylinder Valve Protection & Tests. To avoid this problem:
- Hospital staff must always secure the gas cylinder in an upright position and ensure it is firmly secured to prevent it from falling over or being knocked-over.
- The gas cylinders have to be handled with care, ensuring that they are not abruptly jolted or dropped.
- Only move gas cylinders using an appropriate type and size of vehicles and equipment for such a purpose.
- If an accidental release happens, gaseous NO leaks can be detected by a characteristic orange-brown colour and a sharp sweet and metallic smell. The recommend actions are to evacuate the room and open windows to the outside.
- In cabinet or closet stores, a fan exhausting directly to the outside should be installed to maintain a negative pressure within the cylinder storage area.
- Installation of NO and N2 monitoring systems for continuous monitoring of NO and N2 concentrations in enclosed NO gas cylinder storage areas and respiratory care areas to alert employees in case of an accidental release could be useful. (Nitrogen gas could displace the ambient air and reduce the oxygen level in the environment).
Training prior administration of the product
Specialised professional units and teams should be properly trained on Standard Operating Procedures for the use of the nitric oxide administration system prior administration.
The key elements that must be included in the training of the hospital staff are as
follows:
• Knowledge of the correct method of establishing the configuration and connections between the NOXAP gas cylinder, the administration equipment and the assisted ventilation equipment of the patient.
• Operational aspects
- Consult the check list before use (a series of steps to be undertaken immediately before starting the treatment on each patient in order to guarantee that the system functions correctly and that the NO2 has been purged from the system).
- Configuration of the apparatus for administering the concentration of nitric oxide
- Configuration of the maximum and minimum limits of the alarm in the NO, NO2 and O2 monitoring equipment.
- Use of the manual reserve administration system
- Correct procedures for changing the gas cylinder and purging the system
- Breakdown alarms.
- Calibration of the NO, NO2 and O2 monitoring equipment.
- Monthly checking procedures for the system.
Evaluation of the treatment response
In newborns >34 week gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, a proportion of patients that receive inhaled NO therapy do not respond to the treatment. The range of non-responders varies between 30% and 45% depending on the pre-established clinical values for favourable response. Conventional response indicators include a 20% increase in oxygenation index and/or a 20% reduction in pulmonary arterial pressure. In children, a lower response in oxygenation in new-borns with meconium aspiration syndrome has been indicated. Furthermore, the efficacy of the use of inhaled NO in patients with congenital diaphragmatic hernia has not been demonstrated in clinical trials.
If the clinical response is not considered to be adequate after 4-6 hours of NOXAP administration, the following possibilities should be studied:
- If the patient’s condition continues to deteriorate or there is no improvement, the situation having been defined by pre-established criteria, the employment of a rescue system such as an ECMO will be considered, if it is indicated and possible. Persistently high levels of oxygenation index (>20) or alveolar-arterial oxygen gradient (Aao2>600) after 4 hours of iNO therapy indicate an urgent need to initiate ECMO therapy. In a non-response situation to the administration of NOXAP, the treatment must be suspended, but it must not be interrupted suddenly as it may provoke an increase in the pulmonary arterial pressure (PAP) and/or deterioration in blood oxygenation (PaO2). Both situations may also occur in new-borns showing no obvious response to NOXAP treatment. The gradual withdrawal of inhaled nitric oxide must take place with caution (See 4.2 Posology and method of administration: Weaning).
- In the case of patients that are to be transferred to another hospital, the supply of nitric oxide during the transportation of the patient must be guaranteed in order to avoid any deterioration in their state of health due to a sudden interruption of NOXAP treatment.
Monitoring the ventricular function
With regards to interventricular or interauricular communication, the inhalation of NOXAP causes an increase in the left-right shunt due to the vasodilator effect of the nitric oxide in the lung.
The increase in pulmonary blood flow in patients with left ventricular dysfunction can lead to cardiac insufficiency and the formation of pulmonary oedema. Careful monitoring of cardiac output, left atrial pressure, or pulmonary capillary wedge pressure is important in this situation. It is therefore recommended that before administering nitric oxide, a catheterization of the pulmonary artery or an echocardiographic examination of the central haemodynamics is carried out.
Monitoring the haemostasis
The test in animals have demonstrated that NO can interact with the haemostasis provoking an increase in the bleeding time. The data in adult humans is contradictory, and there has been no increase in significant hemorrhagic complications observed in random controlled trials on new-borns .
A monitoring of the bleeding times is recommended during the course of NOXAP administration for a period of more than 24 hours in patients that suffer numerical or functional anomalies of the platelets, a deficit in the coagulation factors or that are undergoing anticoagulant treatment.
4.5 Interaction with other medicinal products and other forms of interaction
Oxygen: In the presence of oxygen, nitric oxide oxidises rapidly forming derivatives that are toxic for the bronchiolar epithelium and the alveolo-capillar membrane. Nitrogen dioxide (NO2) is the main compound that is formed and during the treatment with nitric oxide, the concentration of NO2 must be < 0.5 ppm in the dose interval of < 20 ppm of nitric oxide. If, at any time, the concentration of NO2 exceeds 1 ppm, the dose of nitric oxide must be reduced immediately. See the information on monitoring NO2 in section 4.2.
NO donors: The donor compounds of nitric oxide, including sodium nitroprusside and nitroglycerine, can have an additive effect to NOXAP increasing the risk of developing methemoglobinemia.
There is a higher risk to develop methemoglobinemia if drugs that increase the methemoglobin concentrations are administrated along with nitric oxide (e.g. alkyl nitrates, sulphonamides and prilocaine). As a consequence, medicinal products that increase methemoglobin must be used with caution during inhaled nitric oxide therapy.
Synergic effects have been reported with the administration of vasoconstrictors (almitrine, phenylephrine), prostacyclin and phosphodiesterase inhibitors, without increasing adverse effects.
Inhaled nitric oxide has been used concomitantly with tolazoline, dopamine, dobutamine, norepinephrine, steroids and surfactants, with no drug interactions observed.
Experimental studies suggest that nitric oxide and also nitrogen dioxide can react chemically with the surfactant and its proteins without proven clinical consequences.
Although controlled studies have not been done, food interactions have not been noticed in clinical trials in patients with prolonged ambulatory administration.
4.6 Fertility, pregnancy and lactation Pregnancy
There are no data from the use of NOXAP in pregnant women.
Animal studies are insufficient with respect to reproductive toxicity. However, harmful effects may be expected as methemoglobin is considered detrimental to the foetus and nitric oxide has shown genotoxic potential (see section 5.3) by inducing structural alterations on DNA. The potential risk for humans is unknown.
NOXAP should not be used during pregnancy unless the clinical condition of the woman requires treatment with NOXAP.
Breast-feeding
It is unknown whether NOXAP or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded.
Breastfeeding should be discontinued during treatment with NOXAP.
Fertility
No fertility studies have been performed.
4.7 Effects on ability to drive and use machines
Infants and hospitalized patients: Not applicable.
4.8 Undesirable effects
Known adverse reactions have been classified for the various organ systems.
Classification based on frequency is not readily achieved because detailed studies are missing. However, for some adverse reactions, the published literature provides data that allow a reasonable estimate of frequency to be made as summarised below.Description of frequencies: 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
Blood system disorders
Methemoglobinemia: The development of methemoglobinemia is dose-dependent, being a frequent complication in the inhalation of NO at high concentrations. Increased levels of methemoglobin will produce tissue hypoxia.
The formation of methemoglobin > 5% with inhaled nitric oxide at concentrations <20 ppm are very rare (<1/10,000).
In the paediatric population, newborns have a reduced MetHb reductase activity and, therefore, are at greater risk of developing methemoglobinemia.
Haemostasis: Although preclinical studies have shown that nitric oxide inhibits platelet aggregation but clinical studies have been contradictory. In controlled clinical trials, no significant differences were found, in regard to hemorrhagic complications, between controls and inhaled nitric oxide-treated patients..
General disorders and administration site conditions
No response: The range of responsiveness to the treatment varies between 30 to 45% of the cases.
Formation of NO2: The reaction between NO and O2 to form NO2 is rapid with high concentrations of NO but slow at the recommended therapeutic concentrations of inhaled nitric oxide. In animals, elevated levels of NO2 (>10 ppm) produce pulmonary edema, alveolar hemorrhage, changes in the activity of the surfactant, hyperplasia of alveolar cells, intrapulmonary accumulation of fibrin, neutrophils and macrophages, and death. Also, the inhalation of NO2 during prolonged periods has been related to degeneration of pulmonary interstitial cells and moderate emphysema.
The inhalation of 2 ppm NO2 in humans increases the alveolar permeability and the reactivity of the airways.
Significant elevations of NO2 levels have not been found at low therapeutic doses (< 20 ppm) of inhaled NO and the evidence of clinical toxicity due to NO2 in most of the clinical trials indicates it as a very rare (<1/10,000) complication. The NO2 concentration must be always maintained as low as possible and <0.5 ppm.
Rebound effect: Following sudden interruption to the inhaled nitric oxide therapy, rapid rebound reactions are very frequent (>1/10), such as intensified pulmonary vasoconstriction and hypoxemia, which precipitate cardiopulmonary collapse.
The cessation of nitric oxide treatment after prolonged inhalation is associated with transitory pulmonary hypertension, lasting approximately one hour, in all the patients.
Clinically it has been observed that after 10-30 hours of inhaled nitric oxide treatment, abrupt cessation of NO will produce rebound symptoms in approximately 75% of the patients with alterations of pulmonary gas exchange and varying degress of reduced oxygen saturation being the main consequence. In a third of cases, hemodynamic instability will occur with the reduction of PaO2 being greater the larger the dose of inhaled nitric oxide. By reducing the dose to 1 ppm before cessation of treatment, the any consequent reduction in PaO2 is minor.
Long term adverse effects: From all the controlled clinical studies that have been conducted out, there is no evidence of adverse reactions to inhaled nitric oxide treatment causing re-hospitalisation, special medical services, pulmonary disease or neurological sequelae.
4.9 Overdose
NOXAP overdose is manifested as increases in methemoglobin and NO2 levels.
“Symptoms and Treatment”
High levels of NO2 can cause acute pulmonary injury.
Increased levels of methemoglobin reduce the capacity to transport oxygen in the circulation. In clinical studies, levels of NO2 > 3 ppm or levels of methemoglobin > 7% were treated by reducing the dose of inhaled nitric oxide or by interrupting its administration.
Methemoglobinemia that does not respond to reduction or interruption of the treatment can be treated intravenously with vitamin C, methylene blue or by blood transfusion, depending on the clinical situation.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other respiratory system products. ATC code: R07AX01
Mechanism of action
Nitric oxide is a natural substance that is produced by many cells of the body. It relaxes the vascular smooth muscle by binding it to the heme part of cytosolic guanylate cyclase, activating the guanylate cyclase and increasing the intracellular levels of cyclic guanosine 3’.5’-monophosphate, which in turn causes vasodilatation. The inhalation of nitric oxide produces pulmonary vasodilatation.
Pharmacodynamic effects:
The therapeutic value of inhaled nitric oxide is that it produces a selective pulmonary vasodilation with minimumal systemic cardiovascular effects. This pulmonary selectivity is because of its fast inactivation through its reaction with the heme groups. The average life of NO in vivois only of a few seconds.
Nitric oxide increases the partial pressure of arterial oxygen (PaO2) by dilating the pulmonary vessels in the better ventilated areas of the lung, redistributing the pulmonary blood flow away from the pulmonary regions with low ventilation/perfusion (V/Q) indexes to regions with normal indexes. Studies show that its pharmacodynamic effects appear in the lung at concentrations as low as 1 ppm within the air-way.
Efficacy and safety
Clinical trials have confirmed that, in different pathological conditions, inhaled nitric oxide is able to diminish the pulmonary vascular resistance and to increase the oxygenation.
The efficacy of inhaled nitric oxide has been investigated in newborns with hypoxic respiratory failure of differing aetiology. In the case of newborns with persistent pulmonary hypertension, the inhalation of NO improves oxygenation and reduces the risk of needing oxygenation through extracorporeal membrane. In the meta-analysis of randomised clinical trials in infants without congenital diaphragmatic hernia with persistent pulmonary hypertension of the newborn (n=548), inhalation of NO reduces the need for ECMO (relative risk: 0.73; 95% CI: 0.60 to 0.90) and improves the oxygenation (PaO2 by a mean of 53.3 mm Hg; 95% CI: 44.8 to 61.4; oxygenation index by a mean of -12.2; 95% CI: -14.1 to -9.9). In newborns with hypoxic respiratory failure, a meta-analysis (n=989) revealed that the inhalation of NO improves the PaO2 with a difference of 46.4 Torr compared with controls (95% CI, 34.2 and 58.5) and significantly decreases the oxygenation index by 10.7 compared with controls (95% CI, -14.1 and -7.4). The incidence of death or need for extracorporeal membrane oxygenation (ECMO) was significantly reduced by treatment with iNO, with a relative risk of 0.72 compared to control (95% CI, 0.60.87).
Pulmonary hypertension and increased pulmonary vascular resistance are frequently seen in patients undergoing cardiac surgery, most often after weaning from cardiopulmonary bypass. This is due to pulmonary vasoconstriction probably caused by an inflammatory response to surgery. Increased pulmonary vascular resistance can lead to right ventricular failure. It is well-established that inhaled nitric oxide reduces pulmonary vascular resistance and attenuates the increased pulmonary artery pressure, which can lead to increase in the right ventricular ejection fraction. These effects lead to hemodynamic stabilisation and improved oxygenation.
5.2 Pharmacokinetic properties
The pharmacokinetics of nitric oxide has been studied in adults.
Nitric oxide, in the dilution procedure before its administration, reacts chemically with oxygen to form nitrogen dioxide, a toxic substance for the body.
Nitric oxide is absorbed systemically following inhalation. The major part passes through the pulmonary capillary bed where it combines with the hemoglobin, which is saturated with 60% - 100% of oxygen. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. With a low saturation level of oxygen, the nitric oxide can combine with deoxyhemoglobin to form transitory nitrosylhemoglobin, which turns into nitrogen oxides and methemoglobin when exposed to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrate respectively, which interact with the oxyhemoglobin to produce methemoglobin and nitrate. Therefore, the final products of nitric oxide that arrive in the systemic circulation are primarily methemoglobin and nitrate.
The formation of methemoglobin depends on the exposure time and concentrations to nitric oxide. The concentrations of methemoglobin increase during the first 8 hours of treatment with inhaled nitric oxide. Methemoglobin levels > 7% have been observed in patients who received high doses of NO (80 ppm).
Nitrate has been identified as the predominant metabolite of nitric oxide excreted in the urine, representing > 70% of the inhaled nitric oxide dose. The kidney eliminates the plasma nitrate at a similar rate to glomerular filtration.
5.3 Preclinical safety data
Single-dose studies on rodents indicate that the lethal dose is around 300 ppm of nitric oxide or above.
Repeated-dose studies show that the rodents can survive exposure to nitric oxide of up to sustained levels of nitric oxide of around 250 ppm. Death is secondary to anoxia derived from high levels of methaemoglobin.
From the studies carried out on dogs, it is possible to deduce that the lethal concentration varies around 640 ppm of NO exposure for 4 hours, while exposure to 320 ppm of NO is not lethal.
Levels of methaemoglobin higher than 30% have been recorded in animals that died due to NO exposure. The recuperation from methaemoglobinaemia is rapid, in less than 24 hours, a full recovery has been recorded. At levels of 80 ppm NO administered for 3 hours, no increase of methaemoglobin was observed in sheep.
In biological tissue, nitric oxide can form peroxinitrite ( OONO) to react with superoxide (O2-), an unstable substance that can damage the tissue through further redox reactions.
Furthermore, nitric oxide has an affinity for metal proteins and might also react with sulfhydryl groups (-SH) in proteins, giving rise to nitrosyl compounds. The clinical importance of the chemical reactivity of nitric oxide in the tissue is unknown.
Bleeding time: In a study conducted on rabbits and healthy humans, it has been found that inhaled nitric oxide approximately doubles the bleeding time.
No studies on toxicity to reproduction or carcinogenicity have been conducted.
Mutagenicity and genotoxicity: Various preclinical genotoxicity tests with nitric oxide show a positive genotoxic potential. Part of its toxicity is mediated by peroxinitrite. Although DNA damage has not been demonstrated in human cells following in vivo exposure, preclinical in vitro and in vivo studies (bacteria and mice), have demonstrated NO-induced chromosomal alterations. This is possibly related to the formation of mutagenic nitrosamines, DNA alteration or impairment of DNA repair mechanisms. The significance of these findings for clinical use in neonates and the potential for effects on the germ cells are unknown.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Nitrogen.
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal product/equipment/devices except those mentioned in section 6.6.
The equipments/devices should not be administered simultaneously: Butylrubber, Polyamide and Polyurethane.
6.3. Shelf life
3 years.
6.4 Special precautions for storage
Follow all the rules regarding the handling of pressurised containers.
Store in the original gas cylinder.
Do not transfer contents from original gas cylinder to another gas cylinder.
Store cylinders vertically in well-ventilated rooms.
Protect the cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of heat or ignition.
The installation of a nitric oxide duct system is prohibited with a cylinder distribution system, a fixed network or terminal units.
Storage in the pharmacy department
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.
Storage in the medical department
The gas cylinders should be stored in a place with the appropriate equipment to ensure that it stays in a vertical position.
6.5 Nature and contents of container
NOXAP is stored in high pressure gas cylinders made out of aluminium or aluminium with an external elastomers layer. The valves which close the gas cylinders are made of stainless steel. The pack sizes of the gas cylinders are 2L, 5L, 10L, 20L, 40L
NOXAP is filled as a gas in these gas cylinders to a pressure of 200bar.
|
Pack sizes (litres) |
Filling Pressure (bar) |
Litres Quantity of the mixture 800 ppm no/n2 |
m3 Quantity of the mixture 800 ppm NON |
|
2 |
200 |
400 |
0.400 |
|
5 |
200 |
945 |
0.945 |
|
10 |
200 |
1890 |
1.890 |
|
20 |
200 |
3780 |
3.780 |
|
40 |
200 |
7560 |
7.560 |
The colour coding of the gas cylinder is a turquoise blue shoulder on a white gas cylinder body.
6.6 Special precautions for disposal
General
All personnel handling NOXAP gas cylinders should have adequate knowledge of the properties of this gas, any necessary precautions to take, the steps to follow in the event of an emergency and the correct operational procedures for its installation.
Transport of gas cylinders
The gas cylinders should be transported with the appropriate equipment to ensure that they are protected from the risk of jolts or drops. When patients undergoing NOXAP treatment are being transferred between different hospitals or within the same, the gas cylinders should be separated and properly secured so that they maintain a vertical position and do not run the risk of drops or inopportune changes to the administration of the medicine. Special attention should be paid to the pressure regulator fixing in order to avoid the risk of accidental breakdowns.
Preparation for use
- The valves of the gas cylinder should be opened slowly.
- The valves of the gas cylinder or of any associated equipment should never be lubricated and should always be kept free of oils and grease.
- When connecting equipment to the gas cylinders, never use excessive force. Utilisation of the gas cylinders
To avoid any type of incident, the following instructions should always be respected:
- Handle the gas cylinders with care, ensuring that they are not abruptly jolted or dropped.
- Only move the gas cylinders using an appropriate type and size lorry for such a purpose.
- Medicinal gases should only be used for medicinal purposes.
- Always ensure the material is in good condition before use.
- Do not use the gas cylinder if its valve is not protected by a cap or cover.
- The valve should not be opened in an abrupt manner.
- Do not attempt to repair the valve if it is defective.
- A specific connection should be used, as well as a pressure regulator that allows a pressure equivalent to at least 1.5 of the maximum functioning pressure of the gas cylinder.
- In order to ensure that NO2 is not inhaled, purge the pressure regulator with a mixture of nitrogen/nitric oxide before each new use.
- The pressure regulator should not be gripped with pliers or pincers since this could damage the gasket.
- Whilst in use, the gas cylinder should be firmly secured in an appropriate support for this type of gas cylinder in order to avoid an accidental drop.
- Release the gas discharged outdoors. It is advisable to ensure possible ventilation at all times which is adequate for the evacuation of the gas in the event of an untimely accident or leak.
- Smoking or sources of ignition are not permitted in the area where the gas cylinders are stored or in the pipe vents.
- After use, close the valves of the gas cylinders with moderate force and release the residual pressure in the regulator.
- Ensure that the valve of the gas cylinder is always closed when not in use.
Compatibility
All the equipment, including tubes, connections and circuits, that are used in nitric oxide administration should be manufactured with materials that are compatible with the gas. As far as corrosion is concerned, the supply system can be divided into two areas: 1) from the gas cylinder valve to the humidifier (dry gas) and 2) from the humidifier to the vent (moist gas that may contain NO2). Evidence shows that the dry NO mixtures can be used with the majority of the materials. Nevertheless, the presence of nitrogen dioxide and humidity create an aggressive atmosphere. Only stainless steel is recommended out of the materials made of metal. Polyethylene (PE) and polypropylene (PP) are two polymers, among others, that have been tested and can be used in nitric oxide administration systems. Polytrifluorochloro ethylene, the hexafluoropropene-vinylidene copolymer and polytetrafluorethylene have been used with pure nitric oxide and other corrosive gases and are considered inert.
Instructions for the disposal of the gas cylinders
Do not throw away empty gas cylinders. They should be immediately sent to an empty cylinder warehouse or an appropriate storage area for collection by the supplier.
7 MARKETING AUTHORISATION HOLDER
Air Products Plc 2 Millennium Gate Westmere Drive Crewe Cheshire CW1 6AP United Kingdom
MARKETING AUTHORISATION NUMBER(S)
8
PL 06183/0029
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
06/11/2009
10 DATE OF REVISION OF THE TEXT
28/09/2015