SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Vasokinox 450 ppm mol/mol, medicinal gas, compressed

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Nitric oxide..........450 ppm mol/mol.

Nitric oxide (NO) 0.450 ml in Nitrogen (N₂) 999.55 ml

A 5-liter cylinder filled to 200 bar supplies 0.94 m of gas at a pressure of 1 bar at 15°C.

A 11-liter cylinder filled to 200 bar supplies 2.1 m of gas at a pressure of 1 bar at 15°C.

A 20-liter cylinder filled to 200 bar supplies 3.8 m of gas at a pressure of 1 bar at 15°C.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Medicinal gas, compressed. Colourless and odourless gas.

4    CLINICAL PARTICULARS

4.1 Therapeutic indications

Vasokinox is indicated, in conjunction with ventilatory support and other appropriate active substances, for the treatment of:

-    newborn infants > 34 weeks gestation with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to improve oxygenation and to reduce the need for extracorporeal membrane oxygenation.

-    perioperative pulmonary hypertension in adults and newborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunction to heart surgery, in order to selectively decrease pulmonary arterial pressure and improve right ventricular function and oxygenation by increasing the pulmonary flow.

4.2 Posology and method of administration

Posology:

Dosage is determined by the patient’s clinical condition (severity of pulmonary arterial hypertension) and patient’s age.

The principle of the lowest effective dose must remain a rule in order to limit the toxic effects relating to the administration of nitric oxide. Vasokinox treatment should not be stopped abruptly to avoid the risk of rebound.

a)    Persistent Pulmonary Hypertension in 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.

Vasokinox should only be delivered according to neonatal physician’s prescription. Inhaled NO should be used only after respiratory support has been optimised according to the more accurate clinical practices. This includes optimising tidal volume/pressures and lung recruitment (surfactant, high frequency oscillatory ventilation, and positive end expiratory pressure) according to the patient needs.

The maximum recommended dose of inhaled NO is 20 ppm.

The starting dose is 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) can be maintained below 60%.

The duration of therapy is variable, but typically less than four days.

Attempts to wean inhaled NO should be initiated as soon as it seems relevant. Infants who cannot be weaned off inhaled NO by 4 days should undergo careful diagnostic work-up for other diseases.

b)    Pulmonary hypertension associated with heart surgery

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. Vasokinox should only be delivered according to an anaesthetist’s or intensive care physician’s prescription.

Vasokinox should be used only after conservative support has been optimised, at any time point in the perioperative course to lower pulmonary pressure. Inhaled NO is usually given in addition to other standard treatment regimens in the perioperative setting, including inotropic and vasoactive medicinal products. Vasokinox should be administered under close monitoring of hemodynamics and oxygenation.

The recommended operating range is 2 to 20 ppm. The maximum recommended is 20 ppm.

In adult, the dose may be increased up to 40 ppm if the lower dose has not provided sufficient clinical effects. In this case the patient’s state should be followed up more regularly and the exposure to this higher dosage should be as limited as possible.

The duration of treatment in this situation is variable according to the pathology, the population treated and pulmonary circulation remodelling.

The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved oxygenation are observed 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 perioperative setting, but common treatment times are 24 -48 hours.

Paediatric population

The safety and efficacy of Vasokinox in premature infants less than 34 weeks of gestation have not yet been established; no recommendation on posology can be made.

Weaning:

The administration of Vasokinox must not be stopped abruptly due to the risk of rebound (see section 4.4: Special warnings and specific precautions of use).

Persistent Pulmonary Hypertension in the Newborn (PPHN)

When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be progressively reduced by 1 ppm every 30 minutes to one hour, with continuous monitoring of oxygenation. If there is no change in oxygenation during administration of inhaled NO at 1 ppm, the FiO₂ should be increased by 10 %, then the inhaled NO administration should be discontinued. If oxygenation falls by more than 20 %, inhaled NO therapy should be resumed at 5 ppm and a further attempt at withdrawal will be considered after 12 to 24 hours.

Pulmonary hypertension associated with heart surgery

Attempts to wean inhaled NO should be started as soon as the haemodynamics have stabilised in conjunction to weaning from ventilator and inotropic support.

The withdrawal of inhaled nitric oxide treatment should be performed in a stepwise manner and under close surveillance of pulmonary arterial pressure.

The following withdrawal technique can be proposed. The dose should be incrementally reduced to 1 ppm for at least 30 minutes, with simultaneous surveillance of systemic and pulmonary arterial pressures and oxygenation, and then turned off.

Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of Vasokinox.

Too rapid weaning from inhaled nitric oxide treatment carries the risk of an increase in pulmonary artery pressure with subsequent haemodynamic instability (re-bound effect).

If, following withdrawal, a rise in pulmonary arterial pressure occurs, nitric oxide will once again be administered at the lowest effective dose. A further attempt at withdrawal will be considered later on.

Method of administration Endotracheopulmonary use

Nitric oxide is administered by ventilation after dilution in an air/oxygen mixture. Direct intratracheal administration must be avoided due to the risk of local lesions occurring on contact with the mucous membrane.

Before initiation of therapy, during set-up, secure that the device setting is in agreement with the cylinder gas concentration.

The system used to administer Vasokinox must allow for inhalation of a stable concentration of nitric oxide, regardless of the ventilator used. Furthermore, the contact time between nitric oxide and oxygen in the inspiration circuit should be kept to a minimum to limit the risk toxic oxidation by-product production in the inhaled gas (see section 4.4: Special warnings and specific precautions of use)

With ventilators in “continuous flow” mode (conventional or high frequency oscillatory) which are recommended in neonatology, Vasokinox can be administered in continuous flow mode on the inspiratory branch, and in any case as close as possible to the patient.

With ventilators in sequential discontinuous flow mode, the nitric oxide administration system must be capable of managing gas peak concentration. Synchronized sequential administration at the inspiratory phase is recommended to avoid nitric oxide concentration peaks and bolus effect induced by continuous administration of the gas.

In certain clinical circumstances with interruption of mechanical ventilation, administration of Vasokinox by CPAP (Continuous Positive Airway Pressure) ventilation is possible. The quantity of nitric oxide inhaled aims to attain the same effects as with mechanical ventilation. In case of transport of patient treated by nitric oxide to another care center, it will be advisable to make sure of the preservation of a continuous administration of the inhaled nitric oxide during the transport.

Training in administration

Hospital personnel have to be trained before using Vasokinox with respect to delivery system and treatment monitoring.

Monitoring of treatment

Nitrogen dioxide (NO2) can form rapidly in gaseous mixtures containing nitric oxide and oxygen (O2), which may cause an inflammatory reaction and airway lesions. The concentrations of inhaled nitric oxide and nitrogen dioxide and FiO2 must be measured continuously in the inspiratory circuit near to the patient using the appropriate certified equipment (medical device with CE marking)

The concentration of NO₂ in the inhaled air must remain as low as possible.

Monitoring formation of nitrogen dioxide (NO2):

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 Vasokinox dose and/or FiO₂ should be reduced if possible. If there is an unexpected change in Vasokinox concentration, the delivery system should be assessed for malfunction and the analyser should be recalibrated.

During treatment:

For the safety of the patient, alert thresholds must be set: nitric oxide ± 2 ppm of the prescribed dosage,

NO₂: 1 ppm .

FiO2 ± 0.05

If at any time the NO₂ concentration exceeds 1 ppm, the nitric oxide dose should immediately be reduced.

For discontinuous-flow volumetric ventilators, spirometry monitoring can detect an increase in Vasokinox flow if a difference is observed between the inspired volume and expired volume.

The pressure in the Vasokinox cylinder must be displayed to allow for rapid replacement of an empty cylinder so as not to abruptly interrupt treatment. Replacement cylinders must be kept available nearby.

Monitoring formation of methaemoglobin:

Neonates and infants are known to have diminished methaemoglobin reductase activity compared to adults. Methaemoglobin level should be measured within one hour after initiation of Vasokinox therapy, using an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is >2.5 %, the Vasokinox 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 Vasokinox therapy. If the fraction of methaemoglobin rises to a level that potentially compromises adequate oxygen delivery, the Vasokinox dose should be decreased and the administration of reducing medicinal products such as methylene blue may be considered.

Exposure limit for medical personnel:

American (NIOSH) and European reference agencies in charge of occupational safety and health recommend the following exposure limits:

-    NO: 25 ppm for 8 hours (30 mg/m³)

-    NO₂: 2 ppm (4 mg/m³)

For the above recommendations to be met, an analysis of nitric oxide and nitrogen dioxide content in the atmosphere must be implemented.

4.3 Contraindications

•    Hypersensitivity to nitric oxide

•    Newborns dependent on a right-to-left shunt or with a “malignant” left-right arterial canal.

4.4 Special warnings and precautions for use

Weaning

Vasokinox treatment must not be stopped abruptly to avoid the risk of increasing pulmonary arterial pressure (PAP) and/or inducing rebound hypoxemia (reduction in PaO2).

Deterioration in oxygenation and elevation in PAP may also occur in patients who are not responsive to Vasokinox.

Weaning from inhaled nitric oxide must be progressive and carried out with precaution (see section 4.2: dosage and route of administration). When patients treated with inhaled nitric oxide are to be transferred to another treatment centre, continuous administration of inhaled nitric oxide should be ensured throughout the transfer.

Special patient populations

Inhaled nitric oxide should also be used with caution in patients with compromised left ventricular function and with elevated baseline pulmonary capillary wedge pressure (PCWP) as they may be at an increased risk of developing cardiac failure (e.g. pulmonary oedema).

Treatment with inhaled nitric oxide might aggravate cardiac insufficiency in a situation with left-to-right shunting.

This is due to unwanted pulmonary vasodilation caused by inhaled nitric oxide, resulting in a further increase of already existing pulmonary hyperperfusion thus potentially giving rise to forward or backward failure. It, therefore, is recommended that prior to the administration of nitric oxide, pulmonary artery catheterisation or echocardiographic examination of central haemodynamics be performed.

Inhaled nitric oxide should be used with caution in patients with complex heart defect, where high pressure in the pulmonary artery is of importance for maintaining circulation

In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with congenital diaphragmatic hernia

Inadequate response when administered in case of refractory hypoxemia In neonates treated for refractory hypoxemia, if it is judged that clinical response is inadequate at 4-6 hours after starting inhaled NO, alternative treatments should be considered based on local circumstances.

Methaemoglobin production:

After inhalation, the terminal compounds of nitric oxide found in the systemic circulation are mainly methaemoglobin and nitrate. Methaemoglobin concentration in the blood should be monitored in all patients.

Although a significant increase in methaemoglobin is uncommon where its initial level is low, this should be tested prior to treatment, then regularly throughout administration. If the methaemoglobin level exceeds 2.5%, the nitric oxide dosage must be reduced. If it exceeds 5%, administration must be stopped. The administration of a reducing agent such as methylene blue should be envisaged.

Formation of NO2:

NO2 rapidly forms in gas mixtures containing nitric oxide and O2, and nitric oxide may in this way cause airway inflammation and damage. The dose of nitric oxide should be reduced if the concentration of nitrogen dioxide exceeds the limits described in section 4.2.

Haemostasis monitoring :

Regular monitoring of haemostasis and measurement of bleeding time is recommended during the administration of Vasokinox for more than 24 hours to patients with functional or quantitative platelet anomalies, a low coagulation factor or receiving anti coagulation treatment. Animal testing has shown that inhaled nitric oxide is likely to interfere with haemostasis and induce an increase in bleeding time. The available data for adult humans are contradictory and do not allow formal conclusions to be drawn.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

In the presence of oxygen, nitric oxide is rapidly oxidized to form superior nitrated derivatives that are toxic for the bronchial epithelium and the alveolocapillary membrane. Nitrogen dioxide (NO₂) is the principal compound formed. The oxidation rate is proportional to the initial concentrations of nitric oxide and oxygen in the inhaled air, and to the duration of contact between NO and O2. Its concentration remains below 0.5 ppm when inhaled nitric oxide is administered at doses of less than 20 ppm and if the measures to reduce the contact time between oxygen and nitric oxide are correctly applied. If the NO₂ concentration exceeds 1 ppm during treatment, the nitric oxide dose and/or FiO₂ must be reduced. See section 4.2 for recommendations concerning NO2 monitoring.

It is possible that nitric oxide donor compounds such as sodium nitroprusside and nitroglycerine, potentiates the risk of developing methaemoglobinemia.

Nitric oxide has been safely administered with dopamine, dobutamine, steroids, surfactant and high frequency ventilation.

Experimental results suggest that nitric oxide and nitrogen dioxide can react chemically with the surfactant and/or the surfactant proteins, without any determined clinical consequences.

The risk of methaemoglobin production is increased by the concomitant administration of nitric oxide with methaemoglobin-generating drugs (e.g.: alkylated nitrates and sulphamides, prilocaine).

Compounds likely to result in an increase in methaemoglobin levels should be used with care during treatment with inhaled nitric oxide.

Available data suggest additive effects of inhaled nitric oxide and other vasodilators acting by the cGMP or cAMP systems (Phosphodiesterase inhibitors, Prostacycline (PGI2) ...), on pulmonary vasodilator effects and right ventricular performance. Therefore, administration of inhaled nitric oxide in combination with these drugs should be done with caution.

A possible synergy between the platelet anti aggregation effects of nitric oxide and prostacyclin and its analogues is suggested but has not been clinically demonstrated or detected.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There are no or limited amount of data from the use of nitric oxide in pregnant-women.

Animal studies are insufficient with respect to reproductive toxicity (see section 5.3). Vasokinox is not recommended during pregnancy.

Breast-feeding:

It is unknown whether nitric oxide/metabolites are excreted in human milk.

The excretion of Vasokinox in milk has not been studied in animals.

A risk to the newborn/infants cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue from Vasokinox therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility:

No fertility studies have been performed.

4.7 Effects on ability to drive and use machines

Not relevant.

Undesirable effects

Summary of safety profile

Abrupt discontinuation of the administration of inhaled nitric oxide may cause rebound reaction. Rebound reaction is the most commonly adverse reaction in association with the clinical use of Vasokinox. The rebound may be seen early as well as late during therapy.

Tabulated list of adverse reactions

Published adverse reactions are listed according to MedDRA frequency convention (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)).

System organ class	Very common	Common	Uncommon	Rare	Very rare	Not known
Blood and lymphatic system disorders	Thrombo- cytopeniaa		Methaemoglo binaemiaa
Nervous system disorders						Headachec Dizzinessc
Cardiac disorders						Bradycardiab (following abrupt discontinuati on of therapy)
Vascular disorders	-	Hypotensiona,b,d	-	-	-	-
Respiratory, thoracic and mediastinal disorders		Atelectasisa				Hypoxiab,d Dyspneac Chest Disconfortc Dry throatc

a: Identified from clinical trial

b: Identified from Post-Marketing experience

c: Identified from Post-Marketing experience, experienced by healthcare personnel following accidental exposure

d: Post Marketing Safety Surveillance (PMSS) data, effects associated with acute withdrawal of the medicinal product, and /or delivery system failures. Rapid rebound reactions such as intensified pulmonary vasoconstriction and hypoxia after sudden withdrawal of inhaled nitric oxide therapy has been described, precipitating cardiovascular collapse.

Description of selected adverse reactions

Inhaled nitric oxide therapy may cause an increase in methaemoglobin.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

A Vasokinox overdose causes an increase in methaemoglobin and NO₂ levels. A high concentration of NO₂ can provoke acute pulmonary lesions and cases of pulmonary oedema have been reported after administration of high concentrations of inhaled nitric oxide.

Course of action in the event of accidental patient overdose:

-    symptomatic treatment of respiratory disorders,

-    in the event of persistent methaemoglobinemia despite the reduction or interruption of the treatment, an intravenous injection of vitamin C or methylene blue, or blood transfusion should be envisaged depending on the patient’s clinical condition.

Course of action in the event of massive inhalation due to accidental leaks:

-    medical observation for at least 24 hours

-    in the event of respiratory disorders, symptomatic treatment should be administered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: OTHER RESPIRATORY SYSTEM PRODUCTS ATC Code : R07AX01.

Mechanism of action

Nitric oxide is produced endogenously by numerous cells within the organism, including those in the vascular endothelium.

It induces the relaxation of smooth vascular muscles thus resulting in vasodilation by combining with cytosolic guanylate cyclase haeminic iron. This activates the guanylate-cyclase and increases intracellular concentrations of cyclic guanosine 3',5'-monophosphate (GMPc). An increase in intra-platelet GMPc may be responsible for platelet aggregation inhibition.

Pharmacodynamic effects

Inhaled nitric oxide exerts a selective action on pulmonary arterial circulation due to its very short lifespan. The haemoglobin circulating in the vicinity of its point of diffusion through the alveolocapillary membrane is responsible for its deactivation. Vasokinox induces a reduction in pulmonary vascular resistance and is effective only in the presence of existing vasoconstriction in the ventilated area of the lung. It improves arterial oxygenation by re-distributing pulmonary blood flow from the unventilated areas of the lung with a low ventilation/perfusion ratio (V/Q) to the ventilated areas, consequently reducing the shunt effect. The effect of nitric oxide is dependent on alveolar recruitment.

Efficacy and safety

The administration of inhaled NO to premature infants of gestational age lower than 34 weeks with hypoxic respiratory failure did not demonstrate any benefit. This may be due to the complications linked to prematurity.

The benefit of the administration of inhaled NO in newborn infants > 34 weeks gestation with hypoxic respiratory failure is established by the controlled randomized clinical trials.

The efficacy of inhaled nitric oxide has been investigated in newborns with hypoxic respiratory failure of different etiologies. In the case of newborns with persistent pulmonary hypertension, the inhalation of NO improves oxygenation and reduces the need of oxygenation through extracorporeal membrane.

A meta-analysis based on 14 randomised trials was conducted in term and near term infants with hypoxaemic respiratory failure.

There is a significant effect in the reduction of requirement for extracorporeal membrane oxygenation (ECMO) (relative risk 0.63, 95% confidence interval (CI)

0.54, 0.75) (n=810).

Oxygenation parameters were reported from six studies included in the meta-analysis. After 30 to 60 minutes of treatment, the Oxygenation Index is significantly lower in the iNO group (weighted mean difference -9.59, 95% CI -12.50, -6.68) (n=698). PaO2 30 to 60 minutes after treatment is significantly higher in the iNO group (weighted mean difference 45.5 mmHg, 95% CI 34.7, 56.3) (n=699). Oxygenation improves in approximately 50% of infants receiving iNO (n=698).

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 several events including 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.

Pharmacokinetic properties

Inhaled nitric oxide is diffused via a systemic pathway. The largest part crosses the alveolocapillary membrane and combines with haemoglobin presenting oxygen saturation of between 60% and 100%. At this level of oxygen saturation the nitric oxide mainly fixes to the oxyhaemoglobin, which transforms into methaemoglobin and nitrates. When oxygen saturation is low, the nitric oxide fixes onto deoxyhaemoglobin to form an intermediate compound, nitrosylhaemoglobin, which then decomposes into nitrogen oxides and methaemoglobin in the presence of oxygen. Nitric oxide reacts with oxygen and water to form nitrogen dioxide and nitrites, which react with oxyhaemoglobin to produce methaemoglobin and nitrates. Thus, the principal metabolites of nitric oxide found in the systemic circulation are methaemoglobin and nitrates.

Nitrates are eliminated mainly in urine whereas methaemoglobin is metabolized in several hours into haemoglobin by endogenic reductases. The nitrates excreted in urine represent over 70% of the inhaled nitric oxide dosage.

5.3 Preclinical safety data

Toxicity studies on single administration have demonstrated that inhalation of 1500 ppm in rats over a 16 minute period and of 320 ppm in mice over 8 hours causes death in 50% of animals.

Toxicity studies following repeated administration of nitric oxide showed pulmonary functional abnormalities suggesting increase in methaemoglobinaemia which constitutes a toxicity biological marker for nitric oxide. Moreover, inhaling 10 ppm of nitric oxide 2 hours per day, 5 days a week, over a period of 5 to 30 weeks caused emphysema lesions in mice.

No deaths occurred in mice following exposure of 10 ppm over a period of 6E2 months or of 2.4 ppm for a whole lifetime.

The NOAEL for rat exposure of 6 hours per day over a period of 27 days (from the 2^nd day following birth, to withdrawal), is 100 ppm. In this study, the exposure of newborn/juvenile and adult rats to 100 ppm NO has not demonstrated any toxicity with regard to post-natal development, including reproductive capability. No reproductive toxicity studies have been performed. A battery of genotoxicity test has demonstrated mutagenic potential of nitric oxide in some in vitro test systems and no clastogenic effect in the in vivo system.

The gas mutagenic properties seem to be partly related to peryoxynitrites and to the oxidative desamination of deoxyribonucleic acid induced by the effect of nitric oxide on the target cell.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. No carcinogenicity studies have been conducted.

6.1 List of excipients

Nitrogen

6.2 Incompatibilities

All equipment, including connectors, tubing and circuits, used in the delivery of nitric oxide must be made of materials compatible with the gas. 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).

6.3 Shelf life

36 months

6.4 Special precautions for storage

The construction of a nitric oxide supply circuit comprising a central installation with centrally stored cylinders and fixed piping and connectors at the patient’s bedside is forbidden.

The cylinders must be stored at a temperature of between -10 and + 50°C Storage in the pharmacy department

Cylinders must be stored in a clean, well-ventilated, locked room reserved for the storage of gases for medical use. A specific area inside this room will be reserved for storing Vasokinox cylinders. These should be protected so as to avoid breakage and falling. They should also be kept away from any oxidizing and/or combustible materials and humidity.

Storage in the user department

The cylinder must be installed in an equipped area with appropriate equipment to maintain it in a vertical position. The cylinder must be protected to avoid breakage or falling and be kept away from any sources of heat or ignition, oxidizing and/or combustible materials and humidity.

Cylinder Transportation

Cylinders must be transported using the appropriate equipment (dolly equipped with chains, barriers or rings) to protect them from breakage or falls. During inter- or intrahospital transfer of patients receiving nitric oxide treatment, the cylinders must be firmly secured to hold them in the vertical position and to avoid the risk of falling. Special attention must also be paid to the securing of the pressure reducer/regulator to avoid the risk of accidental breakage.

6.5 Nature and contents of container

Cylinders have a capacity of 5l, 11l and 20l.

Aluminium alloy cylinders have a white painted body and a turkish blue-painted shoulder.

They are equipped with a stainless steel residual pressure valve with a specific outlet connector.

6.6 Special precautions for disposal and other handling

To avoid any incidents, the following instructions must be strictly adhered to:

-    check that the equipment is in working order before use.

-    firmly secure the cylinders using chains or hooks in the rack to avoid any accidental falls

-    never open a valve abruptly: open it counter-clockwise, slowly and completely, then turn the valve of a quarter of tour clockwise

-    do not handle a cylinder on which the valve is not protected by a bonnet cap and a protective envelope

-    Use a specific ISO 5145 (2004) connector: n°29 specific NO/N₂ (100 ppm< NO < 1000 ppm) W30x2 15.2-20.8 DR

-    a pressure regulator which admits a pressure at least equal to 1.5 the maximum operating pressure (200 bar) of the gas cylinder should be used

-    at each new use, purge the pressure-reducer/flowmeter using the nitric oxide/nitrogen mixture

-    do not attempt to repair a defective valve

-    do not tighten the pressure-reducer/flowmeter using a gripper, otherwise the seal may be crushed and the administration device damaged

-    evacuate exhaled gases outside (avoiding areas in which they may accumulate). Before use, it should be ensured that the room has the appropriate ventilation system for evacuating gases in the event of an accident or accidental leaks.

-    as nitric oxide is colourless and odourless, it is recommended using a detection system in all rooms in which it is to be used or stored.

-    Personnel exposure limits (see section 4.2: Dosage and route of administration)

The installation of a nitric oxide pipeline system with supply station of gas cylinders,

fixed network and terminal units is forbidden.

Instruction for cylinder disposal:

When the cylinder is empty, do not dispose of it. Empty cylinders will be collected by the supplier.

7    MARKETING AUTHORISATION HOLDER

AIR LIQUIDE Sante INTERNATIONAL 75 Quai d’Orsay 75341 PARIS Cedex 07 FRANCE

8    MARKETING AUTHORISATION NUMBER(S)

PL 27513/0002

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/01/2013

10    DATE OF REVISION OF THE TEXT

27/04/2015