INOMAX 800 PPM MOL/MOL inhalations gas medication leaflet

INOmax 800 ppm mol/mol medicinal gas, compressed

Nitric oxide (NO) 800 ppm mol/mol.

A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC.

A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at15oC.

For a full list of excipients, see section 6.1.

Medicinal gas, compressed.

INOmax, in conjunction with ventilatory support and other appropriate active substances, is indicated:▪ for the treatment of newborn infants  34 weeks gestation with hypoxic respiratory failureassociated with clinical or echocardiographic evidence of pulmonary hypertension, in order toimprove oxygenation and to reduce the need for extracorporeal membrane oxygenation.

▪ as part of the treatment of peri- and post-operative pulmonary hypertension in adults andnewborn infants, infants and toddlers, children and adolescents, ages 0-17 years in conjunctionto heart surgery, in order to selectively decrease pulmonary arterial pressure and improve rightventricular function and oxygenation.

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 ofa nitric oxide delivery system. INOmax should only be delivered according to a neonatologist’sprescription.

INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmaxshould be used only after respiratory support has been optimised. This includes optimising tidalvolume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive endexpiratory pressure).

Pulmonary hypertension associated with heart surgery

Prescription of nitric oxide should be supervised by a physician experienced in cardiothoracicanaesthesia & intensive care. Prescription should be limited to those cardio-thoracic units that havereceived adequate training in the use of a nitric oxide delivery system. INOmax should only bedelivered according to an anaesthetist’s or intensive care physician’s prescription.

Persistent Pulmonary Hypertension in the Newborn (PPHN)

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The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In thepivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hoursof therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at thislower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement inthe 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 resolvedand the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, buttypically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4.

Weaning

Attempts to wean INOmax should be made after the ventilator support is substantially decreasedor after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, thedose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenationduring administration of INOmax at 1 ppm, the FiO2 should be increased by 10 %, the INOmax isdiscontinued, 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 bereconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days shouldundergo careful diagnostic work-up for other diseases.

Pulmonary hypertension associated with heart surgery

INOmax should be used only after conservative support has been optimised. In clinical trials INOmaxhas been given in addition to other standard treatment regimes in the peri-operative setting, includinginotropic and vasoactive medicinal products. INOmax should be administered under close monitoringof haemodynamics and oxygenation.

Newborn infants, infants and toddlers, children and adolescents, ages 0-17 years

The starting dose of inhaled nitric oxide is 10 ppm(part per million) of inhaled gas. The dose may beincreased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowesteffective dose should be administered and the dose should be weaned down to 5 ppm provided that thepulmonary 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 beincreased up to 40 ppm if the lower dose has not provided sufficient clinical effects. The lowesteffective dose should be administered and the dose should be weaned down to 5 ppm provided that thepulmonary 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 improvedoxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated aftera minimum of 10 minutes.

Consideration should be given to discontinuation of treatment if no beneficial physiological effects areapparent 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 commontreatment times are 24 -48 hours.

Weaning

Attempts to wean INOmax should be commenced as soon as the haemodynamics have stabilised inconjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide

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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 inpulmonary artery pressure with subsequent circulatory instability.

The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yetbeen established. Currently available data are described in section 5.1 but no recommendation orposology can be made.

For endotracheopulmonary use.

Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/airmixture 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 theventilator. 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 maybe associated with spikes in nitric oxide concentration. The nitric oxide delivery system forintermittent 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 thecircuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured atthe 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 cylinderreplacement without inadvertent loss of therapy and backup gas cylinders must be available to providetimely 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 andreserve nitric oxide delivery system should be available. The power supply for the monitoringequipment should be independent of the delivery device function.

The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker'slegislation is 25 ppm for 8 hours (30 mg/m3) in most countries and the corresponding limit for NO2 is2-3 ppm (4-6 mg/m3).

Training in administration

The key elements that need to be covered in training hospital personnel are as follows.

Correct set-up and connections

- Connections to the gas cylinder and to the ventilator patient breathing circuit

Operation

- Pre-use check list procedure (a series of steps required immediately prior to each patientinitiation to ensure that the system is working properly and that the system is purged of NO2)

- Setting the device for the correct concentration of nitric oxide to be administered

- Setting the NO, NO2 and O2 monitors for high and low alarm limits

- Using the manual backup delivery system

- Procedures for correctly switching gas cylinders and purging system

- Troubleshooting alarms

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- NO, NO2 and O2 monitor calibration

- Monthly system performance check-up procedures

Monitoring formation of methaemoglobin (MetHb)

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, usingan 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 productssuch as methylene blue may be considered. Although it is unusual for the methaemoglobin level toincrease significantly if the first level is low, it is prudent to repeat methaemoglobin measurementsevery one to two days.

In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of theinitiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentiallycompromises adequate oxygen delivery, the INOmax dose should be decreased and the administrationof reducing medicinal products such as methylene blue may be considered.

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 berecalibrated, and the INOmax and/or FiO2 should be reduced if possible. If there is an unexpectedchange in INOmax concentration, the delivery system should be assessed for malfunction and theanalyser should be recalibrated.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood.

Inadequate response

If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the followingshould be considered.

For patients who are to be referred to another hospital, to prevent worsening of their condition onacute discontinuation of INOmax, the availability of nitric oxide during transport should be assured.

Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should beconsidered based on continued deterioration or failure to improve, defined by criteria based on localcircumstances.

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

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 givingraise to forward or backward failure. It, therefore, is recommended that prior to the administration ofnitric oxide, pulmonary artery catheterisation or echocardiographic examination of centralhaemodynamics be performed. Inhaled nitric oxide should be used with caution in patients withcomplex heart defect, where high pressure in the pulmonary artery is of importance for maintainingcirculation.

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

Discontinuation of therapy

The INOmax dose should not be discontinued abruptly as it may result in an increase in pulmonaryartery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenationand elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaningfrom inhaled nitric oxide should be performed with caution. For patients transported to other facilitiesfor additional treatment, who need to continue with inhaled nitric oxide, arrangements should be madeto ensure the continuous supply of inhaled nitric oxide during transportation. The physician shouldhave access at the bedside to a reserve nitric oxide delivery system.

Formation of methaemoglobin

A large portion of nitric oxide for inhalation is absorbed systemically. The end medicinal products ofnitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. Theconcentrations of methaemoglobin in the blood should be monitored, see section 4.2.

Formation of NO2

NO2 rapidly forms in gas mixtures containing nitric oxide and O2, and nitric oxide may in this waycause airway inflammation and damage. The dose of nitric oxide should be reduced if theconcentration of nitrogen dioxide exceeds 0.5 ppm.

Effects on platelets

Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increasedbleeding time. Data in adult humans are conflicting, and there has been no increase in bleedingcomplications in randomised controlled trials in term and near-term neonates with hypoxic respiratoryfailure.

Regular monitoring of haemostasis and measurement of bleeding time is recommended during theadministration of INOmax for more than 24 hours to patients with functional or quantitative plateletanomalies, a low coagulation factor or receiving anticoagulation treatment.

Cases of life-threatening pulmonary oedema have been reported with nitric oxide in patients withpulmonary veno-occlusive disease. Therefore, the possibility of a veno-occlusive disease should becarefully evaluated if signs of pulmonary oedema occur following the administration of nitric oxide topatients with pulmonary hypertension. If confirmed, the treatment is to be discontinued.

No interaction studies have been performed.

A clinically significant interaction with other medicinal products used in the treatment of hypoxicrespiratory failure cannot be excluded based on the available data. There may be an additive effectwith INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances,including sodium nitroprusside and nitroglycerin. INOmax has been safely administered withtolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.

The combined used with other vasodilators (e.g. sildenafil) is not extensively studied. Available datasuggest additive effects on central circulation, pulmonary artery pressure and right ventricularperformance. Inhaled nitric oxide combination with other vasodilators acting by the cGMP or cAMPsystems should be done with caution.

There is an increased risk of methaemoglobin formation if substances with a known tendency toincrease methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkylnitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thusbe used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as

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INOmax is given at the same time as medicinal products containing prilocaine.

In the presence of oxygen, nitric oxide is rapidly oxidised to derivatives which are toxic to thebronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO2) is the main substanceformed, and may cause airway inflammation and damage. There are also animal data suggesting anincreased susceptibility to airway infections upon exposure to low levels of NO2. During treatmentwith nitric oxide, the NO2 concentration should be < 0.5 ppm in the nitric oxide dose range < 20 ppm.

If at any time the NO2 concentration exceeds 1 ppm, the nitric oxide dose should immediately bereduced. See section 4.2 for information on monitoring for NO2.

There are no adequate data from the use of nitric oxide in pregnant women. The potential risk forhumans is unknown.

It is unknown whether nitric oxide is excreted in human milk.

INOmax should not be used during pregnancy or breastfeeding.

No fertility studies have been performed.

Not relevant.

Abrupt discontinuation of the administration of inhaled nitric oxide may cause rebound reaction;decrease in oxygenation and increase in central pressure and subsequent decrease in systemic bloodpressure. Rebound reaction is the most commonly adverse reaction in association with the clinical useof INOmax. The rebound may be seen early as well as late during therapy.

In one clinical study (NINOS), treatment groups were similar with respect to the incidence andseverity of intracranial haemorrhage, Grade IV haemorrhage, periventricular leukomalacia, cerebralinfarction, seizures requiring anticonvulsant therapy, pulmonary haemorrhage, or gastrointestinalhaemorrhage.

The table below presents adverse reactions (ADRs) that have been reported with the use of INOmaxfrom either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months ofage). The displayed frequency categories use the following 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).

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System organ Very Common Uncommon Rare Very Not knownclass common rare

Blood and Thrombo- - Methaemoglobi - - -lymphatic cytopeniaa naemiaasystemdisorders

Cardiac - - - - - Bradycardiabdisorders (following abruptdiscontinuation oftherapy)

Vascular - Hypotensiona,b, - - - -disorders d

Respiratory, - Atelectasisa - - - Hypoxiab,dthoracic and Dyspnoeacmediastinal Chest Discomfortcdisorders Dry throatc

Nervous - - - - - Headachecsystem Dizzinesscdisordersa: Identified from the clinical trialb: Identified from Post-Marketing experiencec: Identified from Post-Marketing experience, experienced by healthcare personnel following accidentalexposured: Post Marketing Safety Surveillance (PMSS) data, effects associated with acute withdrawal of the medicinalproduct, and /or delivery system failures. Rapid rebound reactions such as intensified pulmonaryvasoconstriction and hypoxia after sudden withdrawal of inhaled nitric oxide therapy has been described,precipitating cardiovascular collapse.

Inhaled nitric oxide therapy may cause an increase in methaemoglobin.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdose with INOmax will be manifest by elevations in methaemoglobin and NO2. Elevated NO2may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacityof the circulation. In clinical studies, NO2 levels > 3 ppm or methaemoglobin levels > 7 % weretreated by reducing the dose of, or discontinuing, INOmax.

Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can betreated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon theclinical situation.

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Pharmacotherapeutic group: Other respiratory system products, ATC code R07AX01.

Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle bybinding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase andincreasing intracellular levels of cyclic guanosine 3’,5’-monophosphate, which then leads tovasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation.

INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonaryvessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lungregions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defector as a condition secondary to other diseases such as meconium aspiration syndrome (MAS),pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), andpulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results inhypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus andforamen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significantincreases in PaO2).

The efficacy of INOmax has been investigated in term and near-term newborns with hypoxicrespiratory failure resulting from a variety of aetiologies.

In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 %

O2 with (n=114) or without (n=121) nitric oxide most with an initial concentration of 20 ppm withweaning as possible to lower doses with a median duration of exposure of 40 hours. The objective ofthis double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxidewould reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation(ECMO). Neonates with less than a full response at 20 ppm were evaluated for a response to 80 ppmnitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (theprospectively defined primary endpoint) showed a significant advantage for the nitric oxide treatedgroup (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher doseof nitric oxide. The adverse events collected occurred at similar incidence rates in both groups.

Follow-up exams at 18-24 months of age were similar between the two groups with respect to mental,motor, audiologic, and neurologic evaluations.

In the CINRGI trial, 186 term- and near-term neonates with hypoxic respiratory failure and withoutlung hypoplasia were randomised to receive either INOmax (n=97) or nitrogen gas (placebo; n=89)with an initial dose of 20 ppm weaning to 5 ppm in 4 to 24 hours with median duration of exposure of44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewerneonates in the INOmax group required ECMO compared to the control group (31 % vs. 57 %,p<0.001). The INOmax group had significantly improved oxygenation as measured by PaO2, OI, andalveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with INOmax, 2(2 %)were withdrawn from study drug due to methaemoglobin levels >4 %. The frequency and number ofadverse events were similar in the two study groups.

In patients undergoing heart surgery, an increase in pulmonary artery pressure due to pulmonary vaso-constriction is frequently seen. Inhaled nitric oxide has been shown to selectively reduce pulmonaryvascular resistance and reduce the increased pulmonary artery pressure. This may increase the rightventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenationin the pulmonary circulation.

In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure wererandomised to receive either INOmax (n=395) in a dose of 5 ppm or nitrogen (placebo n=400),beginning within the first 24 hours of life and treated for at least 7 days, up to 21 days. The primary

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Nitric oxide chemically reacts with oxygen to form nitrogen dioxide.

Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitricoxide may form peroxynitrite with superoxide (O -2 ), an unstable compound which may cause tissuedamage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins andmay also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of thechemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibitspulmonary pharmacodynamic effects at intra-airway concentrations as low as 1 ppm.

The European Medicines Agency has waived the obligation to submit the results of studies with

INOmax in all subsets of the paediatric population in persistent pulmonary hypertension and otherpulmonary heart disease. See section 4.2 for information on paediatric use.

The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemicallyafter inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobinthat is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combinespredominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygensaturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin,which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within thepulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide andnitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate.

Thus, the end products of nitric oxide that enter the systemic circulation are predominantlymethaemoglobin and nitrate.

Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposureconcentration in neonates with respiratory failure. Methaemoglobin concentrations increase during thefirst 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in theplacebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5 % in the80 ppm INOmax group. Methaemoglobin levels > 7 % were attained only in patients receiving80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobinwas 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until40 hours.

Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accountingfor > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at ratesapproaching the rate of glomerular filtration.

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of themaximum human exposure indicating little relevance to clinical use.

Acute toxicity is related to anoxia resulting from elevated methaemoglobin levels.

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Nitric oxide is genotoxic in some test systems.. No evidence of a carcinogenic effect was apparent, atinhalation exposures up to the recommended dose (20 ppm), in rats for 20 h/day for up to two years.

Higher exposures have not been investigated.

No reproduction toxicity studies have been conducted.

Nitrogen

In the presence of oxygen NO rapidly forms NO2, see section 4.5.

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 areprotected from rain and direct sunlight.

Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources ofheat or ignition.

Storage in the pharmacy department

The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gasonly. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gascylinders.

Storage in the medical department

The gas cylinder should be put in an equipped site with appropriate material in order to hold the gascylinder vertically.

Transport of gas cylinders

The gas cylinders should be transported with appropriate material in order to protect them from risksof shocks and falls.

During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should befixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall oruntimely modifying output. A particular attention should be also turned to the fastening of the pressureregulator so as to avoid the risks of accidental failures.

A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled undera pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specificoutlet connection and a standard valve hand-wheel.

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A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled undera pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specificoutlet connection and a INOmeter device equipped valve hand-wheel.

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filledunder a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with aspecific outlet connection and a standard valve hand-wheel.

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filledunder a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with aspecific outlet connection and a INOmeter device equipped valve hand-wheel.

Instructions for use/handling INOmax

When connecting an INOmax cylinder to the delivery system, always secure that the cylinderconcentration is of the same concentration for which the system is configured.

In order to avoid all incidents, the following instructions should be absolutely respected.

- the good condition of the material should be checked before use

- the gas cylinders should be fixedly stowed away in order to avoid untimely fall

- the valve should be fully open when used but not be opened with violence

- a defective valve should neither be used nor be repaired. Return to distributor/manufacturer

- a gas cylinder whose valve is not protected by a cap or a shell should not be used

- a specific connection, with a 30 mm thread which is designated for medical use, complying with

ISO 5145 and a pressure regulator which admits a pressure at least equal to 1.5 the maximumoperating pressure (155 bar) of the gas cylinder should be used

- the pressure regulator should be purged by the nitrogen-nitric oxide mixture before each newuse in order to preclude nitrogen dioxide inhalation

- the pressure regulator should not be tightened with pliers, at the risk of crushing the gasket

All equipment, including connectors, tubing, and circuits, used in the delivery of nitric oxide must bemade of materials compatible with the gas. From a corrosion point of view the supply system can bedivided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From thehumidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures canbe used with most materials. However, the presence of nitrogen dioxide and moisture creates anaggressive atmosphere. Among metallic construction materials, only stainless steel can berecommended. Tested polymers which can be used in nitric oxide administration systems includepolyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not beused. Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylenehave been used extensively with pure nitric oxide and other corrosive gases. They were considered soinert that testing was not required.

The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed networkand terminal units is forbidden.

There is in general no need for scavenging of excess gas, the work place ambient air quality shouldhowever be considered and trace concentrations of NO or NO2/NOx must not exceed set nationaloccupational exposure limits. Accidental exposure to INOmax in hospital staff has been associatedwith adverse events (see section 4.8).

Cylinders equipped with a standard valve hand-wheel cannot be used with the INOmax DSIR deliverysystem.

Instruction for disposal of gas cylinder

When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected bythe supplier.

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Linde Healthcare AB

Rättarvägen 3169 68 Solna

Sweden

EU/1/01/194/003, EU/1/01/194/004

Date of first authorisation: 01/08/2001

Date of last renewal: 01/06/2006

MM/YYYY

Detailed information on this product is available on the website of the European Medicines Agencyhttps://www.ema.europa.eu.

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