INOmax

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ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 400 ppm mol/mol medicinal gas, compressed 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Nitric oxide (NO) 400 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 at 
15oC. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Medicinal gas, compressed. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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 failure 

associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to 
improve oxygenation and to reduce the need for extracorporeal membrane oxygenation. 

 
 as part of the treatment of peri- and post-operative 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. 

 
4.2 Posology and method of administration 
 
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. INOmax should only be delivered according to a neonatologist’s 
prescription. 
 
INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmax 
should be used only after respiratory support has been optimised. This includes optimising tidal 
volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end 
expiratory pressure). 
 
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. INOmax should only be 
delivered according to an anaesthetist’s or intensive care physician’s prescription. 
 
 
Posology 



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Persistent Pulmonary Hypertension in the Newborn (PPHN) 
The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In the 
pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours 
of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this 
lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in 
the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) < 0.60.   
 
Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved 
and the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, but 
typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4.  
 
Weaning 
Attempts to wean INOmax should be made after the ventilator support is substantially decreased or 
after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the 
dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation 
during administration of INOmax at 1 ppm, the FiO2 should be increased by 10 %, the INOmax is 
discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20 %, 
INOmax therapy should be resumed at 5 ppm and discontinuation of INOmax therapy should be 
reconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days should 
undergo careful diagnostic work-up for other diseases. 
 
Pulmonary hypertension associated with heart surgery 
INOmax should be used only after conservative support has been optimised. In clinical trials INOmax 
has been given in addition to other standard treatment regimes in the peri-operative setting, including 
inotropic and vasoactive medicinal products. INOmax should be administered under close monitoring 
of haemodynamics and oxygenation. 
 
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 be 
increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest 
effective dose should be administered and the dose should be weaned down to 5 ppm provided that the 
pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.  
 
Clinical data supporting the suggested dose in the age range 12-17 years is limited. 
 
Adults 
The starting dose of inhaled nitric oxide is 20 ppm (part per million) of inhaled gas. The dose may be 
increased up to 40 ppm if the lower dose has not provided sufficient clinical effects. The lowest 
effective dose should be administered and the dose should be weaned down to 5 ppm provided that the 
pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.  
 
The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved 
oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after 
a minimum of 10 minutes. 
 
Consideration should be given to discontinuation of treatment if no beneficial physiological effects are 
apparent after a 30-minute trial of therapy. 
 
Treatment may be initiated at any time point in the peri-operative course to lower pulmonary pressure. 
In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass. 
Inhaled NO has been given for time periods up to 7 days in the peri-operative setting, but common 
treatment times are 24 -48 hours.  
 
Weaning 
Attempts to wean INOmax should be commenced as soon as the haemodynamics have stabilised in 
conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide 



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therapy should be performed in a stepwise manner. The dose should be incrementally reduced to 1 
ppm for 30 minutes with close observation of systemic and central pressure, and then turned off.  
Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of 
INOmax. 
 
Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in 
pulmonary artery pressure with subsequent circulatory instability. 
 
Paediatric population 
The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yet 
been established. Currently available data are described in section 5.1 but no recommendation or 
posology can be made. 
 
Method of administration 
For endotracheopulmonary use. 
 
Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air 
mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, 
during set-up, secure that the device setting is in agreement with the cylinder gas concentration. 
 
The delivery system must provide a constant inhaled INOmax concentration irrespective of the 
ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of 
INOmax into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may 
be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for 
intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration.   
 
The inspired INOmax concentration must be measured continuously in the inspiratory limb of the 
circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at 
the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, 
appropriate alarms must be set for INOmax (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 
(± 0.05). The INOmax gas cylinder pressure must be displayed to allow timely gas cylinder 
replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide 
timely replacement. INOmax therapy must be available for manual ventilation such as suctioning, 
patient transport, and resuscitation. 
  
In the event of a system failure or a wall-outlet power failure, a backup battery power supply and 
reserve nitric oxide delivery system should be available. The power supply for the monitoring 
equipment should be independent of the delivery device function.  
 
The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker's 
legislation is 25 ppm for 8 hours (30 mg/m3) in most countries and the corresponding limit for NO2 is 
2-3 ppm (4-6 mg/m3). 
 
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 patient 

initiation 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, using 
an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is > 
2.5 %, the INOmax dose should be decreased and the administration of reducing medicinal products 
such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to 
increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements 
every one to two days.   
 
In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the 
initiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentially 
compromises adequate oxygen delivery, the INOmax dose should be decreased and the administration 
of reducing medicinal products such as methylene blue may be considered. 
 
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 INOmax and/or FiO2 should be reduced if possible. If there is an unexpected 
change in INOmax concentration, the delivery system should be assessed for malfunction and the 
analyser should be recalibrated. 
 
4.3 Contraindications 
 
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.  
 
4.4 Special warnings and precautions for use 
 
Inadequate response 
If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the following 
should be considered.  
For patients who are to be referred to another hospital, to prevent worsening of their condition on 
acute discontinuation of INOmax, the availability of nitric oxide during transport should be assured. 
Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should be 
considered based on continued deterioration or failure to improve, defined by criteria based on local 
circumstances.  
 
Special patient populations 
In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with 
congenital 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 giving 
raise 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. 
 



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Inhaled nitric oxide should also be used with caution in patients with compromised left ventricular 
function and elevated baseline pulmonary capillary pressure (PCWP) as they may be at an increased 
risk 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 pulmonary 
artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation 
and elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaning 
from inhaled nitric oxide should be performed with caution. For patients transported to other facilities 
for additional treatment, who need to continue with inhaled nitric oxide, arrangements should be made 
to ensure the continuous supply of inhaled nitric oxide during transportation. The physician should 
have 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 of 
nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. The 
concentrations 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 way 
cause airway inflammation and damage. The dose of nitric oxide should be reduced if the 
concentration of nitrogen dioxide exceeds 0.5 ppm. 
 
Effects on platelets 
Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increased 
bleeding time. Data in adult humans are conflicting, and there has been no increase in bleeding 
complications in randomised controlled trials in term and near-term neonates with hypoxic respiratory 
failure.  
 
Regular monitoring of haemostasis and measurement of bleeding time is recommended during the 
administration of INOmax for more than 24 hours to patients with functional or quantitative platelet 
anomalies, a low coagulation factor or receiving anticoagulation treatment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed.  
A clinically significant interaction with other medicinal products used in the treatment of hypoxic 
respiratory failure cannot be excluded based on the available data. There may be an additive effect 
with INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances, 
including sodium nitroprusside and nitroglycerin. INOmax has been safely administered with 
tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation. 
 
The combined used with other vasodilators (e.g. sildenafil) is not extensively studied. Available data 
suggest additive effects on central circulation, pulmonary artery pressure and right ventricular 
performance. Inhaled nitric oxide combination with other vasodilators acting by the cGMP or cAMP 
systems should be done with caution. 
 
There is an increased risk of methaemoglobin formation if substances with a known tendency to 
increase methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkyl 
nitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thus 
be used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as 
oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when 
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 the 
bronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO2) is the main substance 
formed, and may cause airway inflammation and damage. There are also animal data suggesting an 



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increased susceptibility to airway infections upon exposure to low levels of NO2. During treatment 
with 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 be 
reduced. See section 4.2 for information on monitoring for NO2. 
 
4.6 Fertility, pregnancy and lactation 
 
There are no adequate data from the use of nitric oxide in pregnant women. The potential risk for 
humans 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. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
Summary of safety profile 
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 blood 
pressure. Rebound reaction is the most commonly adverse reaction in association with the clinical use 
of 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 and 
severity of intracranial haemorrhage, Grade IV haemorrhage, periventricular leukomalacia, cerebral 
infarction, seizures requiring anticonvulsant therapy, pulmonary haemorrhage, or gastrointestinal 
haemorrhage. 
 
Tabulated list of adverse reactions 
The table below presents adverse reactions (ADRs) that have been reported with the use of INOmax 
from either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months of 
age)). 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 
class 

Very 
common  
 

Common  
 

Uncommon Rare Very 
rare 

Not known  

Blood and 
lymphatic 
system 
disorders 

Thrombo-
cytopeniaa 

- Methaemoglobi
naemiaa 

- - -  

Cardiac 
disorders 

- - - - - Bradycardiab 
(following abrupt 
discontinuation of 
therapy) 
 

Vascular 
disorders 

- Hypotensiona,b,
d 

- - - - 

Respiratory, 
thoracic and 
mediastinal 
disorders 

-  Atelectasisa - - - Hypoxiab,d  
Dyspnoeac 
Chest Discomfortc 
Dry throatc 

Nervous 
system 
disorders 

- - - - - Headachec 
Dizzinessc 
 

 
a: Identified from the 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 national reporting system 
listed in Appendix V 
 
 
4.9 Overdose 
 
Overdose with INOmax will be manifest by elevations in methaemoglobin and NO2. Elevated NO2 
may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity 
of the circulation. In clinical studies, NO2 levels > 3 ppm or methaemoglobin levels > 7 % were 
treated by reducing the dose of, or discontinuing, INOmax. 
 
Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can be 
treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the 
clinical situation. 
 
 
 
 
 
5. PHARMACOLOGICAL PROPERTIES 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5.1  Pharmacodynamic properties 
 
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 by 
binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and 
increasing intracellular levels of cyclic guanosine 3’,5’-monophosphate, which then leads to 
vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation.  
INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary 
vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung 
regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. 
 
Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect 
or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), 
pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and 
pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in 
hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and 
foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant 
increases in PaO2). 
 
The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic 
respiratory 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 with 
weaning as possible to lower doses with a median duration of exposure of 40 hours. The objective of 
this double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxide 
would 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 ppm 
nitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (the 
prospectively defined primary endpoint) showed a significant advantage for the nitric oxide treated 
group (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher dose 
of 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 without 
lung 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 of 
44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewer 
neonates 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, and 
alveolar-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 of 
adverse 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 pulmonary 
vascular resistance and reduce the increased pulmonary artery pressure. This may increase the right 
ventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenation 
in the pulmonary circulation. 
 
In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure were 
randomised 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 
outcome, of the combined efficacy endpoints of death or BPD at 36 weeks GA, was not significantly 



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different between groups, even with adjustment for gestational age as a covariate (p = 0.40), or with 
birth weight as a covariate (p = 0.41). The overall occurrence of intraventricular haemorrhage was 114 
(28.9 %) among the iNO treated as compared to 91 (22.9 %) among the control neonates. The overall 
number of death at week 36 was slightly higher in the iNO group; 53/395 (13.4 %) as compared to 
control 42/397 (10.6 %). The INOT25 trial, studying the effects of iNO in hypoxic preterm neonates, 
did not show improvement in alive without BPD. No difference in the incidence of IVH or death was 
however observed in this study. The BALLR1 study, also evaluating the effects of iNO in preterm 
neonates, but initiating iNO at 7 days and in a dose of 20 ppm, found a significant increase in neonates 
alive without BPD at gestational week 36, 121 (45 % vs. 95 (35.4 %) p<0.028. No signs of any 
increase adverse effects were noted in this study.  
 
Nitric oxide chemically reacts with oxygen to form nitrogen dioxide. 
 
Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric 
oxide may form peroxynitrite with superoxide (O2-), an unstable compound which may cause tissue 
damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and 
may also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of the 
chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits 
pulmonary 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 other 
pulmonary heart disease. See section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically 
after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin 
that is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combines 
predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen 
saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, 
which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the 
pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and 
nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate. 
Thus, the end products of nitric oxide that enter the systemic circulation are predominantly 
methaemoglobin and nitrate. 
 
Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure 
concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the 
first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in the 
placebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5 % in the 
80 ppm INOmax group. Methaemoglobin levels > 7 % were attained only in patients receiving 
80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobin 
was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until 
40 hours. 
 
Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting 
for > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates 
approaching the rate of glomerular filtration. 
 
5.3 Preclinical safety data 
 
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. 
 
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, at 
inhalation 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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Nitrogen 
 
6.2 Incompatibilities 
 
In the presence of oxygen NO rapidly forms NO2, see section 4.5. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
All regulations concerning handling of pressure vessels must be followed.  
 
Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are 
protected from rain and direct sunlight. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition.  
 
Storage in the pharmacy department 
The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas 
only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas 
cylinders. 
 
Storage in the medical department 
The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas 
cylinder vertically.   
 
Transport of gas cylinders 
The gas cylinders should be transported with appropriate material in order to protect them from risks 
of shocks and falls. 
During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should be 
fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or 
untimely modifying output. A particular attention should be also turned to the fastening of the pressure 
regulator so as to avoid the risks of accidental failures.  
 
 
 
 
 
 
6.5 Nature and contents of container 
 
Pack sizes: 



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

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

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

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled 
under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a 
specific outlet connection and a INOmeter device equipped valve hand-wheel. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for use/handling INOmax 
When connecting an INOmax cylinder to the delivery system, always secure that the cylinder 
concentration is of the same concentration for which the system is configured. 
 
In order to avoid all incidents, the following instructions should be absolutely respected. 
- 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 maximum 
operating pressure (155 bar) of the gas cylinder should be used 

- the pressure regulator should be purged by the nitrogen-nitric oxide mixture before each new 
use 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 be 
made of materials compatible with the gas. From a corrosion point of view the supply system can be 
divided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From the 
humidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures can 
be used with most materials. However, the presence of nitrogen dioxide and moisture creates an 
aggressive atmosphere. Among metallic construction materials, only stainless steel can be 
recommended. Tested polymers which can be used in nitric oxide administration systems include 
polyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not be 
used. Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylene 
have been used extensively with pure nitric oxide and other corrosive gases. They were considered so 
inert that testing was not required. 
 
The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed network 
and terminal units is forbidden.   

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

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



13 

 
Instruction for disposal of gas cylinder 
When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by 
the supplier. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/194/001, EU/1/01/194/002 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 01/08/2001 
Date of last renewal: 01/06/2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu. 
 
 



14 

1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 800 ppm mol/mol medicinal gas, compressed 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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 at 
15oC. 
 
For a full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Medicinal gas, compressed. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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 failure 

associated with clinical or echocardiographic evidence of pulmonary hypertension, in order to 
improve oxygenation and to reduce the need for extracorporeal membrane oxygenation. 

 
 as part of the treatment of peri- and post-operative 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. 

 
4.2 Posology and method of administration 
 
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. INOmax should only be delivered according to a neonatologist’s 
prescription. 
 
INOmax should be used in ventilated newborn infants expected to require support >24 hours. INOmax 
should be used only after respiratory support has been optimised. This includes optimising tidal 
volume/pressures and lung recruitment (surfactant, high frequency ventilation, and positive end 
expiratory pressure). 
 
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. INOmax should only be 
delivered according to an anaesthetist’s or intensive care physician’s prescription. 
 
 
Posology 
Persistent Pulmonary Hypertension in the Newborn (PPHN) 



15 

The maximum recommended dose of INOmax is 20 ppm and this dose should not be exceeded. In the 
pivotal clinical trials, the starting dose was 20 ppm. Starting as soon as possible and within 4-24 hours 
of therapy, the dose should be weaned to 5 ppm provided that arterial oxygenation is adequate at this 
lower dose. Inhaled nitric oxide therapy should be maintained at 5 ppm until there is improvement in 
the neonate’s oxygenation such that the FiO2 (fraction of inspired oxygen) < 0.60.   
 
Treatment can be maintained up to 96 hours or until the underlying oxygen desaturation has resolved 
and the neonate is ready to be weaned from INOmax therapy. The duration of therapy is variable, but 
typically less than four days. In cases of failure to respond to inhaled nitric oxide, see section 4.4.  
 
Weaning 
Attempts to wean INOmax should be made after the ventilator support is substantially decreased  
or after 96 hours of therapy. When the decision is made to discontinue inhaled nitric oxide therapy, the 
dose should be reduced to 1 ppm for 30 minutes to one hour. If there is no change in oxygenation 
during administration of INOmax at 1 ppm, the FiO2 should be increased by 10 %, the INOmax is 
discontinued, and the neonates monitored closely for signs of hypoxaemia. If oxygenation falls >20 %, 
INOmax therapy should be resumed at 5 ppm and discontinuation of INOmax therapy should be 
reconsidered after 12 to 24 hours. Infants who cannot be weaned off INOmax by 4 days should 
undergo careful diagnostic work-up for other diseases. 
 
Pulmonary hypertension associated with heart surgery 
INOmax should be used only after conservative support has been optimised. In clinical trials INOmax 
has been given in addition to other standard treatment regimes in the peri-operative setting, including 
inotropic and vasoactive medicinal products. INOmax should be administered under close monitoring 
of haemodynamics and oxygenation. 
 
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 be 
increased up to 20 ppm if the lower dose has not provided sufficient clinical effects. The lowest 
effective dose should be administered and the dose should be weaned down to 5 ppm provided that the 
pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.  
 
Clinical data supporting the suggested dose in the age range 12-17 years is limited. 
 
Adults 
The starting dose of inhaled nitric oxide is 20 ppm (part per million) of inhaled gas. The dose may be 
increased up to 40 ppm if the lower dose has not provided sufficient clinical effects. The lowest 
effective dose should be administered and the dose should be weaned down to 5 ppm provided that the 
pulmonary artery pressure and systemic arterial oxygenation remain adequate at this lower dose.  
 
The effects of inhaled nitric oxide are rapid, decrease in pulmonary artery pressure and improved 
oxygenation is seen within 5-20 minutes. In case of insufficient response the dose may be titrated after 
a minimum of 10 minutes. 
 
Consideration should be given to discontinuation of treatment if no beneficial physiological effects are 
apparent after a 30-minute trial of therapy. 
 
Treatment may be initiated at any time point in the peri-operative course to lower pulmonary pressure. 
In clinical studies treatment was often initiated before separation from Cardio Pulmonary Bypass. 
Inhaled NO has been given for time periods up to 7 days in the peri-operative setting, but common 
treatment times are 24 -48 hours.  
 
 
 
Weaning 
Attempts to wean INOmax should be commenced as soon as the haemodynamics have stabilised in 
conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide 



16 

therapy should be performed in a stepwise manner. The dose should be incrementally reduced to 1 
ppm for 30 minutes with close observation of systemic and central pressure, and then turned off.  
Weaning should be attempted at least every 12 hours when the patient is stable on a low dose of 
INOmax. 
 
Too rapid weaning from inhaled nitric oxide therapy carries the risk of a re-bound increase in 
pulmonary artery pressure with subsequent circulatory instability. 
 
Paediatric population 
The safety and efficacy of INOmax in premature infants less than 34 weeks of gestation has not yet 
been established. Currently available data are described in section 5.1 but no recommendation or 
posology can be made. 
 
Method of administration 
For endotracheopulmonary use. 
 
Nitric oxide is delivered to the patient via mechanical ventilation after dilution with an oxygen/air 
mixture using an approved (CE-marked) nitric oxide delivery system. Before initiation of therapy, 
during set-up, secure that the device setting is in agreement with the cylinder gas concentration. 
 
The delivery system must provide a constant inhaled INOmax concentration irrespective of the 
ventilator. With a continuous flow neonatal ventilator, this may be achieved by infusing a low flow of 
INOmax into the inspiratory limb of the ventilator circuit. Intermittent flow neonatal ventilation may 
be associated with spikes in nitric oxide concentration. The nitric oxide delivery system for 
intermittent flow ventilation should be adequate to avoid spikes in nitric oxide concentration.   
 
The inspired INOmax concentration must be measured continuously in the inspiratory limb of the 
circuit near the patient. The nitrogen dioxide (NO2) concentration and FiO2 must also be measured at 
the same site using calibrated and approved (CE-marked) monitoring equipment. For patient safety, 
appropriate alarms must be set for INOmax (± 2 ppm of the prescribed dose), NO2 (1 ppm), and FiO2 
(± 0.05). The INOmax gas cylinder pressure must be displayed to allow timely gas cylinder 
replacement without inadvertent loss of therapy and backup gas cylinders must be available to provide 
timely replacement. INOmax therapy must be available for manual ventilation such as suctioning, 
patient transport, and resuscitation. 
  
In the event of a system failure or a wall-outlet power failure, a backup battery power supply and 
reserve nitric oxide delivery system should be available. The power supply for the monitoring 
equipment should be independent of the delivery device function.  
 
The upper limit of exposure (mean exposure) to nitric oxide for personnel defined by worker's 
legislation is 25 ppm for 8 hours (30 mg/m3) in most countries and the corresponding limit for NO2 is 
2-3 ppm (4-6 mg/m3). 
 
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 patient 

initiation 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 



17 

- 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, using 
an analyser which can reliably distinguish between foetal haemoglobin and methaemoglobin. If it is > 
2.5 %, the INOmax dose should be decreased and the administration of reducing medicinal products 
such as methylene blue may be considered. Although it is unusual for the methaemoglobin level to 
increase significantly if the first level is low, it is prudent to repeat methaemoglobin measurements 
every one to two days.   
 
In adults undergoing heart surgery, methaemoglobin level should be measured within one hour of the 
initiation of INOmax therapy. If the fraction of methaemoglobin rises to a level that potentially 
compromises adequate oxygen delivery, the INOmax dose should be decreased and the administration 
of reducing medicinal products such as methylene blue may be considered. 
 
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 INOmax and/or FiO2 should be reduced if possible. If there is an unexpected 
change in INOmax concentration, the delivery system should be assessed for malfunction and the 
analyser should be recalibrated. 
 
4.3 Contraindications 
 
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.  
 
4.4 Special warnings and precautions for use 
 
Inadequate response 
If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the following 
should be considered.  
For patients who are to be referred to another hospital, to prevent worsening of their condition on 
acute discontinuation of INOmax, the availability of nitric oxide during transport should be assured. 
Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should be 
considered based on continued deterioration or failure to improve, defined by criteria based on local 
circumstances.  
 
Special patient populations 
In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with 
congenital 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 giving 
raise 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. 
 



18 

Inhaled nitric oxide should also be used with caution in patients with compromised left ventricular 
function and elevated baseline pulmonary capillary pressure (PCWP) as they may be at an increased 
risk 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 pulmonary 
artery pressure (PAP) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation 
and elevation in PAP may also occur in neonates with no apparent response to INOmax. Weaning 
from inhaled nitric oxide should be performed with caution. For patients transported to other facilities 
for additional treatment, who need to continue with inhaled nitric oxide, arrangements should be made 
to ensure the continuous supply of inhaled nitric oxide during transportation. The physician should 
have 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 of 
nitric oxide that enter the systemic circulation are predominantly methaemoglobin and nitrate. The 
concentrations 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 way 
cause airway inflammation and damage. The dose of nitric oxide should be reduced if the 
concentration of nitrogen dioxide exceeds 0.5 ppm. 
 
Effects on platelets 
Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increased 
bleeding time. Data in adult humans are conflicting, and there has been no increase in bleeding 
complications in randomised controlled trials in term and near-term neonates with hypoxic respiratory 
failure.  
 
Regular monitoring of haemostasis and measurement of bleeding time is recommended during the 
administration of INOmax for more than 24 hours to patients with functional or quantitative platelet 
anomalies, a low coagulation factor or receiving anticoagulation treatment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed.  
A clinically significant interaction with other medicinal products used in the treatment of hypoxic 
respiratory failure cannot be excluded based on the available data. There may be an additive effect 
with INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances, 
including sodium nitroprusside and nitroglycerin. INOmax has been safely administered with 
tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation. 
 
The combined used with other vasodilators (e.g. sildenafil) is not extensively studied. Available data 
suggest additive effects on central circulation, pulmonary artery pressure and right ventricular 
performance. Inhaled nitric oxide combination with other vasodilators acting by the cGMP or cAMP 
systems should be done with caution. 
 
There is an increased risk of methaemoglobin formation if substances with a known tendency to 
increase methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkyl 
nitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thus 
be used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as 
oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when 
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 the 
bronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO2) is the main substance 
formed, and may cause airway inflammation and damage. There are also animal data suggesting an 



19 

increased susceptibility to airway infections upon exposure to low levels of NO2. During treatment 
with 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 be 
reduced. See section 4.2 for information on monitoring for NO2. 
 
4.6 Fertility, pregnancy and lactation 
 
There are no adequate data from the use of nitric oxide in pregnant women. The potential risk for 
humans 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. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
Summary of safety profile 
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 blood 
pressure. Rebound reaction is the most commonly adverse reaction in association with the clinical use 
of 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 and 
severity of intracranial haemorrhage, Grade IV haemorrhage, periventricular leukomalacia, cerebral 
infarction, seizures requiring anticonvulsant therapy, pulmonary haemorrhage, or gastrointestinal 
haemorrhage. 
 
Tabulated list of adverse reactions 
The table below presents adverse reactions (ADRs) that have been reported with the use of INOmax 
from either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months of 
age). 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). 



20 

 
System organ 
class 

Very 
common  
 

Common  
 

Uncommon Rare Very 
rare 

Not known  

Blood and 
lymphatic 
system 
disorders 

Thrombo-
cytopeniaa 

- Methaemoglobi
naemiaa 

- - -  

Cardiac 
disorders 

- - - - - Bradycardiab 
(following abrupt 
discontinuation of 
therapy) 
 

Vascular 
disorders 

- Hypotensiona,b,
d 

- - - - 

Respiratory, 
thoracic and 
mediastinal 
disorders 

-  Atelectasisa - - - Hypoxiab,d  
Dyspnoeac 
Chest Discomfortc 
Dry throatc 

Nervous 
system 
disorders 

- - - - - Headachec 
Dizzinessc 
 

 
a: Identified from the 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 national reporting system 
listed in Appendix V 
 
4.9 Overdose 
 
Overdose with INOmax will be manifest by elevations in methaemoglobin and NO2. Elevated NO2 
may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity 
of the circulation. In clinical studies, NO2 levels > 3 ppm or methaemoglobin levels > 7 % were 
treated by reducing the dose of, or discontinuing, INOmax. 
 
Methaemoglobinaemia that does not resolve after reduction or discontinuation of therapy can be 
treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the 
clinical situation. 
 
 
 
 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


21 

5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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 by 
binding to the haeme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and 
increasing intracellular levels of cyclic guanosine 3’,5’-monophosphate, which then leads to 
vasodilation. When inhaled, nitric oxide produces selective pulmonary vasodilation.  
INOmax appears to increase the partial pressure of arterial oxygen (PaO2) by dilating pulmonary 
vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung 
regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios. 
 
Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect 
or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), 
pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and 
pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in 
hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and 
foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant 
increases in PaO2). 
 
The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic 
respiratory 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 with 
weaning as possible to lower doses with a median duration of exposure of 40 hours. The objective of 
this double-blind, randomised, placebo controlled trial was to determine whether inhaled nitric oxide 
would 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 ppm 
nitric oxide or control gas. The combined incidence of death and/or initiation of ECMO (the 
prospectively defined primary endpoint) showed a significant advantage for the nitric oxide treated 
group (46 % vs. 64 %, p=0.006). Data further suggested a lack of additional benefit for the higher dose 
of 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 without 
lung 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 of 
44 hours. The prospectively defined primary endpoint was the receipt of ECMO. Significantly fewer 
neonates 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, and 
alveolar-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 of 
adverse 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 pulmonary 
vascular resistance and reduce the increased pulmonary artery pressure. This may increase the right 
ventricular ejection fraction. These effects in turn lead to improved blood circulation and oxygenation 
in the pulmonary circulation. 
 
In the INOT27 trial, 795 preterm infants (GA<29 weeks) with hypoxic respiratory failure were 
randomised 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 



22 

outcome, of the combined efficacy endpoints of death or BPD at 36 weeks GA, was not significantly 
different between groups, even with adjustment for gestational age as a covariate (p = 0.40), or with 
birth weight as a covariate (p = 0.41). The overall occurrence of intraventricular haemorrhage was 114 
(28.9 %) among the iNO treated as compared to 91 (22.9 %) among the control neonates. The overall 
number of death at week 36 was slightly higher in the iNO group; 53/395 (13.4 %) as compared to 
control 42/397 (10.6 %). The INOT25 trial, studying the effects of iNO in hypoxic preterm neonates, 
did not show improvement in alive without BPD. No difference in the incidence of IVH or death was 
however observed in this study. The BALLR1 study, also evaluating the effects of iNO in preterm 
neonates, but initiating iNO at 7 days and in a dose of 20 ppm, found a significant increase in neonates 
alive without BPD at gestational week 36, 121 (45 % vs. 95 (35.4 %) p<0.028. No signs of any 
increase adverse effects were noted in this study.  
 
Nitric oxide chemically reacts with oxygen to form nitrogen dioxide. 
 
Nitric oxide has an unpaired electron, which makes the molecule reactive. In biological tissue, nitric 
oxide may form peroxynitrite with superoxide (O2-), an unstable compound which may cause tissue 
damage through further redox reactions. In addition, nitric oxide has affinity to metalloproteins and 
may also react with SH-groups in protein forming nitrosyl compounds. The clinical significance of the 
chemical reactivity of nitric oxide in tissue is unknown. Studies show that nitric oxide exhibits 
pulmonary 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 other 
pulmonary heart disease. See section 4.2 for information on paediatric use. 
 
5.2 Pharmacokinetic properties 
 
The pharmacokinetics of nitric oxide has been studied in adults. Nitric oxide is absorbed systemically 
after inhalation. Most of it traverses the pulmonary capillary bed where it combines with haemoglobin 
that is 60 % to 100 % oxygen-saturated. At this level of oxygen saturation, nitric oxide combines 
predominantly with oxyhaemoglobin to produce methaemoglobin and nitrate. At low oxygen 
saturation, nitric oxide can combine with deoxyhaemoglobin to transiently form nitrosylhaemoglobin, 
which is converted to nitrogen oxides and methaemoglobin upon exposure to oxygen. Within the 
pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and 
nitrite, respectively, which interact with oxyhaemoglobin to produce methaemoglobin and nitrate. 
Thus, the end products of nitric oxide that enter the systemic circulation are predominantly 
methaemoglobin and nitrate. 
 
Methaemoglobin disposition has been investigated as a function of time and nitric oxide exposure 
concentration in neonates with respiratory failure. Methaemoglobin concentrations increase during the 
first 8 hours of nitric oxide exposure. The mean methaemoglobin levels remained below 1 % in the 
placebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5 % in the 
80 ppm INOmax group. Methaemoglobin levels > 7 % were attained only in patients receiving 
80 ppm, where they comprised 35 % of the group. The average time to reach peak methaemoglobin 
was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients; but one patient did not exceed 7 % until 
40 hours. 
 
Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting 
for > 70 % of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates 
approaching the rate of glomerular filtration. 
 
5.3 Preclinical safety data 
 
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. 
 
Acute toxicity is related to anoxia resulting from elevated methaemoglobin levels. 



23 

 
Nitric oxide is genotoxic in some test systems.. No evidence of a carcinogenic effect was apparent, at 
inhalation 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. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Nitrogen 
 
6.2 Incompatibilities 
 
In the presence of oxygen NO rapidly forms NO2, see section 4.5. 
 
6.3 Shelf life 
 
3 years 
 
6.4 Special precautions for storage 
 
All regulations concerning handling of pressure vessels must be followed.  
 
Store gas cylinders indoors in well-ventilated rooms or outdoors in ventilated sheds where they are 
protected from rain and direct sunlight. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition.  
 
Storage in the pharmacy department 
The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas 
only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas 
cylinders. 
 
Storage in the medical department 
The gas cylinder should be put in an equipped site with appropriate material in order to hold the gas 
cylinder vertically.   
 
Transport of gas cylinders 
The gas cylinders should be transported with appropriate material in order to protect them from risks 
of shocks and falls. 
During inter- or within-hospital transfers of patients treated with INOmax, the gas cylinders should be 
fixedly stowed away in order to hold the gas cylinders vertically and to avoid the risk of fall or 
untimely modifying output. A particular attention should be also turned to the fastening of the pressure 
regulator so as to avoid the risks of accidental failures.  
 
 
 
 
 
 
6.5 Nature and contents of container 
 
Pack sizes: 



24 

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

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

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

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled 
under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a 
specific outlet connection and a INOmeter device equipped valve hand-wheel. 
 
6.6 Special precautions for disposal and other handling 
 
Instructions for use/handling INOmax 
When connecting an INOmax cylinder to the delivery system, always secure that the cylinder 
concentration is of the same concentration for which the system is configured. 
 
In order to avoid all incidents, the following instructions should be absolutely respected. 
- 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 maximum 
operating pressure (155 bar) of the gas cylinder should be used 

- the pressure regulator should be purged by the nitrogen-nitric oxide mixture before each new 
use 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 be 
made of materials compatible with the gas. From a corrosion point of view the supply system can be 
divided into two zones: 1) From the gas cylinder valve to the humidifier (dry gas) and 2) From the 
humidifier to outlet (moist gas which may contain NO2). Tests show that dry nitric oxide mixtures can 
be used with most materials. However, the presence of nitrogen dioxide and moisture creates an 
aggressive atmosphere. Among metallic construction materials, only stainless steel can be 
recommended. Tested polymers which can be used in nitric oxide administration systems include 
polyethylene (PE) and polypropylene (PP). Butyl rubber, polyamide, and polyurethane should not be 
used. Polytrifluorochloroethylene, hexafluoropropene-vinyliden copolymer and polytetraflourethylene 
have been used extensively with pure nitric oxide and other corrosive gases. They were considered so 
inert that testing was not required. 
 
The installation of a nitric oxide pipeline system with supply station of gas cylinders, fixed network 
and terminal units is forbidden.   

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

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



25 

 
Instruction for disposal of gas cylinder 
When the gas cylinder is empty, it should not be discarded. Empty gas cylinders will be collected by 
the supplier. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/01/194/003, EU/1/01/194/004 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 01/08/2001 
Date of last renewal: 01/06/2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
MM/YYYY 
 
Detailed information on this product is available on the website of the European Medicines Agency 
http://www.ema.europa.eu. 



26 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

ANNEX II 

 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
 



27 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Linde France 
Zone Industrielle de Limay Porcheville 
3 avenue Ozanne 
78440 Porcheville 
France  
 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 
  
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 

C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 Periodic Safety Update Reports  
The marketing authorisation holder shall submit periodic safety update reports for this product 
in accordance with the requirements set out in the list of Union reference dates (EURD list) ) 
provided for under Article 107c(7) of Directive 2001/83/EC and published on the European 
medicines web-portal. 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 
• Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in 
the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 
subsequent updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same 
time 
 
• Additional risk minimisation measures  
Prior to launch of the new indication of the product in each Member State, the Marketing 
Authorisation Holder shall agree the content and format of the educational material with the national 
competent authority. 
 
The Marketing Authorisation Holder (MAH) should ensure that, at launch of the new indication, all 
Healthcare Professionals who are expected to use and/or prescribe INOmax as part of the treatment of 
peri- or post- operative pulmonary hypertension in adults and children in conjunction to heart surgery 
are provided with an Educational pack.  
 



28 

The educational pack should contain the following: 
 Summary of Product Characteristics and Patient Information Leaflet for INOmax 
 
 Educational material for Healthcare Professionals 
 
The educational material should include information on the following key elements: 
 The risk of rebound effect and the precautions to take when discontinuing the treatment 
 The risk of abrupt discontinuation of INOmax therapy in the event of critical failure of the 

delivery system and how to prevent it  
 The monitoring of Methaemoglobin level  
 The monitoring of NO2 formation  
 The potential risk of bleeding and haemostasis disorders 
 The potential risks if used in combination with other vasodilators which act on cGMP or cAMP  
 
 
 



29 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 

ANNEX III 

 
LABELLING AND PACKAGE LEAFLET 

 



30 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING  



31 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
2 litres gas cylinder 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 400 ppm mol/mol medicinal gas, compressed 
Nitric oxide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Nitric oxide (NO) 400 ppm mol/mol. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains nitrogen. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Medicinal gas, compressed 
A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Endotracheopulmonary use.   
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Ensure that the parent or guardian has read and is aware of the indications and cautions presented in 
the package leaflet prior to administration to their baby.   
 
 
8. EXPIRY DATE 
 
EXP 
 
 



32 

 
9. SPECIAL STORAGE CONDITIONS 
 
All regulations concerning handling of pressure vessels must be followed. 
 
Store gas cylinders vertically in well-ventilated rooms. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 
 
EU/1/01/194/002 
 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
 
16. BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable.  
 



33 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 



34 

 
 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
10 litres gas cylinder 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 400 ppm mol/mol medicinal gas, compressed 
Nitric oxide. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Nitric oxide (NO) 400 ppm mol/mol. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains nitrogen. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Medicinal gas, compressed 
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 
15oC. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Endotracheopulmonary use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Ensure that the parent or guardian has read and is aware of the indications and cautions presented in 
the package leaflet prior to administration to their baby. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



35 

 
9. SPECIAL STORAGE CONDITIONS 
 
All regulations concerning handling of pressure vessels must be followed. 
 
Store gas cylinders vertically in well-ventilated rooms. 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/194/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
 
16. BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable. 
 
 
 



36 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 



37 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
2 litres gas cylinder 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 800 ppm mol/mol medicinal gas, compressed 
Nitric oxide 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Nitric oxide (NO) 800 ppm mol/mol. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains nitrogen. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Medicinal gas, compressed 
A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15oC. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Endotracheopulmonary use.   
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Ensure that the parent or guardian has read and is aware of the indications and cautions presented in 
the package leaflet prior to administration to their baby.   
 
 
8. EXPIRY DATE 
 
EXP 
 
 



38 

 
9. SPECIAL STORAGE CONDITIONS 
 
All regulations concerning handling of pressure vessels must be followed. 
 
Store gas cylinders vertically in well-ventilated rooms. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS 
 
EU/1/01/194/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
 
16. BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable.  
 
 



39 

 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 



40 

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
10 litres gas cylinder 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
INOmax 800 ppm mol/mol medicinal gas, compressed 
Nitric oxide. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Nitric oxide (NO) 800 ppm mol/mol. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains nitrogen. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Medicinal gas, compressed 
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 
15oC. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Endotracheopulmonary use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Ensure that the parent or guardian has read and is aware of the indications and cautions presented in 
the package leaflet prior to administration to their baby. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



41 

 
9. SPECIAL STORAGE CONDITIONS 
 
All regulations concerning handling of pressure vessels must be followed. 
 
Store gas cylinders vertically in well-ventilated rooms. 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, sources of 
heat or ignition. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Do not discard used gas cylinders. All gas cylinders should be returned to the supplier for disposal. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/194/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
 
16. BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable.  
 
 
 



42 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
Not applicable. 



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



44 

Package leaflet: Information for the user 
 

INOmax 400 ppm mol/mol medicinal gas, compressed 
Nitric oxide 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.  
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor 
- If you get any side effects, talk to your doctor. This includes any possible side effects not listed 

in this leaflet. See section 4 
 
What is in this leaflet:  
 
1. What INOmax is and what it is used for 
2. What you need to know before you begin a treatment with INOmax  
3. How INOmax is given 
4. Possible side effects 
5. How to store INOmax  
6. Contents of the pack and other information 
 
 
1. What INOmax is and what it is used for 
 
INOmax contains nitric oxide, a gas used for the treatment of 
 newborn babies with lung failure associated with high blood pressure in the lungs, a condition 

known as hypoxic respiratory failure. When inhaled, this gas mixture can improve the flow of 
blood through the lungs, which may help to increase the amount of oxygen that reaches your 
baby’s blood. 

 
 newborn babies, babies, children, teenagers 0-17 years and adults with high blood pressure in 

the lungs, connected with heart surgery. This gas mixture can improve heart function and 
increase the flow of blood through the lungs, which may help to increase the amount of oxygen 
that reaches the blood. 

 
 
2. What you need to know before you begin a treatment with INOmax  
 
Do not use INOmax 
 
- If you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or 

any other ingredients of INOmax. (see section 6 ‘further information’ where the full list of 
ingredients is provided). 

 
- If you have been told that you (as the patient) or your child (as the patient) have an abnormal 

circulation within the heart.  
 
Warnings and precautions 
 
Inhaled nitric oxide may not always be effective and thus other therapies may be considered necessary 
for you or your child. 
 
Inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored 
by blood samples and if required the dose of inhaled nitric oxide must be reduced. 
 



45 

Nitric oxide may react with oxygen forming nitrogen dioxide that may cause airway irritation. Your or 
your child’s doctor will undertake monitoring of nitrogen dioxide and in case of elevated values the 
INOmax therapy will be adjusted, decreased accordingly. 
 
Inhaled nitric oxide may have a mild but influence on the platelets (components that help the blood to 
clot) of you or your child and any signs of bleeding and or haematoma should be observed. If you see 
any signs or symptoms that may be associated to bleeding you should directly inform the doctor. 
 
No effect of inhaled nitric oxide has been documented in newborn babies with a malformation where 
the diaphragm is not fully complete, so called ‘congenital diaphragmatic hernia’. 
 
In newborn babies with special malformations of the heart, ‘what doctors calls congenital heart 
defects’ inhaled nitric oxide may cause a worsening of the circulation.  
 
Children 
 
INOmax should not be used in preterm baby < 34 weeks of gestational age. 
 
Other medicines and INOmax 
 
The doctor will decide when to treat you or your child with INOmax and with other medicines, and 
will carefully supervise the treatment. 
 
Please tell your doctor if you (as the patient) or your child (as the patient) are taking or have recently 
taken or used any other medicines, including medicines obtained without a prescription. 
 
Some medicines can affect the ability of blood to carry oxygen. These include prilocaine (a local 
anaesthetic used for pain relief in association to minor painful procedures e.g. suturing, and minor 
surgical or diagnostic procedures) or glyceryl trinitrate (used to treat chest pain). Your doctor will take 
care to check that the blood can carry enough oxygen when you are taking these medicines. 
 
Pregnancy and breastfeeding 
 
INOmax is not recommended for use during pregnancy and breastfeeding. 
Tell your doctor before treatment with INOmax if you are pregnant, think you could be pregnant or are 
breastfeeding 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Not relevant. 
 
INOmax contains Nitrogen 
 
3. How to use INOmax  
 
Your doctor will decide the correct dose of INOmax and will administer INOmax to you or your 
child’s lungs through a system designed for delivering this gas. This delivery system will ensure that 
the correct amount of nitric oxide is delivered by diluting INOmax with an oxygen/air mixture 
immediately before giving it to you.  
 
For you or your child’s safety, the delivery systems intended for administration of INOmax are fitted 
with devices that constantly measure the amount of nitric oxide, oxygen and nitrogen dioxide (a 
chemical formed when nitric oxide and oxygen are mixed) being delivered to the lungs.   
 
Your doctor will decide how long you or your child should be treated with INOmax. 
 



46 

INOmax is given in dose of 10 to 20 ppm, (maximal dose 20 ppm in children and 40 ppm in adults) 
part per million of the gas that you or your child inhale. The lowest effective dose will be sought. 
Therapy is usually required for about 4 days in newborn infants with lung failure associated with high 
blood pressure in the lungs. In children and adults with high blood pressure in the lungs, connected 
with heart surgery, INOmax is usually given for 24-48 hours. However, therapy with INOmax may 
last longer. 
 
If you or your child receive more INOmax than you should 
 
Too much of inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will 
be monitored by blood samples and if required the INOmax dose will be decreased and the 
administration of medicines such as vitamin C, methylene blue, or eventually blood transfusion, in 
order to improve the oxygen carrying capacity, may be considered. 
 
If you stop using INOmax 
 
Treatment with INOmax should not be stopped suddenly. Low blood pressure or a rebound increase in 
pressure in the lungs has been known to occur if treatment with INOmax is stopped suddenly without 
first lowering the dose. 
 
At the end of treatment, the doctor will slowly lower the amount of INOmax being given to you or 
your child, so that the circulation in the lungs is able to adjust to oxygen/air without INOmax. Thus it 
may take a day or two before you or your child is off INOmax therapy. 
 
If you have any other questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
The doctor will examine you or your child closely for all side effects.   
 
Side effects that are very commonly seen (affects more than 1 user in 10) in association with INOmax 
therapy include: 
 Low platelet count.  
 
Side effects that are commonly seen (affects more than 1 user in 100) in association with INOmax 
therapy include: 
 low blood pressure, airless or collapsed lung. 
 
Side effects that may be seen, but uncommonly (affects between 1 user in 100 and 1 user in 1000) are: 
 increase in methaemoglobin, thus reduced oxygen carrying capacity.  

 
Side effects that may be seen but the frequency is not known (frequency cannot be estimated from the 
available data) are:  
 Bradycardia (low cardiac frequency) or too low amount of oxygen in the blood (oxygen 

desaturation/hypoxemia) due to sudden withdrawal of the treatment,  
 Headache, dizziness, dry throat or shortness of breath following accidental ambient air exposure 

to nitric oxide (e.g. leakage from equipment or cylinder).  
 
You should directly inform the personnel if you experience headache while being in close proximity to 
your child receiving INOmax.  
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, even 
after you or your child leave the hospital, please tell your doctor. 
 
Reporting of side effects 



47 

If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store INOmax 
 
Keep this medicine out of the sight and reach of children 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
INOmax therapy should only be used and handled by hospital personnel.  
 INOmax cylinders should be stored secured in order to avoid falling and thus potentially 

causing harm. 
 

 INOmax should be used and administered only by personnel specially trained in the use and 
handling of INOmax. 

 
 
All regulations concerning handling of pressurised gas cylinders must be followed.  
Storage is supervised by the specialists at the hospital. Gas cylinders are to be stored in well-ventilated 
rooms or in ventilated sheds where they are protected from rain and direct sunlight. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, 
sources of heat or ignition.  
 
Storage in the pharmacy department 
The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas 
only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas 
cylinders. 
 
Storage in the medical department 
The gas cylinder should be put in an equipped site with appropriate material in order to hold the 
cylinder vertically.   
 
When the gas cylinder is empty, do not discard. Empty gas cylinders will be collected by the supplier. 
 
 
6. Contents of the pack and other information 
 
What INOmax contains 
 
The active substance in INOmax is nitric oxide 400 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 at 15oC. 
 
The other ingredient is nitrogen. 
 
What INOmax looks like and contents of the pack 
 
Medicinal gas, compressed 
 

A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under 
a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


48 

outlet connection and a standard valve hand-wheel. 

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

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

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled 
under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a 
specific outlet connection and a INOmeter device equipped valve hand-wheel. 
 
INOmax is available in 2 litre and 10 litre aluminium gas cylinder. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder  
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
Manufacturer 
Linde France 
Z.I. Limay Porcheville 
3 avenue Ozanne 
78440 Porcheville 
France  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Linde Gas Belgium N.V. 
Westvaartdijk 85 
B-1850 Grimbergen  
Tél/Tel.: +32 70 233 826 
info.healthcare.be@linde.com 
 

Lietuva 
UAB "AGA" 
Didlaukio g. 69 
LT-08300, Vilnius 
Tel.: +370 2787787  
administracija@lt.aga.com 
 

България 
Linde Healthcare AB 
SE-181 81 Lidingö 
Sweden 
Tel: +46 8 7311000 
 

Luxembourg/Luxemburg 
Linde Gas Belgium N.V. 
Westvaartdijk 85 
B-1850 Grimbergen  
Tél/Tel.: +32 70 233 826 
info.healthcare.be@linde.com 
 

Česká republika 
Linde Gas a.s. 
U Technoplynu 1324 
198 00 Praha 9 
Tel: +420 800 121 121 
info.cz@linde.com 
 

Magyarország 
Linde Gáz Magyarország Zrt. 
Illatos út 11/A. 
H-1097 Budapest 
Tel.: +361 347 4843 
healthcare@hu.linde-gas.com 
 

Danmark 
Linde Healthcare AGA A/S 

Malta 
Linde Healthcare AB 



49 

Vermlandsgade 55 
DK-2300 Copenhagen S 
Tlf: + 45 70 104 103 
Healthcare@dk.aga.com 
 

SE-181 81 Lidingö 
Sweden 
Tel: +46 8 7311000 
 

Deutschland 
Linde Gas Therapeutics GmbH 
Mittenheimer Straße 62 
85764 Oberschleißheim 
Tel: +49 89 37000-0 
medizinische.gase@de.linde-gas.com 
 
 

Nederland 
Linde Gas Therapeutics Benelux B.V. 
De Keten 7  
NL-5651 GJ Eindhoven 
Tel: +31 40 282 58 25 
info.healthcare.nl@linde.com 
 

Eesti 
AS Eesti AGA 
Pärnu mnt. 141 
EE - 11314 Tallinn 
Tel: +372 650 4500 
aga@aga.ee 
 
 

Norge 
AGA AS, Linde Healthcare 
Postboks 13 Nydalen 
N-0409 Oslo 
Tlf. +47 23177200 
healthcare@no.aga.com 
 

Ελλάδα 
ΛΙΝΤΕ ΕΛΛΑΣ ΜΟΝ ΕΠΕ 
Θέση Τρύπιο Λιθάρι  
GR-19600 Μάνδρα Αττικής  
Τηλ: 0030 211-1045500-510 
healthcare@gr.linde-gas.com 
 

Österreich 
Linde Healthcare 
Linde Gas GmbH 
Modecenterstr.17/ Objekt 1/3.OG 
A-1110 Wien 
Tel: +43(0)50.4273-2200 
Fax: +43(0)50.4273-2260 
healthcare@at.linde-gas.com 
 

España 
Abelló Linde, S.A. 
C/ Bailén 105  
E-08009 (Barcelona) 
Tel: +34 900 941 857 / +34 902 426 462 
hospitalcare@es.linde-gas.com 
 

Polska 
Linde Gaz Polska Sp. z o.o. 
ul. prof. Michała Życzkowskiego 17 
31-864 Krakow 
Tel.: 0 801 142 748 / +48 (12) 643 92 00 
healthcare@pl.linde-gas.com 
 

France 
Linde France - Activité médicale - Linde 
Healthcare 
3 avenue Ozanne 
Z.I. Limay-Porcheville 
78440 Porcheville  
Tél:+33 810 421 000 
infotherapies@linde.com 

Portugal 
Linde Portugal, Lda. 
Av. Infante D. Henrique Lotes 21-24 
P-1800-217 Lisboa 
Tel: + 351 218 310 420 
linde.portugal@pt.linde-gas.com 
 
 
 
 

Hrvatska 
Linde plin d.o.o. 
Kalinovac 2/a 
47000 Karlovac 
Croatia 
Tel. +385 47 609 200 
tg.info@hr.linde-gas.com 
 

România 
Linde Gaz România SRL 
str. Avram Imbroane nr. 9 
Timisoara 300136 - RO 
Tel: +40 256 300 700 
healthcare@ro.linde-gas.com 
 

Ireland 
INO Therapeutics UK 

Slovenija 
Linde plin d.o.o., Celje 



50 

301 Cornforth Drive, Sittingbourne Research 
Centre, Kent Science Park, 
Sittingbourne 
Kent ME9 8PX - UK.  
Tel: +44 1795 411552 
ukcsc@inotherapy.co.uk 
 

Bukovžlak 65/b 
SI-3000 CELJE 
Tel: + 386 (0)3 42 60 746 
prodaja@si.linde-gas.com 
 

Ísland 
Linde Healthcare  
Breiðhöfða 11 
IS-110 Reykjavik 
Sími: + 354 577 3030 
healthcare@is.aga.com 
 

Slovenská republika 
Linde Gas k.s. 
Tuhovská 3 
SK-831 06 Bratislava 
Tel: +421 2 49 10 25 16 
healthcare.sk@linde.com 

Italia 
LINDE MEDICALE S.r.L 
Via Guido Rossa 3 
I-20010 Arluno (MI) 
Tel : +39 02 903731/800 985 597 
 

Suomi/Finland 
Oy AGA Ab, Linde Healthcare 
Itsehallintokuja 6 
FIN-02600 Espoo 
Puh/Tel: + 358 10 2421 
hctilaus@fi.aga.com  
 

Κύπρος 
Linde Hadjikyriakos Gas Ltd 
Λεωφόρος Λεμεσού 260, 2029 Στρόβολος 
Λευκωσία, Κύπρος. 
Τηλ. 77772828 ή +357-22482330 
info@cy.linde-gas.com 
 

Sverige 
AGA Gas AB, Linde Healthcare 
SE-181 81 Lidingö 
Tel: + 46 8 7311800/020 790 151 
healthcare@se.aga.com 

Latvija 
AGA SIA,  
Katrïnas St 5 
Riga, LV-1045 
Tel: +371 80005005 
aga.ksc@lv.aga.com 

United Kingdom 
INO Therapeutics UK 
301 Cornforth Drive, Sittingbourne Research 
Centre, Kent Science Park, 
Sittingbourne 
Kent ME9 8PX - UK.  
Tel: +44 1795 411552 
ukcsc@inotherapy.co.uk 
 

 
This leaflet was last revised in MM/YYYY. 
 
Other sources of information  
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 



51 

PACKAGE LEAFLET: INFORMATION FOR THE USER 
 

INOmax 800 ppm mol/mol medicinal gas, compressed 
Nitric oxide 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.  
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor 
- If you get any of the side effects, talk to your doctor. This includes any possible side effects not 

listed in this leaflet. See section 4. 
 
What is in this leaflet:  
 
1. What INOmax is and what it is used for 
2. What you need to know before you begin a treatment with INOmax  
3. How INOmax is given 
4. Possible side effects 
5. How to store INOmax  
6. Contents of the pack and other information 
 
 
1. WHAT INOmax IS AND WHAT IT IS USED FOR 
 
INOmax contains nitric oxide, a gas used for the treatment of 
 newborn babies with lung failure associated with high blood pressure in the lungs, a condition 

known as hypoxic respiratory failure. When inhaled, this gas mixture can improve the flow of 
blood through the lungs, which may help to increase the amount of oxygen that reaches your 
baby’s blood. 

 
 newborn babies, babies, children, teenagers 0-17 years and adults with high blood pressure in 

the lungs, connected with heart surgery. This gas mixture can improve heart function and 
increase the flow of blood through the lungs, which may help to increase the amount of oxygen 
that reaches the blood. 

 
 
2. What you need to know before you begin a treatment with INOmax  
 
Do not use INOmax 
 
- If you (as the patient) or your child (as the patient) are allergic (hypersensitive) to nitric oxide or 

any other ingredients of INOmax. (see section 6 ‘further information’ where the full list of 
ingredients is provided). 
 

- If you have been told that you (as the patient) or your child (as the patient) have an abnormal 
circulation within the heart.  

 
Warnings and precautions 
 
Inhaled nitric oxide may not always be effective and thus other therapies may be considered necessary 
for you or your child. 
 
Inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will be monitored 
by blood samples and if required the dose of inhaled nitric oxide must be reduced. 
 



52 

Nitric oxide may react with oxygen forming nitrogen dioxide that may cause airway irritation. Your or 
your child’s doctor will undertake monitoring of nitrogen dioxide and in case of elevated values the 
INOmax therapy will be adjusted, decreased accordingly. 
 
Inhaled nitric oxide may have a mild but influence on the platelets (components that help the blood to 
clot) of you or your child and any signs of bleeding and or haematoma should be observed. If you see 
any signs or symptoms that may be associated to bleeding you should directly inform the doctor. 
 
No effect of inhaled nitric oxide has been documented in newborn babies with a malformation where 
the diaphragm is not fully complete, so called ‘congenital diaphragmatic hernia’. 
 
In newborn babies with special malformations of the heart, ‘what doctors calls congenital heart 
defects’ inhaled nitric oxide may cause a worsening of the circulation.  
 
Children 
 
INOmax should not be used in preterm baby < 34 weeks of gestational age. 
 
Other medicines and INOmax 
 
The doctor will decide when to treat you or your child with INOmax and with other medicines, and 
will carefully supervise the treatment. 
 
Please tell your doctor if you (as the patient) or your child (as the patient) are taking or have recently 
taken or used any other medicines, including medicines obtained without a prescription. 
 
Some medicines can affect the ability of blood to carry oxygen. These include prilocaine (a local 
anaesthetic used for pain relief in association to minor painful procedures e.g. suturing, and minor 
surgical or diagnostic procedures) or glyceryl trinitrate (used to treat chest pain). Your doctor will take 
care to check that the blood can carry enough oxygen when you are taking these medicines. 
 
Pregnancy and breastfeeding 
 
INOmax is not recommended for use during pregnancy and breastfeeding. Tell your doctor before 
treatment with INOmax if you are pregnant, think you could be pregnant or are breastfeeding 
 
Ask your doctor or pharmacist for advice before taking any medicine. 
 
Driving and using machines 
Not relevant. 
 
INOmax contains Nitrogen 
 
3. How to use INOmax  
 
Your doctor will decide the correct dose of INOmax and will administer INOmax to you or your 
child’s lungs through a system designed for delivering this gas. This delivery system will ensure that 
the correct amount of nitric oxide is delivered by diluting INOmax with an oxygen/air mixture 
immediately before giving it to you.  
 
For you or your child’s safety, the delivery systems intended for administration of INOmax are fitted 
with devices that constantly measure the amount of nitric oxide, oxygen and nitrogen dioxide (a 
chemical formed when nitric oxide and oxygen are mixed) being delivered to the lungs.   
 
Your doctor will decide how long you or your child should be treated with INOmax. 
 



53 

INOmax is given in dose of 10 to 20 ppm, (maximal dose 20 ppm in children and 40 ppm in adults) 
part per million of the gas that you or your child inhale. The lowest effective dose will be sought. 
Therapy is usually required for about 4 days in newborn infants with lung failure associated with high 
blood pressure in the lungs. In children and adults with high blood pressure in the lungs, connected 
with heart surgery, INOmax is usually given for 24-48 hours. However, therapy with INOmax may 
last longer. 
 
If you or your child receive more INOmax than you should 
 
Too much of inhaled nitric oxide may influence the oxygen carrying capacity of the blood. This will 
be monitored by blood samples and if required the INOmax dose will be decreased and the 
administration of medicines such as vitamin C, methylene blue, or eventually blood transfusion, in 
order to improve the oxygen carrying capacity, may be considered. 
 
If you stop using INOmax 
 
Treatment with INOmax should not be stopped suddenly. Low blood pressure or a rebound increase in 
pressure in the lungs has been known to occur if treatment with INOmax is stopped suddenly without 
first lowering the dose. 
 
At the end of treatment, the doctor will slowly lower the amount of INOmax being given to you or 
your child, so that the circulation in the lungs is able to adjust to oxygen/air without INOmax. Thus it 
may take a day or two before you or your child is off INOmax therapy. 
 
If you have any other questions on the use of this medicine, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. The doctor 
will examine you or your child closely for all side effects.   
 
Side effects that are very commonly seen (affects more than 1 user in 10) in association with INOmax 
therapy include: 
 Low platelet count. 
 
Side effects that are commonly seen (affects more than 1 user in 100) in association with INOmax 
therapy include: 
 low blood pressure, airless or collapsed lung. 
 
Side effects that may be seen, but uncommonly (affects between 1 user in 100 and 1 user in 1000) are: 
 increase in methaemoglobin, thus reduced oxygen carrying capacity. 
 
Side effects that may be seen but the frequency is not known (frequency cannot be estimated from the 
available data) are:  
 Bradycardia (low cardiac frequency) or too low amount of oxygen in the blood (oxygen 

desaturation/hypoxemia) due to sudden withdrawal of the treatment 
 

 Headache, dizziness, dry throat or shortness of breath following accidental ambient air exposure 
to nitric oxide (e.g. leakage from equipment or cylinder).  

 
You should directly inform the personnel if you experience headache while being in close proximity to 
your child receiving INOmax.  
 
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, even 
after you or your child leave the hospital, please tell your doctor. 
 



54 

Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store INOmax 
 
Keep this medicine out of the sight and reach of children 
 
Do not use this medicine after the expiry date which is stated on the label after EXP. The expiry date 
refers to the last day of that month. 
 
INOmax therapy should only be used and handled by hospital personnel.  
 INOmax cylinders should be stored secured in order to avoid falling and thus potentially 

causing harm. 
 

 INOmax should be used and administered only by personnel specially trained in the use and 
handling of INOmax. 

 
 
All regulations concerning handling of pressurised gas cylinders must be followed.  
Storage is supervised by the specialists at the hospital. Gas cylinders are to be stored in well-ventilated 
rooms or in ventilated sheds where they are protected from rain and direct sunlight. 
 
Protect the gas cylinders from shocks, falls, oxidising and flammable materials, moisture, 
sources of heat or ignition.  
 
Storage in the pharmacy department 
The gas cylinders should be stored in an airy, clean and locked place, for storage of medicinal gas 
only. Inside this place, a separate premise should be dedicated to the storage of nitric oxide gas 
cylinders. 
 
Storage in the medical department 
The gas cylinder should be put in an equipped site with appropriate material in order to hold the 
cylinder vertically.   
 
When the gas cylinder is empty, do not discard. Empty gas cylinders will be collected by the supplier. 
 
 
6. contents of the pack and other information 
 
What INOmax contains 
 
The active substance in INOmax is nitric oxide 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 at 15oC. 
 
The other ingredient is nitrogen. 
 
What INOmax looks like and contents of the pack 
 
Medicinal gas, compressed 
 

A 2 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled under 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


55 

a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a specific 
outlet connection and a standard valve hand-wheel. 

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

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

A 10 litre aluminium gas cylinder (identification with aquamarine shoulder and white body) filled 
under a pressure of 155 bar, equipped with a stainless steel positive pressure (residual) valve with a 
specific outlet connection and a INOmeter device equipped valve hand-wheel. 
 
INOmax is available in 2 litre and 10 litre aluminium gas cylinder. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder  
Linde Healthcare AB 
Rättarvägen 3 
169 68 Solna 
Sweden 
 
Manufacturer 
Linde France 
Z.I. Limay Porcheville 
3 avenue Ozanne 
78440 Porcheville 
France  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Linde Gas Belgium N.V. 
Westvaartdijk 85 
B-1850 Grimbergen  
Tél/Tel.: +32 70 233 826 
info.healthcare.be@linde.com 
 

Lietuva 
UAB "AGA" 
Didlaukio g. 69 
LT-08300, Vilnius 
Tel.: +370 2787787  
administracija@lt.aga.com 
 

България 
Linde Healthcare AB 
SE-181 81 Lidingö 
Sweden 
Tel: +46 8 7311000 
 

Luxembourg/Luxemburg 
Linde Gas Belgium N.V. 
Westvaartdijk 85 
B-1850 Grimbergen  
Tél/Tel.: +32 70 233 826 
info.healthcare.be@linde.com 
 

Česká republika 
Linde Gas a.s. 
U Technoplynu 1324 
198 00 Praha 9 
Tel: +420 800 121 121 
info.cz@linde.com 
 

Magyarország 
Linde Gáz Magyarország Zrt. 
Illatos út 11/A. 
H-1097 Budapest 
Tel.: +361 347 4843 
healthcare@hu.linde-gas.com 
 

Danmark Malta 



56 

Linde Healthcare AGA A/S 
Vermlandsgade 55 
DK-2300 Copenhagen S 
Tlf: + 45 70 104 103 
Healthcare@dk.aga.com 
 

Linde Healthcare AB 
SE-181 81 Lidingö 
Sweden 
Tel: +46 8 7311000 
 

Deutschland 
Linde Gas Therapeutics GmbH 
Mittenheimer Straße 62 
85764 Oberschleißheim 
Tel: +49 89 37000-0 
medizinische.gase@de.linde-gas.com 
 
 

Nederland 
Linde Gas Therapeutics Benelux B.V. 
De Keten 7  
NL-5651 GJ Eindhoven 
Tel: +31 40 282 58 25 
info.healthcare.nl@linde.com 
 

Eesti 
AS Eesti AGA 
Pärnu mnt. 141 
EE - 11314 Tallinn 
Tel: +372 650 4500 
aga@aga.ee 
 
 

Norge 
AGA AS, Linde Healthcare 
Postboks 13 Nydalen 
N-0409 Oslo 
Tlf. +47 23177200 
healthcare@no.aga.com 
 

Ελλάδα 
ΛΙΝΤΕ ΕΛΛΑΣ ΜΟΝ ΕΠΕ 
Θέση Τρύπιο Λιθάρι  
GR-19600 Μάνδρα Αττικής  
Τηλ: 0030 211-1045500-510 
healthcare@gr.linde-gas.com 
 

Österreich 
Linde Healthcare 
Linde Gas GmbH 
Modecenterstr.17/ Objekt 1/3.OG 
A-1110 Wien 
Tel: +43(0)50.4273-2200 
Fax: +43(0)50.4273-2260 
healthcare@at.linde-gas.com 
 

España 
Abelló Linde, S.A. 
C/ Bailén 105  
E-08009 (Barcelona) 
Tel: +34 900 941 857 / +34 902 426 462 
hospitalcare@es.linde-gas.com 
 

Polska 
Linde Gaz Polska Sp. z o.o. 
ul. prof. Michała Życzkowskiego 17 
31-864 Krakow 
Tel.: 0 801 142 748 / +48 (12) 643 92 00 
healthcare@pl.linde-gas.com 
 

France 
Linde France - Activité médicale - Linde 
Healthcare 
3 avenue Ozanne 
Z.I. Limay-Porcheville 
78440 Porcheville  
Tél: +33 810 421 000 
infotherapies@linde.com 

Portugal 
Linde Portugal, Lda. 
Av. Infante D. Henrique Lotes 21-24 
P-1800-217 Lisboa 
Tel: + 351 218 310 420 
linde.portugal@pt.linde-gas.com 

 
 
Hrvatska 
Linde plin d.o.o. 
Kalinovac 2/a 
47000 Karlovac 
Croatia 
Tel. +385 47 609 200 
tg.info@hr.linde-gas.com 
 

 
 
România 
Linde Gaz România SRL 
str. Avram Imbroane nr. 9 
Timisoara 300136 - RO 
Tel: +40 256 300 700 
healthcare@ro.linde-gas.com 
 

Ireland Slovenija 



57 

INO Therapeutics UK 
301 Cornforth Drive, Sittingbourne Research 
Centre, Kent Science Park, 
Sittingbourne 
Kent ME9 8PX - UK.  
Tel: +44 1795 411552 
ukcsc@inotherapy.co.uk 
 

Linde plin d.o.o., Celje 
Bukovžlak 65/b 
SI-3000 CELJE 
Tel: + 386 (0)3 42 60 746 
prodaja@si.linde-gas.com 
 

Ísland 
Linde Healthcare  
Breiðhöfða 11 
IS-110 Reykjavik 
Sími: + 354 577 3030 
healthcare@is.aga.com 
 

Slovenská republika 
Linde Gas k.s. 
Tuhovská 3 
SK-831 06 Bratislava 
Tel: +421 2 49 10 25 16 
healthcare.sk@linde.com 

Italia 
LINDE MEDICALE S.r.L 
Via Guido Rossa 3 
I-20010 Arluno (MI) 
Tel : +39 02 903731/800 985 597 
 

Suomi/Finland 
Oy AGA Ab, Linde Healthcare 
Itsehallintokuja 6 
FIN-02600 Espoo 
Puh/Tel: + 358 10 2421 
hctilaus@fi.aga.com  
 

Κύπρος 
Linde Hadjikyriakos Gas Ltd 
Λεωφόρος Λεμεσού 260, 2029 Στρόβολος 
Λευκωσία, Κύπρος. 
Τηλ. 77772828 ή +357-22482330 
info@cy.linde-gas.com 
 

Sverige 
AGA Gas AB, Linde Healthcare 
SE-181 81 Lidingö 
Tel: + 46 8 7311800/020 790 151 
healthcare@se.aga.com 

Latvija 
AGA SIA,  
Katrïnas St 5 
Riga, LV-1045 
Tel: +371 80005005 
aga.ksc@lv.aga.com 

United Kingdom 
INO Therapeutics UK 
301 Cornforth Drive, Sittingbourne Research 
Centre, Kent Science Park, 
Sittingbourne 
Kent ME9 8PX - UK.  
Tel: +44 1795 411552 
ukcsc@inotherapy.co.uk 
 

 
This leaflet was last revised in MM/YYYY. 
 
Other sources of information  
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET