ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
INOmax 400 ppm mol/mol inhalation gas
2.
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 15
o
C.
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at
15
o
C.
For a full list of excipients, see section 6.1.
3.
Inhalation gas.
4.
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.
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.
2
Posology
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 FiO
2
(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 FiO
2
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 hemodynamics 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 hemodynamics have stabilised in
conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide
3
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 (NO
2
) concentration and FiO
2
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), NO
2
(1 ppm), and FiO
2
( 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/m
3
) in most countries and the corresponding limit for NO
2
is
2-3 ppm (4-6 mg/m
3
).
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 NO
2
)
-
Setting the device for the correct concentration of nitric oxide to be administered
-
Setting the NO, NO
2
and O
2
monitors for high and low alarm limits
-
Using the manual backup delivery system
-
Procedures for correctly switching gas cylinders and purging system
-
Troubleshooting alarms
4
-
NO, NO
2
and O
2
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 (NO
2
)
Immediately prior to each patient initiation, proper procedure must be applied to purge the system of
NO
2
. The NO
2
concentration should be maintained as low as possible and always < 0.5 ppm. If the
NO
2
is > 0.5 ppm, the delivery system should be assessed for malfunction, the NO
2
analyser should be
recalibrated, and the INOmax and/or FiO
2
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.
Hypersensitivity to the active substance or any of the excipients.
Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood.
Inadequate response
If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the 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.
5
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 (PaO
2
). 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 NO
2
NO
2
rapidly forms in gas mixtures containing nitric oxide and O
2
, 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 hemostasis 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.
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 (NO
2
) is the main substance
formed, and may cause airway inflammation and damage. There are also animal data suggesting an
6
increased susceptibility to airway infections upon exposure to low levels of NO
2.
During treatment
with nitric oxide, the NO
2
concentration should be < 0.5 ppm in the nitric oxide dose range < 20 ppm.
If at any time the NO
2
concentration exceeds 1 ppm, the nitric oxide dose should immediately be
reduced. See section 4.2 for information on monitoring for NO
2
.
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.
Not relevant.
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 adverse reactions listed are derived from CINGRI study, review of public domain scientific
literature and post marketing safety surveillance (the table below shows adverse reactions that
occurred in at least 5 % of patients receiving INOmax in the CINRGI study). Adverse reactions are
listed according to MedDRA frequency convention: very common (1/10), common (1/100 to
<1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not
known (cannot be estimated from the available data).
System organ
class
Very
common
Common
Not known
Blood and
lymphatic
system
disorders
Thrombo-
cytopenia
-
-
Metabolism
and nutrition
disorders
Hypokalemia -
-
Nervous
system
disorders
-
Headache*
7
Vascular
diorders
Hypotension
-
Pulmonary
artery pressure
increased**
Hypotension**
Respiratory,
thoracic and
mediastinal
disorders
Atelectasis
-
-
Hepatobiliary
disorders
Hyper-
bilirubinemia
Investigations
Methaemo
globin
increased,
Hypoxemia**
* Post-Marketing Safety Surveillance (PMSS) data, symptom experienced by personnel associated to
accidental environmental exposure
**PMSS data, effects associated with acute withdrawal of the medicinal product, and dose errors
associated with the delivery system. Rapid rebound reactions such as intensified pulmonary
vasoconstriction 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.
may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity
of the circulation. In clinical studies, NO
2
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.
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 (PaO
2
) 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
8
foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant
increases in PaO
2
).
The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic
respiratory failure resulting from a variety of etiologies.
In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 %
O
2
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 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 PaO
2
, 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
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 BDP. 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 was 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 (O
2
-
), 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
9
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.
Nitric oxide is genotoxic in some test systems. A low incidence in uterine adenocarcinomas in rats
following daily exposure to the recommended human dose for two years was tentatively considered
treatment related.
No reproduction toxicity studies have been conducted.
6.
6.1 List of excipients
Nitrogen
6.2 Incompatibilities
In the presence of oxygen NO rapidly forms NO
2,
see section 4.5.
10
6.3 Shelf life
2 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
A 2 litre and 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.
Pack sizes:
2 litre aluminium gas cylinder
10 litre aluminium gas cylinder
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 not be violently opened
-
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
11
-
a gas cylinder whose valve is not protected by a cap or a shell should not be used
-
a defective valve should not be repaired
-
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 NO
2
). 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.
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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
8.
EU/1/01/194/001, EU/1/01/194/002
9.
Date of first authorisation: 01/08/2001
Date of last renewal: 01/06/2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
12
1.
INOmax 800 ppm mol/mol inhalation gas
2.
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 15
o
C.
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at
15
o
C.
For a full list of excipients, see section 6.1.
3.
Inhalation gas.
4.
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.
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.
13
Posology
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 FiO
2
(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 FiO
2
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 hemodynamics 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 hemodynamics have stabilised in
conjunction to weaning from ventilator and inotropic support. The withdrawal of inhaled nitric oxide
14
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 (NO
2
) concentration and FiO
2
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), NO
2
(1 ppm), and FiO
2
( 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/m
3
) in most countries and the corresponding limit for NO
2
is
2-3 ppm (4-6 mg/m
3
).
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 NO
2
)
-
Setting the device for the correct concentration of nitric oxide to be administered
-
Setting the NO, NO
2
and O
2
monitors for high and low alarm limits
-
Using the manual backup delivery system
-
Procedures for correctly switching gas cylinders and purging system
-
Troubleshooting alarms
15
-
NO, NO
2
and O
2
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 (NO
2
)
Immediately prior to each patient initiation, proper procedure must be applied to purge the system of
NO
2
. The NO
2
concentration should be maintained as low as possible and always < 0.5 ppm. If the
NO
2
is > 0.5 ppm, the delivery system should be assessed for malfunction, the NO
2
analyser should be
recalibrated, and the INOmax and/or FiO
2
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.
Hypersensitivity to the active substance or any of the excipients.
Neonates known to be dependent on right-to-left, or significant left-to-right, shunting of blood.
Inadequate response
If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the 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.
16
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 (PaO
2
). 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 NO
2
NO
2
rapidly forms in gas mixtures containing nitric oxide and O
2
, 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 hemostasis 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.
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 (NO
2
) is the main substance
formed, and may cause airway inflammation and damage. There are also animal data suggesting an
17
increased susceptibility to airway infections upon exposure to low levels of NO
2.
During treatment
with nitric oxide, the NO
2
concentration should be < 0.5 ppm in the nitric oxide dose range < 20 ppm.
If at any time the NO
2
concentration exceeds 1 ppm, the nitric oxide dose should immediately be
reduced. See section 4.2 for information on monitoring for NO
2
.
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.
Not relevant.
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 adverse reactions listed are derived from CINGRI study, review of public domain scientific
literature and post marketing safety surveillance (the table below shows adverse reactions that
occurred in at least 5 % of patients receiving INOmax in the CINRGI study). Adverse reactions are
listed according to MedDRA frequency convention: very common (1/10), common (1/100 to
<1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1,000), very rare (<1/10,000), not
known (cannot be estimated from the available data).
System organ
class
Very
common
Common
Not known
Blood and
lymphatic
system
disorders
Thrombo-
cytopenia
-
-
Metabolism
and nutrition
disorders
Hypokalemia -
-
Nervous
system
disorders
-
Headache*
18
Vascular
diorders
Hypotension
-
Pulmonary
artery pressure
increased**
Hypotension**
Respiratory,
thoracic and
mediastinal
disorders
Atelectasis
-
-
Hepatobiliary
disorders
Hyper-
bilirubinemia
Investigations
Methaemo
globin
increased,
Hypoxemia**
* Post-Marketing Safety Surveillance (PMSS) data, symptom experienced by personnel associated to
accidental environmental exposure
**PMSS data, effects associated with acute withdrawal of the medicinal product, and dose errors
associated with the delivery system. Rapid rebound reactions such as intensified pulmonary
vasoconstriction 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.
may cause acute lung injury. Elevations in methaemoglobinaemia reduce the oxygen delivery capacity
of the circulation. In clinical studies, NO
2
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.
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 (PaO
2
) 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
19
foramen ovale. In neonates with PPHN, INOmax can improve oxygenation (as indicated by significant
increases in PaO
2
).
The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic
respiratory failure resulting from a variety of etiologies.
In the NINOS trial, 235 neonates with hypoxic respiratory failure were randomised to receive 100 %
O
2
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 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 PaO
2
, 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
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 BDP. 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 was 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 (O
2
-
), 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
20
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.
Nitric oxide is genotoxic in some test systems. A low incidence in uterine adenocarcinomas in rats
following daily exposure to the recommended human dose for two years was tentatively considered
treatment related.
No reproduction toxicity studies have been conducted.
6.
6.1 List of excipients
Nitrogen
6.2 Incompatibilities
In the presence of oxygen NO rapidly forms NO
2,
see section 4.5.
21
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
A 2 litre and 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.
Pack sizes:
2 litre aluminium gas cylinder
10 litre aluminium gas cylinder
6.7
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 not be violently opened
-
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
22
-
a gas cylinder whose valve is not protected by a cap or a shell should not be used
-
a defective valve should not be repaired
-
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 NO
2
). 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.
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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
8.
9.
Date of first authorisation: 01/08/2001
Date of last renewal: 01/06/2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
23
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
24
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Linde France
Zone Industrielle de Limay Porcheville
2 rue Gustave Eiffel - 3 avenue Ozanne
78440 Gargenville
France
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product
Characteristics, section 4.2).
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
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.
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 be a pocket size guide that includes 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 NO
2
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
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, presented in Module 1.8.1. of the
Marketing Authorisation, is in place and functioning before and whilst the product is on the
market.
25
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 8 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
At the request of the European Medicines Agency
PSURs
The MAH will submit periodic safety update reports on a 6-monthly cycle, unless the CHMP decides
otherwise.
26
ANNEX III
LABELLING AND PACKAGE LEAFLET
27
A. LABELLING
28
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
2 litres gas cylinder
1.
INOmax 400 ppm mol/mol inhalation gas
Nitric oxide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Nitric oxide (NO) 400 ppm mol/mol.
3.
LIST OF EXCIPIENTS
Also contains nitrogen.
4.
Inhalation gas
A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15
o
C.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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
29
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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS
EU/1/01/194/002
13. MANUFACTURER’S 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
30
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
10 litres gas cylinder
1.
INOmax 400 ppm mol/mol inhalation gas
Nitric oxide.
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Nitric oxide (NO) 400 ppm mol/mol.
3.
LIST OF EXCIPIENTS
Also contains nitrogen.
Inhalation gas
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at
15
o
C.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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
31
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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
EU/1/01/194/001
13. MANUFACTURER’S 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
32
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
2 litres gas cylinder
1.
INOmax 800 ppm mol/mol inhalation gas
Nitric oxide
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Nitric oxide (NO) 800 ppm mol/mol.
3.
LIST OF EXCIPIENTS
Also contains nitrogen.
4.
Inhalation gas
A 2 litre gas cylinder filled at 155 bar absolute brings 307 litres of gas under pressure of 1 bar at 15
o
C.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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
33
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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
12. NUMBER(S) IN THE COMMUNITY REGISTER OF MEDICINAL PRODUCTS
13. MANUFACTURER’S 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
34
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
10 litres gas cylinder
1.
INOmax 800 ppm mol/mol inhalation gas
Nitric oxide.
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Nitric oxide (NO) 800 ppm mol/mol.
3.
LIST OF EXCIPIENTS
Also contains nitrogen.
Inhalation gas
A 10 litre gas cylinder filled at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at
15
o
C.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight 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.
INO Therapeutics AB
SE-181 81 Lidingö
Sweden
13. MANUFACTURER’S 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
36
B. PACKAGE LEAFLET
37
PACKAGE LEAFLET: INFORMATION FOR THE USER
INOmax 400
ppm mol/mol inhalation gas
Nitric oxide
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1. What INOmax is and what it is used for
2. Before beginning treatment with INOmax
3.
How INOmax is given
4.
Possible side effects
5.
How to store INOmax
6.
Further 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.
2.
BEFORE BEGINNING 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.
Take special care with INOmax
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.
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.
38
-
Keep this leaflet. You may need to read it again.
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 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.
Using other medicines
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.
3.
HOW INOmax IS GIVEN
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.
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.
39
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.
Stopping treatment with 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, INOmax 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, abnormally low potassium concentration in the blood (hypokalemia), low
blood pressure, airless or collapsed lung, abnormally high amounts of bile pigment (bilirubin) in
the blood.
Side effects that may be seen but the frequency is not known
(frequency cannot be estimated from the
available data)
are:
Rebound high blood pressure in the lungs (increase in pulmonary artery pressure), and too low
amount of oxygen in the blood (oxygen desaturation/hypoxemia) due to sudden withdrawal of
the treatment, increase in methemoglobin, thus reduced oxygen carrying capacity.
Accidental ambient air exposure to nitric oxide, e.g. leakage from equipment or cylinder may
cause headache.
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.
5.
HOW TO STORE INOmax
Keep out of the reach and sight of children
Do not use INOmax after the expiry date which is stated on the label after EXP. The expiry date refers
to the last day of that month.
40
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.
FURTHER 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 15
o
C. A 10 litre gas cylinder filled
at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15
o
C.
The other ingredient is nitrogen.
What INOmax looks like and contents of the pack
Inhalation gas
A 2 litre and 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.
INOmax is available in 2 litre and 10 litre aluminium gas cylinder.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
INO Therapeutics AB
SE-181 81 Lidingo
Sweden
41
Manufacturer
Linde France
Zone Industrielle de Limay Porcheville
2 rue Gustave Eiffel - 3 avenue Ozanne
78440 Gargenville
France
This leaflet was last approved in
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
42
PACKAGE LEAFLET: INFORMATION FOR THE USER
INOmax 800
ppm mol/mol inhalation gas
Nitric oxide
Read all of this leaflet carefully before you start using this medicine.
-
If you have any further questions, ask your doctor
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor.
In this leaflet:
1. What INOmax is and what it is used for
2. Before beginning treatment with INOmax
3.
How INOmax is given
4.
Possible side effects
5.
How to store INOmax
6.
Further 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.
2.
BEFORE BEGINNING 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.
Take special care with INOmax
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.
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.
43
-
Keep this leaflet. You may need to read it again.
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 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.
Using other medicines
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.
3.
HOW INOmax IS GIVEN
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.
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.
44
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.
Stopping treatment with 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, INOmax 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, abnormally low potassium concentration in the blood (hypokalemia), low
blood pressure, airless or collapsed lung, abnormally high amounts of bile pigment (bilirubin) in
the blood.
Side effects that may be seen but the frequency is not known
(frequency cannot be estimated from the
available data)
are:
Rebound high blood pressure in the lungs (increase in pulmonary artery pressure), and too low
amount of oxygen in the blood (oxygen desaturation/hypoxemia) due to sudden withdrawal of
the treatment, increase in methemoglobin, thus reduced oxygen carrying capacity.
Accidental ambient air exposure to nitric oxide, e.g. leakage from equipment or cylinder may
cause headache.
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.
5.
HOW TO STORE INOmax
Keep out of the reach and sight of children
Do not use INOmax after the expiry date which is stated on the label after EXP. The expiry date refers
to the last day of that month.
45
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.
FURTHER 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 15
o
C. A 10 litre gas cylinder filled
at 155 bar absolute brings 1535 litres of gas under pressure of 1 bar at 15
o
C.
The other ingredient is nitrogen.
What INOmax looks like and contents of the pack
Inhalation gas
A 2 litre and 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.
INOmax is available in 2 litre and 10 litre aluminium gas cylinder.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
INO Therapeutics AB
SE-181 81 Lidingo
Sweden
46
Manufacturer
Linde France
Zone Industrielle de Limay Porcheville
2 rue Gustave Eiffel - 3 avenue Ozanne
78440 Gargenville
France
This leaflet was last approved in
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
47
Source: European Medicines Agency
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