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NEOPHYR 450 PPM MOL/MOL MEDICINAL GAS COMPRESSED

Active substance(s): NITRIC OXIDE

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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 (parts per million) of inhaled gas.
The dose may be increased up to 40 ppm if the
lower dose has not provided sufficient clinical
effect. 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 perioperative course to lower pulmonary
pressure.
In clinical studies treatment was often initiated
before separation from Cardio Pulmonary
Bypass.
Inhaled NO has been given for time periods up to
7 days in the perioperative setting, but common
treatment times are 24-48 hours.
Weaning
Attempts to wean Neophyr 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 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 Neophyr.
Too rapid weaning from inhaled nitric oxide
therapy carries the risk of a re-bound increase in
pulmonary artery pressure with subsequent
circulatory instability.
Additional information on special populations:
No relevant information for dosage adjustment
recommendation on special populations, such as
renal/hepatic impairment or geriatric, has been
found. Therefore caution is recommended in
these populations.
The safety and efficacy of inhaled nitric oxide in
premature infants less than 34 weeks of
gestation has not yet been established, no
recommendation or posology can be made.
Method of administration
For inhalation use.
Modalities of administration of Neophyr can
modify the toxicity profile of the drug.
Administration recommendations have to be
followed.
Nitric oxide is normally administered by
inhalation in patients via mechanical ventilation
after it has been diluted with a mix of oxygen/air
using a nitric oxide administration device that has
been approved for clinical use as per the
European Community standards (CE marked).
Direct endotracheal administration without
dilution is contra-indicated due to the risk of local
lesion of the mucous membrane when it comes
into contact with the gas.
NO must correctly mix with other gases in the
ventilator circuit. It is advisable to ensure the
least amount of contact time possible between
the nitric oxide and the oxygen in the inspiratory
circuit in order to limit the risk of the formation of

toxic oxidation derivatives in the inhaled gas.
It is therefore recommended dilution of nitric
oxide is administered in the inspiratory branch
of the ventilation circuit and after the humidifier.
The administration system should supply a
constant concentration of inhaled Neophyr,
notwithstanding the ventilation equipment and
ventilation modality utilised.
In order to avoid errors in the dosage, the
concentration of Neophyr inhaled must be
continually regulated in the inhalation branch of
the circuit close to the patient, and near the tip
of the endotracheal tube. The concentration of
nitrogen dioxide (NO2) and FiO2 must also be
regulated in the same place using a calibrated
and EC-approved monitoring apparatus.
The concentration of NO2 in the inhaled mix
must be as low as possible. If the concentration
of NO2 exceeds 1 ppm, the dose of Neophyr
and/or FiO2 must be reduced, ruling out any
possible malfunction in the administration
system.
For the safety of the patient, appropriate alarms
must be configured for Neophyr
(± 2 ppm of the prescribed dose), NO2
(maximum 1 ppm) and FiO2 (± 0.05).
If an unexpected change in the concentration of
Neophyr is produced, the administration
system will have to be checked for defects and
the analyser will have to be calibrated again.
The pressure of the Neophyr gas cylinder must
be monitored in order to allow the gas cylinder
to be changed without interruptions or changes
to the treatment. There must also be a reserve
supply of gas cylinders to allow changes at the
appropriate moment.
In case of failure of the system or a cut in the
electricity supply, there must be an emergency
battery electricity supply and a back-up system
for the administration of the nitric oxide.
The electricity supply of the monitoring
equipment must be independent of the function
of the administration device.
Neophyr therapy must be available for
mechanical and manual ventilation, during
transportation of the patient and during
resuscitation. The doctor must have access
near the head of the patient to place a reserve
nitric oxide administration system.
Monitoring of the formation of nitrogen
dioxide
Nitrogen dioxide (NO2) forms rapidly in gaseous
mixtures that contain nitric oxide and O2.
Nitric oxide, in reaction with oxygen, will
produce nitrogen dioxide (NO2) in variable
quantities depending on the NO and O2
concentrations. NO2 is a toxic gas that can
provoke an inflammatory reaction in the
respiratory tract; it is for this reason that its
production must be closely monitored.
Immediately before starting the treatment on
each patient, it is necessary to apply the
appropriate procedures to purge the system of
NO2. The NO2 concentration must be kept as
low as possible and always < 0,5 ppm.
If NO2 is > 0,5 ppm, the administration system
must be checked for defects, the NO2 analyser
must be recalibrated and, if possible, the levels
of Neophyr and/or FiO2 must be reduced.
If there is an unexpected change in Neophyr
concentration, the delivery system should be
assessed for malfunction and the analyser
should be recalibrated.
Monitoring the formation of
methaemoglobin (MetHb)
Following its inhalation, the terminal
compounds of nitric oxide that arrive in the
systemic circulation are primarily
methaemoglobin and nitrate. The nitrate is
fundamentally excreted through the urinary
system and the methaemoglobin is reduced by
the methaemoglobin reductase. Newborns and

infants have diminished levels of MetHb
reductase activity compared to adults; therefore
the methaemoglobin concentrations in the
blood must be monitored. The level of MetHb
must be measured within 1 hour of the start of
Neophyr therapy using an analyser that
correctly distinguishes the fetal hemoglobin
from the MetHb. If the MetHb is > 2.5%, the
dose of Neophyr will have to be reduced and
the necessity for the administration of reducing
agents such as methylene blue will be
assessed. Although considerable increases in
the level of MetHb are infrequent, since the level
is low during the first determination, it is
advisable to repeat the MetHb measurements
every 12-24 hours thereafter.
In adults undergoing heart surgery,
methaemoglobin level should be measured
within one hour of the initiation of Neophyr
therapy. If the fraction of methaemoglobin rises
to a level that potentially compromises
adequate oxygen delivery, the Neophyr dose
should be decreased and the administration of
reducing medicinal products such as methylene
blue may be considered.
Exposure limits for hospital personnel
The maximum exposure limit (average
exposure) of hospital personnel to nitric oxide
has been determined by labour legislation and
is 25 ppm over a period of 8 hours (30 mg/m3)
and the corresponding limit for NO2 is 2-3 ppm
(4-6 mg/m3) in the majority of European
countries. Extrapolating these limits to intensive
care units where the inhalation of NO can be
administered for a period of 24 hours, it would
be prudent to keep the atmospheric levels of
NO2 below 1.5 ppm.
Continuous monitoring of atmospheric levels of
NO2 is mandatory.
Training in administration
The key elements that need to be covered in
training hospital personnel are as follows.
Correct set-up and connections
· Connections to the gas cylinder and to the
ventilator patient breathing circuit
Operation
· Pre-use check list procedure (a series of steps
required immediately prior to each patient
initiation to ensure that the system is working
properly and that the system is purged of NO2)
· Setting the device for the correct
concentration of nitric oxide to be administered
· Setting the NO, NO2 and O2 monitors for high
and low alarm limits
· Using the manual backup delivery system
· Procedures for correctly switching gas
cylinders and purging system
· Troubleshooting alarms
· NO, NO2 and O2 monitor calibration
· Monthly system performance check-up
procedures
4.3 Contraindications
· Newborns with known dependency to
right-left blood shunt or newborns with
significant left-right shunt.
· Patients with congenital or acquired
deficiency of methaemoglobin reductase
(MetHb reductase) or glucose 6 phosphate
dehydrogenase (G6PD).
· Hypersensitivity to the active substance to or
any of the excipients listed in section 6.1.
4.4 Special warnings and precautions for use
Precautions to avoid exposures during
inhaled Neophyr therapy
· Follow Standard Operating Procedures when
preparing and using Neophyr.
· Install scavenging systems on ventilators to
capture the patient’s exhaled breath.
· Take air samples when training therapists on
how to use the iNO treatment.

· Portable personal alarm devices, which warn
staff if environmental levels of NO or NO2 rise
above occupational safety limits, can be
provided.
Precautions to avoid accidental emptying of
a gas cylinder and further actions
A spontaneous leak of nitric oxide from a gas
cylinder is very rare due the exhaustive controls
in the filling areas. Accidental release can
happen if the cylinder falls heavily such that the
valve is damaged and release occurs.
To avoid that:
· Hospital staff must always secure the gas
cylinder in an upright position and ensure it is
firmly secured to prevent it from falling over or
being knocked-over.
· The gas cylinders have to be handled with
care, ensuring that they are not abruptly jolted
or dropped.
· Only move gas cylinders using an appropriate
type and size of vehicles and equipment for
such a purpose.
· If an accidental release happens, gaseous NO
leaks can be detected by a characteristic
orange-brown colour and a sharp sweet and
metallic smell.
The recommended actions are to evacuate the
room and open windows to the outside.
· In cabinet or closet stores, a fan exhausting
directly to the outside should be installed to
maintain a negative pressure within the cylinder
storage area.
· Installation of NO and N2 monitoring systems
for continuous monitoring of NO and N2
concentrations in enclosed NO gas cylinder
storage areas and respiratory care areas to alert
employees in case of an accidental release
could be useful (Nitrogen gas could displace
the ambient air and reduce the oxygen level in
the environment).
Evaluation of the treatment response
In newborns >34 week gestation with hypoxic
respiratory failure associated with clinical or
echocardiographic evidence of pulmonary
hypertension, a proportion of patients that
receive inhaled NO therapy do not respond to
the treatment. The range of non-responders
varies between 30% and 45% depending on
the pre-established clinical values for
favourable response. Conventional response
indicators include a 20% increase in
oxygenation index and/or a 20% reduction in
pulmonary arterial pressure. In children, a lower
response in oxygenation in new-borns with
meconium aspiration syndrome has been
indicated.
Furthermore, the efficacy of the use of inhaled
NO in patients with congenital diaphragmatic
hernia has not been demonstrated in clinical
trials.
If the clinical response is not considered to be
adequate after 4-6 hours of Neophyr
administration, the following possibilities should
be considered:
· If the patient’s condition continues to
deteriorate or there is no improvement, the
situation having been defined by preestablished criteria, the employment of a rescue
system such as an ECMO will be considered, if
it is indicated and possible. Persistently high
levels of oxygenation index (>20) or alveolararterial oxygen gradient (Aao2>600) after
4 hours of iNO therapy indicate an urgent need
to initiate ECMO therapy.
· In a non-response situation to the
administration of Neophyr, the treatment must
be suspended, but it must not be interrupted
suddenly as it may provoke an increase in the
pulmonary arterial pressure (PAP) and/or
deterioration in blood oxygenation (PaO2).
Both situations may also occur in new-borns

showing no obvious response to the Neophyr
treatment. The gradual withdrawal of inhaled
nitric oxide must take place with caution (See
4.2 Posology and method of administration:
Withdrawal).
· In the case of patients that are to be
transferred to another hospital, the supply of
nitric oxide during the transportation of the
patient must be guaranteed in order to avoid
any deterioration in their state of health due to
a sudden interruption of Neophyr treatment.
Monitoring the ventricular function
With regards to interventricular or interauricular
communication, the inhalation of Neophyr
causes an increase in the left-right shunt due
to the vasodilator effect of the nitric oxide in
the lung.
The increase in pulmonary blood flow in
patients with left ventricular dysfunction can
lead to cardiac insufficiency and the formation
of pulmonary oedema. Careful monitoring of
cardiac output, left atrial pressure, or
pulmonary capillary wedge pressure is
important in this situation. It is therefore
recommended that before administering nitric
oxide, a catheterization of the pulmonary artery
or an echocardiographic examination of the
central haemodynamics is carried out.
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.
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).
For identifying recipients for heart transplant in
dilated cardiomyopathy patients, intravenous
vasodilator and inotropic therapy contribute to
better ventricular compliance and prevent
further elevation in left-sided filling pressures
resulting from enhanced pulmonary venous
return.
Monitoring haemostasis
Tests in animals have demonstrated that NO
can interact with the haemostasis provoking
an increase in the bleeding time. The data in
adult humans is contradictory, and there has
been no increase in significant bleeding
complications observed in random controlled
trials on new-borns.
A monitoring of the bleeding times is
recommended during the course of Neophyr
administration for a period of more than
24 hours in patients that suffer numerical or
functional anomalies of the platelets, a deficit
in the coagulation factors or that are
undergoing anticoagulant treatment.
Discontinuation of therapy
The Neophyr dose should not be discontinued
abruptly as it may result in an increase in
pulmonary artery pressure (PAP) and/or
worsening of blood oxygenation (PaO2).
Deterioration in oxygenation and elevation in
PAP may also occur in neonates with no
apparent response to Neophyr.
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

Package leaflet:
Information for the user

Neophyr
225 ppm mol/mol
450 ppm mol/mol
1000 ppm mol/mol

UK_NEOPHYR_P_2014-11

Neophyr

UK_NEOPHYR_P_2014-11

Neophyr should be used in ventilated newborn
infants expected to require support >24 hours.
Neophyr 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
225 ppm mol/mol
pressure).
450 ppm mol/mol
Pulmonary hypertension associated with heart
surgery
1000 ppm mol/mol
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
Medicinal gas, compressed
of a nitric oxide delivery system. Neophyr
Nitric oxide
should only be delivered according to an
225 ppm, 450 ppm, 1000 ppm mol/mol
anaesthetist’s or intensive care physician’s
prescription.
Posology
1. NAME OF THE MEDICINAL PRODUCT
The posology will be determined in accordance
with the medical condition of the patient.
Neophyr 225 ppm mol/mol medicinal gas,
Due to the potential risk of NO2 formation,
compressed
continuous monitoring of NO2 must be
Neophyr 450 ppm mol/mol medicinal gas,
performed.
compressed
Neophyr 1000 ppm mol/mol medicinal gas,
Persistent Pulmonary Hypertension in the
compressed
Newborn (PPH)
Newborns > 34 weeks gestation: The maximum
2. QUALITATIVE AND QUANTITATIVE
recommended dose of Neophyr is 20 ppm and
COMPOSITION
this dose should not be exceeded. Starting as
Nitric oxide 225ppm mol/mol.
soon as possible, and in the first 4-24 hours of
Nitric oxide 450ppm mol/mol.
therapy, the dosage must be reduced gradually
Nitric oxide 1000ppm mol/mol.
to 5 ppm or less, titrating it to the needs of the
individual patient, as long as the clinical
For Nitric oxide (NO) 225 ppm mol/mol
parameters (oxygenation, arterial pulmonary
Nitric oxide (NO) 0.225 ml in
pressure) are within the desired limits. Inhaled
Nitrogen (N2) 999.775 ml.
nitric oxide therapy must be maintained at
For Nitric oxide (NO) 450 ppm mol/mol
5 ppm until an improvement in the oxygenation
Nitric oxide (NO) 0.450 ml in
is observed in the newborn in such as way that
Nitrogen (N2) 999.55 ml.
the fraction of inhaled oxygen is diminished to
For Nitric oxide (NO) 1000 ppm mol/mol
below 60% (FiO2 < 0.60).
Nitric oxide (NO) 1 ml in
The treatment can be pursued up to 96 hours or
Nitrogen (N2) 999 ml.
until the oxygen de-saturation is resolved and
A 10-liter gas cylinder filled to 150 bar supplies
the patient is ready for gradual withdrawal from
1500 l of gas at a pressure of 1 bar at 15°C.
Neophyr treatment. The duration of the
treatment should be limited to be as short as
For a full list of exicipients, see section 6.1.
possible. The duration is variable, but typically,
3. PHARMACEUTICAL FORM
less than 4 days. If there is no response to the
inhaled nitric oxide, consult section 4.4.
Medicinal gas, compressed.
Colourless and odourless gas.
Weaning
Attempts to wean Neophyr should be made
4. CLINICAL PARTICULARS
after the ventilator support is substantially
4.1 Therapeutic indications
decreased or after 96 hours of therapy. When
Neophyr, in conjunction with ventilatory support the decision is made to discontinue inhaled
nitric oxide therapy, the dose should be
and other appropriate active substances, is
reduced to 1 ppm for 30 minutes to one hour.
indicated:
If there is no change in oxygenation during
· for the treatment of newborn infants  34
weeks gestation with hypoxic respiratory failure administration of Neophyr at 1 ppm, the FiO2
should be increased by 10%, the Neophyr is
associated with clinical or echocardiographic
discontinued, and the neonates monitored
evidence of pulmonary hypertension, in order
to improve oxygenation and to reduce the need closely for signs of hypoxaemia. If oxygenation
falls >20%, Neophyr therapy should be
for extracorporeal membrane oxygenation.
resumed at 5 ppm and discontinuation of
· as part of the treatment of perioperative
pulmonary hypertension in adults and newborn Neophyr therapy should be reconsidered after
12 to 24 hours. Infants who cannot be weaned
infants, infants and toddlers, children and
adolescents, ages 0-17 years in conjunction to off Neophyr by 4 days should undergo careful
diagnostic work-up for other diseases.
heart surgery, in order to selectively decrease
pulmonary arterial pressure and improve right
Pulmonary hypertension associated with heart
ventricular function and oxygenation.
surgery.
Neophyr should be used only after conservative
4.2 Posology and method of administration
support has been optimised. Neophyr should
Persistent Pulmonary Hypertension in the
be administered under close monitoring of
Newborn (PPHN)
hemodynamics and oxygenation.
Prescription of nitric oxide should be supervised
Newborn infants, infants and toddlers, children
by a physician experienced in neonatal
and adolescents, ages 0-17 years
intensive care.
The starting dose of inhaled nitric oxide is
Prescription should be limited to those neonatal
10 ppm (parts per million) of inhaled gas.
units that have received adequate training in the
The dose may be increased up to 20 ppm if the
use of a nitric oxide delivery system. Neophyr
lower dose has not provided sufficient clinical
should only be delivered according to a
effects. The lowest effective dose should be
neonatologist’s prescription.
administered and the dose should be weaned
The following information is intended
for healthcare professionals only.

Medicinal gas, compressed
Nitric oxide
225 ppm, 450 ppm, 1000 ppm mol/mol

Read all of this leaflet carefully before you
start using this medicine because it contains
important information for you.
· Keep this leaflet. You may need to read it again.
· If you have any further questions, ask your
doctor.
· This medicine has been prescribed for you
only. Do not pass it on to others. It may harm
them, even if their signs of illness are the same
as yours.
· If you get any side effects, talk to your doctor.
This includes any possible side effects not listed
in this leaflet. See section 4.
In this leaflet:
1. What Neophyr is and what it is used for
2. What you need to know before you use
Neophyr
3. How to use Neophyr
4. Possible side effects
5. How to store Neophyr
6. Contents of the pack and other information
1. WHAT NEOPHYR IS AND WHAT IT IS USED
FOR?
Neophyr is a gas mixture for inhalation use.
Neophyr is a medicinal gas, compressed,
consisting of a mixture of gases that contains
225 ppm, 450 ppm or 1000 ppm mol/mol of
nitric oxide.
What are its uses?
Neophyr must be administered exclusively by
healthcare professionals and it is only for strict
hospital use.
Neophyr is indicated in the following conditions:
· 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. WHAT YOU NEED TO KNOW BEFORE
YOU USE NEOPHYR
Do not use Neophyr:
· If you (as the patient) or your child (as the
patient) are allergic (hypersensitive) to nitric oxide
or any of the other ingredients of this medicine
(listed in section 6).
· If you have been told that you (as the patient) or
your child (as the patient) have an abnormal
circulation within the heart.
· If you (as the patient) or your child (as the
patient) have congenital or acquired deficiency of
methemoglobin reductase (MetHb reductase) or
glucose 6 phosphate dehydrogenase (G6PD).

Warnings and precautions
Talk to your doctor before using Neophyr.
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 Neophyr therapy will be
adjusted, decreased accordingly.Inhaled nitric
oxide may have a mild but influence on the
platelets (components that help the blood to
clot) of you or your child and any signs of
bleeding and or haematoma should be
observed. If you see any signs or symptoms that
may be associated to bleeding you should
directly inform the doctor.
No effect of inhaled nitric 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
Neophyr should not be used in preterm baby
< 34 weeks of gestational age.
Other medicines and Neophyr
The doctor will decide when to treat you or your
child with Neophyr and with other medicines,
and will carefully supervise the treatment.
Tell your doctor if you (as the patient) or your
child (as the patient) are taking, have recently
taken or might take any other medicine.
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 taken these medicines.
Pregnancy, breast-feeding and fertility
Neophyr should not be used during pregnancy
unless clearly necessary, such as in situations of
life support.
Exposure to nitric oxide in humans during
lactation should be avoided.
If you are pregnant or breast-feeding, think you
may be pregnant or are planning to have a baby,
ask your doctor for advice before taking this
medicine.
3. HOW TO USE NEOPHYR
Your doctor will decide the correct dose of
Neophyr and will administer Neophyr 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 Neophyr 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 Neophyr
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 Neophyr.
Neophyr is given in dose of 10 to 20 ppm,
(maximal dose 20 ppm in children and 40 ppm in
adults) parts 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, Neophyr
is usually given for 24-48 hours. However,
therapy with Neophyr may last longer.
If you receive more Neophyr 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 Neophyr dose will be decreased and
the administration of medicines such as vitamin
C, methylene blue, or eventually blood
transfusion, in order to improve the oxygen
carrying capacity, may be considered.
If you stop receiving Neophyr
Treatment with Neophyr 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 Neophyr is stopped
suddenly without first lowering the dose.
At the end of treatment, the doctor will slowly
lower the amount of Neophyr being given to you
or your child, so that the circulation in the lungs
is able to adjust to oxygen/air without Neophyr.
Thus it may take a day or two before you or your
child is off Neophyr therapy.
If you have any further questions on the use of
this medicine ask your doctor or other healthcare
professionals.
4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side
effects, although not everybody gets them.
Your doctor will notice and closely monitor any
side effects. It is not likely that you will
experience these side effects yourself.
Side effects that are very commonly seen (affects
more than 1 user in 10) in association with
Neophyr 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 Neophyr.
If any of the side effects become serious, or if
you notice any side effects not listed in this
leaflet, please tell your doctor.
If you have any further questions on the use of
this product ask your doctor or other healthcare
professionals.
Reporting of side effects
If you get any side effects, talk to your doctor.
This includes any possible side effects not listed
in this leaflet. You can also report side effects
directly via the Yellow Card Scheme (Website:
www.mhra.gov.uk/yellowcard).
By reporting side effects you can help provide
more information on the safety of this medicine.
5. HOW TO STORE NEOPHYR
Keep this medicine out of the sight and reach of
children.
Neophyr therapy should only be used and
handled by hospital personnel.

· Neophyr cylinders should be stored secured in
order to avoid falling and thus potentially causing
harm.
· Neophyr should be used and administered
only by personnel specially trained in the use and
handling of Neophyr.
All regulations concerning handling of
pressurised cylinders must be followed.
Storage is supervised by 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.
The cylinders must be stored at a temperature
between -10 and +50°C.
Protect the cylinders from shocks, falls,
oxidising and flammable materials, moisture,
sources of heat or ignition.
Storage in the pharmacy department
The gas cylinders should be kept in a place
designated exclusively for medicinal gas storage
that is well ventilated, clean and under lock and
key. This place should house a separate, special
facility for the storage of nitric oxide gas
cylinders.
Storage in medical department
The cylinder should be placed in an area with
appropriate equipment to ensure that the
cylinder is held vertically.
When the cylinder is empty, do not dispose of it.
Empty cylinders will be collected by the supplier.
Do not use this medicine after the expiry date
which is stated on the gas cylinder label.
The expiry date refers to the last day of that
month.
6. CONTENTS OF THE PACK AND OTHER
INFORMATION
What Neophyr contains
· The active substance is nitric oxide
225 ppm mol/mol, 450 ppm mol/mol or
1000 ppm mol/mol
· The other ingredient is nitrogen
What Neophyr looks like and contents of the
pack
Gas cylinders with a capacity of 10 l.
A 10-liter gas cylinder filled to 150 bar contains
about 1,77 kg of gas.
Aluminum alloy cylinders have a white painted
body and a turquoise-painted shoulder.
They are equipped with a stainless steel residual
pressure valve with a specific ISO 5145 (2004)
type outlet connector.
Marketing Authorisation Holder and
Manufacturer
Marketing Authorisation Holder
SOL SpA
via Borgazzi 27,
20900 Monza (Italy)
Manufacturer
SOL SpA
via Libertà 247,
20900 Monza (Italy)
This medicinal product is authorized in the
Member States of the EEA under the
following names:
Austria: Neophyr
Belgium: Neophyr
Bulgaria: Neophyr
Germany: Neophyr
Ireland: Neophyr
Italy: Neophyr
Luxemburg: Neophyr
The Netherlands: Neophyr
Romania: Neophyr
United Kingdom: Neophyr
This leaflet was last revised in 11/2014

products of nitric oxide that enter the systemic
circulation are predominantly methaemoglobin
and nitrate. The concentrations of
methaemoglobin in the blood should be
monitored, see section 4.2.
Formation of NO2
NO2 rapidly forms in gas mixtures containing
nitric oxide and O2, and nitric oxide may in this
way cause airway inflammation and damage.
The dose of nitric oxide should be reduced if
the concentration of nitrogen dioxide exceeds
0.5 ppm.
4.5 Interaction with other medicinal
products and other forms of interaction
No interaction studies have been performed.
A clinically significant interaction with other
medicinal products used in the treatment of
hypoxic respiratory failure cannot be excluded
based on the available data.
Oxygen: In the presence of oxygen, nitric oxide
oxidises rapidly forming derivatives that are
toxic for the bronchiolar epithelium and the
alveolo-capillar membrane. Nitrogen dioxide
(NO2) is the main compound that is formed and
may cause airway inflammation and damage.
There are also animal data suggesting an
increased susceptibility to airway infections
upon exposure to low levels of NO2. During the
treatment with nitric oxide, the concentration
of NO2 must be < 0,5 ppm in the dose interval
of < 20 ppm of nitric oxide. If, at any time, the
concentration of NO2 exceeds 1 ppm, the dose
of nitric oxide must be reduced immediately.
See the information on monitoring NO2 in
section 4.2.
NO donors: The donor compounds of nitric
oxide, including sodium nitroprusside and
nitroglycerine, can have an additive effect to
Neophyr with regards to the risk of developing
methaemoglobinaemia.
Methaemoglobin inducers: There is a higher
risk to develop methaemoglobinaemia if drugs
that increase the methaemoglobin
concentrations are administrated along with
nitric oxide (e.g. alkyl nitrates, sulphonamides
and prilocaine). As a consequence, medicinal
products that increase methaemoglobin must
be used with caution during inhaled nitric oxide
therapy.
Prilocaine, whether administered as oral,
parenteral, or topical formulations may cause
methaemoglobinaemia. Care must be taken
when Neophyr is given at the same time as
medicinal products containing prilocaine.
Synergic effects have been reported with the
administration of vasoconstrictors (almitrine,
phenylephrine), prostacyclin and
phosphodiesterase inhibitors, without
increasing adverse effects.
Inhaled nitric oxide has been used
concomitantly with tolazoline, dopamine,
dobutamine, steroids, surfactants and high
frequency ventilation, with no drug interactions
observed.
Experimental studies suggest that nitric oxide
and also nitrogen dioxide can react chemically
with the surfactant and its proteins without
proven clinical consequences.
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.
Although controlled studies have not been
done, food interactions have not been noticed
in clinical trials in patients with prolonged
ambulatory administration.

System organ class

Very common

Common

Not known

Blood and lymphatic system
disorders

Thrombocytopenia

-

-

Metabolism and nutrition
disorders

Hypokalemia

-

-

Nervous system disorders

-

-

Headache*

Vascular diorders

Hypotension

-

Pulmonary artery pressure
increased**, Hypotension**

Respiratory, thoracic and
mediastinal disorders

Atelectasis

-

-

Hepatobiliary disorders

Hyperbilirubinemia

-

-

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.

4.6 Fertility, pregnancy and lactation
Fertility
No fertility studies have been performed.
Pregnancy
The effect of the administration of Neophyr in
pregnant women is unknown. Animal studies
are insufficient (see section 5.3).
The potential risk for humans is unknown.
Neophyr should not be used during pregnancy
unless clearly necessary, such as in situations
of life support.
Lactation
It is not known whether Neophyr passes into
human breast milk. The excretion of Neophyr in
milk has not been studied in animals.
Exposure to nitric oxide in humans during
lactation should be avoided.
4.7 Effects on ability to drive and use
machines
Infants and hospitalized patient: Not relevant.
4.8 Undesirable effects
Summary of safety profile
Abrupt discontinuation of the administration of
inhaled nitric oxide may cause rebound
reaction; decrease in oxygenation and increase
in central pressure and subsequent decrease in
systemic blood pressure. Rebound reaction is
the most commonly adverse reaction in
association with the clinical use of Neophyr.
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
iNO 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).
Description of selected adverse reactions
Inhaled nitric oxide therapy may cause an
increase in methaemoglobin.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after
authorisation of the medicinal product is
important. It allows continued monitoring of the

benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report
any suspected adverse reactions via the
Yellow Card Scheme
(Website: www.mhra.gov.uk/yellowcard).
4.9 Overdose
Overdose with Neophyr will be manifest by
elevations in methaemoglobin and NO2.
Elevated NO2 may cause acute lung injury.
Elevations in methaemoglobinaemia reduce the
oxygen delivery capacity of the circulation.
In clinical studies, NO2 levels > 3 ppm or
methaemoglobin levels > 7% were treated by
reducing the dose of, or discontinuing, iNO.
Methaemoglobinaemia that does not resolve
after reduction or discontinuation of therapy can
be treated with intravenous vitamin C,
intravenous methylene blue, or blood
transfusion, based upon the clinical situation.
5. PHARMACOLOGICAL PROPERTIES
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.
iNO appears to increase the partial pressure of
arterial oxygen (PaO2) by dilating pulmonary
vessels in better ventilated areas of the lung,
redistributing pulmonary blood flow away from
lung regions with low ventilation/perfusion (V/Q)
ratios toward regions with normal ratios.
Persistent pulmonary hypertension of the
newborn (PPHN) occurs as a primary
developmental defect or as a condition
secondary to other diseases such as meconium
aspiration syndrome (MAS), pneumonia, sepsis,
hyaline membrane disease, congenital
diaphragmatic hernia (CDH), and pulmonary
hypoplasia. In these states, pulmonary vascular
resistance (PVR) is high, which results in
hypoxemia secondary to right-to-left shunting
of blood through the patent ductus arteriosus
and foramen ovale. In neonates with PPHN,
iNO can improve oxygenation (as indicated by
significant increases in PaO2).
The efficacy of iNO 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% O2 with (n=114) or without (n=121) nitric

oxide most with an initial concentration of
20 ppm with weaning as possible to lower
doses with a median duration of exposure of
40 hours. The objective of this double-blind,
randomised, placebo controlled trial was to
determine whether inhaled nitric oxide would
reduce the occurrence of death and/or initiation
of extracorporeal membrane oxygenation
(ECMO). Neonates with less than a full response
at 20 ppm were evaluated for a response to
80 ppm nitric oxide or control gas.
The combined incidence of death and/or
initiation of ECMO (the prospectively defined
primary endpoint) showed a significant
advantage for the nitric oxide treated group
(46% vs. 64%, p=0.006). Data further
suggested a lack of additional benefit for the
higher dose of nitric oxide.
The adverse events collected occurred at
similar incidence rates in both groups.
Follow-up exams at 18-24 months of age were
similar between the two groups with respect to
mental, motor, audiologic, and neurologic
evaluations.
In the CINRGI trial, 186 term- and near-term
neonates with hypoxic respiratory failure were
randomised to receive either iNO (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 iNO group required ECMO
compared to the control group (31% vs 57%,
p<0.001). The iNO group had significantly
improved oxygenation as measured by PaO2,
OI, and alveolar-arterial gradient (p<0.001 for all
parameters). Of the 97 patients treated with,
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 vasoconstriction 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 iNO (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 (O2 -), an unstable compound which
may cause tissue damage through further redox
reactions. In addition, nitric oxide has affinity to
metalloproteins and may also react with
SH-groups in protein forming nitrosyl
compounds. The clinical significance of the
chemical reactivity of nitric oxide in tissue is
unknown. Studies show that nitric oxide
exhibits pulmonary pharmacodynamic effects
at intra-airway concentrations as low as 1 ppm.
The European Medicines Agency has waived
the obligation to submit the results of studies
with iNO 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 iNO groups, but reached approximately
5% in the 80 ppm iNO 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 seen in single and repeat dose-toxicity
studies in rodents were observed only at
exposures considered sufficiently in excess of
the maximum human exposure indicating little
relevance to clinical use. Toxicity is related to
anoxia resulting from elevated methaemoglobin
levels.
No reproductive and developmental toxicity
studies have been performed.
A battery of genotoxicity tests has
demonstrated mutagenic potential of nitric
oxide in some in vitro test systems and no
clastogenic effect in the in vivo system.

This is possibly related to the formation of
mutagenic nitrosamines, DNA alterations or
impairment of DNA repair mechanisms. A low
incidence in uterine adenocarcinomas in rats
following daily exposure to the recommended
human dose for two years was tentatively
considered treatment related.
The significance of these findings for clinical
and the potential for effects on the germ cells
are unknown.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Nitrogen
6.2 Incompatibilities
This medicinal product must not be mixed with
other medicinal product/equipment/devices
except those mentioned in section 6.6.
The following materials should not be used or
be present in any equipment/device(s) used in
nitric oxide administration: Butylrubber,
Polyamide and Polyurethane.
6.3 Shelf life
3 years
6.4 Special precautions for storage
All regulations concerning handling of
pressurised cylinders must be followed.
Storage is supervised by the specialists at the
hospital. Cylinders are to be stored in wellventilated rooms or in ventilated sheds where
they are protected from rain and direct sunlight.
The cylinders must be stored at a temperature
between -10 and +50°C.
Protect the cylinders from shocks, falls,
oxidising and flammable materials, moisture,
sources of heat or ignition.
Storage in the pharmacy department
The gas cylinders should be kept in a place
designated exclusively for medicinal gas
storage that is well ventilated, clean and under
lock and key. This place should house a
separate, special facility for the storage of nitric
oxide gas cylinders.
Storage in medical department
The cylinder should be placed in an area with
appropriate equipment to ensure that the
cylinder is held vertically.
Transport of gas cylinders
The gas cylinders should be transported with
appropriate material in order to protect them
from the risk of shocks and falls.During inter- or
within-hospital transfers of patients treated with
Neophyr, the gas cylinders should be securely
stowed away in order to hold the gas cylinders
vertically and to avoid the risk of falls or
untimely modifying output. Particular attention
should be also turned to the fastening of the
pressure regulator so as to avoid the risk of
accidental failures.
Do not use Neophyr after the expiry date which
is stated on the gas cylinder label. The expiry
date refers to the last day of that month.
6.5 Nature and contents of container
Gas cylinders with a capacity of 10l.
A 10-liter gas cylinder filled to 150 bar contains
about 1,77 kg of gas.
Aluminum alloy cylinders have a white painted
body and a turquoise-painted shoulder.
They are equipped with a stainless steel
residual pressure valve with a specific ISO 5145
(2004) type outlet connector.
6.6 Special precautions for disposal
All equipment, including connectors, tubing and
circuits, used in the delivery of nitric oxide must
be made of materials compatible with the gas.
From a corrosion point of view the supply
system can be divided into two zones:

1) From the gas cylinder valve to the humidifier
(dry gas) and
2) From the humidifier to outlet (moist gas which
may contain NO2).
Tests show that dry nitric oxide mixtures can be
used with most materials. However, the
presence of nitrogen dioxide and moisture
creates an aggressive atmosphere. Among
metallic construction materials, only stainless
steel can be recommended. Tested polymers
which can be used in nitric oxide administration
systems include polyethylene (PE) and
polypropylene (PP). Butyl rubber, polyamide,
and polyurethane should not be used.
Polytrifluorochloroethylene, hexafluoropropenevinyliden 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.
To avoid any incidents, the following
instructions must be strictly adhered to:
· check that the equipment is in working order
before use.
· firmly secure the cylinders using chains or
hooks in the rack to avoid any accidental falls
· do not use if the cylinder pressure is below
10 bar
· never open a valve abruptly
· do not handle a cylinder on which the valve is
not protected by a bonnet cap
· use a specific ISO 5145 (2004) connector: n°29
specific NO/N2 (100 ppm< NO < 1000 ppm)
W30x2 15,2-20,8 DR
· at each new use, purge the pressure- reducer/
flowmeter 3 times using the nitric oxide/nitrogen
mixture
· do not attempt to repair a defective valve
· do not tighten the pressure-reducer/flowmeter
using a gripper, otherwise the seal may be
crushed and the administration device
damaged
· evacuate exhaled gases outside (avoiding
areas in which they may accumulate). Before
use, it should be ensured that the room has the
appropriate ventilation system for evacuating
gases in the event of an accident or accidental
leaks.
· as nitric oxide is colorless and odorless, it is
recommended using a detection system in all
rooms in which it is to be used or stored.
· personnel exposure limits (see section 4.2:
Dosage and route of administration)
Instruction for cylinder disposal:
When the cylinder is empty, do not dispose of it.
Empty cylinders will be collected by the
supplier.
7. MARKETING AUTHORISATION HOLDER
SOL SpA
via Borgazzi 27,
20900 Monza (Italy)
8. MARKETING AUTHORISATION
NUMBER(S)
Neophyr 225ppm: PL 35326/0003
Neophyr 450ppm: PL 35326/0002
Neophyr 1000ppm: PL 35326/0001
9. DATE OF FIRST AUTHORISATION/
RENEWAL OF THE AUTHORISATION
16/02/2012
10. DATE OF REVISION OF THE TEXT
13/11/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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