Noxap

PATIENT LEAFLET: INFORMATION FOR THE USER

NOXAP 200 ppm mol/mol, medicinal compressed gas

nitric oxide
Please 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 questions, ask your doctor or pharmacist.
• If you get any side effects, talk to your doctor or pharmacist. This includes any side effects not listed in this leaflet. See section 4.

Contents of this leaflet:

1. What NOXAP is and what it is used for
2. What you need to know before you use NOXAP
3. How to use NOXAP
4. Possible side effects
5. How to store NOXAP
6. Contents of the pack and other information

1. What NOXAP is and what it is used for

NOXAP is a gas mixture for inhalation use.
NOXAP is a compressed medicinal gas consisting of a gas mixture containing 200 ppm
mol/mol of nitric oxide.
How is it used?
NOXAP must be administered exclusively by healthcare professionals and is intended solely
for hospital use. NOXAP is indicated in the following conditions:

1. In neonates with low blood oxygen levels (hypoxaemic respiratory failure) due to various causes. NOXAP improves oxygenation and reduces the need for extracorporeal circulation.
2. In paediatric and adult patients undergoing cardiac surgery with acute pulmonary hypertension (pulmonary hypertension). NOXAP reduces pulmonary hypertension and the risk of right heart failure.

2. What you should know before using NOXAP

Do not use NOXAP in the following cases:

• Newborns with documented tendency to right-to-left shunt or affected by significant left-to-right shunt.
• Patients with congenital or acquired deficiency of methemoglobin reductase (MetHb reductase) or glucose-6-phosphate dehydrogenase (G6PD).

Take particular care with NOXAP:

• In patients with left ventricular dysfunction, because NOXAP may cause heart failure and pulmonary edema.
• In patients with complex congenital heart defects.

Use of other medicines
Inform your doctor if you are taking or have recently taken any other medicines, including those
obtained without a prescription.

• Oxygen: in the presence of oxygen, nitric oxide is rapidly oxidized, producing substances that are toxic to the lungs. To avoid this situation, treatment with NOXAP is accompanied by continuous monitoring.
• Nitric oxide donors: certain cardiovascular medications, such as sodium nitroprusside and nitroglycerin, may have an additive effect with NOXAP, increasing the risk of methemoglobinemia.
• Medicines that increase methemoglobin concentrations: when drugs such as alkyl nitrates, sulfonamides, and prilocaine are administered together with nitric oxide, there is an increased risk of methemoglobinemia.
• Administration of vasoconstrictors (almitrine, phenylephrine), prostacyclin, and phosphodiesterase inhibitors has been associated with synergistic effects, but without an increase in adverse events.
• Inhaled nitric oxide has been used concomitantly with tolazoline, dopamine, dobutamine, noradrenaline, steroids, and surfactants, without observing pharmacological interactions.

Your doctor will decide whether NOXAP can be used with other medicines and will closely monitor the
treatment.
Pregnancy and breastfeeding
NOXAP must not be used during pregnancy unless the woman's clinical condition requires treatment with NOXAP.
Harmful effects are expected because methemoglobin is considered harmful to the fetus, and nitric oxide has shown genotoxic potential due to induction of structural DNA alterations.
Breastfeeding must be discontinued during treatment with NOXAP.
Driving and using machines
No adverse events related to the ability to drive vehicles or use machinery have been reported.

3. How to use NOXAP

NOXAP must be administered exclusively by healthcare professionals and is intended solely for hospital use.
NOXAP is administered by inhalation through a system that delivers the prescribed concentration of nitric oxide to the lungs, by diluting NOXAP in an oxygen and air mixture.
The doctor will determine the dosage and duration of treatment with NOXAP.
If you receive more NOXAP than prescribed, the delivery system will activate an alarm signal. At that point, the doctor will reduce or stop the administration of NOXAP and will then determine the most appropriate course of treatment.
If you stop receiving NOXAP
Towards the end of treatment, the doctor will gradually reduce the dosage of NOXAP.
Treatment with NOXAP must not be stopped abruptly, but must be gradually tapered to allow the lungs to adapt to the normal oxygen concentration in the air.
If you have any doubts about the use of this medicine, consult your doctor or other healthcare professionals.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Your doctor will report and closely monitor any potential side effects. It is unlikely that you will be able to detect these side effects on your own.

Disorders of the hematopoietic and lymphatic systems

• Elevated levels of nitric oxide in the blood may increase the risk of methemoglobinemia. In such cases, the blood's ability to carry oxygen may be reduced. If this occurs, the doctor will immediately reduce the dose of nitric oxide to allow the blood to recover its normal oxygen-carrying capacity. This risk may be higher in pediatric patients and other individuals with reduced levels of the enzyme methemoglobin reductase. Formation of methemoglobin at serum levels > 5% with inhaled nitric oxide at concentrations < 20 ppm is very rare (may affect up to 1 in 10,000 people).
• Bleeding time: A preclinical study has shown that inhaled nitric oxide may prolong bleeding time. However, controlled clinical studies have not shown significant differences between the control group and the treatment group regarding hemorrhagic complications.

Systemic disorders and administration site conditions

• Lack of response to treatment may occur in 30–45% of cases.
• Significant increases in NO levels at low therapeutic doses (< 20 ppm) of inhaled NO, as well as clinical evidence of NO toxicity, are very rare complications (may affect up to 1 in 10,000 people).
• Abrupt discontinuation of inhaled nitric oxide therapy very often (very common frequency: may affect more than 1 in 10 people) causes rapid rebound reactions characterized by intense pulmonary vasoconstriction and hypoxemia.

If any side effect worsens, or if you notice any side effects not listed in this leaflet, contact your doctor or other healthcare professionals.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, contact your doctor or pharmacist. You can also report side effects directly via the national reporting system at the website
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NOXAP

Keep out of the sight and reach of children.
Do not use NOXAP after the expiry date stated on the cylinder label after "EXP".
Follow all regulations concerning the handling of pressurized cylinders.
Storage is supervised by local specialists at the hospital. Store cylinders
in well-ventilated rooms or sheds, protected from rain and direct sunlight.
Protect cylinders from impact, falls, oxidizing and flammable materials, moisture, heat sources, or
ignition sources.

Storage in the pharmacy department
Keep cylinders in a dedicated area reserved exclusively for the storage of medical gases, which must be
well-ventilated, clean, and locked. This area must include a separate special facility for the storage of nitric oxide cylinders.

Storage in the medical department
Cylinders must be stored in a location equipped with appropriate fixtures to ensure they remain in an upright position.

6. Package contents and other information

What X contains
NOXAP is a combination gas.

• The active substance is: nitric oxide 200 ppm (mol/mol)
• The other component is: nitrogen.

Description of the appearance of NOXAP and contents of the container
NOXAP is a compressed medicinal gas.
NOXAP is stored in high-pressure cylinders made of aluminum or aluminum with an outer elastomeric layer. The valves sealing the cylinders are made of stainless steel. The cylinder pack sizes are 2 l, 5 l, 10 l, 20 l, and 40 l.
NOXAP is introduced into these cylinders in gaseous form at a pressure of 200 bar. Not all pack sizes may be marketed.

The colour code of the cylinder is light blue for the shoulder and white for the body.
Marketing Authorization Holder and Manufacturer
SOCIEDAD ESPANOLA DE CARBUROS METALICOS, S.A.
AVDA DE LA FAMA, 1
08940 CORNELLA DE LLOBREGAT
Sales Licensee
Sapio Life S.r.l.
Via S. Pellico 48
20900 Monza
Italy
Tel. +39 039 83981
Manufacturer:
S.E. de Carburos Metálicos, S.A.
Polígon Nord-Est, C-35 km 59
08470 Sant Celoni (Barcelona)
Spain
This medicinal product is authorized in the European Economic Area Member States under the
following names:
Belgium: NOXAP 200 ppm mol/mol, medicinaal gas, samengeperst
Netherlands: NOXAP 200 ppm mol/mol, medicinaal gas, samengeperst
France: NOXAP 200 ppm mol/mol, gaz médicinal comprimé
Portugal: NOXAP 200 ppm mol/mol, gás medicinal comprimido
Czech Republic: NOXAP 200 ppm mol/mol, medicinální plyn, stlačený
Germany: NOXAP 200 ppm Mol/Mol Gas zur medizinischen Anwendung, druckverdichtet
Spain: NOXAP 200 ppm mol/mol, gas medicinal comprimido
Poland: NOXAP 200 ppm mol/mol, gaz medyczny, sprężony
Italy: NOXAP 200 ppm mol/mol, gas medicinale compresso
To be completed with national information

INSTRUCTIONS FOR USE: INFORMATION FOR THE USER

NOXAP 800 ppm mol/mol, compressed medicinal gas

nitric oxide

Please read this leaflet carefully before using this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor or pharmacist.
• If you experience any side effects, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.

Contents of this leaflet:

1. What NOXAP is and what it is used for
2. What you need to know before using NOXAP
3. How to use NOXAP
4. Possible side effects
5. How to store NOXAP
6. Contents of the pack and other information

1. What NOXAP is and what it is used for

NOXAP is a gas mixture for inhalation use.
NOXAP is a compressed medicinal gas consisting of a gas mixture containing 800 ppm mol/mol of nitric oxide.
How is it used?
NOXAP must be administered exclusively by healthcare professionals and is intended solely for hospital use. NOXAP is indicated in the following conditions:

1. In neonates with low blood oxygen levels (hypoxaemic respiratory failure) due to various causes. NOXAP improves oxygenation and reduces the need for extracorporeal circulation.
2. In paediatric and adult patients undergoing cardiac surgery with acute pulmonary hypertension (pulmonary hypertension). NOXAP reduces pulmonary hypertension and the risk of right heart failure.

2. What you need to know before using NOXAP

Do not use NOXAP in the following cases:

• Newborns with documented tendency to right-to-left shunt or affected by significant left-to-right shunt.
• Patients with congenital or acquired deficiency of methemoglobin reductase (MetHb reductase) or glucose-6-phosphate dehydrogenase (G6PD).

Take special care with NOXAP:

• In patients with left ventricular dysfunction, because NOXAP may cause heart failure and pulmonary edema.
• In patients with complex congenital heart defects.

Use of other medicines
Inform your doctor if you are taking or have recently taken any other medicines, including those
obtained without a prescription.

• Oxygen: in the presence of oxygen, nitric oxide is rapidly oxidized, producing substances that are toxic to the lungs. To avoid this, treatment with NOXAP is accompanied by continuous monitoring.
• Nitric oxide donors: certain cardiovascular medications, such as sodium nitroprusside and nitroglycerin, may have an additive effect with NOXAP, increasing the risk of methemoglobinemia.
• Medicines that increase methemoglobin levels: when drugs such as alkyl nitrates, sulfonamides, and prilocaine are administered together with nitric oxide, there is an increased risk of methemoglobinemia.
• Synergistic effects have been reported with the administration of vasoconstrictors (almitrine, phenylephrine), prostacyclin, and phosphodiesterase inhibitors, but without an increase in adverse events.
• Inhaled nitric oxide has been used concomitantly with tolazoline, dopamine, dobutamine, noradrenaline, steroids, and surfactants, without observing pharmacological interactions.

Your doctor will decide whether NOXAP can be used with other medicines and will closely monitor the
treatment.
Pregnancy and breastfeeding
NOXAP must not be used during pregnancy unless the clinical condition of the woman requires treatment with NOXAP.
Harmful effects are expected, as methemoglobin is considered harmful to the fetus, and nitric oxide has shown genotoxic potential due to induction of structural DNA alterations.
Breastfeeding must be discontinued during treatment with NOXAP.
Driving vehicles and using machinery
No adverse events related to the ability to drive vehicles or use machinery have been reported.

3. How to use NOXAP

NOXAP must be administered exclusively by healthcare professionals and is intended solely for hospital use.
NOXAP is administered by inhalation through a system that delivers the prescribed concentration of nitric oxide to the lungs, by diluting NOXAP in a mixture of oxygen and air.
Your doctor will determine the dosage and duration of treatment with NOXAP.
If you receive more NOXAP than you should, the delivery system will activate an alarm signal. At that point, the doctor will reduce or stop the administration of NOXAP and will decide on the most appropriate treatment to follow.
If you stop receiving NOXAP
Towards the end of treatment, your doctor will gradually reduce the dosage of NOXAP.
Treatment with NOXAP must not be stopped abruptly, but must be gradually tapered to allow the lungs to adapt to the normal oxygen concentration in the air.
If you have any doubts about the use of this medicine, consult your doctor or other healthcare professionals.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone experiences them.
Your doctor will report and closely monitor any possible side effects. It is unlikely that you will be able to detect these side effects on your own.

Disorders of the hematopoietic and lymphatic system

• Elevated levels of nitric oxide in the blood may increase the risk of methemoglobinemia. In such cases, the blood's ability to transport oxygen may be reduced. If this occurs, your doctor will immediately reduce the dose of nitric oxide to allow the blood to recover its normal oxygen-carrying capacity. This risk may be increased in pediatric patients and other individuals with reduced levels of the enzyme methemoglobin reductase. Formation of methemoglobin at serum levels > 5% with inhaled nitric oxide at concentrations < 20 ppm is very rare (may affect up to 1 in 10,000 people).
• Bleeding time: A preclinical study showed that inhaled nitric oxide may increase bleeding time. However, controlled clinical studies have not shown significant differences between the control group and the treated group regarding hemorrhagic complications.

Systemic disorders and administration site conditions

• Lack of response to treatment may occur in 30–45% of cases.
• Significant increases in NO levels with low therapeutic doses (< 20 ppm) of inhaled NO, as well as clinical evidence of NO toxicity, are very rare complications (may affect up to 1 in 10,000 people).
• Abrupt discontinuation of inhaled nitric oxide therapy very frequently (very common frequency: may affect more than 1 in 10) causes rapid rebound reactions characterized by intense pulmonary vasoconstriction and hypoxemia.

If any side effect worsens, or if you notice any side effects not listed in this leaflet, contact your doctor or other healthcare professionals.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at the following website:
https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store NOXAP

Keep this medicine out of the sight and reach of children.
Do not use NOXAP after the expiry date stated on the cylinder label after “EXP”.
Follow all regulations regarding the handling of pressurized cylinders.
Storage is supervised by local specialists at the hospital. Store cylinders
in well-ventilated rooms or storage areas protected from rain and direct sunlight.
Protect cylinders from impact, falls, oxidizing and flammable materials, moisture, heat sources, or
ignition sources.
Storage in the pharmacy department
Keep cylinders in a dedicated, locked, clean, and well-ventilated area reserved exclusively for the storage of medicinal gases. This area must include a separate, dedicated facility for the storage of nitric oxide cylinders.
Storage in the medical department
Cylinders must be stored in a location equipped with appropriate fixtures to ensure they remain in an upright position.

6. Package contents and other information

What NOXAP contains
NOXAP is a combination gas.

• The active substance is: nitric oxide 800 ppm (mol/mol)
• The other component is: nitrogen.

Description of the appearance of NOXAP and the contents of the pack
NOXAP is a compressed medicinal gas.
NOXAP is stored in high-pressure cylinders made of aluminum or aluminum with an outer elastomeric layer. The valves sealing the cylinders are made of stainless steel. The cylinder pack sizes are 2 l, 5 l, 10 l, 20 l, and 40 l.
NOXAP is introduced into these cylinders in gaseous form at a pressure of 200 bar. Not all pack sizes may be commercialized.

The color code for the cylinder is light blue for the dome and white for the body.
Marketing Authorization Holder and Manufacturer
SOCIEDAD ESPANOLA DE CARBUROS METALICOS, S.A.
AVDA DE LA FAMA, 1
08940 CORNELLA DE LLOBREGAT
Spain
Marketing Authorization Holder in Italy:
Sapio Life S.r.l.
Via S. Pellico 48
20900 Monza
Italy
Tel. +39 039 83981
Manufacturer:
S.E. de Carburos Metálicos, S.A.
Polígon Nord-Est, C-35 km 59
08470 Sant Celoni (Barcelona)
Spain
This medicinal product is authorized in the European Economic Area Member States under the following names:
Belgium: NOXAP 800 ppm mol/mol, medicinaal gas, samengeperst
Netherlands: NOXAP 800 ppm mol/mol, medicinaal gas, samengeperst
France: NOXAP 800 ppm mol/mol, gaz médicinal comprimé
Portugal: NOXAP 800 ppm mol/mol, gás medicinal comprimido
Czech Republic: NOXAP 800 ppm mol/mol, medicinální plyn, stlačený
Germany: NOXAP 800 ppm Mol/Mol Gas zur medizinischen Anwendung, druckverdichtet
Spain: NOXAP 800 ppm mol/mol, gas medicinal comprimido
Poland: NOXAP 800 ppm mol/mol, gaz medyczny, sprężony
Italy: NOXAP 800 ppm mol/mol, gas medicinale compresso
To be completed with national information