INOXGEN 400 PPM MOL/MOL COMPRESSED MEDICAL GAS

Introduction

Package Leaflet: Information for the User

Inoxgen 400 ppm mol/mol compressed medicinal gas

Inoxgen 800 ppm mol/mol compressed medicinal gas

Inoxgen 1000 ppm mol/mol compressed medicinal gas

Nitric Oxide

Read all of this leaflet carefully before you start using this medicine because it contains important information for you.

• Keep this leaflet, you may need to read it again.
• If you have any further questions, ask your doctor or your child's doctor or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.
• If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.

Contents of the pack:

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

1. What Inoxgen is and what it is used for

Inoxgen contains nitric oxide, a gas indicated for the treatment of:

• Newborns with pulmonary insufficiency associated with high blood pressure in the lungs, a condition known as hypoxic respiratory failure. When inhaled, this gas mixture can improve blood flow through the lungs, which can contribute to increasing the amount of oxygen that reaches the child's blood.
• Newborns, infants, children, and adolescents from 0 to 17 years and adults with pulmonary hypertension related to cardiac surgery. This gas mixture can improve cardiac function and increase blood flow in the lungs, which can help increase the amount of oxygen that reaches the blood.

2. What you need to know before you use Inoxgen

Do not use Inoxgen:

• if you (as a patient) or your child (as a patient) are allergic (hypersensitive) to nitric oxide or any of the other components of Inoxgen (listed in section 6).
• If you have been informed that you (as a patient) or your child (as a patient) have abnormal circulation in the heart.

Warnings and precautions

Consult your doctor or nurse before starting to use Inoxgen.

Inhaled nitric oxide may not always be effective, so it may be necessary to consider alternative therapies for you or your child.

Inhaled nitric oxide may affect the blood's ability to transport oxygen. This should be monitored through blood samples, and if necessary, the dose of inhaled nitric oxide should be reduced.

Nitric oxide can react with oxygen to form nitrogen dioxide, which can irritate the respiratory tract. You or your child's doctor can monitor the nitrogen dioxide levels, and in the case of high values, the treatment with Inoxgen should be adjusted by reducing it accordingly.

Inhaled nitric oxide may have a mild effect on platelets (components that help blood clotting) or those of your child, so it should be observed, and any signs of bleeding or hematoma should be reported directly to the doctor.

No effect has been documented in newborns with malformations where the diaphragm is not completely present, also called "congenital diaphragmatic hernia".

In the case of newborns with special cardiac malformations, which doctors call "congenital heart disease", the use of inhaled nitric oxide may worsen circulation.

Children

The use of Inoxgen is not recommended in premature children less than 34 weeks of gestation.

Other medicines and Inoxgen

Your doctor will decide when to treat you or your child with Inoxgen and other medicines and will carefully monitor the treatment.

Inform your doctor if you (as a patient) or your child (as a patient) are using or have recently used any other medicine.

Some medicines may affect the blood's ability to transport oxygen. These include prilocaine (a local anesthetic used to relieve pain in minor procedures, such as sutures or minor surgical or diagnostic procedures) or glyceryl trinitrate (used to treat angina pectoris). Your doctor will check that the blood contains enough oxygen when taking these medicines.

Pregnancy and breastfeeding

The use of Inoxgen should be avoided during pregnancy and breastfeeding.

If you are pregnant or breastfeeding, think you may be pregnant, or plan to become pregnant, consult your doctor before using Inoxgen.

Consult your doctor or pharmacist before starting to take any medicine.

3. How to use Inoxgen

Follow exactly the administration instructions of this medicine indicated by your doctor. In case of doubt, consult your doctor again.

Your doctor will determine the correct dose of Inoxgen and will administer Inoxgen to your lungs or those of your child through a system designed for the administration of this gas. This administration system will ensure that the correct amount of nitric oxide is administered by diluting Inoxgen with an oxygen/air mixture immediately before administration.

For your safety or that of your child, the systems intended for the administration of Inoxgen are equipped with devices that constantly measure the amount of nitric oxide, oxygen, and nitrogen dioxide (a chemical substance obtained by mixing nitric oxide and oxygen) being administered to the lungs.

Your doctor will determine how long the treatment with Inoxgen should last for you or your child.

The recommended dose of Inoxgen is 10 to 20 ppm (maximum dose for children of 20 ppm and for adults of 40 ppm) parts per million of gas for inhalation by you or your child. The lowest effective dose should be sought.

Usually, treatment is required for around 4 days in newborns with pulmonary insufficiency associated with high blood pressure in the lungs. In children and adults with pulmonary hypertension associated with cardiac surgery, Inoxgen is normally administered for 24-48 hours. However, treatment with Inoxgen may be prolonged.

If you use more Inoxgen than you should

Excess inhaled nitric oxide may affect the blood's ability to transport oxygen. This will be controlled through blood samples, and if necessary, the amount of Inoxgen will be reduced, as well as considering the administration of medicines such as vitamin C, methylene blue, or eventually a blood transfusion to improve oxygen transport capacity.

If you stop treatment with Inoxgen

Treatment with Inoxgen should not be stopped abruptly.

There have been cases of low blood pressure or a rebound effect of increased pressure in the lungs when treatment with Inoxgen is suddenly stopped without first reducing the dose.

Your doctor will gradually reduce the amount of Inoxgen prescribed for you or your child when treatment is about to end, to allow the circulation in the lungs to adjust to oxygen/air without Inoxgen. Consequently, this may take one or two days before you or your child finish treatment with Inoxgen.

If you have any other questions about the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Your doctor will examine you or your child for side effects.

Very common side effects (may affect more than 1 in 10 patients)associated with treatment with Inoxgen include:

-Low platelet count.

Common side effects (may affect up to 1 in 100 people)associated with treatment with Inoxgen include:

• Hypotension, shortness of breath, or pulmonary collapse.

Uncommon side effects (may affect between 1 in 100 and 1 in 1,000 people)are:

-Increased methemoglobin, and therefore lower oxygen transport capacity.

Side effects of unknown frequency (cannot be estimated from the available data)are:

-Bradycardia (low heart rate) or excessively low oxygen level in the blood (oxygen desaturation/hypoxemia) due to sudden interruption of treatment.

-Headache, dizziness, dry throat, or difficulty breathing after accidental exposure to nitric oxide in the ambient air (e.g., equipment leak or cylinder leak).

You should report directly to the staff if you experience a headache while near your child when they receive Inoxgen.

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if they are possible side effects not listed in this leaflet. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: www.notificaRAM.es.

By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Inoxgen

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date stated on the packaging. The expiry date is the last day of the month indicated.

All rules related to the handling of pressure vessels must be followed.

Gas cylinders must be protected to avoid breakage or falls.

They should be kept away from any combustible or flammable material, humidity, heat sources, or ignition, and should be stored at a temperature between -10°C and +50°C.

The cylinders must be protected to avoid breakage, falls, combustible and flammable materials, humidity, heat sources, or ignition.

Storage in the pharmacy department

The cylinders should be stored in a well-ventilated, clean, and locked area, exclusively for the storage of medicinal gas. Within this area, there should be a separate installation dedicated to the storage of nitric oxide cylinders.

Storage in the medical department

The cylinder should be placed in an area equipped with suitable material to keep it upright.

The cylinders should be stored in well-ventilated areas.

When the cylinder is empty, do not throw it away. The supplier will collect the empty gas cylinders.

6. Container Content and Additional Information

Inoxgen Composition

The active ingredient is nitric oxide 400 ppm mol/mol, 800 ppm mol/mol, and 1000 ppm mol/mol

The other component is: nitrogen

Product Appearance and Container Content

Inoxgen is an inhalation gas supplied in aluminum cylinders at 150 bar pressure and at 15°C with a positive pressure valve made of stainless steel or brass.

The gas cylinders are presented with the following volumes expressed in liters of water: 5L, 10L, 20L, 40L, and 50L.

5L cylinder with 0.75 m3 of gas that weighs 0.85 kg.

10L cylinder with 1.5 m3 of gas that weighs 1.7 kg. 20L cylinder with 3.0 m3 of gas that weighs 3.4 kg

40L cylinder with 6.0 m3 of gas that weighs 6.8 kg. 50L cylinder with 7.5 m3 of gas that weighs 8.5 kg

Only some container sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Marketing Authorization Holder

NIPPON GASES ESPAÑA, S.L.U.

c/ Orense, 11

28020 Madrid

Manufacturer

Nippon Gases España S.L.U.

Calle Embajadores 474,.

28053 Madrid.

Spain

This Medicinal Product is Authorized in the Member States of the European Economic Area under the Following Names

Date of the Last Revision of this Prospectus:February 2021

Other Sources of Information

Detailed and updated information on this medicinal product is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es/

----------------------------------------------------------------------------------------------------------------

This information is intended only for healthcare professionals:

Dosage

Persistent Pulmonary Hypertension in the Newborn (PPHN)

Inoxgen should only be used once respiratory support has been optimized. The maximum recommended dose of Inoxgen is 20 ppm. It is recommended not to exceed the maximum dose of 20 ppm. The maximum dose may be increased exceptionally according to the patient's response.

Inoxgen is used in ventilated newborns whose assisted ventilation is expected to last > 24 hours. As soon as possible, and within the first 4-24 hours of therapy, the dose should be reduced to 5 ppm as long as arterial oxygenation is adequate at this lower dose.

Inhaled nitric oxide therapy should be maintained at 5 ppm until an improvement in the newborn's oxygenation is observed, such that FiO2 (fraction of inspired air) is <0.60.

Treatment can be maintained for up to 96 hours or until oxygen desaturation has been resolved and the newborn is ready for gradual withdrawal of Inoxgen treatment. The duration of treatment is variable, usually less than 4 days.

Gradual Withdrawal

An attempt should be made to withdraw Inoxgen treatment once assisted ventilation has decreased substantially or after 96 hours of treatment. When the decision is made to discontinue inhaled nitric oxide therapy, the dose should be reduced by 1 ppm every 30 or 60 minutes, according to the prescription. If there are no changes in oxygenation during the administration of Inoxgen at 1 ppm (FiO2 should be increased by 10%), Inoxgen administration should be discontinued, and the newborn should be closely monitored for signs of hypoxemia. If oxygenation decreases by more than 20%, Inoxgen therapy should be resumed at 5 ppm, and its discontinuation should be re-evaluated after 12 to 24 hours.

Pulmonary Hypertension Associated with Cardiac Surgery

Inoxgen should only be used after conservative treatment has been optimized.

Newborns, infants, children, and adolescents from 0 to 17 years: The initial dose of inhaled nitric oxide is 10 ppm (parts per million) of inhaled gas. The dose may be increased up to 20 ppm if the minimum dose has not produced sufficient clinical effects. The minimum effective dose should be administered, and then this dose should be slowly reduced to 5 ppm as long as pulmonary arterial pressure and systemic arterial oxygenation remain adequate at this lower dose.

Adults: The initial dose of inhaled nitric oxide is 20 ppm (parts per million) of inhaled gas. This dose may be increased up to 40 ppm if the minimum dose has not produced sufficient clinical effects. The minimum effective dose should be administered, and then it should be slowly reduced to 5 ppm as long as pulmonary arterial pressure and systemic arterial oxygenation remain adequate at this lower dose. Treatment discontinuation should be considered if no beneficial physiological effects are observed after a 30-minute trial treatment

In children and adults with pulmonary hypertension associated with cardiac surgery, Inoxgen is usually administered for 24-48 hours. However, Inoxgen treatment may be prolonged.

Gradual Withdrawal

An attempt should be made to gradually withdraw Inoxgen treatment once hemodynamic parameters have stabilized, along with the withdrawal of ventilation and inotropic support.

The dose should be progressively reduced to 1 ppm over 30 minutes, continuously monitoring systemic and central pressure, and then the discontinuation should be performed. Gradual withdrawal should be attempted at least every 12 hours when the patient is stable with a low dose of Inoxgen.

Instructions for Use/Administration

All equipment, including connectors, tubes, and circuits, used in the administration of nitric oxide must be made of materials compatible with the gas.

From the point of view of corrosion, the administration system can be divided into two zones: 1) from the cylinder valve to the humidifier (dry gas) and 2) from the humidifier to the outlet (humid gas that may contain NO2).

Studies demonstrate that dry nitric oxide mixtures can be used with most materials. However, the presence of nitrogen dioxide and humidity creates an aggressive atmosphere.

Among metal construction materials, only stainless steel is recommended. The analyzed polymers that can be used in nitric oxide administration systems include polyethylene (PE) and polypropylene (PP).

Butyl rubber, polyamide, and polyurethane should not be used. Polychlorotrifluoroethylene, hexafluoropropene-vinylidene copolymer, and polytetrafluoroethylene have been extensively used with pure nitric oxide and other corrosive gases. They are considered inert, so their verification is not necessary.

To avoid any type of incident, the following instructions must be absolutely respected.

• before use, the good condition of the material must be checked.
• the cylinders must be kept away and well secured to avoid an unfortunate fall
• the valve must not be opened violently.
• a specific connection for medical use, in total compliance with the guidelines, and a pressure regulator that allows a pressure equivalent to at least 1.5 times the possible maximum operating pressure (200 bars) of the cylinder must be used.
• the pressure regulator must be purged with the nitrogen/nitric oxide mixture before each new use to prevent the inhalation of nitrogen dioxide.
• the pressure regulator should not be tightened with pliers, as the gasket could be crushed.