Nitric oxide messer

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT OXYDE D'AZOTE MESSER (NITRIC OXIDE MESSER)

Composition:

Active substance: nitric oxide (NO) 800 ppm (v/v);

2-liter gas cylinder filled at an absolute pressure of 200 bar contains 381 liters of gas at a pressure of 1 bar at a temperature of 15 °C;

10-liter gas cylinder filled at an absolute pressure of 200 bar contains 1903 liters of gas at a pressure of 1 bar at a temperature of 15 °C;

Excipient: nitrogen.

Pharmaceutical form. Medical gas. Compressed.

Main physicochemical properties: external appearance of cylinders: white body, turquoise-blue shoulder; absence of visible damage or external contamination, no leaks.

Pharmacotherapeutic group.

Other respiratory drugs.

ATC code R07AX01.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Nitric oxide is a substance produced in many cells of the body. It causes relaxation of vascular smooth muscle by binding to the heme portion of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, resulting in vasodilation. When administered by inhalation, nitric oxide induces selective dilation of pulmonary vessels.

Pharmacodynamic Effects

Inhaled nitric oxide increases arterial oxygen partial pressure (PaO₂) by dilating pulmonary vessels in better-ventilated regions of the lungs, thereby redistributing pulmonary blood flow from lung areas with low ventilation/perfusion ratio (V/Q) to areas where this ratio is within normal range.

Persistent pulmonary hypertension of the newborn may result from a primary developmental defect or may be a secondary condition arising from disorders such as meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia, and pulmonary hypoplasia. In these conditions, pulmonary vascular resistance is elevated, leading to secondary hypoxemia due to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In newborns with persistent pulmonary hypertension, inhaled nitric oxide may improve oxygenation (defined by a significant increase in PaO₂).

Clinical Efficacy and Safety

The efficacy of inhaled nitric oxide has been studied in term and near-term newborn infants with hypoxemic respiratory failure of various etiologies.

In the NINOS study, 235 newborn infants with hypoxemic respiratory failure were randomly assigned to two groups: one group (n = 114) received 100% O₂ with nitric oxide, and the other (n = 121) received 100% O₂ without nitric oxide. Nitric oxide was administered initially at a dose of 20 ppm, which was gradually reduced when possible to lower doses, with a mean duration of treatment of 40 hours. The objective of this double-blind, randomized, placebo-controlled study was to determine whether inhaled nitric oxide would reduce mortality and/or the need for extracorporeal membrane oxygenation (ECMO). In newborns who did not respond adequately to the 20 ppm dose, efficacy was tested at 80 ppm or with a control gas. The combined outcome of mortality and/or need for ECMO (prospectively defined primary endpoint) showed a significant benefit in the nitric oxide group (46% vs. 64%, p = 0.006). Data also indicated no additional benefit from higher doses of nitric oxide. Adverse events occurred with similar frequency in both groups. Follow-up assessments at 18 and 24 months of age showed comparable results in cognitive, motor, auditory, and neurological evaluations.

In the CINRGI study, 186 term and near-term newborn infants with hypoxemic respiratory failure and without hypoplasia were randomized into two groups: one received nitric oxide (n = 97), and the other received gaseous nitrogen (placebo; n = 89), initially at 20 ppm, gradually reduced to 5 ppm over 4–24 hours, with a mean treatment duration of 44 hours. The prospectively defined primary endpoint was the need for ECMO. A significantly lower proportion of infants in the nitric oxide group required ECMO compared to the control group (31% vs. 57%, p < 0.001). The nitric oxide group also showed significant improvement in oxygenation, as measured by PaO₂, oxygenation index, and alveolar-arterial oxygen gradient (p < 0.001 for all parameters). Of the 97 patients receiving nitric oxide, 2 (2%) discontinued the study due to methemoglobin levels exceeding 4%. The frequency and number of adverse reactions were similar in both study groups.

During cardiac surgery, patients often experience increased pulmonary artery pressure due to pulmonary vasoconstriction. Inhaled nitric oxide selectively reduces pulmonary vascular resistance and lowers elevated pulmonary artery pressure. This enhances right ventricular ejection fraction. These effects, in turn, improve circulation and oxygenation in the pulmonary circulation.

In the INOT27 study, 795 preterm infants (with gestational age up to 29 weeks) with hypoxemic respiratory failure were randomized into two groups: the first received nitric oxide (n = 395) at 5 ppm, and the second received nitrogen (placebo, n = 400), starting within the first 24 hours of life; treatment lasted at least 7 days, with a maximum duration of 21 days. The primary combined endpoint of death or bronchopulmonary dysplasia at 36 weeks' gestational age showed no significant difference between the two groups, even after adjusting for gestational age as a covariate (p = 0.40) or birth weight as a covariate (p = 0.41). The overall incidence of intraventricular hemorrhage was 114 cases (28.9%) in the nitric oxide group and 91 cases (22.9%) in the control group. Overall mortality at 36 weeks' gestational age was slightly higher in the nitric oxide group: 53/395 (13.4%) compared to 42/397 (10.6%) in the control group.

In the INOT25 study, which evaluated the efficacy of nitric oxide administration in preterm infants with hypoxia, no improvement in survival without bronchopulmonary dysplasia was demonstrated. However, this study also failed to show differences in the incidence of intraventricular hemorrhage or mortality.

In the BALLR1 study, which also assessed the efficacy of nitric oxide in preterm infants, but where therapy was initiated on day 7 at a dose of 20 ppm, a significant improvement in survival without bronchopulmonary dysplasia at 36 weeks' gestational age was observed: 121 (45%) vs. 95 (35.4%), p < 0.028. No increase in adverse events during the study was observed.

Nitric oxide chemically reacts with oxygen to form nitrogen dioxide.

Nitric oxide has an unpaired electron, making this molecule reactive. In biological tissue, nitric oxide can form peroxynitrite with superoxide (O₂^–), an unstable compound that may cause further tissue damage through redox reactions. Additionally, nitric oxide has affinity for metalloproteins and may also react with SH-groups of proteins to form nitroso compounds. The clinical significance of nitric oxide's chemical reactivity in tissue is unknown. Studies show that nitric oxide exerts pulmonary pharmacodynamic effects even at very low airway concentrations as low as 1 ppm.

The European Medicines Agency has waived the obligation to submit results of studies investigating the efficacy of inhaled nitric oxide in all pediatric patient groups with persistent pulmonary hypertension and other cardiorespiratory disorders.

Pharmacokinetics

Absorption and Distribution

The pharmacokinetics of nitric oxide have been studied in clinical trials involving adult patients. After inhaled administration, nitric oxide is systemically absorbed. The majority passes through the pulmonary capillary membrane and binds to hemoglobin that is 60–100% oxygen-saturated. At this level of oxygen saturation, nitric oxide primarily combines with oxyhemoglobin to form methemoglobin and nitrate. At low oxygen saturation, nitric oxide binds to deoxyhemoglobin, temporarily forming nitrosylhemoglobin, which under the influence of oxygen is converted into nitrogen oxides and methemoglobin. Within the pulmonary system, nitric oxide may react with oxygen and water to form nitrogen dioxide and nitrite, respectively, which then interact with oxyhemoglobin to form methemoglobin and nitrates. Thus, the main end products of nitric oxide metabolism entering the systemic circulation are methemoglobin and nitrates.

Biotransformation

The pharmacokinetics of methemoglobin were studied as a function of time and nitric oxide concentration administered to newborns with respiratory failure. Methemoglobin concentration increases during the first 8 hours after initiation of nitric oxide administration. Mean methemoglobin levels were less than 1% in the placebo group and in groups receiving nitric oxide at 5 and 20 ppm, but increased to approximately 5% in patients receiving 80 ppm nitric oxide. Methemoglobin levels exceeding 7% were observed only in 35% of patients in the group receiving 80 ppm. The mean time to peak methemoglobin concentration was 10 ± 9 (standard deviation) hours (average 8 hours) in these patients; however, in one patient, levels above 7% were observed only after 40 hours.

Elimination

Nitrates are the main metabolites of nitric oxide excreted in urine, accounting for more than 70% of the inhaled nitric oxide dose. Nitrates are eliminated from plasma by the kidneys at a rate close to the glomerular filtration rate.

Clinical characteristics.

Indications:

"Nitric Oxide Messer" in combination with mechanical ventilation and other appropriate active substances is indicated for:

• treatment of neonates with gestational age ≥ 34 weeks with hypoxic respiratory failure associated with clinical and echocardiographic signs of pulmonary hypertension, to improve oxygenation and reduce the need for extracorporeal membrane oxygenation;
• use as one component in the management of intra- and postoperative pulmonary hypertension in adults and neonates, infants, toddlers, older children, and adolescents (aged 0 to 17 years) undergoing cardiac surgery, aimed at selectively reducing pulmonary artery pressure, improving right ventricular function and oxygenation.

Contraindications.

Hypersensitivity to the active or any excipient substance.

Contraindicated in neonates with confirmed right-to-left or significant left-to-right shunting of blood.

Special safety precautions.

Inadequate response

If there is no appropriate clinical response within 4–6 hours after initiation of therapy with "Nitric Oxide Messer", appropriate measures should be taken.

To prevent deterioration associated with abrupt discontinuation of "Nitric Oxide Messer" inhalation during patient transport to another hospital, nitric oxide must remain available during transport. Decisions regarding the use of rescue therapies such as extracorporeal membrane oxygenation, if available, should be made based on patient deterioration or lack of improvement, in accordance with current guidelines.

Special patient groups

Clinical studies have not demonstrated benefit from nitric oxide inhalation in patients with congenital diaphragmatic hernia.

Nitric oxide inhalation therapy may exacerbate heart failure in cases of left-to-right shunting. This is due to undesirable pulmonary vasodilation caused by nitric oxide, leading to further increase in existing pulmonary hyperperfusion and potentially worsening forward or backward heart failure. Therefore, pulmonary artery catheterization or central hemodynamic assessment via echocardiography is recommended prior to initiating nitric oxide. Inhaled nitric oxide should be administered with caution in patients with complex cardiac defects where elevated pulmonary artery pressure is essential for maintaining circulation.

Inhaled nitric oxide should also be used cautiously in patients with left ventricular dysfunction and elevated pulmonary capillary wedge pressure, as this increases the risk of developing heart failure (e.g., pulmonary edema).

Discontinuation of therapy

Abrupt cessation of "Nitric Oxide Messer" administration must not occur, as it may lead to increased pulmonary artery pressure (PA) and/or worsening of blood oxygenation (PaO2). Deterioration in oxygenation and increased PA pressure may also be observed in neonates who do not show a clear response to "Nitric Oxide Messer" therapy. Discontinuation of nitric oxide inhalation should be performed gradually. Patients being transported to other medical facilities for further treatment who require nitric oxide inhalation must receive continuous nitric oxide delivery during transport. The physician must have a backup nitric oxide delivery system available at the patient’s bedside.

Methemoglobin formation

Large amounts of inhaled nitric oxide are systemically absorbed. The main systemic metabolites of nitric oxide are methemoglobin and nitrates.

Formation of nitrogen dioxide (NO2)

NO2 is rapidly formed in gas mixtures containing nitric oxide and O2, and thus nitric oxide may cause inflammation and airway injury. Nitric oxide dosing should be reduced if NO2 levels exceed 0.5 ppm.

Effect on platelets

Animal models have shown that nitric oxide may impair hemostasis by increasing bleeding time. Data in adult humans are conflicting, and results from randomized controlled trials in term and near-term neonates with hypoxic respiratory failure showed no increase in bleeding time.

Regular monitoring of hemostasis parameters and measurement of bleeding time are recommended if "Nitric Oxide Messer" therapy lasts longer than 24 hours, especially in patients with functional or quantitative platelet disorders, low levels of coagulation factors, or those receiving anticoagulant therapy.

Pulmonary veno-occlusive disease

Cases of life-threatening pulmonary edema have been reported following nitric oxide administration in patients with pulmonary veno-occlusive disease. Therefore, veno-occlusive disease should be carefully considered if signs of pulmonary edema develop in a patient with pulmonary hypertension after nitric oxide administration. If veno-occlusive disease is confirmed, nitric oxide administration must be discontinued.

Use and storage of "Nitric Oxide Messer"

When connecting a "Nitric Oxide Messer" cylinder to the delivery system, always verify that the cylinder concentration matches the concentration for which the system is calibrated.

To avoid all adverse outcomes, the following instructions must always be followed:

• Equipment integrity should be checked before use.
• Gas cylinders must be securely fastened to prevent falling.
• Valves must not be opened abruptly; opening should be gradual.
• Cylinders without a protective cap or shroud must not be used.
• The pressure regulator must be flushed with a nitrogen and nitric oxide mixture before each new use to prevent inhalation of nitrogen dioxide.
• Damaged valves must not be used or attempted to be repaired. Return them to the distributor or manufacturer.
• The pressure regulator must not be tightened with pliers, as this risks damaging the sealing gasket.

All equipment, including connectors, tubing, and circuits used for nitric oxide delivery, must be made of materials compatible with this gas. From a corrosion standpoint, the delivery system can be divided into two zones: 1 — from the gas cylinder to the humidifier (dry gas), and 2 — from the humidifier to the outlet (humidified 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 environment. Among metallic materials, only stainless steel is recommended. Among polymers validated for use in nitric oxide delivery systems are polyethylene and polypropylene. Butyl rubber, polyamide, and polyurethane must not be used. Polychlorotrifluoroethylene, hexafluoropropylene-vinylidene copolymer, and polytetrafluoroethylene are widely used with pure nitric oxide and other corrosive gases and are considered so inert that testing is not required.

Connecting a pipeline system for nitric oxide to cylinder gas supply systems, fixed pipeline networks, and air distributors is prohibited.

Generally, there is no need to remove excess gas, but attention must be paid to ambient air quality at the workplace, and minor concentrations of NO or NO2/NOx must not exceed established threshold levels for occupational exposure. Accidental exposure of hospital personnel to nitric oxide has been associated with adverse reactions.

Disposal of gas cylinders

Empty gas cylinders must not be discarded. Spent gas cylinders must be returned to the supplier.

Interaction with other medicinal products and other forms of interaction.

Interaction studies have not been conducted.

Based on available information, clinically significant interactions with other medicinal products used in the treatment of hypoxic respiratory failure cannot be excluded. "Nitric Oxide Messer" may increase the risk of methemoglobinemia when used concomitantly with nitric oxide donors, including sodium nitroprusside and nitroglycerin. Inhalation of nitric oxide has been safely performed together with tolazoline, dopamine, dobutamine, steroids, surfactant, and during high-frequency ventilation.

Combined use with other vasodilators (e.g., sildenafil) has not been widely studied. Available data suggest an additive effect on systemic circulation, pulmonary artery pressure, and right ventricular function. Inhalation of nitric oxide concomitantly with other vasodilators acting via cGMP or cAMP pathways should be performed with caution.

There is an increased risk of methemoglobin formation when substances that may elevate methemoglobin levels are administered together with nitric oxide (e.g., alkyl nitrates and sulfonamides). Therefore, substances that increase methemoglobin levels should be used cautiously during inhaled nitric oxide therapy. Oral, parenteral, and topical use of prilocaine may cause methemoglobinemia. Patients receiving both "Nitric Oxide Messer" and medicinal products containing prilocaine should be closely monitored.

In the presence of oxygen, nitric oxide is rapidly oxidized into metabolites toxic to bronchial epithelium and the alveolar-capillary membrane. Nitrogen dioxide (NO2) is the primary substance formed, which may cause airway inflammation and injury. Animal model studies indicate that even low levels of NO2 increase susceptibility to respiratory infections. During nitric oxide therapy, NO2 concentration must remain below 0.5 ppm when the nitric oxide dose is within the range up to 20 ppm. If NO2 concentration exceeds 1 ppm at any time, the nitric oxide dose must be immediately reduced.

Usage characteristics.

Use during pregnancy or breastfeeding.

Pregnancy

There is insufficient information regarding the use of nitric oxide in pregnant women. The potential risk to humans is unknown.

Lactation

It is unknown whether nitric oxide is excreted in human milk.

Nitric oxide Messer should not be used during pregnancy or lactation.

Fertility

Studies on the effect on fertility have not been conducted.

Ability to affect reaction speed when driving or operating machinery.

Not applicable.

Method of Administration and Dosage

Persistent Pulmonary Hypertension of the Newborn

Nitric oxide should be administered under the supervision of a physician specialized in neonatal intensive care. The product should only be used in neonatal units where the staff have received appropriate training in the use of nitric oxide delivery systems. "Nitric Oxide Messer" may only be used as prescribed by a neonatologist.

"Nitric Oxide Messer" may be administered to newborns who are on mechanical ventilation and require respiratory support for 24 hours or longer. "Nitric Oxide Messer" should only be used after optimization of mechanical ventilation. Such measures include adjustment of tidal volume, pressure, and lung volume recruitment (surfactant, high-frequency ventilation, and positive end-expiratory pressure).

Pulmonary Hypertension Associated with Cardiac Surgery

Nitric oxide should be administered under the supervision of a physician specialized in anesthesia and intensive care of cardiothoracic patients. The product should only be used in cardiothoracic units where the staff have received appropriate training in the use of nitric oxide delivery systems. "Nitric Oxide Messer" may only be used as prescribed by an anesthesiologist or intensive care physician.

Dosage

Persistent Pulmonary Hypertension of the Newborn

The maximum recommended dose of "Nitric Oxide Messer" is 20 ppm (parts per million); this dose must not be exceeded. In pivotal clinical trials, the initial dose was 20 ppm. As soon as possible within 4–24 hours after initiation of therapy, the dose should be reduced to 5 ppm, provided arterial blood oxygenation remains adequate at this lower dose. Inhalation of nitric oxide at a dose of 5 ppm should be continued until improvement in oxygenation occurs in the newborn, for example, when FiO2 (fraction of inspired oxygen) is < 0.60.

Treatment may be continued for up to 96 hours or until the cause of desaturation is resolved and the newborn is ready to discontinue therapy with "Nitric Oxide Messer." The duration of treatment may vary but usually does not exceed four days.

Weaning from Mechanical Ventilation

Attempts to discontinue "Nitric Oxide Messer" should be made after significant reduction in ventilatory support or 96 hours after initiation of therapy. After the decision to discontinue inhaled nitric oxide has been made, the dose should be reduced to 1 ppm over a period of 30 minutes to 1 hour. If there are no changes in oxygenation during administration of nitric oxide at 1 ppm, FiO2 should be increased by 10%, the administration of "Nitric Oxide Messer" should be stopped, and the newborn should be closely monitored for signs of hypoxemia. If oxygenation decreases by more than 20%, therapy with "Nitric Oxide Messer" should be resumed at a dose of 5 ppm, and another attempt to discontinue therapy should be made after 12–24 hours. Newborns in whom discontinuation of "Nitric Oxide Messer" is not possible within 4 days should be carefully evaluated to exclude the presence of other diseases.

Pulmonary Hypertension Associated with Cardiac Surgery

"Nitric Oxide Messer" may only be used after optimization of the main parameters of mechanical ventilation. In clinical studies, nitric oxide was administered in conjunction with standard treatment regimens during surgery, including inotropic and vasoactive drugs. Hemodynamic parameters and oxygenation should be closely monitored during inhalation of "Nitric Oxide Messer."

Newborns, Infants, Toddlers, Older Children, and Adolescents (aged
0 to 17 years)

The initial dose of nitric oxide is 10 ppm (parts per million) of inhaled gas. This dose may be increased to 20 ppm if lower concentrations do not achieve the desired clinical effect. The lowest effective dose should be used and subsequently reduced to 5 ppm if pulmonary artery pressure and systemic arterial blood oxygenation remain adequate.

Clinical data on the recommended dose for patients aged 12–17 years are limited.

Adults

The initial dose of nitric oxide is 20 ppm (parts per million) of inhaled gas. This dose may be increased to 40 ppm if lower concentrations do not achieve the desired clinical effect. The lowest effective dose should be used and subsequently reduced to 5 ppm if pulmonary artery pressure and systemic arterial blood oxygenation remain adequate.

The effect of inhaled nitric oxide is rapid, with reduction in pulmonary artery pressure and improvement in oxygenation observed within 5–20 minutes. If the response is inadequate, the dose may be titrated with intervals of at least 10 minutes.

Discontinuation of therapy should be considered if no beneficial physiological effect is observed within 30 minutes of initiation of treatment.

Therapy may be initiated at any point during surgery if reduction of pulmonary pressure is required. In clinical studies, treatment often began prior to weaning from cardiopulmonary bypass. Nitric oxide inhalation was continued for up to 7 days in the postoperative period, although the average duration of treatment was 24–48 hours.

Discontinuation of Therapy

Attempts to discontinue "Nitric Oxide Messer" therapy should begin as soon as hemodynamic parameters stabilize and the patient no longer requires respiratory or inotropic support. Discontinuation of nitric oxide inhalation must be gradual. The dose should be stepwise reduced to 1 ppm over 30 minutes, with careful monitoring of systemic and central pressures, before completely stopping gas delivery. Attempts to discontinue therapy should be made at least every 12 hours if the patient remains stable on low-dose "Nitric Oxide Messer" inhalation.

Too rapid discontinuation of inhaled nitric oxide is associated with the risk of rebound increase in pulmonary artery pressure and associated circulatory failure.

Method of Administration

For endotracheopulmonary use.

The patient receives nitric oxide via mechanical ventilation, with the gas delivered in an oxygen-air mixture using a nitric oxide delivery device. Before initiating therapy and during device setup, ensure that device settings correspond to the concentration parameters of the gas cylinder.

The delivery system must ensure a constant concentration of inhaled "Nitric Oxide Messer," independent of the operation of the mechanical ventilator. When using mechanical ventilators for newborns with continuous oxygen delivery, this can be achieved by infusing a low flow of "Nitric Oxide Messer" through the inspiratory limb of the ventilator circuit. Mechanical ventilators for newborns with intermittent oxygen delivery may cause rapid fluctuations in nitric oxide concentration. The nitric oxide delivery system used with such ventilators must be appropriately configured to avoid sharp variations in nitric oxide concentration.

The concentration of inhaled "Nitric Oxide Messer" must be continuously monitored at the inspiratory limb of the ventilator circuit. Simultaneously, at the same site, the concentration of nitrogen dioxide (NO₂) and FiO₂ must be determined using appropriately calibrated monitoring equipment. For patient safety, the alarm system must be set to detect changes in the dosage of "Nitric Oxide Messer" (± 2 ppm from the prescribed dose), NO₂ (1 ppm), and FiO₂ (± 0.05). The pressure in the "Nitric Oxide Messer" gas cylinder should also be continuously displayed to allow timely cylinder replacement and ensure uninterrupted gas delivery; spare cylinders must always be available for this purpose. Therapy with "Nitric Oxide Messer" must remain possible during manual ventilation, for example, during suctioning, patient transport, or resuscitation procedures.

An emergency battery power source and a backup nitric oxide delivery system must be available in case of system failure or power interruption. The power source for monitoring equipment must operate independently of the mechanical ventilator.

The upper occupational exposure limit (time-weighted average) for nitric oxide according to most countries' regulations is 25 ppm over 8 hours (30 mg/m³), and the corresponding limit for NO₂ is 2–3 ppm (4–6 mg/m³).

Personnel Training on Use

During hospital staff training, the following issues must be addressed:

Proper setup and connections:

• Connecting the gas cylinder to the ventilator circuit.

Use:

• Procedure for checking key parameters before use (a checklist of steps to be performed before each initiation of therapy to ensure proper system function and removal of NO₂ from the system).
• Setting the correct inhaled nitric oxide concentration on the device.
• Setting alarm limits on the monitor for upper and lower limits of acceptable concentrations of NO, NO₂, and O₂.
• Use of a backup manual gas delivery system.
• Procedure for proper replacement of gas cylinders and purging system.
• Error and malfunction signals.
• Calibration of monitors for NO, NO₂, and O₂.
• Procedure for monthly system function checks.

Monitoring Methemoglobin (MetHb) Formation

Newborns and infants have lower methemoglobin reductase activity compared to adults. Methemoglobin levels should be measured one hour after initiation of "Nitric Oxide Messer" therapy using an analyzer capable of distinguishing fetal hemoglobin and methemoglobin. If levels exceed 2.5%, the dose of "Nitric Oxide Messer" should be reduced and administration of methylene blue should be considered. Although the likelihood of significant methemoglobin increase is low when baseline levels are low, it is extremely important to repeat methemoglobin measurements daily or every other day.

In adult patients undergoing cardiac surgery, methemoglobin levels should be measured one hour after initiation of "Nitric Oxide Messer" therapy. If methemoglobin fraction rises to levels that may impair oxygen delivery, the dose of "Nitric Oxide Messer" should be reduced and administration of methylene blue should be considered.

Monitoring Nitrogen Dioxide (NO₂) Formation

Immediately after initiating treatment for each patient, steps must be taken to clear the system of NO₂. The lowest possible NO₂ concentration should be maintained, always below 0.5 ppm. If NO₂ levels exceed 0.5 ppm, possible system malfunctions should be investigated and the NO₂ analyzer recalibrated; the dose of "Nitric Oxide Messer" and/or FiO₂ should also be reduced if possible. If unexpected changes in "Nitric Oxide Messer" concentration occur, possible system malfunctions should be investigated and the analyzer recalibrated.

Children.

The safety and efficacy of "Nitric Oxide Messer" in preterm infants with gestational age less than 34 weeks have not been established. Based on available information, clear recommendations or appropriate dosage cannot be determined.

Overdose

Symptoms

Overdose of "Nitric Oxide Messer" may manifest as elevated levels of methemoglobin and NO₂. Increased NO₂ concentration may cause acute lung injury. Elevated methemoglobin levels reduce oxygen delivery through the circulation.

Treatment

In clinical studies, NO₂ levels > 3 ppm and methemoglobin levels > 7% were managed by reducing the dose or discontinuing nitric oxide inhalation.

Methemoglobinemia that persists after dose reduction or discontinuation of therapy may be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, depending on the clinical situation.

Adverse reactions

Sudden discontinuation of nitric oxide may cause a rebound effect; decreased oxygenation and increased central pressure followed by a reduction in systemic blood pressure. The rebound effect is the most common adverse reaction associated with clinical use of inhaled nitric oxide. This effect may occur both at the beginning of therapy and after prolonged treatment.

In one clinical study (NINOS), the following events were observed in the treatment group: intracranial hemorrhage, grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring initiation of anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage.

The table below lists adverse reactions observed during administration of inhaled nitric oxide or during the CINGRI study involving 212 newborn infants, or during post-marketing surveillance in newborns (age < 1 month).

The frequency of occurrence is defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000), unknown (cannot be estimated based on available information).

Body systems	Very common	Common	Uncommon	Rare	Very rare	Unknown
Blood and lymphatic system	Thrombocytopeniaa	-	Methemoglobinemiaa	-	-	-
Heart	-	-	-	-	-	Bradycardiab (after sudden discontinuation of therapy)
Vascular	-	Hypotensiona,b,d	-	-	-	-
Respiratory, thoracic and mediastinal system	-	Atelectasisa	-	-	-	Hypoxiab,d Dyspneac Chest discomfortc Throat drynessc
Nervous system	-	-	-	-	-	Headachec Dizzinessc

a Observed during clinical trials.

b Observed during post-marketing surveillance.

c Observed during post-marketing surveillance; occurred in healthcare professionals who accidentally inhaled the substance.

d Post-marketing safety monitoring: effects associated with sudden discontinuation of the medicinal product and/or malfunction of the delivery system. Rapid rebound reactions such as increased pulmonary vasoconstriction and hypoxia have been reported following abrupt withdrawal of inhaled nitric oxide therapy, which may accelerate cardiovascular collapse.

Specific adverse reactions

Inhaled nitric oxide may increase blood methemoglobin levels.

Incompatibility. In the presence of oxygen, NO rapidly forms NO₂.

Shelf life.

4 years.

Storage conditions.

Store at a temperature not exceeding +50 °C.

All regulations regarding handling of compressed gas cylinders must be observed.

Store in the original gas cylinder. The contents of the original gas cylinder must not be transferred to another gas cylinder.

Store gas cylinders in well-ventilated areas or outdoors under shelters with good ventilation, where they will be protected from rain and direct sunlight.

Gas cylinders must be protected from impact, dropping, contact with oxidizing and flammable materials, moisture, and sources of heat or ignition.

Storage in a pharmacy

Gas cylinders should be stored in a ventilated, clean, and secured area designated exclusively for storage of medical gases. A separate area within this location should be allocated specifically for storage of nitric oxide gas cylinders.

Storage in a healthcare facility

The gas cylinder should be placed on a specially equipped platform with appropriate securing to maintain the cylinder in an upright position.

Transportation of gas cylinders

Gas cylinders must be transported with proper securing to prevent falling or impact.

During patient transport while receiving "Nitric Oxide Messer", gas cylinders must be securely fastened to maintain them in an upright position and prevent falling or disconnection. Particular attention should also be paid to securing the pressure regulator to avoid accidental malfunctions.

Packaging.

Medicinal gas under pressure 200 bar, in 2 L or 10 L cylinders.

Prescription status.

Prescription only.

Manufacturer.

Messer Austria GmbH.

Manufacturer's address and location of operations.

Industriestrasse 5, 2352 Gumpoldskirchen, Austria.