NEOPHYR Medicinal gas, compressed Ref.[49856] Active ingredients: Nitric oxide (NO)

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 pre-established 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 alveolar-arterial 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 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.

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.

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.

Breast-feeding

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.

Infants and hospitalized patient: Not relevant.

Summary of safety profile

Abrupt discontinuation of the administration of inhaled nitric oxide may cause rebound reaction; decrease in oxygenation and increase in central pressure and subsequent decrease in systemic blood pressure. Rebound reaction is the most commonly adverse reaction in association with the clinical use of 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).

^* Post-Marketing Safety Surveillance (PMSS) data, symptom experienced by personnel associated to accidental environmental exposure
^** PMSS data, effects associated with acute withdrawal of the medicinal product, and dose errors associated with the delivery system. Rapid rebound reactions such as intensified pulmonary vasoconstriction after sudden withdrawal of inhaled nitric oxide therapy has been described, precipitating cardiovascular collapse.

Description of selected adverse reactions

Inhaled nitric oxide therapy may cause an increase in methaemoglobin.

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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

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.