INOMAX Inhalation gas Ref.[8674] Active ingredients: Nitric oxide (NO)

Inadequate response

If it is judged that clinical response is inadequate at 4-6 hours after starting INOmax, the following should be considered.

For patients who are to be referred to another hospital, to prevent worsening of their condition on acute discontinuation of INOmax, the availability of nitric oxide during transport should be assured.

Rescue, such as Extra Corporeal Membrane Oxygenation (ECMO) where available, should be considered based on continued deterioration or failure to improve, defined by criteria based on local circumstances.

Special patient populations

In clinical trials, no efficacy has been demonstrated with the use of inhaled nitric oxide in patients with congenital diaphragmatic hernia.

Treatment with inhaled nitric oxide might aggravate cardiac insufficiency in a situation with left-to-right shunting. This is due to unwanted pulmonary vasodilation caused by inhaled nitric oxide, resulting in a further increase of already existing pulmonary hyperperfusion thus potentially giving raise to forward or backward failure. It, therefore, is recommended that prior to the administration of nitric oxide, pulmonary artery catheterisation or echocardiographic examination of central haemodynamics be performed. 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).

Discontinuation of therapy

The INOmax 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 INOmax. 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.

Effects on platelets

Animal models have shown that nitric oxide may interact with haemostasis, resulting in an increased bleeding time. Data in adult humans are conflicting, and there has been no increase in bleeding complications in randomised controlled trials in term and near-term neonates with hypoxic respiratory failure.

Regular monitoring of haemostasis and measurement of bleeding time is recommended during the administration of INOmax for more than 24 hours to patients with functional or quantitative platelet anomalies, a low coagulation factor or receiving anticoagulation treatment.

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. There may be an additive effect with INOmax on the risk of developing methaemoglobinemia with nitric oxide donor substances, including sodium nitroprusside and nitroglycerin. INOmax has been safely administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.

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.

There is an increased risk of methaemoglobin formation if substances with a known tendency to increase methaemoglobin concentrations are administered concomitantly with nitric oxide (e.g. alkyl nitrates and sulphonamides). Substances known to cause increased methaemoglobin levels should thus be used with caution during therapy with inhaled nitric oxide. Prilocaine, whether administered as oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when INOmax is given at the same time as medicinal products containing prilocaine.

In the presence of oxygen, nitric oxide is rapidly oxidised to derivatives which are toxic to the bronchial epithelium and alveolo-capillary membrane. Nitrogen dioxide (NO₂) is the main substance 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 treatment with nitric oxide, the NO₂ concentration should be <0.5 ppm in the nitric oxide dose range <20 ppm. If at any time the NO₂ concentration exceeds 1 ppm, the nitric oxide dose should immediately be reduced. See section 4.2 for information on monitoring for NO₂.

There are no adequate data from the use of nitric oxide in pregnant women. The potential risk for humans is unknown.

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

INOmax should not be used during pregnancy or breastfeeding.

No fertility studies have been performed.

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 INOmax. 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 table below presents adverse reactions (ADRs) that have been reported with the use of INOmax from either the CINRGI trial of 212 neonates or post marketing experience in neonates (<1 months of age). The displayed frequency categories use the following 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).

Blood and lymphatic system disorders

Very common: Thrombocytopenia^a

Uncommon: Methaemoglobi naemia^a

Cardiac disorders

Not known: Bradycardia^b (following abrupt discontinuation of therapy)

Vascular disorders

Common: Hypotension^a,b,d

Respiratory, thoracic and mediastinal disorders

Common: Atelectasis^a

Not known: Hypoxia^b,d, Dyspnoea^c, Chest Discomfort^c, Dry throat^c

Nervous system disorders

Not known: Headache^c, Dizziness

^a Identified from the clinical trial
^b Identified from Post-Marketing experience
^c Identified from Post-Marketing experience, experienced by healthcare personnel following accidental exposure
^d Post Marketing Safety Surveillance (PMSS) data, effects associated with acute withdrawal of the medicinal product, and/or delivery system failures. Rapid rebound reactions such as intensified pulmonary vasoconstriction and hypoxia 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 the national reporting system listed in Appendix V.

In the presence of oxygen NO rapidly forms NO₂, see section 4.5.