Nitric oxide (NO)

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.

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 nitrous oxide on the risk of developing methaemoglobinemia with nitric oxide donor substances, including sodium nitroprusside and nitroglycerin.

Prilocaine, whether administered as oral, parenteral, or topical formulations may cause methaemoglobinaemia. Care must be taken when nitrous oxide is given at the same time as medicinal products containing prilocaine.

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 are no adequate data from the use of nitric oxide in pregnant women. The potential risk for humans is unknown. Nitric oxide should not be used during pregnancy.

It is unknown whether nitric oxide is excreted in human milk. Nitric oxide should not be used during 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 nitric oxide. 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.

List of adverse reactions

The list below presents adverse reactions (ADRs) that have been reported with the use of nitric oxide 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.