KINOX Inhalation gas Ref.[27898] Active ingredients: Nitric oxide (NO)

WARNINGS

Left to Right Shunting

Treatment with 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. It, therefore, is recommended that prior to the administration of nitric oxide, pulmonary artery catheterization or echocardiographic examination of central hemodynamics be performed.

PRECAUTIONS

General

Initiate any alternative therapies as soon the infant’s condition demands, regardless of the response or lack of response to nitric oxide.

If it is judged that clinical response is inadequate at 4-6 hours after starting nitric oxide, 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 nitric oxide, the availability of nitric oxide during transport should be assured. Rescue, such as ECMO where available, should be considered based on continued deterioration or failure to improve, defined by local hospital criteria.

Long-term effects, particularly with regard to pulmonary and neurodevelopmental outcomes associated with nitric oxide, have not been established beyond 18-24 months. The 18-24 months follow-up study of NINOS subjects was based on a relatively small number of patients treated with placebo (n=84) and inhaled nitric oxide (n=88), and the one-year follow-up data of CINRGI subjects was based on 71 patients in the placebo and 74 patients in the inhaled nitric oxide groups. In view of the potential long-term sequelae associated with the underlying condition, persistent pulmonary hypertension of the newborn, and the unknown long-term effects of nitric oxide, it is recommended that these babies be monitored long-term regarding pulmonary, neurodevelopmental, growth and auditory outcomes.

Health professional at neonatal units that administer nitric oxide should be properly trained (see Training in Administration) and familiar with the instructions for use of the nitric oxide delivery system. They should have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of inhaled nitric oxide.

In order to avoid errors in the delivery of nitric oxide, health professionals that administer nitric oxide should ensure that the mode and make of mechanical ventilation being utilized are compatible with the nitric oxide delivery system.

Rebound Pulmonary Hypertension following Abrupt Discontinuation

Nitric oxide should not be discontinued abruptly as it may result in rebound pulmonary hypertension (increase in pulmonary artery pressure and worsening of blood oxygenation). If rebound pulmonary hypertension occurs, reinstate therapy immediately.

Rapid rebound reactions have been described and can precipitate cardiopulmonary collapse, even in patients without substantial oxygenation improvement. The patient should be treated with increased FiO₂ and by reinstallment of therapy with inhaled nitric oxide. When possible, inhaled nitric oxide should be continued until the underlying disease has resolved. Weaning from inhaled nitric oxide should be performed with caution. See Dosage and Administration section.

Deterioration in oxygenation and elevation in pulmonary artery pressure may also occur in neonate with no apparent response to nitric oxide. Again, weaning from nitric oxide should be performed with caution. See Dosage and Administration section.

Methemoglobinemia

Neonates are known to have diminished methemoglobin reductase activity compared to adults and could therefore be at greater risk of developing methemoglobinemia. The concentrations of methemoglobin in the blood should be monitored as nitric oxide for inhalation is absorbed systemically and the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate. See Monitoring Methemoglobin under Dosage and Administration.

Methemoglobinemia increases with the dose of nitric oxide. If methemoglobin levels are >2.5%, the nitric oxide dose should be decreased and the administration of reducing agent such as methylene blue may be considered. Following discontinuation or reduction of nitric oxide methemoglobin levels should return to baseline over a period of hours. If methemoglobin levels do not resolve after discontinuation or reduction of therapy additional measures may be warranted, see Symptoms and Treatment of Overdosage section.

Airway injury from 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. See Monitoring Nitrogen Dioxide under Dosage and Administration.

In one study, NO₂ levels were <0.5 ppm when neonates were treated with placebo, 5 ppm, and 20 ppm nitric oxide over the first 48 hours. The 80 – ppm group had a mean peak NO₂ level of 2.6 ppm.

Heart Failure

Patients with left ventricular dysfunction treated with inhaled nitric oxide, even for short durations, experienced serious adverse events (e.g., pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systematic hypotension, bradycardia and cardiac arrest). Discontinue nitric oxide while providing symptomatic care.

Bleeding Time

Animal models have shown that nitric oxide may interact with homeostasis, resulting in an increased bleeding time. Data in adult humans are conflicting. Inhaled nitric oxide has been found to approximately double bleeding time in a limited study in rabbits and humans. However, there has been no statistically significant increase in bleeding complications in randomized controlled trials in term and late pre-term neonates with hypoxic respiratory failure.

Adults

Nitric oxide is not indicated for use in the adult population.

Use in Pregnancy

Animal reproduction studies have not been conducted with inhaled nitric oxide. It is not known if nitric oxide can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Passive exposure to nitric oxide during pregnancy and lactation should be avoided. Nitric oxide is not intended for use in adults.

Nursing Mothers

Nitric oxide is not indicated for use in the adult population, including nursing mothers. It is not known whether nitric oxide is excreted in human milk.

Pediatric Use

Nitric oxide for inhalation has been studied in a neonatal population up to 14 days of age who were ≥34 weeks gestational age. No information about its effectiveness in other age populations is available. Although clinical studies are ongoing, the efficacy and safety of nitric oxide for neonates less than 34 weeks gestational age has not been established. Nitric oxide is not indicated for neonates less than 34 weeks gestational age.

Drug Interactions

Experimental studies have suggested that nitric oxide and nitrogen dioxide may react chemically with surfactant and/or surfactant proteins. No formal drug-interaction studies have been performed, and a clinically significant interaction with other medications used in the treatment of hypoxic respiratory failure cannot be excluded based on the available data. In particular, although there are no data to evaluate the possibility nitric oxide donor compounds, including sodium nitroprusside and nitroglycerin, may have an additive effect with nitric oxide on the risk of developing methemoglobinemia. Nitric oxide has been administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation. Nitric oxide should be used with caution in patients receiving NO donor compounds (e.g. nitroprusside, nitroglycerine, prilocaine and substances known to increase methemoglobin) because of the potential of methemoglobinemia.

Laboratory Tests

Nitric oxide should be administered with monitoring for PaO₂, methemoglobin, and NO₂. Methemoglobin levels should be measured within one hour after initiation of nitric oxide therapy and periodically throughout the treatment period using an analyzer, which can reliably distinguish between fetal hemoglobin and methemoglobin. See Monitoring Methemoglobin and Monitoring Nitrogen Dioxide under Dosage and Administration.

The NINOS and CINRGI studies were not powered to detect statistically significant differences with regards to adverse events between the placebo and inhaled nitric oxide treatment groups.

In the NINOS trial, treatment groups were similar with respect to the incidence and severity of intracranial hemorrhage, Grade IV hemorrhage, periventricular leukomalacia, cerebral infarction, seizures requiring anticonvulsant therapy, pulmonary hemorrhage, or gastrointestinal hemorrhage. The following post-hoc analysis shows the distribution of selected adverse events in the NINOS trial for the actual-drug-received population (n=235).

Selected adverse events in the NINOS trial* - Actual-Gas-Received Population:

The table below shows adverse events with an incidence of at least 5% on nitric oxide in the CINRGI study, and that were more common on nitric oxide than on placebo.

Adverse events in the CINRGI trial:

Data from a post-hoc analysis among patients in the CINRGI study who did not receive ECMO (not randomized sample) showed that inhaled nitric oxide patients had numerical increases in the following adverse events: tachycardia, hypokalemia, infection, fever, cellulites, coagulation disorder, hemorrhage, deafness, and hematuria.

In the NINOS study, doses of inhaled nitric oxide up to 80 ppm and duration of therapy up to 14 days were permitted. Also the delivery devices used in the NINOS study were not able to provide a consistent dose of inhaled nitric oxide, on the other hand, the standardized delivery devices were used in CINRGI study to provide a consistent dose of inhaled nitric oxide. Consequently, 42.9% of patients in the NINOS study (at maximum dose of 20 ppm) exceeded the proposed 0.5 ppm threshold for NO2 while only 9.7% of patients exceeded this threshold in the CINRGI study. Similarly, 26.4% patients in the NINOS study and 3.6% in the CINRGI study exceeded the proposed 2.5% threshold for methemoglobin level. These results indicate the importance of using standard delivery devices for the safe administration of inhaled nitric oxide therapy.

Long-term Safety

Follow-up exams were performed at 18-24 months for the infants enrolled in the NINOS study. In the infants with available follow-up, there were no statistically significant differences between the two treatment groups with respect to their mental, motor, audiologic, visual or neurologic evaluations. Seventy-four and one-half percent (74.5%) of infants in inhaled nitric oxide group and 76.1% in placebo group were classified as neurologically normal. Mental development of the infants, as assessed by the Bayley scale of mental developmental index (MDI) was similar between the treatment groups. However, a post-hoc analysis of adverse events for the actualgas-received population showed some numerical differences between treatment groups (see the table below).

Adverse Events at 18-24 months of follow-up in NINOS subjects – Actual-gas-received population:

^* Patients received maximum 20 ppm or 80 ppm inhaled nitric oxide as per the study protocol.

Long-term effects of nitric oxide, particularly with regard to pulmonary and neurodevelopmental outcomes, have not been established beyond 18-24 months.

Data from the one-year follow-up of CINRGI study subjects (85% follow-up rate) showed that patients in the inhaled nitric oxide group had a higher percentage of hearing loss (4%) than those in the placebo group (0%)¹. Additionally, patients treated with inhaled nitric oxide had higher percentages of cerebral palsy (4%) than those treated with placebo (1%).

Data from the one-year follow-up of 145 patients of the original 155 infants in the non-pivotal study INO-01/02 showed that 23% of patients in the inhaled nitric oxide group and 14% in placebo group had severe impairment of overall assessment of neurologic status at one year. The patients in this study were treated with three doses of inhaled nitric oxide (5 ppm, 20 ppm and 80 ppm). However, there was no clear dose–response relationship between the adverse event and the inhaled nitric oxide dose.

The overall 5-year follow-up rate of NINOS and CINRGI study subjects was only 25%. The 5-year follow-up data were based on 43 patients in the placebo group and 55 patients in the inhaled nitric oxide group. Patients treated with inhaled nitric oxide had a significantly higher incidence of gait disturbance at 5-year follow-up (16% in inhaled nitric oxide group versus 2% in placebo group, p=0.04). Additionally, the percentage of vision problems, recurrent non-febrile seizures was numerically higher among inhaled nitric oxide patients. Due to the 25% follow-up rate, valid conclusions cannot be made.

Post-marketing Experience

In addition to adverse events reported from clinical trials, the following adverse drug reactions have been identified in neonates (≤1 month of age):

Cardiac Disorders: bradycardia following abrupt discontinuation of therapy.

Respiratory, Thoracic and Mediastinal Disorders: hypoxia following abrupt discontinuation of therapy.

Vascular Disorders: hypotension following abrupt discontinuation of therapy.

Accidental Exposure: Chest discomfort, dizziness, dry throat, dyspnea and headache have been reported in hospital staff after accidental exposure.