INOmax

Dosage Forms And Strengths

INOmax (nitric oxide) gas is available in an 800 ppm concentration.

Storage And Handling

INOmax (nitric oxide) is available in the following sizes:

Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F).

All regulations concerning handling of pressure vessels must be followed.

Protect the cylinders from shocks, falls, oxidizing and flammable materials, moisture, and sources of heat or ignition.

Occupational Exposure

The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm, and for NO2 the limit is 5 ppm.

Distributed by INO Therapeutics LLC 675 McDonnell Blvd. Hazelwood, MO 63042, USA. Revised: Oct 2015

INOmax® is indicated to improve oxygenation and reduce the need for extracorporeal membrane oxygenation in term and near-term ( > 34 weeks gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension in conjunction with ventilatory support and other appropriate agents.

Dosage

Term and Near-Term Neonates with Hypoxic Respiratory Failure

The recommended dose of INOmax is 20 ppm. Maintain treatment up to 14 days or until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned from INOmax therapy.

Doses greater than 20 ppm are not recommended.

Administration

Training in Administration

The user of INOmax and Nitric Oxide Delivery Systems must satisfactorily complete a comprehensive periodic training program for health care professionals provided by the delivery system and drug manufacturers. Health professional staff that administers nitric oxide therapy have access to supplier-provided 24 hour/365 days per year technical support on the delivery and administration of INOmax at 1-877-566-9466.

Nitric Oxide Delivery Systems

INOmax must be administered using a calibrated INOmax DSIR ® Nitric Oxide Delivery System. Only validated ventilator systems should be used in conjunction with INOmax. Consult the Nitric Oxide Delivery System label or call 877.566.9466/visit inomax.com for a current list of validated systems.

Keep available a backup battery power supply and an independent reserve nitric oxide delivery system to address power and system failures.

Monitoring

Measure methemoglobin within 4-8 hours after initiation of treatment with INOmax and periodically throughout treatment.

Monitor for PaO2 and inspired NO2 during INOmax administration.

Weaning and Discontinuation

Avoid abrupt discontinuation of INOmax. To wean INOmax, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.

INOmax is contraindicated in neonates dependent on right-to-left shunting of blood.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Rebound Pulmonary Hypertension Syndrome Following Abrupt Discontinuation

Wean from INOmax. Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary artery pressure, i.e., Rebound Pulmonary Hypertension Syndrome. Signs and symptoms of Rebound Pulmonary Hypertension Syndrome include hypoxemia, systemic hypotension, bradycardia, and decreased cardiac output. If Rebound Pulmonary Hypertension occurs, reinstate INOmax therapy immediately.

Hypoxemia From Methemoglobinemia

Nitric oxide combines with hemoglobin to form methemoglobin, which does not transport oxygen. Methemoglobin levels increase with the dose of INOmax; it can take 8 hours or more before steady-state methemoglobin levels are attained. Monitor methemoglobin and adjust the dose of INOmax to optimize oxygenation.

If methemoglobin levels do not resolve with decrease in dose or discontinuation of INOmax, additional therapy may be warranted to treat methemoglobinemia.

Airway Injury From Nitrogen Dioxide

Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO2 concentration, or if the NO2 concentration reaches 3 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the Nitric Oxide Delivery System O&M Manual troubleshooting section, and the NO2 analyzer should be recalibrated. The dose of INOmax and/or FiO2 should be adjusted as appropriate.

Worsening Heart Failure

Patients with left ventricular dysfunction treated with INOmax may experience pulmonary edema, increased pulmonary capillary wedge pressure, worsening of left ventricular dysfunction, systemic hypotension, bradycardia and cardiac arrest. Discontinue INOmax while providing symptomatic care.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of a carcinogenic effect was apparent, at inhalation exposures up to the recommended dose (20 ppm), in rats for 20 hr/day for up to two years. Higher exposures have not been investigated.

Nitric oxide has demonstrated genotoxicity in Salmonella (Ames Test), human lymphocytes, and after in vivo exposure in rats. There are no animal or human studies to evaluate nitric oxide for effects on fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with INOmax. It is not known if INOmax can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. INOmax is not indicated 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

The safety and efficacy of nitric oxide for inhalation has been demonstrated in term and near-term neonates with hypoxic respiratory failure associated with evidence of pulmonary hypertension. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy. No information about its effectiveness in other age populations is available.

Geriatric Use

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

SIDE EFFECTS

The following adverse reactions are discussed elsewhere in the label;

Hypoxemia

Worsening Heart Failure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Controlled studies have included 325 patients on INOmax doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on INOmax, a result adequate to exclude INOmax mortality being more than 40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalization was similar in INOmax and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is available for 278 patients who received INOmax and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.

In the NINOS study, 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.

In CINRGI, the only adverse reaction ( > 2% higher incidence on INOmax than on placebo) was hypotension (14% vs. 11%).

Post-Marketing Experience

Post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

DRUG INTERACTIONS

Nitric Oxide Donor Agents

Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

Pregnancy Category C

Animal reproduction studies have not been conducted with INOmax. It is not known if INOmax can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. INOmax is not indicated for use in adults.

The following adverse reactions are discussed elsewhere in the label;

Hypoxemia

Worsening Heart Failure

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from the clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Controlled studies have included 325 patients on INOmax doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on INOmax, a result adequate to exclude INOmax mortality being more than 40% worse than placebo.

In both the NINOS and CINRGI studies, the duration of hospitalization was similar in INOmax and placebo-treated groups.

From all controlled studies, at least 6 months of follow-up is available for 278 patients who received INOmax and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurological sequelae.

In the NINOS study, 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.

In CINRGI, the only adverse reaction ( > 2% higher incidence on INOmax than on placebo) was hypotension (14% vs. 11%).

Post-Marketing Experience

Post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff has been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

Overdosage with INOmax is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO2. Elevated NO2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO2 levels > 3 ppm or methemoglobin levels > 7% were treated by reducing the dose of, or discontinuing, INOmax.

Methemoglobinemia that does not resolve after reduction or discontinuation of therapy can be treated with intravenous vitamin C, intravenous methylene blue, or blood transfusion, based upon the clinical situation.

Effects on Pulmonary Vascular Tone in PPHN

Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH), and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, INOmax improves oxygenation (as indicated by significant increases in PaO2).

The pharmacokinetics of nitric oxide has been studied in adults.

Absorption and Distribution

Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.

Metabolism

Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration- time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm INOmax are shown in Figure 1.

Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80 ppm INOmax

Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20 ppm INOmax groups, but reached approximately 5% in the 80 ppm INOmax group. Methemoglobin levels > 7% were attained only in patients receiving 80 ppm, where they comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD) hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.

Elimination

Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine, accounting for > 70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the kidney at rates approaching the rate of glomerular filtration.