INOMAX

1 INDICATIONS AND USAGE 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. INOmax is a vasodilator 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.

2 DOSAGE AND ADMINISTRATION The recommended dose is 20 ppm, maintained for up to 14 days or until the underlying oxygen desaturation has resolved ( 2.1 ). Doses greater than 20 ppm are not recommended ( 2.1 , 5.2 ) Administration: Avoid abrupt discontinuation ( 2.2 , 5.1 ). 2.1 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 [see Warnings and Precautions (5.2) ] . 2.2 Administration Nitric Oxide Delivery Systems INOmax must be administered using a calibrated, FDA-cleared Nitric Oxide Delivery System (NODS). There are various FDA-cleared NODS; refer to the NODS labeling to determine which NODS to use with this drug product and for needed information on training and technical support for users of this drug product with the NODS. When utilizing a nitric oxide delivery system specifically cleared for use in the MRI suite (e.g., the INOmax DSIR ® Plus MRI) only use INOmax MR conditional cylinders at 100 gauss or less [see How Supplied/Storage and Handling (16) ]. 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 [see Warnings and Precautions (5.2) ] . Monitor for PaO 2 and inspired NO 2 during INOmax administration [see Warnings and Precautions (5.3) ] . Weaning and Discontinuation Avoid abrupt discontinuation of INOmax [see Warnings and Precautions (5.1) ]. To wean INOmax, downtitrate in several steps, pausing several hours at each step to monitor for hypoxemia.

3 DOSAGE FORMS AND STRENGTHS INOmax (nitric oxide) gas is available in 800 and 4,880 ppm concentrations. INOmax (nitric oxide) is a gas available in 800 and 4,880 ppm concentrations ( 3 ).

4 CONTRAINDICATIONS INOmax is contraindicated in neonates dependent on right-to-left shunting of blood. Neonates dependent on right-to-left shunting of blood ( 4 ).

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the label; Hypoxemia [see Warnings and Precautions (5.2) ] Worsening Heart Failure [see Warnings and Precautions (5.4) ] The most common adverse reaction is hypotension. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact INO Therapeutics at 1-877-566-9466 and http://www.inomax.com/ or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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%). 6.2 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.

7 DRUG INTERACTIONS Nitric oxide donor compounds may increase the risk of developing methemoglobinemia ( 7 ). 7.1 Nitric Oxide Donor Agents Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may increase the risk of developing methemoglobinemia.

8 USE IN SPECIFIC POPULATIONS 8.4 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 [see Clinical Studies (14.1) ]. Additional studies conducted in premature neonates for the prevention of bronchopulmonary dysplasia have not demonstrated substantial evidence of efficacy [see Clinical Studies (14.3) ]. No information about its effectiveness in other age populations is available. 8.5 Geriatric Use Nitric oxide is not indicated for use in the adult population.

12.1 Mechanism of Action Nitric oxide relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'-monophosphate, which then leads to vasodilation. When inhaled, nitric oxide selectively dilates the pulmonary vasculature, and because of efficient scavenging by hemoglobin, has minimal effect on the systemic vasculature. INOmax appears to increase the partial pressure of arterial oxygen (PaO 2 ) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

11 DESCRIPTION INOmax (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in INOmax, is a pulmonary vasodilator. INOmax 800 ppm is a gaseous blend of nitric oxide (0.08%) and nitrogen (99.92%). INOmax 4,880TM ppm is a gaseous blend of nitric oxide (0.488%) and nitrogen (99.51%). INOmax 800 ppm is supplied in aluminum cylinders as a compressed gas under high pressure (2,000 pounds per square inch [psi]). INOmax 4,880 ppm is supplied in aluminum cylinders as a compressed gas under high pressure (3,000 psi). The structural formula of nitric oxide (NO) is shown below: Chemical Structure

10 OVERDOSAGE Overdosage with INOmax is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO 2 . Elevated NO 2 may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO 2 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.

16 HOW SUPPLIED/STORAGE AND HANDLING INOmax (nitric oxide) is available in the following sizes: Size D Portable aluminum cylinders containing 353 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 344 liters) (NDC 64693-002-01) Size 88 Aluminum cylinders containing 1963 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 1918 liters) (NDC 64693-002-02) 0.4 liter Portable aluminum cylinders containing 78 liters at STP of nitric oxide gas in 4,880 ppm concentration in nitrogen (delivered volume 70 liters) (NDC 64693-003-01) Store at 25°C (77°F) with excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. 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. INOmax MR conditional labeled cylinders (i.e., size 88 aluminum cylinder) may be used at 100 gauss or less. Use of any other cylinders (e.g., size D or 0.4 liter aluminum cylinder) may create a projectile hazard. Occupational Exposure The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric oxide is 25 ppm, and for NO 2 the limit is 5 ppm. For a list of patents, see https://www.mallinckrodt.com/patents/