Noxivent 102

ADVERSE REACTIONS The most common adverse reaction is hypotension. ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Linde, Inc. at 1-800-772-9247 and http://www.linde.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CONTRAINDICATIONS Neonates dependent on right-to-left shunting of blood ( 4 ).

11 DESCRIPTION Noxivent™ (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance in Noxivent™, is a pulmonary vasodilator. Noxivent™ is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm). Noxivent™ is supplied in aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]). The structural formula of nitric oxide (NO) is shown below: formula

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: • Use only with a NOxBOXi® operated by trained personnel ( 2.2 ) • Avoid abrupt discontinuation ( 2.2 , 5.1 ).

INDICATIONS AND USAGE Noxivent™ 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.

10 OVERDOSAGE Overdosage with Noxivent™ 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, nitric oxide. 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.

DRUG INTERACTIONS Nitric oxide donor compounds may increase the risk of developing methemoglobinemia ( 7 ).

12 CLINICAL PHARMACOLOGY

20230119

7

DOSAGE FORMS AND STRENGTHS Noxivent™ (nitric oxide) is a gas available in 100 ppm and 800 ppm concentrations ( 3 ).

Noxivent 102 Noxivent 102 NITROGEN NITRIC OXIDE NITRIC OXIDE

13 NONCLINICAL TOXICOLOGY 13.1 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.

ANDA207141

Noxivent 102

Noxivent 102

59579-102

HUMAN PRESCRIPTION DRUG

RESPIRATORY (INHALATION)

Noxivent 102-01 NDC 59579-102-01 Noxivent™ nitric oxide for inhalation 800 PPM Rx only CAUTION: HIGH PRESSURE GAS, CAN CAUSE RAPID SUFFOCATION WITHOUT WARNING. Use equipment rated for cylinder pressure. Store and use with adequate ventilation. Secure cylinder in use and storage. Close valve after each use and when empty. USE IN ACCORDANCE WITH APPROPRIATE SDS. WARNING: Administration of this gas mixture may be hazardous or contraindicated. For use only by or under the supervision of a licensed practioner who is experienced in the use and administration of gas mixtures, and is familiar with the indications, effects, dosages, methods, and frequency and duration of administration, and with the hazards, contraindications, and side effects and precautions to be taken. FIRST AID: IF INHALED, remove person to fresh air. If not breathing, give artificial respiration. If breathing is difficult, give oxygen. Get medical help. RETURN WITH 25 PSIG. TO BE REFILLED ONLY BY LICENSED FACILITY AUTHORIZED BY LINDE GAS & EQUIPMENT INC. DO NOT REMOVE THIS PRODUCT LABEL. Store at 25 ° C (77 ° F) with excursions permitted between 15-30 ° C (59-86 ° F). Volume: 2082 Liters Linde Gas & Equipment Inc. 145 Shimersville Road Bethlehem, PA 18015 UN1956 COMPRESSED GAS, N.O.S. (NITRIC OXIDE, NITROGEN) 2.2 Net Weight: 2.5 kg MDB-7800-AQ (Rev. 01) 59579-102-01 Linde Medipure By Linde aq

RECENT MAJOR CHANGES Dosage and Administration (2.2) 10/2015

14 CLINICAL STUDIES

8 USE IN SPECIFIC POPULATIONS

16 HOW SUPPLIED/STORAGE AND HANDLING Noxivent™ (nitric oxide) is available in the following sizes: Size AD Portable aluminum cylinders containing 362 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 323 liters) (NDC 59579-102-02) Size AQ Aluminum cylinders containing 2154 liters at STP of nitric oxide gas in 800 ppm concentration in nitrogen (delivered volume 2082 liters) (NDC 59579-102-01) Size AD Portable aluminum cylinders containing 362 liters at STP of nitric oxide gas in 100 ppm concentration in nitrogen (delivered volume 323 liters) (NDC 59579-101-02) Size AQ Aluminum cylinders containing 2154 liters at STP of nitric oxide gas in 100 ppm concentration in nitrogen (delivered volume 2082 liters) (NDC 59579-101-01) Store at 25°C (77°F) with excursions permitted between 15-30°C (59-86°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. 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.