GENOSYL

GENOSYL (nitric oxide) is administered by inhalation. Nitric oxide is a pulmonary vasodilator. Nitric oxide is generated from liquid dinitrogen tetroxide (N 2 O 4 ) by the Cassette in the GENOSYL Delivery System. Upon initiation of GENOSYL Delivery System, the liquid N 2 O 4 is heated and the equilibrium shifts to nitrogen dioxide (NO 2 ) gas. The NO 2 is then converted into nitric oxide (NO) using the antioxidant Cartridges, and nitric oxide is delivered to the patient by means of a ventilator or a nasal cannula. The amount of nitric oxide administered to the patient is set by controlling the temperature of the N 2 O 4 liquid module, which controls the pressure inside the liquid module, which in turn controls the mass of NO 2 that is sent to the primary Cartridges, and hence the mass of nitric oxide. The mass flow of nitric oxide, together with the air from the pump, control the nitric oxide concentration. A nitric oxide sensor monitors the nitric oxide in the patient line. GENOSYL Delivery System is designed to deliver a controlled level of nitric oxide blended with breathing air or oxygen-enriched breathing air. The GENOSYL Delivery System controls the flow of nitric oxide mixed with air delivered to the patient. The structural formula of nitric oxide (NO) is shown below: Chemical Structure

GENOSYL ® 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. GENOSYL 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 ( 1 ).

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 GENOSYL 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 GENOSYL therapy. Doses greater than 20 ppm are not recommended [see Warnings and Precautions (5.2) ]. 2.2 Administration Nitric Oxide Delivery System GENOSYL must be administered using a calibrated GENOSYL Delivery System. Only validated ventilator systems should be used in conjunction with GENOSYL [see Description (11) ]. Consult the GENOSYL Delivery System Operator's Manual or call 1-877-337-4118 or visit www.vero-biotech.com for needed information on training and technical support for users of GENOSYL with the GENOSYL Delivery System . Keep available a backup power supply to address power failures. The GENOSYL Delivery System consists of a primary system and a fully functional second system that can be used as backup in the event of primary system failure. Monitoring Measure methemoglobin within 4-8 hours after initiation of treatment with GENOSYL and periodically throughout treatment [see Warnings and Precautions (5.2) ]. Monitor for PaO 2 and inspired NO 2 during GENOSYL administration [see Warnings and Precautions 5.3) ]. Weaning and Discontinuation Avoid abrupt discontinuation of GENOSYL [see Warnings and Precautions (5.1) ]. To wean GENOSYL, down titrate in several steps, pausing several hours at each step to monitor for hypoxemia.

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

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 Vero Biotech at 1-877-337-4118 and http://www.vero-biotech.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 nitric oxide doses of 5 to 80 ppm and 251 patients on placebo. Total mortality in the pooled trials was 11% on placebo and 9% on nitric oxide gas for inhalation, a result adequate to exclude nitric oxide mortality being more than 40% worse than placebo. In both the NINOS and CINRGI studies, the duration of hospitalization was similar in nitric oxide gas for inhalation and placebo-treated groups. From all controlled studies, at least 6 months of follow-up is available for 278 patients who received nitric oxide gas and 212 patients who received placebo. Among these patients, there was no evidence of an adverse effect of treatment on the need for re-hospitalization, special medical services, pulmonary disease, and 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 nitric oxide gas for inhalation than on placebo) was hypotension (14% vs. 11%). 6.2 Postmarketing Experience Post marketing reports of accidental exposure to nitric oxide for inhalation in hospital staff have been associated with chest discomfort, dizziness, dry throat, dyspnea, and headache.

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.

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. The GENOSYL Delivery System must be used with antioxidant Cartridges not older than 12 months from the manufacturing date. 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. Rx Only VERO Biotech and GENOSYL are registered trademarks of VERO Biotech. © 2024 VERO Biotech Manufactured by: VERO BIOTECH 387 Nerem Street NW Suite 125 Atlanta, GA 30313, USA [602604]