These Highlights Do Not Include All The Information Needed To Use Genosyl ®

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, nitric oxide gas for inhalation improves oxygenation (as indicated by significant increases in PaO ₂).

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C –30°C (59°F –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.

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)].

Overdosage with nitric oxide gas is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO ₂. Elevated NO ₂may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO ₂levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide gas.

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.

GENOSYL (nitric oxide) is administered by inhalation. Nitric oxide is a pulmonary vasodilator. Nitric oxide is generated from liquid dinitrogen tetroxide (N ₂O ₄) by the cassette in the GENOSYL Delivery System. Upon initiation of GENOSYL Delivery System, the liquid N ₂O ₄is heated and the equilibrium shifts to nitrogen dioxide (NO ₂) gas. The NO ₂is 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 ₂O ₄liquid module, which controls the pressure inside the liquid module, which in turn controls the mass of NO ₂that 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:

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.

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

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 ₂and inspired NO ₂during GENOSYL administration [see Warnings and Precautions (5.3)].

The concentration of nitric oxide, nitrogen dioxide and air is constantly monitored. The GENOSYL Delivery System will shutdown if nitrogen dioxide reaches 3 ppm.

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.

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)]

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

The pharmacokinetics of nitric oxide has been studied in adults.

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.

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.

GENOSYL 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.

Rebound Pulmonary Hypertension: Abrupt discontinuation of GENOSYL may lead to worsening oxygenation and increasing pulmonary artery pressure ( 5.1).

Methemoglobinemia: Methemoglobin increases with the dose of nitric oxide; following discontinuation or reduction of nitric oxide, methemoglobin levels return to baseline over a period of hours ( 5.2).

Elevated NO ₂Levels: Monitor NO ₂levels ( 5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, GENOSYL may increase pulmonary capillary wedge pressure leading to pulmonary edema ( 5.4).

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).

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

GENOSYL (nitric oxide) is a gas available at concentrations up to 800 ppm [see Description (11)] . 

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.

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

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%).

GENOSYL Delivery System cassettes produce at least 216 liters of 800 ppm nitric oxide gas (at standard temperature and pressure, STP) (NDC 72385-001-01).

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

If methemoglobin levels do not resolve with decrease in dose or discontinuation of GENOSYL, additional therapy may be warranted to treat methemoglobinemia [see Overdosage (10)] .

Nitrogen dioxide (NO ₂) forms in gas mixtures containing NO and O ₂. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO ₂concentration, or if the NO ₂concentration reaches 0.5 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the GENOSYL Delivery System Operator's Manual troubleshooting section, and the NO ₂analyzer should be recalibrated. The dose of GENOSYL and/or FiO ₂should be adjusted as appropriate.

The efficacy of nitric oxide gas was investigated in term and near-term newborns with hypoxic respiratory failure (HRF) resulting from a variety of etiologies. Inhalation of nitric oxide gas reduces the oxygenation index (OI= mean airway pressure in cm H ₂O × fraction of inspired oxygen concentration [FiO ₂]× 100 divided by systemic arterial concentration in mm Hg [PaO ₂]) and increases PaO ₂  [see Clinical Pharmacology (12.1)] .

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 gas 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.

In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO ₂/FiO ₂<250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide gas (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of nitric oxide gas on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). GENOSYL (nitric oxide) for inhalation is not indicated for use in ARDS.

GENOSYL ^®(nitric oxide) for inhalation

NDC 72385-001-01

LOT Z-XXXX-YYYY

SN  ZZXXZXXX

EXP YYYY-MMM-DD

VERO BIOTECH INC.

387 Technology Circle NW, Suite 125

Atlanta, GA 30313 USA

www.vero-biotech.com/patents

601468-01 Rev K

Rx Only

GENOSYL ^®(nitric oxide) for inhalation

(For use with GENOSYL ^®Delivery System only)

NDC 72385-001-01

800 PPM

LOT Z-XXXX-YYYY

SN  ZZXXZXXX

EXP YYYY-MMM-DD

72385-001-01ZZXXZXXX

Store at 25°C (77°F) with excursions permitted between

15°C - 30°C (59°F - 86°F).

[see USP Controlled Room Temperature]

Recommended Dosage: See prescribing information.

Manufactured by:

VERO BIOTECH INC.

387 Technology Circle NW, Suite 125

Atlanta, GA 30313 USA

VĒRO

BIOTECH

www.vero-biotech.com/patents

601431-02 Rev M

The safety and efficacy of nitric oxide gas for the prevention of chronic lung disease [bronchopulmonary dysplasia (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large previously conducted multicenter, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity.

The use of GENOSYL (nitric oxide) for prevention of BPD in preterm neonates ≤34 weeks gestational age is not recommended.

Wean from GENOSYL [see Dosage and Administration (2.2)]. Abrupt discontinuation of GENOSYL 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 GENOSYL therapy immediately.

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, nitric oxide gas for inhalation improves oxygenation (as indicated by significant increases in PaO ₂).

Store at 20°C to 25°C (68°F to 77°F) with excursions permitted between 15°C –30°C (59°F –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.

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)].

Overdosage with nitric oxide gas is manifest by elevations in methemoglobin and pulmonary toxicities associated with inspired NO ₂. Elevated NO ₂may cause acute lung injury. Elevations in methemoglobin reduce the oxygen delivery capacity of the circulation. In clinical studies, NO ₂levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of, or discontinuing, nitric oxide gas.

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.

GENOSYL (nitric oxide) is administered by inhalation. Nitric oxide is a pulmonary vasodilator. Nitric oxide is generated from liquid dinitrogen tetroxide (N ₂O ₄) by the cassette in the GENOSYL Delivery System. Upon initiation of GENOSYL Delivery System, the liquid N ₂O ₄is heated and the equilibrium shifts to nitrogen dioxide (NO ₂) gas. The NO ₂is 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 ₂O ₄liquid module, which controls the pressure inside the liquid module, which in turn controls the mass of NO ₂that 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:

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.

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

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 ₂and inspired NO ₂during GENOSYL administration [see Warnings and Precautions (5.3)].

The concentration of nitric oxide, nitrogen dioxide and air is constantly monitored. The GENOSYL Delivery System will shutdown if nitrogen dioxide reaches 3 ppm.

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.

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)]

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

The pharmacokinetics of nitric oxide has been studied in adults.

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.

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.

GENOSYL 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.

Rebound Pulmonary Hypertension: Abrupt discontinuation of GENOSYL may lead to worsening oxygenation and increasing pulmonary artery pressure ( 5.1).

Methemoglobinemia: Methemoglobin increases with the dose of nitric oxide; following discontinuation or reduction of nitric oxide, methemoglobin levels return to baseline over a period of hours ( 5.2).

Elevated NO ₂Levels: Monitor NO ₂levels ( 5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, GENOSYL may increase pulmonary capillary wedge pressure leading to pulmonary edema ( 5.4).

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).

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

GENOSYL (nitric oxide) is a gas available at concentrations up to 800 ppm [see Description (11)] . 

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.

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

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%).

GENOSYL Delivery System cassettes produce at least 216 liters of 800 ppm nitric oxide gas (at standard temperature and pressure, STP) (NDC 72385-001-01).

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

If methemoglobin levels do not resolve with decrease in dose or discontinuation of GENOSYL, additional therapy may be warranted to treat methemoglobinemia [see Overdosage (10)] .

Nitrogen dioxide (NO ₂) forms in gas mixtures containing NO and O ₂. Nitrogen dioxide may cause airway inflammation and damage to lung tissues.

If there is an unexpected change in NO ₂concentration, or if the NO ₂concentration reaches 0.5 ppm when measured in the breathing circuit, then the delivery system should be assessed in accordance with the GENOSYL Delivery System Operator's Manual troubleshooting section, and the NO ₂analyzer should be recalibrated. The dose of GENOSYL and/or FiO ₂should be adjusted as appropriate.

The efficacy of nitric oxide gas was investigated in term and near-term newborns with hypoxic respiratory failure (HRF) resulting from a variety of etiologies. Inhalation of nitric oxide gas reduces the oxygenation index (OI= mean airway pressure in cm H ₂O × fraction of inspired oxygen concentration [FiO ₂]× 100 divided by systemic arterial concentration in mm Hg [PaO ₂]) and increases PaO ₂  [see Clinical Pharmacology (12.1)] .

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 gas 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.

In a randomized, double-blind, parallel, multicenter study, 385 patients with adult respiratory distress syndrome (ARDS) associated with pneumonia (46%), surgery (33%), multiple trauma (26%), aspiration (23%), pulmonary contusion (18%), and other causes, with PaO ₂/FiO ₂<250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or nitric oxide gas (n=192), 5 ppm, for 4 hours to 28 days or until weaned because of improvements in oxygenation. Despite acute improvements in oxygenation, there was no effect of nitric oxide gas on the primary endpoint of days alive and off ventilator support. These results were consistent with outcome data from a smaller dose ranging study of nitric oxide (1.25 to 80 ppm). GENOSYL (nitric oxide) for inhalation is not indicated for use in ARDS.

GENOSYL ^®(nitric oxide) for inhalation

NDC 72385-001-01

LOT Z-XXXX-YYYY

SN  ZZXXZXXX

EXP YYYY-MMM-DD

VERO BIOTECH INC.

387 Technology Circle NW, Suite 125

Atlanta, GA 30313 USA

www.vero-biotech.com/patents

601468-01 Rev K

Rx Only

GENOSYL ^®(nitric oxide) for inhalation

(For use with GENOSYL ^®Delivery System only)

NDC 72385-001-01

800 PPM

LOT Z-XXXX-YYYY

SN  ZZXXZXXX

EXP YYYY-MMM-DD

72385-001-01ZZXXZXXX

Store at 25°C (77°F) with excursions permitted between

15°C - 30°C (59°F - 86°F).

[see USP Controlled Room Temperature]

Recommended Dosage: See prescribing information.

Manufactured by:

VERO BIOTECH INC.

387 Technology Circle NW, Suite 125

Atlanta, GA 30313 USA

VĒRO

BIOTECH

www.vero-biotech.com/patents

601431-02 Rev M

The safety and efficacy of nitric oxide gas for the prevention of chronic lung disease [bronchopulmonary dysplasia (BPD)] in neonates ≤ 34 weeks gestational age requiring respiratory support has been studied in four large previously conducted multicenter, double-blind, placebo-controlled clinical trials in a total of 2,600 preterm infants. Of these, 1,290 received placebo, and 1,310 received inhaled nitric oxide at doses ranging from 5-20 ppm, for treatment periods of 7-24 days duration. The primary endpoint for these studies was alive and without BPD at 36 weeks postmenstrual age (PMA). The need for supplemental oxygen at 36 weeks PMA served as a surrogate endpoint for the presence of BPD. Overall, efficacy for the prevention of bronchopulmonary dysplasia in preterm infants was not established. There were no meaningful differences between treatment groups with regard to overall deaths, methemoglobin levels, or adverse events commonly observed in premature infants, including intraventricular hemorrhage, patent ductus arteriosus, pulmonary hemorrhage, and retinopathy of prematurity.

The use of GENOSYL (nitric oxide) for prevention of BPD in preterm neonates ≤34 weeks gestational age is not recommended.

Wean from GENOSYL [see Dosage and Administration (2.2)]. Abrupt discontinuation of GENOSYL 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 GENOSYL therapy immediately.