Inomax

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)].

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.

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.

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 4,880™ 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:

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.

INOmax 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.

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.

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 (PaO₂) 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: Abrupt discontinuation of INOmax 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 NO₂ Levels: Monitor NO₂ levels (5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, INOmax 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 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.

INOmax (nitric oxide) gas is available in 800 and 4,880 ppm concentrations.

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 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%).

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

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 [see Overdosage (10)].

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.

INOmax^®

nitric oxide

FOR INHALATION

4,880 PPM

2

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. 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

practitioner 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 the 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.

Manufactured Under Pharmaceutical

Current Good Manufacturing Practices (cGMPs).

Manufactured by: Mallinckrodt Manufacturing LLC

1060 Allendale Dr., Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO (566-9466)

Recommended Dosage: See prescribing information.

Storage: Store at 25°C (77°F) [see USP Controlled Room Temperature].

Net Weight: 0.1 Kg Volume: 78 Liters

DO NOT REMOVE THIS PRODUCT LABEL.

Mallinckrodt™

Pharmaceuticals

NDC 64693-003-01

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen) 2.2

MADE IN USA

To be refilled only by a pharmaceutical facility authorized by INO Therapeutics LLC

SPC-LBL-0900 R1

do not discard

The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of INOmax reduces the oxygenation index (OI= mean airway pressure in cm H₂O × fraction of inspired oxygen concentration [FiO₂]× 100 divided by systemic arterial concentration in mm Hg [PaO₂]) and increases PaO₂ [see Clinical Pharmacology (12.1)] .

Rx only

INOmax^®

nitric oxide

FOR

INHALATION

800 PPM

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 practitioner 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 the 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 A PHARMACEUTICAL FACILITY AUTHORIZED BY INO Therapeutics LLC

Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGMPs).

DO NOT REMOVE THIS PRODUCT LABEL.

Store at 25°C (77°F)

[see USP Controlled Room Temperature].

Volume 1963 Liters

Mallinckrodt™

Pharmaceuticals

Manufactured by:

Mallinckrodt Manufacturing LLC

1060 Allendale Dr.

Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO

(566-9466)

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen)

2.2

Net Weight: 2.5 Kg

NDC 64693-002-02

MADE IN USA

Label No. SPC-LBL-0060 R8

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.

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 PaO₂/FiO₂ <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or INOmax (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 INOmax 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). INOmax is not indicated for use in ARDS.

The safety and efficacy of INOmax 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, multi-center, 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 INOmax for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not recommended.

Wean from INOmax [see Dosage and Administration (2.2)]. 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.

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)].

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.

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.

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 4,880™ 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:

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.

INOmax 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.

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.

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 (PaO₂) 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: Abrupt discontinuation of INOmax 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 NO₂ Levels: Monitor NO₂ levels (5.3).

Heart Failure: In patients with pre-existing left ventricular dysfunction, INOmax 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 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.

INOmax (nitric oxide) gas is available in 800 and 4,880 ppm concentrations.

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 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%).

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

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 [see Overdosage (10)].

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.

INOmax^®

nitric oxide

FOR INHALATION

4,880 PPM

2

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. 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

practitioner 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 the 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.

Manufactured Under Pharmaceutical

Current Good Manufacturing Practices (cGMPs).

Manufactured by: Mallinckrodt Manufacturing LLC

1060 Allendale Dr., Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO (566-9466)

Recommended Dosage: See prescribing information.

Storage: Store at 25°C (77°F) [see USP Controlled Room Temperature].

Net Weight: 0.1 Kg Volume: 78 Liters

DO NOT REMOVE THIS PRODUCT LABEL.

Mallinckrodt™

Pharmaceuticals

NDC 64693-003-01

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen) 2.2

MADE IN USA

To be refilled only by a pharmaceutical facility authorized by INO Therapeutics LLC

SPC-LBL-0900 R1

do not discard

The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of INOmax reduces the oxygenation index (OI= mean airway pressure in cm H₂O × fraction of inspired oxygen concentration [FiO₂]× 100 divided by systemic arterial concentration in mm Hg [PaO₂]) and increases PaO₂ [see Clinical Pharmacology (12.1)] .

Rx only

INOmax^®

nitric oxide

FOR

INHALATION

800 PPM

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 practitioner 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 the 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 A PHARMACEUTICAL FACILITY AUTHORIZED BY INO Therapeutics LLC

Manufactured Under Pharmaceutical Current Good Manufacturing Practices (cGMPs).

DO NOT REMOVE THIS PRODUCT LABEL.

Store at 25°C (77°F)

[see USP Controlled Room Temperature].

Volume 1963 Liters

Mallinckrodt™

Pharmaceuticals

Manufactured by:

Mallinckrodt Manufacturing LLC

1060 Allendale Dr.

Port Allen, LA 70767 USA

For Product Inquiry 1-877-KNOW INO

(566-9466)

UN 1956

Compressed Gas, N.O.S.

(Nitric Oxide, Nitrogen)

2.2

Net Weight: 2.5 Kg

NDC 64693-002-02

MADE IN USA

Label No. SPC-LBL-0060 R8

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.

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 PaO₂/FiO₂ <250 mm Hg despite optimal oxygenation and ventilation, received placebo (n=193) or INOmax (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 INOmax 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). INOmax is not indicated for use in ARDS.

The safety and efficacy of INOmax 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, multi-center, 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 INOmax for prevention of BPD in preterm neonates ≤ 34 weeks gestational age is not recommended.

Wean from INOmax [see Dosage and Administration (2.2)]. 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.