------------------------------CONTRAINDICATIONS------------------------------­
`
`
`
`
`
` Neonates known to be dependent on right-to-left shunting of blood (4).
`
`-----------------------WARNINGS AND PRECAUTIONS-----------------------­
`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 continuously with a suitable Nitric
`
`
`
`
`
`
`
`
`Oxide Delivery System (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).
`
`------------------------------ADVERSE REACTIONS-------------------------------
`
`
`Methemoglobinemia and NO2 levels are dose dependent. 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.
`
`
`-------------------------------DRUG INTERACTIONS-----------------------------­
`Nitric oxide donor agents: Nitric oxide donor compounds, such as prilocaine,
`
`
`
`
`
`
`
`sodium nitroprusside, and nitroglycerin, when administered as oral, parenteral,
`
`
`
`or topical formulations, may have an additive effect with INOmax on the risk
`
`of developing methemoglobinemia (7).
`
`
`
`
`Revised: 3/2013
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`8.2 Labor and Delivery
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`8.5 Geriatric Use
`10 OVERDOSAGE11 DESCRIPTION
`
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`
`14.1 Treatment of Hypoxic Respiratory Failure (HRF)
`
`
`14.2 Ineffective in Adult Respiratory Distress Syndrome (ARDS)
`
`
`
`14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD)
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
`
`* Sections or subsections omitted from the full prescribing information
`
`
`
`
`are not listed
`
`
`
`
`
`
`
`
`
`
` INOMAX - nitric oxide gas
` INO Therapeutics
`
`----------
` HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`
`
` These highlights do not include all the information needed to use INOmax
` safely and effectively. See full prescribing information for INOmax.
`
`
`
`INOmax (nitric oxide) for inhalation
`
`
`
`Initial U.S. Approval: 1999
`
`
`
`--------------------------RECENT MAJOR CHANGES-------------------------­
`
`
`Dosage and Administration (2.2)
`3/2013
`
`
`
`
`
`
`
`
`---------------------------INDICATIONS AND USAGE---------------------------
`
`INOmax is a vasodilator, which, in conjunction with ventilatory support and
`
`
`other appropriate agents, is indicated for the treatment of term and near-term
`
`
`
`
`
`
`(>34 weeks gestation) neonates with hypoxic respiratory failure associated
`
`
`
`with clinical or echocardiographic evidence of pulmonary hypertension,
`
`where it improves oxygenation and reduces the need for extracorporeal
`
`membrane oxygenation (1.1).
`
`
`Monitor for PaO2, methemoglobin, and inspired NO2 during INOmax
`
`
`
`administration (1.1).
`
`
`Utilize additional therapies to maximize oxygen delivery (1.1).
`
`-----------------------DOSAGE AND ADMINISTRATION----------------------­
`
`
`
`
`
`Dosage: The recommended dose of INOmax is 20 ppm, maintained for up to
`
`
`
`14 days or until the underlying oxygen desaturation has resolved (2.1).
`
`Administration:
`
`•
` ®, INOmax® DS, or INOvent®
`Use only with an INOmax DSIR
`
`
`operated by trained personnel (2.2)
`
` • Wean from INOmax gradually (2.2).
`
`
`
`
`
`
`
`
`
`
`
`----------------------DOSAGE FORMS AND STRENGTHS---------------------
`INOmax (nitric oxide) is a gas available in 100 ppm and 800 ppm
`
`
`
`
`
`concentrations (3).
`
`
`
`
`
`
`
`
`
`FULL PRESCRIBING INFORMATION:
`
`
`CONTENTS*
`
`
`1 INDICATIONS AND USAGE
`
`
`1.1 Treatment of Hypoxic Respiratory Failure
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosage
`
`2.2 Administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt
`
`Discontinuation
`
`
`
`5.2 Hypoxia from Methemoglobinemia
`
`
`
`
`5.3 Airway Injury from Nitrogen Dioxide
`
`5.4 Heart Failure
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`
`
`
`
`Reference ID: 3270345
`
`
`
` 1
`
`INO THERAPEUTICS EXHIBIT 2001
`Praxair Distribution v. INO Therapeutics
`IPR2015-00889
`
`

`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`
` 1 INDICATIONS AND USAGE
`
` 1.1 Treatment of Hypoxic Respiratory Failure
`
`
`INOmax® is a vasodilator, which, in conjunction with ventilatory support and other appropriate
`
`
`
`
`agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic
`
`respiratory failure associated with clinical or echocardiographic evidence of pulmonary
`
`hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane
`
`oxygenation.
`
`
`Utilize additional therapies to maximize oxygen delivery with validated ventilation systems [see
`
`
`
`
`Dosage and Administration (2.2)]. In patients with collapsed alveoli, additional therapies might
`
`
`include surfactant and high-frequency oscillatory ventilation.
`
`
`The safety and effectiveness of INOmax have been established in a population receiving other
`
`
`
`
`therapies for hypoxic respiratory failure, including vasodilators, intravenous fluids, bicarbonate
`
`therapy, and mechanical ventilation. Different dose regimens for nitric oxide were used in the
`
`
`clinical studies [see Clinical Studies (14)].
`
`
`Monitor for PaO2, methemoglobin, and inspired NO2 during INOmax administration.
`
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
`
`
` To ensure safe and effective administration of INOmax to avoid adverse events associated with
`nitric oxide or NO2, administration of INOmax should only be performed by a health care
`
`
`
`
`professional who has completed and maintained training on the safe and effective use of a Nitric
`
`
`
`Oxide Delivery System provided by the manufacturer of the delivery system and the drug.
`
`
`2.1 Dosage
`
`Term and near-term neonates with hypoxic respiratory failure
`
` The recommended dose of INOmax is 20 ppm. Treatment should be maintained up to 14 days or
`
`
`until the underlying oxygen desaturation has resolved and the neonate is ready to be weaned
`
`
`from INOmax therapy.
`
`
`
`
`
`
` As the risk of methemoglobinemia and elevated NO2 levels increases significantly when
`
` INOmax is administered at doses >20 ppm; doses above this level are not recommended.
`
`
`
`
` 2.2 Administration
`
` Methemoglobin should be measured within 4-8 hours after initiation of treatment with INOmax
`
`
`
`
` and periodically throughout treatment [see Warnings and Precautions (5.2)].
`
`Nitric Oxide Delivery Systems
`
`
`
`
`
`
`
`
`Reference ID: 3270345
`
`
`
` 2
`
`

`
`
`
` ®, INOmax® DS, or INOvent® Nitric
`
`
` INOmax must be administered using the INOmax DSIR
`
`
`
`Oxide Delivery Systems, which deliver operator-determined concentrations of nitric oxide in
`conjunction with a ventilator or breathing gas administration system after dilution with an
`
`oxygen/air mixture. A Nitric Oxide Delivery System includes a nitric oxide administration
`
`
`
`
` apparatus, a nitric oxide gas analyzer and a nitrogen dioxide gas analyzer. Failure to calibrate the
`
`
`
`
`
` Nitric Oxide Delivery System could result in under- or over- dosing of nitric oxide.
`
`
`
` To address potential power failure, keep available a backup battery power supply. To address
`
`
` potential system failure, keep available an independent reserve nitric oxide delivery system.
`
`
`
`
`
` Failure to transition to a reserve nitric oxide delivery system can result in abrupt or prolonged
`
` discontinuation of nitric oxide [see Warnings and Precautions (5.1)].
`
`
`
`Training in Administration
`
`The user of INOmax and Nitric Oxide Delivery Systems must complete a comprehensive
`
`training program for health care professionals provided by the delivery system and drug
`
`
`manufacturers.
`
`Health professional staff that administers nitric oxide therapy have access to supplier-provided
`
`
`24 hour/365 days per year technical support on the delivery and administration of INOmax at 1­
`
`
`
`877-566-9466.
`
`Weaning and Discontinuation
`
`Abrupt discontinuation of INOmax may lead to increasing pulmonary artery pressure (PAP) and
`
`
`
`
`
`worsening oxygenation even in neonates with no apparent response to nitric oxide for inhalation.
`
`
`
`
` 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) for inhalation is a gas available in 100 ppm and 800 ppm concentrations.
`
`
`4 CONTRAINDICATIONS
`
`INOmax is contraindicated in the treatment of neonates known to be dependent on right-to-left
`shunting of blood.
`
`
`5 WARNINGS AND PRECAUTIONS
`
`
`
`5.1 Rebound Pulmonary Hypertension Syndrome following Abrupt Discontinuation
`
`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.
`
`
`
`5.2 Hypoxemia from Methemoglobinemia
`
`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
`
`
`
` 3
`
`
`
`Reference ID: 3270345
`
`

`
`
`
`
`
`
`
`
`
`
`
` 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)].
`
`
`
` 5.3 Airway Injury from Nitrogen Dioxide
` Nitrogen dioxide (NO2) forms in gas mixtures containing NO and O2. Nitrogen dioxide may
`
`cause airway inflammation and damage to lung tissues. If the concentration of NO2 in the
`
`
`
`
` breathing circuit exceeds 0.5 ppm, decrease the dose of INOmax.
`
`
` If there is an unexpected change in NO2 concentration, 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.
`
` 5.4 Heart Failure
`
`
`
`
`
`
`
` 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.
`
`
`6 ADVERSE REACTIONS
`
`
`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.
`
`
`6.1 Clinical Trials Experience
`
`
`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.
`
`
`
` 4
`
`
`
`Reference ID: 3270345
`
`

`
`In CINRGI, the only adverse reaction (>2% higher incidence on INOmax than on placebo) was
`
`
`hypotension (14% vs. 11%).
`
`
`6.2 Post-Marketing Experience
`
`Accidental Exposure
`
`Based upon post-marketing experience, 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
`
`No formal drug-interaction studies have been performed, and a clinically significant interaction
`
`with other medications used in the treatment of hypoxic respiratory failure cannot be excluded
`
`
`
`based on the available data. INOmax has been administered with dopamine, dobutamine,
`steroids, surfactant, and high-frequency ventilation. Although there are no study data to evaluate
`
`the possibility, nitric oxide donor compounds, including sodium nitroprusside and nitroglycerin,
`may have an additive effect with INOmax on the risk of developing methemoglobinemia. An
`association between prilocaine and an increased risk of methemoglobinemia, particularly in
`infants, has specifically been described in a literature case report. This risk is present whether the
`drugs are administered as oral, parenteral, or topical formulations.
`
`
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`Pregnancy Category C
`
`Animal reproduction studies have not been conducted with INOmax. It is not known if INOmax
`
`
`can cause fetal harm when administered to a pregnant woman or can affect reproductive
`
`capacity. INOmax is not intended for adults.
`
`
`8.2 Labor and Delivery
`
`The effect of INOmax on labor and delivery in humans is unknown.
`
`
`
`8.3 Nursing Mothers
`
`Nitric oxide is not indicated for use in the adult population, including nursing mothers. It is not
`
`
`known whether nitric oxide is excreted in human milk.
`
`
`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
`
`
` 5
`
`
`
`Reference ID: 3270345
`
`

`
`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.
`
`
`
`10 OVERDOSAGE
`
`Overdosage with INOmax will be 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.
`
`
`11 DESCRIPTION
`
`
`INOmax (nitric oxide gas) is a drug administered by inhalation. Nitric oxide, the active substance
`in INOmax, is a pulmonary vasodilator. INOmax 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).
`
`
`INOmax 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:
`
`
`
`
`12 CLINICAL PHARMACOLOGY
`
`
`12.1 Mechanism of Action
`
`
`Nitric oxide is a compound produced by many cells of the body. It 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.
`
`
`
` 6
`
`
`
`Reference ID: 3270345
`
`

`
` 12.2 Pharmacodynamics
`
` 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, INOmax improves oxygenation (as
`
`indicated by significant increases in PaO2).
`
`
`
`
`
`12.3 Pharmacokinetics
`
`
`The pharmacokinetics of nitric oxide has been studied in adults.
`
`
`Uptake and Distribution
`
`Nitric oxide is absorbed systemically after inhalation. Most of it traverses the pulmonary
`
`capillary bed where it combines with hemoglobin that is 60% to 100% oxygen-saturated. At this
`
`level of oxygen saturation, nitric oxide combines predominantly with oxyhemoglobin to produce
`methemoglobin and nitrate. At low oxygen saturation, nitric oxide can combine with
`
`deoxyhemoglobin to transiently form nitrosylhemoglobin, which is converted to nitrogen oxides
`
`and methemoglobin upon exposure to oxygen. Within the pulmonary system, nitric oxide can
`combine with oxygen and water to produce nitrogen dioxide and nitrite, respectively, which
`
`interact with oxyhemoglobin to produce methemoglobin and nitrate. Thus, the end products of
`
`
`nitric oxide that enter the systemic circulation are predominantly methemoglobin and nitrate.
`
`
`Metabolism
`
`Methemoglobin disposition has been investigated as a function of time and nitric oxide exposure
`concentration in neonates with respiratory failure. The methemoglobin (MetHb) concentration-
`
`time profiles during the first 12 hours of exposure to 0, 5, 20, and 80 ppm INOmax are shown in
`
`Figure 1.
`
`Figure 1: Methemoglobin Concentration-Time Profiles Neonates Inhaling 0, 5, 20 or 80
`ppm INOmax
`
`
`
`
`Reference ID: 3270345
`
`
`
` 7
`
`

`
`
` Methemoglobin concentrations increased during the first 8 hours of nitric oxide exposure. The
`
`mean methemoglobin level remained below 1% in the placebo group and in the 5 ppm and 20
` ppm INOmax groups, but reached approximately 5% in the 80 ppm INOmax group.
`
`
`
`
`
` Methemoglobin levels >7% were attained only in patients receiving 80 ppm, where they
`
` comprised 35% of the group. The average time to reach peak methemoglobin was 10 ± 9 (SD)
`hours (median, 8 hours) in these 13 patients, but one patient did not exceed 7% until 40 hours.
`
`
`
`
` Elimination
`
`Nitrate has been identified as the predominant nitric oxide metabolite excreted in the urine,
`
` accounting for >70% of the nitric oxide dose inhaled. Nitrate is cleared from the plasma by the
`
` kidney at rates approaching the rate of glomerular filtration.
`
`
`
`
`
`
`
`
`
` 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.
`
`
`
`
`Reference ID: 3270345
`
`
`
` 8
`
`

`
`
`
` 14 CLINICAL STUDIES
`
`
`
`
`
`
` 14.1 Treatment of Hypoxic Respiratory Failure (HRF)
` 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)].
`
`
`NINOS Study
`
`
`
`
`
` The Neonatal Inhaled Nitric Oxide Study (NINOS) was a double-blind, randomized, placebo-
`
`
` controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the
`
`
` study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or
`
` initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of
`
`
` term or near-term neonates with hypoxic respiratory failure unresponsive to conventional
` therapy. Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%),
`
`
` pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN;
`
` 17%), or respiratory distress syndrome (RDS; 11%). Infants ≤14 days of age (mean, 1.7 days)
`
` with a mean PaO2 of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H2O / mm Hg
`
`
`
`
`
`were initially randomized to receive 100% O2 with (n=114) or without (n=121) 20 ppm nitric
`
`
`
`oxide for up to 14 days. Response to study drug was defined as a change from baseline in PaO2
`
`
`
`30 minutes after starting treatment (full response = >20 mm Hg, partial = 10–20 mm Hg, no
`
`
`
`response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to
`
`80 ppm nitric oxide or control gas. The primary results from the NINOS study are presented in
`
`Table 2.
`
`
`
` Death or ECMO*,†
`
` Death
` ECMO
`
`
` * Extracorporeal membrane oxygenation
`
`
`† Death or need for ECMO was the study's primary end point
`
`
`
`Although the incidence of death by 120 days of age was similar in both groups (NO, 14%;
`control, 17%), significantly fewer infants in the nitric oxide group required ECMO compared
`
`
`with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of
`
`ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p =
`
`
`
` 0.006). The nitric oxide group also had significantly greater increases in PaO2 and greater
` decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for
`
`
`all parameters). Significantly more patients had at least a partial response to the initial
`
`
`administration of study drug in the nitric oxide group (66%) than the control group (26%,
`
`
`p<0.001). Of the 125 infants who did not respond to 20 ppm nitric oxide or control, similar
`
`percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80
`
` 9
`
`
`
` P value
`
`
` 0.006
`
` 0.60
` 0.014
`
`
`
`
` Table 2: Summary of Clinical Results from NINOS Study
`
`
`Control
` NO
`
` (n=114)
`(n=121)
`
` 52 (46%)
`
` 77 (64%)
`
` 16 (14%)
`
` 20 (17%)
`
` 44 (39%)
`
` 66 (55%)
`
`
`
`
`
`
`
`Reference ID: 3270345
`
`

`
`
`
`
`
` ppm nitric oxide for inhalation or control drug, suggesting a lack of additional benefit for the
`
` higher dose of nitric oxide. No infant had study drug discontinued for toxicity. Inhaled nitric
`
` oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial
`
`
`
` occurred at similar incidence rates in both treatment groups [see Adverse Reactions (6.1)].
`
` Follow-up exams were performed at 18–24 months for the infants enrolled in this trial. In the
`
`
`
` infants with available follow-up, the two treatment groups were similar with respect to their
`
`
` mental, motor, audiologic, or neurologic evaluations.
`
` CINRGI Study
`This study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and
`
`near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary
`
`objective of the study was to determine whether INOmax would reduce the receipt of ECMO in
`
`these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%),
`
`pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO2 of 54 mm Hg and a mean OI
`
`
`
`
`
`
`
`of 44 cm H2O / mm Hg were randomly assigned to receive either 20 ppm INOmax (n=97) or
`
`
`nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a
` PaO2 >60 mm Hg and a pH < 7.55 were weaned to 5 ppm INOmax or placebo. The primary
`
`
`
` results from the CINRGI study are presented in Table 3.
`
`
`
` Table 3: Summary of Clinical Results from CINRGI Study
`
`
` Placebo
` INOmax
`
`
` 51/89 (57%)
` 30/97 (31%)
`
`
` 5/89 (6%)
` 3/97 (3%)
`
`
` P value
`
` <0.001
`
` 0.48
`
`
`
` ECMO*,†
` Death
`
`
` * Extracorporeal membrane oxygenation
`
`
`† ECMO was the primary end point of this study
`
`
` Significantly fewer neonates in the INOmax group required ECMO compared to the control
`
` group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups
`
` (INOmax, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was
`
` decreased in the INOmax group (33% vs. 58%, p<0.001).
`
`
`
`
`
`In addition, the INOmax group had significantly improved oxygenation as measured by PaO2,
`
`
`OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with
`
`INOmax, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The
`
`
`frequency and number of adverse events reported were similar in the two study groups [see
`
`
`Adverse Reactions (6.1)].
`
`
`
`In clinical trials, reduction in the need for ECMO has not been demonstrated with the use of
`
`
`
`
`
`
`inhaled nitric oxide in neonates with congenital diaphragmatic hernia (CDH).
`
`14.2 Ineffective in Adult Respiratory Distress Syndrome (ARDS)
`
`
`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
`
`
`
`
`
`
` 10
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`
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`Reference ID: 3270345
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`

`
` 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.
`
`
`14.3 Ineffective in Prevention of Bronchopulmonary Dysplasia (BPD)
`
`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 three large, multi-center, double-blind, placebo-controlled
`
`clinical trials in a total of 2,149 preterm infants. Of these, 1,068 received placebo, and 1,081
`
`
`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 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 indicated.
`
`
`
`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 D Portable aluminum cylinders containing 353 liters at STP of nitric oxide gas in 100
`
`
`
` ppm concentration in nitrogen (delivered volume 344 liters) (NDC 64693-001-01)
` 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)
`
` Size 88 Aluminum cylinders containing 1963 liters at STP of nitric oxide gas in 100 ppm
`
`
` concentration in nitrogen (delivered volume 1918 liters) (NDC 64693-001-02)
`
`
`
`
`
`
` 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.
`
`
`
`
`The cylinders should be appropriately transported to protect from risks of shocks and falls.
`
`
`Occupational Exposure
`
`
`
`
`
`
`Reference ID: 3270345
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`
`
` 11
`
`

`
`The exposure limit set by the Occupational Safety and Health Administration (OSHA) for nitric
`
`
`oxide is 25 ppm, and for NO2 the limit is 5 ppm.
`
`
`
`
`INO Therapeutics
`
`
`Perryville III Corporate Park
`
`53 Frontage Road, Third Floor
`
`P.O. Box 9001
`
`
`
`Hampton, NJ 08827-9001
`
`
`USA
`
`
`
`© 2013 INO Therapeutics
`
`
`
`
`Reference ID: 3270345
`
`
`
`
` 12