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 _________________
`
`
`Warnings and Precautions, Heart Failure (5.4)
`8/2009
`
`_________________
`__________________ 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 must be delivered via a system which does not cause
`•
`
`generation of excessive inhaled nitrogen dioxide (2.2).
`
`
`
`Do not discontinue INOmax abruptly (2.2).
`•
`
`_____________
`______________ DOSAGE FORMS AND STRENGTHS
`
`INOmax (nitric oxide) is a gas available in 100 ppm and 800 ppm
`concentrations.
`
`
`
`
`2.
`
`
`
`6.
`
`
`7.
`
`8.
`
`___________________ 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: NO2 levels should be monitored (5.3).
`
`Heart Failure: In patients with pre-existing left ventricular dysfunction, inhaled
`nitric oxide may increase pulmonary capillary wedge pressure leading to
`
`
`pulmonary edema (5.4).
`
`
`____________________ADVERSE REACTIONS____________________
`Methemoglobinemia and elevated NO2 levels are dose dependent adverse
`events. Worsening oxygenation and increasing pulmonary artery pressure
`
`
`occur if INOmax is discontinued abruptly. Other adverse reactions that
`occurred in more than 5% of patients receiving INOmax in the CINRGI study
`were: thrombocytopenia, hypokalemia, bilirubinemia, atelectasis, and
`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: August 2009
`
`
`
`
`
`8.3 Nursing Mothers
`
`
`8.4
`Pediatric Use
`
`
`8.5 Geriatric Use
`
`OVERDOSAGE
`
`DESCRIPTION
`
`CLINICAL PHARMACOLOGY
`
`
`12.1. Mechanism of Action
`
`
`12.2. Pharmacodynamics
`
`
`12.3. Pharmacokinetics
`
`
`12.4 Pharmacokinetics: Uptake and Distribution
`
`
`12.5 Pharmacokinetics: Metabolism
`
`
`12.6 Pharmacokinetics: Elimination
`
`NONCLINICAL TOXICOLOGY
`
`
`13.1. Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`CLINICAL STUDIES
`
`
`14.1 Treatment of Hypoxic Respiratory Failure (HRF)
`
`
`14.2
`Ineffective in Adult Respiratory Distress Syndrome (ARDS)
`
`HOW SUPPLIED/STORAGE AND HANDLING
`
`
`10.
`
`11.
`
`12.
`
`
`13.
`
`
`14.
`
`
`16.
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1.
`INDICATIONS AND USAGE
`
`
`1.1 Treatment of Hypoxic Respiratory Failure
`
`
`DOSAGE AND ADMINISTRATION
`
`2.1 Dosage
`
`
`2.2 Administration
`
`
`DOSAGE FORMS AND STRENGTHS
`3.
`
`
`CONTRAINDICATIONS
`4.
`
`
`5. WARNINGS AND PRECAUTIONS
`
`
`5.1 Rebound
`
`
`5.2 Methemoglobinemia
`
`
`5.3 Elevated NO2 Levels
`
`
`
`
`5.4 Heart Failure
`
`ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2
`Post-Marketing Experience
`
`DRUG INTERACTIONS
`
`USE IN SPECIFIC POPULATIONS
`
`
`8.1
`Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
`
`
`
`

`

`FULL PRESCRIBING INFORMATION
`
`INDICATIONS AND USAGE
`1
`
`Treatment of Hypoxic Respiratory Failure
`1.1
`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. In patients with collapsed alveoli, additional therapies
`might include surfactant and high-frequency oscillatory ventilation.
`
`The safety and effectiveness of inhaled nitric oxide 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.
`
`DOSAGE AND ADMINISTRATION
`2
`
`Dosage
`2.1
` 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.
`
`An initial dose of 20 ppm was used in the NINOS and CINRGI trials. In CINRGI, patients whose oxygenation
`improved with 20 ppm were dose-reduced to 5 ppm as tolerated at the end of 4 hours of treatment. In the
`NINOS trial, patients whose oxygenation failed to improve on 20 ppm could be increased to 80 ppm, but those
`patients did not then improve on the higher dose. As the risk of methemoglobinemia and elevated NO2 levels
`increases significantly when INOmax is administered at doses >20 ppm, doses above this level ordinarily
`should not be used.
`
`Administration
`2.2
`The nitric oxide delivery systems used in the clinical trials provided operator-determined concentrations of
`nitric oxide in the breathing gas, and the concentration was constant throughout the respiratory cycle. INOmax
`
` must be delivered through a system with these characteristics and which does not cause generation of excessive
`inhaled nitrogen dioxide. The INOvent® system and other systems meeting these criteria were used in the
`clinical trials. In the ventilated neonate, precise monitoring of inspired nitric oxide and NO2 should be
`instituted, using a properly calibrated analysis device with alarms. The system should be calibrated using a
`precisely defined calibration mixture of nitric oxide and nitrogen dioxide, such as INOcal®. Sample gas for
`analysis should be drawn before the Y-piece, proximal to the patient. Oxygen levels should also be measured.
`
`In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric
`oxide delivery system should be available.
`
`Do not discontinue INOmax abruptly, as it may result in an increase in pulmonary artery pressure (PAP) and/or
`worsening of blood oxygenation (PaO2). Deterioration in oxygenation and elevation in PAP may also occur in
`children with no apparent response to INOmax. Discontinue/wean cautiously.
`
`
`

`

`DOSAGE FORMS AND STRENGTHS
`3
`Nitric oxide is a gas available in 100 ppm and 800 ppm concentrations.
`
`CONTRAINDICATIONS
`4
`INOmax is contraindicated in the treatment of neonates known to be dependent on right-to-left shunting of
`blood.
`
`WARNINGS AND PRECAUTIONS
`5
`
`Rebound
`5.1
`Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary artery
`pressure.
`
`5.2 Methemoglobinemia
`Methemoglobinemia increases with the dose of nitric oxide. In clinical trials, maximum methemoglobin levels
`usually were reached approximately 8 hours after initiation of inhalation, although methemoglobin levels have
`
`peaked as late as 40 hours following initiation of INOmax therapy. In one study, 13 of 37 (35%) of neonates
`treated with INOmax 80 ppm had methemoglobin levels exceeding 7%. Following discontinuation or reduction
`of nitric oxide, the methemoglobin levels returned to baseline over a period of hours.
`
`Elevated NO2 Levels
`5.3
`In one study, NO2 levels were <0.5 ppm when neonates were treated with placebo, 5 ppm, and 20 ppm nitric
`oxide over the first 48 hours. The 80 ppm group had a mean peak NO2 level of 2.6 ppm.
`
`5.4 Heart Failure
`Patients who had pre-existing left ventricular dysfunction treated with inhaled nitric oxide, even for short
`durations, experienced serious adverse events (e.g., pulmonary edema).
`
`
`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.
`
`Clinical Trials Experience
`6.1
`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.
`
`

`

`Placebo (n=89)
`9 (10%)
`
`
` 9 (10%)
`
` 8 (9%)
`
` 5 (6%)
`
` 6 (7%)
`
` 2 (2%)
`
` 3 (3%)
`3 (3%)
`
`
` 0 (0%)
`
`USE IN SPECIFIC POPULATIONS
`
`Inhaled NO (n=97)
`13 (13%)
`
`
` 12 (12%)
`
` 9 (9%)
`
` 8 (8%)
`
` 8 (8%)
`
` 7 (7%)
`
` 6 (6%)
`5 (5%)
`
`
` 5 (5%)
`
`
`The table below shows adverse reactions that occurred in at least 5% of patients receiving INOmax in the
`CINRGI study with event rates >5% and greater than placebo event rates. None of the differences in these
`adverse reactions were statistically significant when inhaled nitric oxide patients were compared to patients
`receiving placebo.
`
`Table 1: Adverse Reactions in the CINRGI Study
`Adverse Event
`Hypotension
`Withdrawal
`Atelectasis
`Hematuria
`Hyperglycemia
`Sepsis
`Infection
`Stridor
`Cellulitis
`
`Post-Marketing Experience
`6.2
`The following adverse reactions have been identified during post-approval use of INOmax. Because these
`reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their
`frequency reliably or to establish a causal relationship to drug exposure. The listing is alphabetical: dose errors
`associated with the delivery system; headaches associated with environmental exposure of INOmax in hospital
`staff; hypotension associated with acute withdrawal of the drug; hypoxemia associated with acute withdrawal of
`the drug; pulmonary edema in patients with CREST syndrome.
`
`DRUG INTERACTIONS
`7
`
`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 tolazoline, 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
`
`Pregnancy
`8.1
`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.
`
`
`Labor and Delivery
`8.2
`The effect of INOmax on labor and delivery in humans is unknown.
`
`Nursing Mothers
`8.3
`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.
`
`

`

`OVERDOSAGE
`
`
`Pediatric Use
`8.4
`Nitric oxide for inhalation has been studied in a neonatal population (up to 14 days of age). 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 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 methemoglobinemia 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.
`
`DESCRIPTION
`11
`
`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:
`
`
`
`
`
` CLINICAL PHARMACOLOGY
`
`
`
`
`12
`
`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.
`
`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.
`
`

`

`
`12.4 Pharmacokinetics: 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.
`
`12.5 Pharmacokinetics: 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
`
`
`
`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.
`
`12.6 Pharmacokinetics: 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
`
`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.
`
`
`14
`
`14.1 Treatment of Hypoxic Respiratory Failure (HRF)
`
`NONCLINICAL TOXICOLOGY
`
`
`CLINICAL STUDIES
`
`

`

`
` 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) group conducted 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.
`
`Table 2: Summary of Clinical Results from NINOS Study
`Control
`
`(n=121)
`77 (64%)
`20 (17%)
`66 (55%)
`
`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 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
`
`
`
`NO
`(n=114)
`52 (46%)
`16 (14%)
`44 (39%)
`
`P value
`
`0.006
`0.60
`0.014
`
`

`

`P value
`<0.001
`0.48
`
`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
`Death or ECMO*, †
`51/89 (57%)
`30/97 (31%)
`Death
`5/89 (6%)
`3/97 (3%)
` * 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)].
`
`14.2
`Ineffective in Adult Respiratory Distress Syndrome (ARDS)
`
`ARDS Study
`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.
`
`HOW SUPPLIED/STORAGE AND HANDLING
`16
`
`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)
`
`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)
`
`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)
`
`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)
`
`Size D
`
`Size 88
`
`Size 88
`
`
`
`Store at 25°C (77°F) with excursions permitted between 15–30°C (59–86°F) [see USP Controlled Room
`Temperature].
`
`Occupational Exposure
`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
`
`

`

`6 Route 173 West
`Clinton, NJ 08809
`USA
`© 2009 INO Therapeutics
`
`