QENTER F; LR DRIIQ EVALUATIQN AND RESEARLZH
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`APPLIQATI1 LN NUMBER: NDA 20845
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`FINAL PRINTED LAB ELLINQ
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`PRAXAIR ET AL. 1010
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`INOmaxTM (nitric oxide) for inhalation
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`100 and 800ppm (parts per million)
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`DESCRIPTION
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`INOmaxTM (nitric oxide gas) is a dmg administered by inhalation. Nitric oxide, the active substance in INOmax, is a
`pulmonary vasodilator. INOmax is a gaseous blend of nitric oxide (0.8%) and nitrogen (99.2%). INOmax is supplied in
`aluminum cylinders as a compressed gas under high pressure (2000 pounds per square inch gauge [psig]). _
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`The structural fonnula of nitric oxide (NO) is shown below:
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`In
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`CLINICAL PHARMACOLOGY
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`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 cyelase and increasing intracellular levels of cyclic guanosine
`3’,5’-monophosphate, which then leads to vasodilation. When inhaled; nitric oxide produces pulmonary vasodilation.
`A
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`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 ventilationjperfusion
`(V/Q) ratios toward regions with normal ratios.
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`Effects on Pulmonary Vascular Tone in PPHN: Persistent pulmonary hypertension of the newbom (PPHN) occurs as a
`primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome
`(MAS), pneumonia,
`sepsis, hyaiine 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 arteriosu_s and foramen ovale; In neonates with PPHN, INOmax
`improves oxygenation (as indicated by significant increases in PaO2).
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`PHARMACOKINETICS
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`The pharmacokinetics of nitric oxide has been studied in adults.
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`Uptake and Distribution: Nitric oxide is absorbed systemically afier -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.
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`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.
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`Methemoglobin Concentration- Time Profiles
`Neonates Inhaling 0, 5, 20 or 80 ppm INOmax
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`Figure I
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`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 lNOmax groups, but reached approximately 5% in
`the 80 ppm 1NOmax 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 :1: 9 (SD) hours (median, 8 hours) in
`these 13 patients; but one patient did not exceed 7% until 40 hours.
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`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.
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`CLINICAL TRIALS
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`The efficacy of 1NOmax 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 (O1= mean airway pressure in cm H20
`x fraction of inspired oxygen concentration {FiO2] x l00 divided by systemic arterial concentration in mm Hg [PaO2]) and
`increases PaO2 (See CLINICAL PHARMACOLOGY.)
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`(i) 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 tenn or near-tenn 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 if the newborn (PPHN; 17%), or respiratory-
`distress syndrome (RDS; 11%). Infants S 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 H20 / mm Hg were initially randomized to receive 100% 02 with (n=l 14) 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 1.
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`Table 1
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`Summary of Clinical Results from NINOS Study
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`2 Control
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`I NO
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`1 Pvalue
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`Q (n=l14)
`(n=i21)
`‘
`5
`"
`'
`l
`% 5“‘‘6‘’’°) T
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`V
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`l *“”%> T
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`1
`* “<“°”°>
`l“‘”39%) W i
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`a Extra-corporeal membrane oxygenation
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`b Death or need for ECMO was the study’s primary end point.
`a
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`Although the incidence of death by 120 days of age was similar in both groups (N0, 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 2 0.006). The nitric oxide group also had significantly greater increases in Pa02 and greater decreases in the O]
`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<0.00l). 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. lnhalednitric 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.) Follow-up
`exams were performedat 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 theirmental, motor, audiologic, or neurologic evaluations.
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`(ii) 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 detennine 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 Pa02 of 54
`mm Hg and a mean (01) of 44 cm H20 / mm Hg were randomly assigned to receive either 20 ppm INOrr_1ax (n=97) or
`nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a Pa02 >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 2.
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`Table 2
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`Summary of Clinical Results from CINRGI Study
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`3°'97<3‘%> 5
`’*9<57%>
`4 W 7 3’”<3%) i
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`a Extra-corporeal membrane oxygenation
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`“ ECMO was the primary end point of this study.
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`Significantly fewer neonates in the INOmax group required ECMO compared to the control group (31% vs. 57%,
`p<0.00l). 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<0.0Dl).
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`In addition, the INOmax group had significantly improved oxygenation as measured by Pa02, 01, and alveolar-arterial
`gradient (p<0.00I for all parameters). Of the 97 patients treated with INOmax, 2 (2%) were withdrawn fi'om study drug
`due to methemoglobin levels >4%. The fiequency and number of adverse events reported were similar in the two study
`groups. (See ADVERSE REACTIONS.)
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`INDICATIONS
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`INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and
`near-tenn (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of
`pulmonary hypertension, where it improves oxygenation and reduces me need for extracorporeal membrane oxygenation.
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`CONTRAINDICATIONS
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`INOmax should not be used inthe treatment of neonates known to be dependent on right-to-left shunting of blood.
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`PRECAUTIONS
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`Rebound
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`Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary artery pressure.
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`_ Methemoglobinemia
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`Methemogloginemia increases with the close of nitric oxide. In the clinical trials, maximum methemoglobin levels usually
`were reached approximately 8 hours afier initiation of inhalation, although methemoglobin levels have peaked as late as
`40 hours following initiation of INOmax therapy. In one study._]3 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 remmed to baseline over a period of hours.
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`Elevated N02 Levels
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`In one study, N02 levels were <0.5 ppm when neonates were treated with placebo, 5 ppm, and 20 ppm nitric oxideover
`the first 48 hours. The 80 ppm group had a mean peak N02 level of 2.6 ppm.
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`Drug Interactions
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`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. In particular, although
`there are no 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. INOmax has been
`administered with tolazoline, dopamine, dobutamine, steroids, surfactant, and high-frequency ventilation.
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`Carcinogenesis, Mutagenesis, Impairment of Fertility
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`No long-tenn studies in animals to evaluatethe carcinogenic potential of nitric oxide have been perfonned. 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 or harm to the developing fetus.
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`Pregnancy: Category C
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`Animal reproduction studies have not been conducted with lNOmax. It is not known whether lNOmax can cause fetal
`harm when administered to a pregnant woman or can affect reproduction capacity. lNOmax is not intended for adults.
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`' Pediatric Use
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`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.
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`Nursing Mothers
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`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.
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`ADVERSE REACTIONS
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`Controlled studies have included 325 patients on "lNOmax doses of 5 to 80 ppm and 251 patients on placebo. Total
`mortality in the pooled trials was 11% on placebo and 9% on iN0max, a result adequate to exclude lNOmax mortality
`being more than 40% worse than placebo.
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`in both the NINOS and CINRGI studies, the duration of hospitalization was similar in INOmax- and placebo- treated
`groups.
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`From all controlled studies,‘ at least 6 months of follow-up is available for 278 patients who received lNOmax 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.
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`In the NINOS, 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.
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`The table below shows adverse events with an incidence of at least 5% on lNOmax in the CINRGI study, and that were
`more common on lNOmax than on placebo.
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`ADVERSE EVENTS IN THE CINRGI TRIAL
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`I Aerse Event
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`Placebo (n=8)
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`Inhaled N0 (n=97)
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`i" 9 (9%)
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`OVERDOSAGE
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`36%)
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`Overdosage with lNOmax will be manifest by elevations in methemoglobin and N02. Elevated N02 may cause acute lung
`injury. Elevations in rnethemoglobinemia reduce the oxygen delivery capacity of the circulation. In clinical studies, N02
`levels >3 ppm or methemoglobin levels >7% were treated by reducing the dose of or discontinuing INOrnax.
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`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.
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`DOSAGE AND ADMINISTRATION
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`Dosage
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`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.
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`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 who
`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 N02 levels increases significantly when lNOmax is
`administered at_,doses >20 ppm, doses above this level ordinarily should not be used.
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`Administration
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`Additional therapies should be used to maximize oxygen delivery. In patients with collapsed alveoli, additional therapies
`might includelsurfactant and high frequency oscillatory ventilation.
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`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 clinicalstudies (see CLINICAL STUDIES).
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`INOmax should be administered with monitoring for PaO2, methemoglobin, and N02.
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`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 IN0ventTM system and other systems meeting these criteria were used in the clinical trials. In the ventilated neonate,
`precise monitoring of inspired nitric oxide and N02 should be instituted, using a properly calibrated analysis device with
`alarms. This 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.
`*
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`In the event of a system failure or a wall-outlet power failure, a backup battery power supply and reserve nitric oxide i
`delivery system should be available.
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`The lNOmax dose should not be discontinued abruptly as it may result in an increase in pulmonary artery pressure 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.
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`HOW SUPPLIED
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`INOmaxT” (nitric oxide} is available in the following sizes:
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`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-D1)
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`Size D Portable aluminum cylinders containing 353 liters at STP of nitric oxide gas in 100 ppm
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`concentration in nitrogen (delivered volume 344 liters) (NDC 64693-001-01)
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`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 )
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`Size 88_Aluminum cylinders containing 1963 liters at STP of nitric oxide gas in I00 ppm concentration in
`nitrogen (delivered volume 1918 liters) (NDC 64693-001-02)
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`Store at 25°C (77°F) with excursions permitted between 15-30°C (59-86°F). '[See USP Controlled Room Temperature}
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`Occupational Exposure
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`The exposure limit set by me Occupational Safety and-Health Administration (OSHA) for nitric oxide is 25 ppm and for
`N02 the limit is 5 ppm.
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`CAUTION
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`Federal law prohibits dispensing without a prescription.
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`[NO Therapeutics, Inc
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`54 Old Highway 22
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`Clinton, NJ 08_809 USA
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`http://www.fda.gov/cder/foi/label/1 999/20845lb1.htm
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`007