CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`NDA 20845/ S17
`
`INOMAX
`
`
`Trade Name:
`
`Nitric Oxide
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indications:
`
`Mallinckrodt Hospital
`
`10/09/2015
`
`
`
`INOmax is a vasodilator 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.
`
`
`
`
`
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`NDA 20845/S17
`
`CONTENTS
`
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Other Review(s)
`Administrative/Correspondence Document(s)
`
`
`
`X
`
`
`
`
`
`
`X
`
`
`
`X
`
`
`
`
`X
`X
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 20845/S17
`NDA 20845/S 17
`
`APPLICA TION NUMBER:
`
`APPROVAL LETTER
`
`APPROVAL LETTER
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
` NDA 20845/S-016, S-017
`
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`
`SUPPLEMENT APPROVAL
`
`
`
`
`
`
`Mallinckrodt Hospital Products IP Limited
`
`
`c/o: INO Therapeutics
`
`Attention: Mary Ellen Anderson
`
`
`Senior Director, Regulatory Affairs
`
`
`Perryville III Corporate Park
`
`53 Frontage Road, Third Floor, Box 9001
`
`Hampton, NJ 08827
`
`
`
`
`Dear Ms. Anderson:
`
`
`
`
`
`
`Please refer to your Supplemental New Drug Applications (sNDAs) dated December 8, 2014 (S­
`
`
`
`016) and December 11, 2014 (S-017) submitted under section 505(b) of the Federal Food, Drug,
`
`
`and Cosmetic Act (FDCA) for INOmax (nitric oxide) for inhalation.
`
`
`We acknowledge receipt of your amendments dated August 27, 2015 (S-016) and January 30 and
`
`February 13, 2015 (S-017).
`
`
`
`
`
`The August 27, 2015 submission constituted a complete response to our June 4, 2015 action
`
`
`letter for S-016.
`
`
`
`
`
`
`These “Prior Approval” supplemental new drug applications propose the following:
`
` S-016
`
`The removal of the 100 ppm nitric oxide concentration from the labeling and revisions to the
`
`DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS sections of
`
`
`
`the INOmax package inserts.
`
`
`S-017
`
`Revisions to the labeling based on the clinical study entitled “Bronchopulmonary Dysplasia
`
`
`(BPD) in Preterm Infants Requiring Mechanical Ventilation or Positive Pressure Support on
`Days 5 to 14 After birth (IK-3001-BPD-301)”.
`
`
`APPROVAL & LABELING
`
`
`We have completed our review of these supplemental applications, as amended. They are
`
`
`
`
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`
`upon labeling text.
`
`
`Reference ID: 3831195
`
`

`

`
`
`
`
`
`
` NDA 20845/S-016 & 017
`
` Page 2
`
`
` CONTENT OF LABELING
`
`
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`
`
`
`
`
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`
`automated drug registration and listing system (eLIST), as described at
`
`
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert), with the
`
`
`
`
`addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as
`
`
`
`well as annual reportable changes not included in the enclosed labeling.
`
`
`
`
` Information on submitting SPL files using eList may be found in the guidance for industry titled
` “SPL Standard for Content of Labeling Technical Qs and As at
`
`
`
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
`
`
`The SPL will be accessible from publicly available labeling repositories.
`
`
`
`Also within 14 days, amend all pending supplemental applications that includes labeling changes
`
`
`
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`
`
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`
`
`
`
`
`changes approved in this supplemental application, as well as annual reportable changes and
`
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`
`
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`
`should provide appropriate annotations, including supplement number(s) and annual report
`
`
`
`
`
`
`
`date(s).
`
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`
`the product misbranded and an unapproved new drug.
`
`
`PROMOTIONAL MATERIALS
`
`
`
`You may request advisory comments on proposed introductory advertising and promotional
`
`
`
`
`
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`
`
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
`
`
`
`OPDP Regulatory Project Manager
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`5901-B Ammendale Road
`
`Beltsville, MD 20705-1266
`
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`
`
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`
`
`
`Reference ID: 3831195
`
`

`

`
`
` NDA 20845/S-016 & 017
`
` Page 3
`
`
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`
`
` CM443702.pdf ).
`
` Information and Instructions for completing the form can be found at
`
`
`
` http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`
`
`
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`
`All promotional materials that include representations about your drug product must be promptly
`
`
`revised to be consistent with the labeling changes approved in this supplement, including any
`
`
`
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`
`
`
`should include prominent disclosure of the important new safety information that appears in the
`
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`
`
`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
`
`
`
`electronically in eCTD format. For more information about submitting promotional materials in
`
`
`
`eCTD format, see the draft Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`
`
`REPORTING REQUIREMENTS
`
`
`
`
`
`We remind you that you must comply with reporting requirements for an approved NDA
`
`
`(21 CFR 314.80 and 314.81).
`
`
`
`
`
`If you have any questions, please call Brian Proctor, Regulatory Project Manager, at (240) 402­
`
`3596.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Mary Ross Southworth, Pharm.D.
`
`
`
`Deputy Director for Safety
`
`Division of Cardiovascular and Renal Products
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`
`
`ENCLOSURE(S):
`
`
`Content of Labeling
`
`
`Reference ID: 3831195
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MARY R SOUTHWORTH
`10/09/2015
`
`Reference ID: 3831195
`
`

`

`CENTER FOR DRUG EVALUATION AND
`
` CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`NDA 20845/S17
`NDA 20845/S 17
`
`APPLICA TION NUMBER:
`
`LABELING
`
`LABELING
`
`
`
`
`
`

`

`
`
`
`
`
`
`
`
`
` 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) gas, for inhalation
`
`
`
` Initial U.S. Approval: 1999
` ---------------------------RECENT MAJOR CHANGES --------------------------­
`
`
`
` Dosage and Administration (2.2)
`
`
`
` 10/2015
`
`
` --------------------------- INDICATIONS AND USAGE----------------------------
`
`
`
`
` INOmax is a vasodilator 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.
`
`
`
`-----------------------DOSAGE AND ADMINISTRATION ---------------------­
`
`
`
`
`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:
`
`
`
`• Use only with an INOmax DSIR
`
` ®operated by trained personnel (2.2)
`
`
`
`
` • Avoid abrupt discontinuation (2.2, 5 1).
`
`
` --------------------- DOSAGE FORMS AND STRENGTHS----------------------
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` INOmax (nitric oxide) is a gas available in an 800 ppm concentration (3).
`
` ------------------------------ CONTRAINDICATIONS -----------------------------­
`
`
` Neonates 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 (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 -----------------------------­
`
`
`
`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 compounds may increase the risk of developing
`
`methemoglobinemia (7).
`
`
`
`Revised: 10/2015
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1 INDICATIONS AND USAGE
`
`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 Hypoxemia from Methemoglobinemia
`
`
`
`5.3 Airway Injury from Nitrogen Dioxide
`
`
`
`5.4 Worsening Heart Failure
`
`6 ADVERSE REACTIONS
`
`
`6.1 Clinical Trials Experience
`
`
`6.2 Post-Marketing Experience
`
`7 DRUG INTERACTIONS
`
`
`
`7.1 Nitric Oxide Donor Compounds
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`
`
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`10 OVERDOSAGE
`
`11 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
`
`Reference ID: 3831195
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
` 1 INDICATIONS AND USAGE
`
`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.
`
`
`
` 2 DOSAGE AND ADMINISTRATION
`
` 2.1 Dosage
`
`
` 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)].
`
`
`
`
`
`2.2 Administration
`
`Training in Administration
`
`The user of INOmax and Nitric Oxide Delivery Systems must satisfactorily complete a
`
`
`comprehensive periodic 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.
`
`
`Nitric Oxide Delivery Systems
`
`INOmax must be administered using a calibrated INOmax DSIR
`
`
` ® Nitric Oxide Delivery System.
` Only validated ventilator systems should be used in conjunction with INOmax. Consult the
`
` Nitric Oxide Delivery System label or call 877.566.9466/visit inomax.com for a current list of
`
`
` validated systems.
`
`
` Keep available a backup battery power supply and an independent reserve nitric oxide delivery
`
` system to address power and system failures.
`
`
`
` Monitoring
`
`
`
`Measure methemoglobin within 4-8 hours after initiation of treatment with INOmax and
`
`periodically throughout treatment [see Warnings and Precautions (5.2)].
`
`
` Monitor for PaO2 and inspired NO2 during INOmax administration [see Warnings and
`
`
`
`
`
`
` Precautions 5.3)].
` Weaning and Discontinuation
`
`
`
`
`
`
`
`Reference ID: 3831195
`
`

`

`Avoid abrupt discontinuation of INOmax [see Warnings and Precautions (5.1)]. 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) gas is available in an 800 ppm concentration.
`
`
`
`
`
`4 CONTRAINDICATIONS
`
`INOmax is contraindicated in neonates 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
`
`
`
`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 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.
`
`
`5.4 Worsening 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.
`
`Reference ID: 3831195
`
`

`

`
`
`6 ADVERSE REACTIONS
`
`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)]
`
`
`
`
`
` 6.1 Clinical Trials Experience
`
`
`
` 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%).
`
`
`6.2 Post-Marketing Experience
`
`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.
`
`
`7 DRUG INTERACTIONS
`
`Nitric Oxide Donor Agents
`7.1
`
`
`Nitric oxide donor agents such as prilocaine, sodium nitroprusside and nitroglycerine may
`
`increase the risk of developing methemoglobinemia.
`
`
`Reference ID: 3831195
`
`

`

`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 indicated for use in adults.
`
`
`
`
`
`
`
`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
`
`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 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.
`
`
`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). 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:
`
`
`Reference ID: 3831195
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`

`

`
`
`
`
` 12 CLINICAL PHARMACOLOGY
`
` 12.1 Mechanism of Action
`
`
` 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.
`
`
`
`
`
`
`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.
`
`
` Absorption 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-
`
`Reference ID: 3831195
`
`

`

` 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.
`
`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.
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`Reference ID: 3831195
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`

`

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`
` 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 1.
`
`
`
`
` Table 1: Summary of Clinical Results from NINOS Study
`
` Control
`
` NO
`
`
` (n=121)
` (n=114)
`
` 52 (46%)
`
` 77 (64%)
`
` 20 (17%)
`
` 16 (14%)
`
` 66 (55%)
`
` 44 (39%)
`
`
` 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
`
`
`
`
`
`
` P value
`
`
` 0.006
`
` 0.60
` 0.014
`
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`Reference ID: 3831195
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`

`

`
`
` 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 2.
`
`
`
`
` Table 2: Summary of Clinical Results from CINRGI Study
`
`
`
` Placebo
` INOmax
`
` P value
`
`
` ECMO*,†
`
`
` 51/89 (57%)
` 30/97 (31%)
`
` <0.001
`
`
`
` 5/89 (6%)
` Death
`
` 3/97 (3%)
` 0.48
` * 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)