`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`NDA 20845/S-014
`
`
`
`
`
`
`Food and Drug Administration
`
`
` Silver Spring MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`INO Therapeutics
`
`Attention: Mary Ellen Anderson
`
`
`Senior Director, Regulatory Affairs
`
`Perryville III Corporate Park
`
`53 Frontage Road, Third Floor
`
`Hampton, NJ 08827-9001
`
`
`
`Dear Ms. Anderson:
`
`
`
`Please refer to your Supplemental New Drug Application (sNDA) dated June 25, 2012, submitted under
`
`
`
`
`
`
`section 505(b)/pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`
`
`
`INOmax (nitric oxide) for inhalation.
`
`
`This “Prior Approval” supplemental new drug application provides for labeling revised as follows:
`
`
`
`
`
`
`
`1. Under HIGHLIGHTS/RECENT MAJOR CHANGES, changes to Dosage and Administration have
`
`
`
`
`
`been noted.
`
`
`2. Under HIGHLIGHTS/DOSAGE AND ADMINISTRATION, the first bullet under “Administration”
`
`
`
`has been changed from:
`
`
`
`INOmax must be delivered via a system which does not cause generation of excessive inhaled nitrogen
`
`
`
`dioxide (2.2).
`
`
`
`To:
`
`
`
`Use only with an INOmax DSIR
`
`®, INOmax® DS, or INOvent® operated by trained personnel (2.2)
`
`
`
`
`
`
`
`3. Under HIGHLIGHTS/DOSAGE AND ADMINISTRATION, the second bullet under “Administration”
`
`
`has been changed from:
`
`
`Do not discontinue INOmax abruptly (2.2).
`
`
`To:
`
`
`
`Wean from INOmax gradually (2.2).
`
`
`
`
`4. Under HIGHLIGHTS/WARNING AND PRECAUTIONS, the third paragraph has been changed from:
`
`
`
`
`Elevated NO2 Levels: NO2 levels should be monitored (5.3)
`
`
`
`
`
`
`
`
`Reference ID: 3270345
`
`

`

`
`
` NDA 20845/S-014
`
`
`
`
`
`
`
` Page 2
`
`
` To:
`
`
`
`
` Elevated NO2 Levels: Monitor NO2 levels continuously with a suitable Nitric Oxide Delivery System
`
`
`(5.3)
`
`
`
`
`
`
`
`
`
`
`
`5. The HIGHLIGHTS/ADVERSE REACTIONS section has been changed from:
`
`
`
`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:
`
`
`Methemoglobinemia and NO2 levels are dose dependent. The most common adverse reaction is
`
`
`
`
`hypotension (6).
`
`
`
`
`
`6. FULL PRESCRIBING INFORMATION: CONTENTS has been revised in accordance with changes
`
`
`made to the FULL PRESCRIBING INFORMATION.
`
`
`7. Under INDICATIONS AND USAGE, “with validated ventilation systems [see Dosage and
`
`
`
`Administration (2.2)]” has been added to the first sentence of the second paragraph.
`
`
`
`
`
`
`8. Under DOSAGE AND ADMINISTRATION, the following has been added as a new first paragraph:
`
`
`
`
`
`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.
`
`
`9. Under DOSAGE AND ADMINISTRATION, the Administration section has been significantly revised
`
`
`
`and now reads as follows:
`
`
`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
`
`®, INOmax® DS, or INOvent® Nitric Oxide
`
`
`
`
`INOmax must be administered using the INOmax DSIR
`
`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)].
`
`
`
`Reference ID: 3270345
`
`

`

`
`
` NDA 20845/S-014
`
`
`
`
`
`
`
` Page 3
`
` 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.
`
`
` 10. Under WARNINGS AND PRECAUTIONS, section 5.1 has been revised from:
`
`
`
` Rebound
` Abrupt discontinuation of INOmax may lead to worsening oxygenation and increasing pulmonary
`
` artery pressure.
`
`
`
`To:
`
`
`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.
`
`
`
`
`
`
`
`11. Under WARNINGS AND PRECAUTIONS, section 5.2 has been revised from:
`
`
`
`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.
`
`
`To:
`
`
`
`Hypoxia 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)].
`
`
`
`12. Under WARNINGS AND PRECAUTIONS, section 5.3 has been revised from:
`
`
`
`Reference ID: 3270345
`
`

`

`
`
` NDA 20845/S-014
`
`
`
`
`
`
`
`
` Page 4
`
`Elevated NO2 Levels
`
`
`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.
`
`
`
`
`
`
`
`To:
`
`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.
`
`
`
`
`13. Under WARNINGS AND PRECAUTIONS, section 5.4 has been revised from:
`
`
`
`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).
`
`
`To:
`
`
`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.
`
`
`
`
`
`14. Under ADVERSE REACTIONS/Clinical Trials Experience, Table 1 and the paragraph preceding it
`
`
`
`
`
`have been deleted and replaced with the following text:
`
`
`
`In CINRGI, the only adverse reaction (>2% higher incidence on INOmax than on placebo) was
`
`
`hypotension (14% vs. 11%).
`
`
`
`15. Under ADVERSE REACTIONS, the Post-Marketing Experience section has been revised and now
`
`
`reads as follows:
`
`
`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.
`
`
`
`
`
`
`
`16. Under DRUG INTERACTION, the reference to tolazoline has been deleted.
`
`
`
`
`17. Under CLINICAL PHARMACOLOGY/Pharmacokinetics, the numerical subheadings for 12.4, 12.5,
`
`
`
`and 12.6 have been deleted.
`
`
`
`18. Under CLINCAL STUDIES/CINRGI Study, the following has been added to the end of the section:
`
`
`
`
`
`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).
`
`
`
`Reference ID: 3270345
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Page 5
`
`
`
`
`
`
`
`
`
` NDA 20845/S-014
`
`
`
` 19. All REFERENCES in section 15 have been deleted.
`
`
` 20. Under HOW SUPPLIED/STORAGE AND HANDLING, the following text has been added:
`
`
` 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.
`
`
`
`
`
`
`
`
` 21. Various editorial changes and corrections have been made throughout.
`
`
` 22. The revision dates have been updated.
`
`
` We have completed our review of this supplemental application. It is approved, effective on the date of this
`
`
`
`
`
` letter, for use as recommended in the enclosed, agreed-upon labeling text.
`
` 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, text for the patient package
`
`
`
`
`
`insert, Medication Guide), 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/UCM072392
`
`.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).
`
`
`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:
`
`
`
`
`
`
`
`
`
`
`
`
`Food and Drug Administration
`
`Center for Drug Evaluation and Research
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`Reference ID: 3270345
`
`

`

`
`
`
`
` Page 6
`
`
`
`
`
`
`
` You must submit final promotional materials and package insert(s), accompanied by a Form FDA 2253, at
` the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at
`
`
`
`
`
`
`
` http://www.fda.gov/opacom/morechoices/fdaforms/cder.html; instructions are provided on page 2 of the
`
`
`form. 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.
`
`
`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 Russell Fortney, Regulatory Project Manager, at (301) 796-1068.
`
`
`
`
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Norman Stockbridge, M.D., Ph.D.
`
`Director
`
`Division of Cardiovascular and Renal Products
`
`
`Office of Drug Evaluation I
`
`Center for Drug Evaluation and Research
`
`
`
`
` NDA 20845/S-014
`
`
`
` 5901-B Ammendale Road
`
`
` Beltsville, MD 20705-1266
`
`
`
`
`Enclosure: Content of Labeling
`
`
`Reference ID: 3270345
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`NORMAN L STOCKBRIDGE
`03/04/2013
`
`Reference ID: 3270345
`
`