NDA 20-845 Nitric Oxide
`
`8.2.1.2 Cardiovascular System Adverse Events Possibly, Probably, or Definitely Related to l-NO (cont)
`2.1mm
`‘
`
`a 4.] kg black female was born after 42 weeks of gestation by om'rcult vaginal delivery
`2) Subject 01-06006:
`including shoulder dystocia and a nuchal cord that had to be cut and clamped 4 minutes before delivery. The mother had
`gestational diabetes. The patient's Apgars were 1 and 6 and she required resuscitation in the delivery room. She developed
`PPHN and was started on study gas (l-NO 80 ppm). Due to methernoglobinemia (>7%) she was weaned to 32 ppm, and
`her PaO; remained between 60 and too (baseline 60) for 5 days. l-NO was discontinued after 6 days, and she was given
`HFOV. She developed a series of pneumothoraces, became bradycardic and progressively hypoxemic, and died 17 days
`after therapy started.
`
`3) Subject l2~A01 became hypertensive and bradycardic after acute withdrawal from I-NO (20 ppm). Reinstitution
`of the l-NO caused a partial reversal of the bradycardia, and the infant was ultimately weaned off l-NO and was discharged.
`
`In the published literature, an acute decrease in heart rate has also been reported following l-NO administration(5).
`
`Qormlusirtn
`
`No effect of I-NO on heart rate was seen in the overall population exposed to I-NO. Following abrupt withdrawal
`of I-NO, some infants may be at risk for changes in heart rate, particularly bradycardia. For the purposes of this safety
`review, bradycardia should be considered to be possibly related to l-NO administration.
`
`.
`
`8.2.1.3 Cardiovascular System Adverse Events Considered Unlikely to be Related to I-NO
`Two subjects were identified from the INO-Ol/ —02 trial with specific adverse events related to the cardiovascular
`:
`'
`
`system.
`
`] Agni; Valve Vegetation
`I
`Patient 01-05006, developed PPHN with pneumonia and received I—NO 5 ppm for 13 hours. The infant later
`required ECMO and developed an aortic valve vegetation. Alter therapy, he was recorded to have 'improved' with regards
`to vegetation. On one year follow-up, no cardiovascular abnormalities were noted, had had no hospitalimtions since
`discharge.
`Qonslusion
`
`No evidence exists to link the development of the vegetation to the use of l-NO.
`
`2:
`i
`II
`1
`.
`received control gas. She later
`Patient 01-07008, developed PPH'N alter rneconium aspiration and sepsis,
`developed an aortic thrombosis which was recorded as moderate in severity and improved with treatment.
`QQHCIQSIQD
`
`No evidence exists to link the development of aortic thrombosis to the administration of l-NO.
`
`‘APPEARS THIS WAY
`ON ORIGINAL
`
`
`
`188
`
`

`

`NDA 20445 Niuie Oxide
`
`.
`8.2.2 Gastrointestinal System
`The following potential adverse events related to the gastrointestinal system were identified from the NDA, from '
`secondary sources, or are adverse events normally explored as part of a safety review:
`- .
`l) Hepatotoxicity, reflected in abnormal liver function tests (Ll-Ts).
`2) Gastrointestinal bleeding.
`
`-.
`
`‘
`
`8.2.2.1 Adequacy of Development Program in Assessing Gastrointestinal Risk l‘or I-NO
`The NDA database collected data on all adverse events in the INO-Ol/ INC-02 and -03 trials only, as detailed in
`section 8.1.7. This includes gastrointestinal adverse events, as shown in the table below. For overall gastrointestinal
`adverse events, then, the database included 41 control subjects and 128 subjects exposed to I-NO.
`
`Table 8.2.2.1.]
`Body System!
`adverse ex - erience
`Gastrointestinal system
`Gastrointestinal
`hemorrhage
`Gastrointestinal anomaly
`
`from table 8.1.5.4.2 Gastrointestinal adverse events from IND-01! -02 and INC-03 trials“.
`
`Control Group ‘
`l-NO 5 ppm
`l-NO 20 ppm
`I-NO 80 ppm Combined l-NO
`n=41
`n=45
`n=44
`n=39
`n=128
`
`1 (2%)
`1 (3%)
`2 (2%)
`l (3%)
`
`I (<1%)
`
`
`
`l (2%)
`1 (<l%)
`
`
`
`
`
`
`
`
`
`
`
`a. Data from NDA, volume 2.17, page 089808 to 092408, volume 2.29 page 353108 to 353308, and from individual case report forms.
`Gastrointestinal bleeding was a specific adverse events looked for in the NINOS trial, where it was defined as
`'frank blood per rectum or NO tube'. In this trial, data on GI bleeding before and after randomization was collected. For GI
`bleeding, then, data flour “in additional 121 controls and 114 l-NO subjects was collected (169 controls and 242 I-NO
`subjects total).
`'
`The, collection of lab data, available floor the INO-Ol/ -02 and /-03 trials, has been discussed previously in
`section 8.1.6.1 and 8.1.6.2. Two values, one at baseline and one within 12 hours of discontinuation of l-NO, are
`available. Follow-up for markedly abnormal labs, and labs which were identified as adverse events by the investigators was
`requested from the sponsor. Whenever available, this has been included in this review. For overall gastrointestinal adverse
`laboratory events, then, the database includes 41 control subjects and 128 subjects exposed to I-NO.
`The interpretation of I-NO effects on LFTs is complicated four things.
`1) the. high incidence of abnormal LFTs at baseline. The table below shows the number of subjects with
`abnormal labs at baseline, including high percentages of both alkaline phosphatase and LDH abnormalities at baseline.
`
`Table 8.2.2.12 (from table 8.1.6.2.1) Number of subjects with normal baseline LFTs from INO-OI/ -02“.
`W05 mm mm I-NO 80 --m
`«g,
`'_\‘.
`16/34 (47%)___
`Alkaline Phosphatase
`12132 (38%) _
`1912.9..(65V
`‘
`_l9/29_‘(66"Z
`
`
`
`LDH
`,
`.
`.7
`.2/28 (7%) fit; 45/31 (16%)
`*1/25.:"(4%)‘
`- -2129'(7%)‘;-
`.
`SGOT”
`. 8f33-.(251%);:;1 .JBZ-_(22%).
`=15122;(11%l..
`.‘ sauna)
`.1
`:-.
`
`Total Bilirubin
`19/34 (56%)
`22/39 (56%)
`16/32 (52%)
`19/32 (59%)
`a. Data from NDA volume 2.18, Table T-21.
`b. SGOT (serum glutamate pyruvate transaminase) = AS‘I‘ (aspartate transaminase); SGPT (serum glutamic-oxaloacetic transaminase) or
`ALT ( alanine lransaminase); GGT (gamma-glutarnyl tnnsl‘erase).
`c. No data was collected during the [NO-01] —02 and {-03 trials on GGT or SGP’I levels.
`
`2) the absence of data on changes in SGPT (serum glutamic-oxaloacetic transaminase)
`glutamyl transferase).
`No data was collected during the lNO-Ol/ ~02 and l-03 trials on GGT or SGPT levels. This limits the ability cf
`this database to detect hepatocellular injury largely to detected changes in SGOT (in the context of altered alkaline
`phosphatase, LDH, and total bilirubin, which were collected).
`.
`
`and GGT(gamma-
`
`3) the lack of available follow-up for abnormal labs.
`As discussed above, two sets of labs were collected, and no follow-up labs are available for abnormalities
`identified on the second set._
`
`4) the changing normal ranges for individual labs shortly afier birth.
`The normal values for some labs (total bilirubin in particular) change from day to day in the early neonatal
`period. Labs were deemed normal or abnormal depending on the limits associated with each individual lab sample and
`subject.
`
`
`
`189
`
`

`

`NDA 20445 Nitric Oxide
`
`,
`
`8.222 Gastrointestinal System Adverse Events Possibly, Probably, or Definitely Related to l-NO
`Wm
`No subjects were identified by the investigators as having an adverse events related to hepatic injury (Table
`8. l. 5.4.2). The following subjects had an elevation in serum bilirubin identified as an adverse event. Control and I-NO
`subjects had a similar incidence of bilirubinemia as an adverse event. No other LFT abnormalities were identified as
`adverse events in the INC-011’ -02 trial.
`
`Table 8.2.2.2.] H erbilirubinemia identified as an adverse events from [NO-01! -02 and IND-03 trials'.
`Meta hello 8.-
`Control Group
`l-NO 5 ppm
`[-NO 20 ppm
`Combined l-NO
`Nutritional
`n=41
`n=45
`n=44
`n=128
`
`n=39
`
`
`
`
`
`a. Data from NDA, volume 217, page 089808 to 092408, volume 2.29 page 353108 to 353308, and from individual case report forms.
`
`Available subject identified with increased bilirubin as an adverse event in the INO-Ol/ -02 and [-03 trials.
`Controls
`1) Subject Oi 15001 received control gas for 56 hours and was discharged without ECMO, chronic lung disease
`or seizures.
`2) Subject 02- 15003 received control gas for 3 hours and was discharged without ECMO, chronic lung disease or
`
`seizures.
`
`3) Subject 02- 15004 received control gas for 8 hours. The infant had dysrnorphic features and his karyotype was
`XXXXY Given the poor prognosis support was withdrawn and he ultimately died
`I-NO 5 ppm
`1) Subject 01-06009 received l-NO 5 ppm for 3 hours, and recovered without ECMO Other long-term data15
`
`missing.
`
`2) Subject 01- 14003 received I-NO 5 ppm for 24 hours, and was discharged without ECMO, chronic lung disease
`or seizures.
`3) Subject 02-11004 received INC 5 ppm for 115 hours, and was discharged without ECMO, chronic lung
`disease or seizures.
`
`4) Subject 02- 11008 received 1—NO 5 ppm for 58 hours, and was discharged without ECMO, but with reactive
`airways disease.
`
`I-NO 20 ppm
`'
`"
`1) Subject 02-07007 received l-NO 20 ppm for 2 hours, was declared a therapeutic failure, and recovered after
`
`ECMO.
`
`2) Subject 02- 15002 received l-NO 20 ppm for 6 hours recovered and was discharged without ECMQ, chronic
`lung disease or seizures.
`3) Third subjectin the 20 ppm group was not identified from the electronic datasets.
`
`1—N0 80ppm
`1) Subject 01-01002 received I-NO 80 ppm for 8 hours, recovered, and was discharged without ECMO, but with
`a seizure disorder.
`
`
`
`Drop-outs due to abnormal LFI‘s
`There was one individual who dropped out of the IND-011r -02 study with an elevation in LDH listed as a
`contributing factor.
`Table 8.22.22 (from table 8.1.3.211) Subject from the INO-01/ -02 and INC3 trials who dropped out, in part,
`due to an elevated LDl-l. No follow-u . of the elevated LDHis available
`
`mum—man—
`
`[4‘10 5 ppm
`01-01004
`Acute pulmonary
`ECMO, HFOV,
`
`
`decompensation
`Discharged without
`
`
` Elevated LDH
`chronic lung disease
`
`
`
`
`
`
`
`
`
`1'90
`
`

`

`NDA 20445 Nitric Oxide
`
`8.2.2.2 Gastrointestinal System Adverse Events Possibly, Probably, or Definitely Related to l-NO (cont)
`
`W O
`
`verall, the mean LFTs tended to fall from baseline to post-1N0”. In all groups except I-NO 20 ppm, alkaline
`phosphatase fell significantly. Mean values for LDH and SGOT also fell, but the differences were nu. significant.
`
`l-NO 80 --m
`Post-I-NO m POSI-I-NO
`
`
`
`Table 8.2.2.2.3 Mean LFT values from INO-Oll 432“".
`
`l-NOS um
`
`emu—m Post-I-NO
`
`Alkaline
`
`
`
`1555:217
`353:552
`5465:5317
`302.8:313
`16432063
`
`
`
`
`3661514
`l"l75:1:285 7.
`1413:92
`
`
`(n-3fl)
`(n=30)
`(n=36)
`. ‘r(n=:3_8)
`(n=40)
`'
`Phosphatase
`. __f_‘(n=34)'
`(n=34)‘ _'
`(n=33)
`
`
`
`
`
`
`
`
`
`LDH
`1617 21:151' 1069 1127 1479 1109:
`1134 i937 3060 i661‘ 1218 i178
`1976 i216! 1338 1:127
`
`
`
`
`
`
`
`
`n=3 8
`n=32
`n=36
`n=33
`n=32
`n=29
`=34
`n=3]
`
`
`
`
`
`
`
`
`
`
`SGOT
`. 312 $760
`109 :1:101
`69 £72
`121 189.
`64 153
`81 186
`258 1:584
`78 21:61
`
`
`
`
`
`
`
`
`n=39
`n=34
`n=3 8
`n=34
`n=35
`n=3 0
`n=34
`n=3l
`
`
`
`
`
`
`
`
`
`
`Total
`4.8 $3.1
`5.0 14.8
`5.3 14.9
`5.0 13.6
`6.8 16.3
`4.6 13.2
`5.1 flat
`4.2 $2.?
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`n=40
`n=31
`- n=34
`n=36
`Bilirubin
`n=41
`n=35
`W140
`n=35
`
`
`
`
`
`
`
`a. Source: NDA volume 2.50. pages 341010—341510 and volume 2.25.
`b. Per protocol, follow-up labs were to be taken no more than 12 hours afler end of exposure to treatment gas.
`c. Data shown as meanistandard deviation (it of subjects with data). Shaded boxes indicate that baseline and post-study gas labs differ
`significantly using 2-sided unpaired t test.
`-
`
`1'
`
`In the database from IND-01! [NO-02 and ~03, newly-abnormal SGOT occurred in 1 control subject (2%) and in 3
`llNO subjects (2%). SGOT values which became more abnormal, including those who started with abnormal baselines,
`occurred in 5% of control subjects and 11% of I-NO subjects. The table below shows the number of subjects in each l-NO
`group. The numbers are too small to infer a relationship between I-NO dose and SGOT abnormalities.
`
`
`
`
`
`Table 8.2.2.24 from Table 8.1.6.221 Abnormal LFTs from IND-01! -02 and IND-03°.
`Control
`l-NO 5 ppm
`l-NO 20 ppm
`l-NO 80 ppm
`n=38
`n=45
`n=41
`n=3?
`
`l-NO combined
`n=123
`.
`
`1 (3%)
`3 (8%)
`
`l (3%)
`2 (5%)
`
`4 (9%)
`4 (9%)
`
`l (2%)
`6 (13%)
`'
`
`1 (2%)
`5 (12%)
`
`0 (0%)
`2 (5%)
`
`l (3%)
`3 (8%)
`
`2 (5%)
`6 16%)
`
`6 (5%)
`12 (10%)
`
`3 (2%)
`14 (11%)
`
`0 (0%)
`0 (0%)
`
`l (2%)
`2 (4%)
`
`0 (0%)
`0 (0%)
`
`0 (0%)
`0 (0%)
`
`1 (<1%)
`2 (2%)
`
`abnon'nallties 1’
`
`Elevated Total Bilirubin
`
`New abnormalities'
`Values >12
`Elevated SGOT .
`
`New abnonnalities'
`New or worsening
`abnonnalitiesb
`
`Elevated Alkaline
`Phosphatase
`New abnormalities'
`New or worsening
`
`
`it. These subjects had a normal value at baseline and an abnormal value within 12 hours of discontinuation of lnNO.
`b. These subjects include all of those in the 'new abnormalities' category, as well as any subject who had an abnormal value at baseline
`which was more abnormal on the follow-up lab.
`c. Data was obtained from NDA volume 2.31. Data Listing 13.1; volume 2.25, Appendix 16.22.12; and volume 2.18, Table T-30, and
`electronic datasetsn
`‘
`
`191
`
`

`

`8.2.2.2 Gastrointestinal System Adverse Events Possibly, Probably, or Definitely Related to l-NO (cont)
`t
`'
`‘
`ev'
`c
`
`Another source of data on the efi'ects of l-NO on LFTs is the individual subject lab data. The subjects who
`experienced amarkedly abnormal SGOT from the individual labs was identified ( fiom Table 8...d.2.2.la.l). While no
`control subject was identified, 4 l-NQ subjects (3%) Were identified. No follow-up labs are available for the subjects listed.
`
`NDA 20-045 Nitric Oxide
`
`'
`
`Table 82.2.2.5 Individuals with markedly abnormal SGOT ost—I-NO from INO-Ol/ -02 and [-03“.
`
`Post-I-NO value _
`
`Placebo
`
`with CU.)c
`
`l-NO 5 ppm
`02-11003
`
`I-NO 20 ppm
`01-03025
`01-03008
`
`l-NO so ppm
`01-02003
`
`_
`
`-
`
`Discharged without ECMO
`
`.
`Died (see below)
`Discharged without ECMO
`with seizures
`
`Discharged without ECMO
`data missin-
`
`
`
`a. Data from NDA. volume 2.25, individual patient listings, and from electronic datasets.
`b. Lab tests were identified as markedly abnormal were >2X upper limits of normal on post-l-NO value. Normal values were taken {tom
`individual lab ranges associated with each specimen.
`'
`e. CLD chronic lung disease.
`
`A similar trend is seen towards increased numbers of markedly abnormal LDH and total bilirubin values in the 1-
`NO group, relative to the control group. No markedly abnormal alkaline phosphatase values were identified.
`
`Table 8.2.2.26 (from table 8.1.6.2.2.1a.l) Individuals with markedly abnormal LDH and total bilirubin post-I-
`NO chemistry labs from mo-or/ -02 and 1-03 trials“.
`
`
`
`Post-l-NO value
`
`Placebo
`01-03013
`01-04001
`02-14004
`01-14002 '
`01-07007
`
`l-NO 5 ppm
`01-03002
`01-06002
`02-14001
`02-15001
`01-01004
`
`I-NO 20 ppm
`01-17006
`01-07003
`01-07005
`01-09003
`0l-l400l
`03-52001
`
`LDH
`LDH
`Bilirubin
`Bilirubin
`Bilirubin
`
`LDH
`LDH
`LDH
`LDH
`Bilirubin
`
`LDH
`Bilirubin
`Bilirubin
`Bilirubin
`Bilirubin
`Bilirubin
`
`‘
`
`l-NO 80 ppm
`LDH
`01-03003
`LDH
`01-06003
`LDH
`01-l1004
`LDH'
`02-04004
`LDH
`01-02003 -
`LDH
`02-11007
`LDH
`03-59003
`Biiirubin
`01-05003
`.
`Bilirubin
`01-03005
`13.1
`.
`Bilirubin
`02-13001
`a. Data from NDA, volume 2.25, individual patient listings. and electronic datasets.
`1). Lab tests were identified as markedly abnormal were >2X upper limiLs of normal on post-I-NO value.
`
`
`
`

`

`NDA 20-345 Nitric Oxide
`
`8.2.2.2 Gastrointestinal System Adverse Events Possibly, Probably, or Definitely Related to I-NO (cont)
`e
`t
`'
`'
`v'
`ed
`v
`
`No follow-up on any of these abnormal labs is available. No subject is known to have chronic LFT abnormalities
`or chronic liver failure, as recorded at the one-year follow-up.
`
`No subjects deaths related to liver failure, and no chronic liver abnormalities were identified from the database.
`One subject was known to have died with abnormal LFTs.
`1). Subject Ol-03025, a 4.1 kg white male, developed PPHN and RDS. He was started on treatment gas (I-NO
`20 ppm) with no acute increase in PaO; (43 at baseline to 42 after 30 minutes). He showed gradual improvement, and was
`continued on I-NO for 104 hours, after which he was weaned successfully. Evaluation of the infant revealed severe
`periventricular leukomalacia and a burst pattern on EEG, and persistent renal failure. Decision was made to withdraw
`therapy, and the infant died 1 day after weaning off l-NO.
`'
`’
`
`As another index of the clinical consequences of the hyperbilirubinemia, the sponsor was asked to determine the
`number of subjects who received phototherapy andfor exchange transfusion for elevated bilirubin levels. This information
`has not been submitted to the FDA.
`
`There was no data flow the secondary sources suggesting an effect of I-NO on LFTs.
`
`APPEARS THIS WAY
`
`0N ORlGiNAL
`
`193
`
`
`
`

`

`Gastrointestinal
`svstem
`
`Control Group
`n=41
`
`l-NO 5 ppm
`n=45
`
`Gastrointestinal
`hemorrhage
`
`‘
`
`0 (0%)
`
`
`
`
`
`
`l-NO 20 ppm
`n=44
`
`I-NO 80 ppm Combined l-NO
`n=39
`n=128
`
`l (3%)
`
`l (<l%)
`
`
`
`
`
`
`FDA 20445 Nitric Oxide
`
`8.2.2.2 Gastrointestinal System Adverse Events Possibly, Probably, or Definitely Related to l-NO
`e atot
`’
`'
`v'de
`evat
`
`-.
`
`E
`
`l
`
`-
`
`Overall, these data suggest that exposure to‘I-NO is possibly associated with an increase in the incidence d“
`abnormal liver function tests, especially SGOT. No chronic damage, and no deaths due to hepatic failure were identified in
`the database. No firm conclusions can be drawn about the dose—relationship of this probable efi‘ect of I-NO. For
`the
`purposes of this safety review, elevated LFTs,
`in particular SGOT, should be considered to be possibly related to I—NO
`administration.
`
`8.2.2.3 Gastrointestinal System Adverse Events Considered Unlikely to‘ be Related to I-NO
`| i gastrointestinal bleeding
`In the [NO-Oil -D2 and [-03 trials, one subject in the l-NO group was reported by the investigators to have had an
`adverse event related to gastrointestinal bleeding.
`
`Table 8.2.2.3.! (from table 8.1.5.4.2) Reported adverse events related to bleeding identified by investigators in
`the INO-Ol/ -02 and IND-03 trials".
`
`a, Data from NDA, volume 2. l7, page 089808 to 092408, volume 2.29 page 353108 to 353308, and from individual case report forms.
`
`Subjects identified as having GI bleeding as an adverse event in the INO-Ol/ -02 and [-03 trials.
`1) Patient #02-15006 received l-NO 80 ppm group, but did not have thrombocytopenia. The gastric hemorrhage
`lasted 8 days, but began after the I-NO had been discontinued for 8 days. Other details are not available regarding the
`etiology of the GI bleed. The subject recovered completely.
`
`In the NINOS trial, one control and 4 l-NO subjects had GI bleeding before receiving study gas. After starting
`study gas, one control and one l-NO subject had GI bleeding. These two individuals (I l-AOl and l2-A06) both received
`ECMO, and both survived. No further details of their cases are available.
`
`No data on long-term GI function or bleeding is available.
`No increased risk of GI bleeding has been suggested in any trial if I-NO in the secondary database.
`
`Qonclusiog
`
`Overall, the data do not support an association between l-NO and increased GI bleeding. For the purposes of this
`safety review, increased GI bleeding is unlikely to be linked to l-NO administration.
`
`APPEARS rms wrw
`0N ORIGINAL
`
`
`
`
`194 .
`
`

`

`NDA 20-845 Nitric Oxide
`
`
`
`-
`.
`8.2.3 Hemic and Lymphatic System
`The following potential adverse events related to the hemic & lymphatic system were identified born the
`secondary sources or are adverse events normally explored as part of a safety review:
`' -
`1) Elevated methemoglobin levels
`2) Elevated NO; levels
`3) Thrombocytopenia
`4) Alteration in coagulation, with increased bleeding
`5) Neutropenia
`6) Eosinophilia
`
`‘
`
`8.2.3.1 Adequacy of Development Program in Assessing Hemic and Lymphatic Risk for LNG
`The NDA database collected data on all adverse events in the [NO-01! IND-02 and -03 trials only, as detailed in
`section 8.1.7. This includes hemic and lymphatic adverse events, as shown in the table below. For overall hemic and
`lymphatic adverse events, then, the database includes 41 control subjects and 128 subjects exposed to f-NO. There was an
`increase in hemic & lymphatic adverse events in the I—NO group, driven the incidence of methetnoglobinemia.
`
`
`
`Table 8.2.3.1.1 (from table 8.1.5.4.2) Reported adverse events from INO-Ol/ -02 and IND-03 trials with
`reported frequency >l% or having serious clinical implications, presented by frequency within each body system for
`subjects receivina control -as and each of the l-NO dosage - ou -s'.
`
`I-NO 80 ppm Combined l-NO
`Body System!
`Control Group
`l-NO 5 ppm
`l-NO 20 ppm
`n=39
`n=128
`adverse ex . erience
`n=41
`n=45
`-
`n=44
`
`)
`16 (41%)
`22 (17%)
`Hemic a- Lymphatic.
`2 (5%)
`1 (2%
`5 (11%)
`
`
`
`1 (3%)
`.2 (2%) -
`Anemia
`1 (2%)
`1 (2%)
`
`
`
`
`
`‘
`~
`1 :~
`.
`-
`13 (35%)
`Methemoglobinemia
`13 (11%)
`
`
`
`
`
`
`1 (3%)
`Ecchymoses
`1 (<1%)
`
`
`
`Hypovolemia
`
`
`
`1 (2%)
`1 «1%)
`
`
`
`Thrombocytopenia
`-
` 1 (2%)
`3 (7%)
`1 (2%)
`4 (3%)
`
`
`
`
`
`
`
`
`a. Data from NDA, volume 2.17. page 089808 to 092408, volume 2.29 page 353108 to 353308, and from individual case report forms.
`
`
`
`
`Specific adverse events in the hemic and lymphatic system included methemoglobin and NO; levels. Elevated
`methemoglobin were collected prospectively in the NINOS and INOSG trials, while NO; levels were also followed in the
`NINOS trial. Overall, then, 179 control and 278 l-NO subjects have methemoglobin data collected. For NO; levels, 151
`controls and 258 I-NO subjects had data collected.
`i-‘
`The collection of lab data, available from the INO~01I -02 and [-03 trials, has been discussed previously in
`section 8.1.6.1 and 8.1.6.2. Two values, one at baseline and one within 12 hours of discontinuation of I-NO, are
`' available. Follow-up for markedly abnormal labs, and labs which were identified as adverse events by the investigators was
`requested from the sponsor. Whenever available, this has been included in this review. For overall hemic and lymphatic
`adverse laboratory events, then, the database includes, at most, 41 control subjects and 128 subjects exposed to l-NO. The
`actual number of subjects with data for each lab is given when possible.
`
`8.2.3.2 Hemic and Lymphatic System Adverse Events Possibly, Probably, or Definitely Related to l-NO
`
`W T
`
`he definite association between the administration of LNG and elevated methemoglobin levels has been
`discussed extensively in sections 8.1.6213 and 8.1.6.222 above. In the NINOS, INOSG and INO-Ol/ -02 trials there
`was a statistically signifith association between the use of I-NO and elevated peak and mean methemoglobin levels.
`In the INO-DI/ -02 trial, elevated methemoglobin levels were identified as an adverse event in 13 subjects, which
`led to their discontinuation fi'om l-NO (see table 8.1.3.2.].1 above).
`In the NINOS trial, methemoglobin was defined as >5%, and a total of 11 subjects (4 controls, 7 l-NO) had their
`study gas decreased because their methemoglobin levels exceeded this level. All of these subjects continued on study gas
`at lower flow rate. No subject was discontinued because ofNO; >7 ppm or methemoglobin >10%.
`
`
`
`
`
`Table 8.2.3.2.] Elevated methemo- lobin levels identified as adverse events from lNO-Ol/ -02 and [NO-03 trials”.
`Hemic 6.- Lymphatic
`Control Group
`l-NO 5 ppm
`l-NO 20 ppm
`I-NO 80 ppm Combined l-NO
`nail
`n=45
`“=44
`n=39
`n=128
`
`
`
`a. Data from NDA, volume 2.17, page 089808 to 092408, volume 2.29 page 353108 to 353308, and from individual case report forms.
`
`I95
`
`
`
`
`

`

`8.2.3.2 Hemic and Lymphatic System Adverse Events Possibly, Probably, or Definitely Related to I-NO (cont)
`v
`'
`ev
`
`the dose-response curve was examined betVVw'u I-NO and elevated
`in the INO-Ol/ -02 trial,
`Additionally,
`methemoglobin levels. In that study, the risk of elevated methemoglobin was significantly elevated in the 80 ppm l-NO
`group when compared with the 20 or 5 ppm groups (data from table 8.l.6.2.l.3c.l).
`
`N'DA 20-“5 Nitric Oxide
`
`Figure 8.2.3.2.2 Peak MetHgb levels
`vs I—NO Concentrations
`
`(0%))mona.monNIcoto
`PeakMetHgb
`
`Placebo
`
`I-NO
`
`5 ppm
`
`I-NO
`
`'
`
`I-NO
`
`20 ppm
`
`80 ppm
`
`I-NO Concentration ppm
`
`All 13 subjects in the INO-Ol/ -02 trial who were withdrawn due to elevated methemoglobin levels were in the
`80 ppm group.
`
`-
`
`‘
`
`This data on the association of 80 ppm I-NO with art-increased risk of elevated methemoglobin levels is also in
`agreement with the reported effects of I-NO on methemoglobin levels in the secondary database, where elevated
`methemoglobin levels have been primarily reported following the use of l—NO 80 ppm(35, 57).
`-
`
`The clinical consequences of elevated methemoglobin clinically are less clearly demonstrated in the database. As
`discussed in section 8.1.6.222, examination of the 13 subjects in the INO-Ol/ -0.2 trial who were deemed treatment
`failure due to elevated methemoglobin levels did not demonstrate a link between them and any long-term adverse
`outcome, including death, need for ECMO or any marker of chronic pulmonary disease.
`
`mm
`The use of l-NO is definitely linked to the development of elevated methemoglobin levels (defined as >5% in the
`‘ NiNOS and INOSG trials, and >7% in the INO-Ol/ -02 and 1-03 trials). Further, there is a dose-response relationship such
`that subjects who received 80 ppm l-NO are at significantly higher risk for elevated methemoglobin levels. Thirty-five
`percent of the subjects receiving 80 ppm I-NO had elevated methemoglobin as an adverse event in the [NO-Oil -02 and l-
`03 trials.
`'
`No clinically measurable adverse effect of methemoglobinemia was demonstrated in this trial, probably due to the
`short time of exposure and the small number of subjects who developed methemoglobinemia in the INO-Ol/ -02 trial. For
`the purposes of this safety review, the development of methemoglobin levels >5% should be considered to be definitely
`associated with l-NO administration. Further, the risks for this are significantly higher in the 80 ppm group than in the 5
`or 20 ppm groups.
`‘
`
`
`
`1‘96
`
`

`

`
`
`
`
`NDA 10-845 Nitric Oxide
`
`8.2.3.2 Hemic and Lymphatic System Adverse Events Possibly, Probably, or Definitely Related to l-lVlO (cont)
`V
`a
`V
`‘
`
`levels has been discussed
`The definite association between the administration of I-NO and elevated- NO;
`extensively in sections 8.1.6.2.].2 and 8.1.6.221 above. In the NINOS and INO-Ol/ -02 trials time was a statistically
`significant association between the use of l-NO and elevated peak and mean methemoglobin levels.
`
`Elevations in NO; levels were not identified as adverse events by the investigators in the lNO-Ol/ -02 and /-03
`trials for any subject. One subject in the INO—Ol/ ~02 trial, #02-1300], was discontinued due to elevated N02 levels(see
`table 8.1.3.2.I.l above).
`-
`'
`
`The dose-response curve for the development of elevated NO; levels was also looked at in INO-Ol/ -02 (see
`section 8.1.6. 2.1.2). in the NINOS, but not in the lNO-Ol/ -02 trials, the peak NO; level, measured at any time during
`study gas administration, was higher in the 20 ppm l-NO group when compared with placebo.
`
`Table 82.3.2.3 Mean neak NO; after l-NO 20 . m from the NlNOS and INO-Ol/ -02 trials'.
`
`_— l-NO 20 ..m
`NINOS
`'
`0.l_i0.3
`0.8i1.2
`INOrfll/ -02
`0.59i0.8
`0.48i.62
`
`<0.001
`NS
`
`
`
`
`a. Data from section 8. 1 6.2.1.2 and electronic datasets, and is shown as average: standard deviation.
`
`.
`
`
`
`
`
`
`However, all of the subjects in the INO-Ol/ -02 who developed NO; levels >5 ppm were in the 80 ppm group.
`Additionally, 7 of the ll subjects who developed NO: levels >3 (the definition of elevated NO: in the trials) were in the
`80 ppm group.
`.
`.-
`
`Table 8.2.32.4 (from table 8.1.6.2.].2c.1) Peak NO: levels in O m from the lNO-Ol/ ~02 trial.
`'
`
`
`Chan-esfin safetv end-aims —mamn-m l-NO 80 - m
`
`
`Peak NO; level at any time (ppm)
`
`
`
`0.0- 1.0
`
`34/41 (83%)
`32/42 (75%)
`0/37 (0%)
`30/35 (86%)
`
`
`
`
`
`6/41 (15%)
`8/42 (19%)
`1.1-3.0
`4/35 (11%)
`29/37 (78%)
`
`
`
`
`
`
`1/41 (1%)
`2/42 (5%)
`3.0- 5.0
`1/35 (1%)
`4/37 (11%)
`
`
`
`
`
`0/41 (0%)
`0/41 (0%)
`5.1-7.0
`0/35 (0%)
`3/37 (8%)
`
`
`
`
`
`
`7.1 to 10
`0/41 (0%)
`0/41 (0%)
`0/35 (0%)
`0 (0%)
`
`
`
`
`
`
`
`in section 8.1.6.221, the clinical consequences of elevated NO; levels were considered in the individual subjects
`where this occurred. As noted above, no link between an elevated N02 level and short-term clinical toxicity could be
`detected, perhaps related to the small number of subjects available for examination.
`
`gingham
`There is a definite link between exposure to l-NO and the development of elevated NO; levels. Whether subjects '
`exposed to I-NO 20 ppm are at increased risk for elevations in N01 could not be determined, as the two studies who
`examined that group found differing conclusions.
`The clinical consequences of elevated NO; concentrations has not been clearly established in the neonatal
`population, but the link to reactive airways disease and to chronic pulmonary damage (i.e., emphysema) in adults has been
`made in the literature (see section 5.2.2.2). The NDA database supports a possible association between I-NO and acute and'
`chronic pulmonary damage (see respiratory section below), with a role for NO; in this process.
`For the purposes of this review, the development of NO; levels >3 ppm should be considered definitely linked to
`the administration of I-NO. Further, there is good evidence that infants who received 80 ppm l-NO are at significantly
`higher risk of developing elevated NO; levels, compared with either 5 or 20 ppm I-N0.'
`
`197
`
`

`

`8.2.3.2 Hemic and Lymphatic System Adverse EVents Possibly, Probably, or Definitely Related to l-NO (cont)
`5
`E
`.
`l
`.1.
`No subjects were identified by the investigators as having an adverse events related to eosinophilia (Table
`8.15.4.2).
`‘
`
`.
`
`In the lNO-Ol/ -02 study, there was a trend towards a higher mean eosinophil count in the subjects who received
`I-NO, especially the 80 ppm group
`
`NDA 20-545 Nitric Oxide
`
`
`
`
`
`Table 8.2.3.25 from table 8.1.6.2112 Mean hematolo values from IND-01f ~02“.
`Placebo
`l-NO
`I-NO
`5.
`,
`. m
`so I
`I [11
`I
`r
`
`After Study Gas Baseline
`After l-NO Baseline Afierl-NO Baseline
`Afierl-NO
`Baseline
`
`Eosinophils
`3.6 15.1
`1.1 $1.8
`
`
`
`(% of WBCs
`
`
`n=36
`n=41
`
`
`
`a. Source: NDA volume 2.50, pages 341010441510 and volume 2.25.
`b. Per protocol, afier values to be taken no more than 12 hours after end of exposure to treatment gas.
`c. Data shown as meanistandard deviation (it of subjects with data).
`
`
`
`-
`
`
`
`This same data is presented as a graph below.
`
`Figure 8.2.3.2.6 Eosinophils in
`the INO-Ol/UZ Trial
`D Baseline Lab
`
`2.9
`
`2.9
`
`3.6 I Follow-Up Lab
`
`
`m
`«1.1
`g
`
`3
`'f
`
`Placebo
`
`I-NO 5
`
`'ILNO
`
`l-NO
`
`ppm
`
`20 ppm
`
`80 ppm
`
`Study Gas Administered
`
`4
`m
`E 3-5
`3
`a.
`o 2.5
`
`e 1.5
`H 1
`°\° 0.5
`
`0 '
`
`:
`
`There were also subjects who had a markedly abnormal number of eosinophils after exposure to l-NO, identified
`through examination of the individual laboratory records.
`
`Table 8.2.3.2.? Individuals with markedly abnormal post-study gas eosinophil counts from INO-Ol/ -02 and /-03
`
`trials“.
`
`
`
`Baseline
`value
`
`Post-l-NO
`value
`
`I
`
`8
`
`Notes on FIU
`
`Discharge without ECMO
`
`
`
`
`Eosinophils
`
`Eosinophils
`
`
`Placebo
`01-08001
`Eosinophils
`
`
`l-NOSppm
`
`
`
`Ol-10002
`
`Eosinophils
`No discharge data available
`
`
`Ol-11012
`
`Eosinophils
`Died without ECMO of progressive hypoxia
`
`
`
`
`[-NO 20 ppm
`
`
`03-67002
`Discharged without ECMO, with seizures
`
`
`
`
`
`l-NO 80 ppm
`
`
`02-11007
`
`
`Discharged after ECMO, with seizures and
`
`
`chronic lung disease (CLD)
`01-05005
`
`
`
`
`Eosinophils
`Discharged without ECMO, no seizures or CLD
`02-! 5006
`
`
`Eosinophils
`
`
`Discharged without ECMO, no seizures or CLD
`
`a. Data from NDA, volume 2.25. individual patient listings and table 8.1.6.2.2.la.l.
`b. Lab tesu identified as markedly abnormal were >2X upper limits of normal.
`
`
`
`l98
`
`
`
`L_—‘_*
`
`

`

`
`
`
`
`_
`
`N'DA 20445 Nitric Oxide
`
`8.2.3.2 Hemic and Lymphatic System Adverse Events Possibly, Probably, or Definitely Related to I-NO (cont)
`3 E
`.
`1
`'1'
`:
`I
`The summary of the subject who died who also had eosinophilia is below.
`1. Patient 01-11012: 3 3.2 kg white male, developed PPl-TN, possibly due to sepsis. He was started on treatment
`‘ '
`gas (l-NO 5 ppm), but was discontinued after 10 hours 20 minutes because of persistent hypoxemia (PaO; baseline 56, 30
`minute value, 57). He subsequently received HFOV, HFJV, and surfactant. 0n approximately day 20, the patient suffered a
`right pneumothorax, and had progressive hypoxemia. A decision was made to withdraw therapy, and the subject died 2]
`days afier initiation of study gas. No association between the death and eosinophilia is evident.
`
`No follow-up of the eosinophilia is available for any subject.
`No subjects were identified as having an adverse event or death as a consequence of eosinophilia.
`No report in the secondary database links with use of l-NO with eosinophilia.
`
`’
`
`9219mm
`There is a trend towards an increased mean % of eosinophils in the database from the [NO-01! -02 trial. There is
`also a numerical excess of cases of eosinophilia gin the I-NO group. For purposes of this review,
`there is a possible
`relationship between exposu