HIGHLIGHTS OF PRESCRIBING INFORMATION 5.

3 PlateletAggregation Pretemn infants with signifint impairment of 1111111111111111

These highlights do not include all e informa on 5 .4Bilirubin Displacement renal function. 111111111111111

needed to use NeoProfen safely and effectively. 5.5 Administration 5 WARNINGS AND PRECAUTIONS
See full prescribing information for NeoProfen. 6 ADVERSE REACTIONS 5.1 General
There are no long-term evaluations of the infants treated with
6.1 Clinical Trials Experience
NeoProfen@ 6.2 RenalFunction
6.3 Additional Adverse Events
ibuprofen at durations greater than the 36 weeks post-conceptual
age observation periOd. Ibuprofen's effects on neurodevelopmental
outcome and growth as well as disease processes associated with
6 .4Post arketing Ex perience prematurity (such as retinopathy of prematurity and chronic lung
disease) have not en assessed.
Injectionr intravenous use 7 DRUG INTERACTIONS
5.2 Infection
Initial U.S. Approval: 2006 10 OVERDOSAGE
N
Pofen m
1
RECENT MAJOR CHANGES 11 DESCRIPTION bec
onltin
lU
alI
y on the alert and stulid use the drug WI Ith efacarei
n

Adverse ReactionsPost-marketing Experience- June 2008 12 CLINICAL PHARMACOLOGY the presence of contr
011
ed inflcticy
1and antsat risk of infection.
in int<
Added the terms gastrointestinal perfora on and necrotizing 12.1 Mechanism of Action 5.3 Platelet Aggregation
entenolitis. NeoProf like other non- al anti-inflammatory age n
12.2 Pharmacokinetics and BioavailabilityStudies
INDICATIONS AND USAGE inhibit platelet aggration. Preterm infants should be observed for
14 CLINIC Al STUDIES signs of bleeding. Ibuprofen has been shown to prolong bleeding time
1JeoProfen is indicated to close a clinically Sl gnifica t ductus
16 HOW SUPPLIED/STORAGE AND HANDLING (b ut within the nomnalrange) in normal adult su cts. This effect may
arteriosus(P DA)in p mature infantsweighing IJJtween500 d 1500 g
who are no more an 32 weeks gestational age when usual medical 17 PATIENT COUNSELING INFORMATION be eaggerated in patients with underlying hemostatic defects (see
management is ineffective e clinical trial. was nducted among 17.1 General CONTRAINDICATIONS).
infants with an asymptomatic PDA.Howev e consequenc s beyond 17.2 Infection 5.4 Bilirubin Di splacement
8 weeks after treatment have not been evaluated;therefoeatment Ibuprofen has been shown to displace bilirubin from albumin binding-
should be reserved for innts w clear evidence of a clinlIy 17.3 PlateletAggregation sites; therefo it should be used with caution in patients with elevated
significant PDA 17 .4 Bilirubin Displacement total bilirubin
- DOSAGE AND ADMINISTRATION 17.5
ctions or
Ad ministration
bsecons omitted from the full prescribing infomnation
5.5 Adminis ation
A se of therapy is three doses administ~red LV NeoProfen should be administered carefully to avoid extravascular
in I dose of 10 mg is followed by twd doses of 5 mg/k g each are not list injection or leakageas solution may be irritating to tissue
after 24 and 48 hou 6 ADVERSE REACTIONS
FUll PRESCRIBING INFORMATION
All do should be based on birth weight
If anuria or marked oliguria 0.6 mUlIh r) ident at the
scheduled time of the second or third dOlllno additional dosage
1 INDICATIONS AND USAGE
NeoProfen is indicated to close a clinically signifnt patent ductus
6.1 Clinical Trials Ex
Th
perience
e most fp uently reed adverse events wi NeoProfen as
shown in Table 1.
should be given until labora ry studies imjicate that renal function arterios (P DA)in pmature inlts weighing between5 d 1500g
Table 1. Adverse Events wi in 30 Days of Th erapy in
has returned to normal who are no more than 32 weeks gestational age when usual medical
If the ductus arteriosus closes or is significalltly reduced in size after
completion of the fi t coue no further dooesa necessary
management (e.g.fluid restrictiondiureti spiratory supt etc.)
is ineffective. Th e clinl trial was conducted among infants with an
the Multicenter S d y*
% Incidence
If the ductus arteriosus failsclose then a second course of
NeoProfaltemative phamnacologicaltherapyor su may be
asymptomatic PDA Howeverthe consequences beyond 8 weeks after
treatment have not been evaluated; therefore ea lent should be
Adverse Event w NeoProfen Pia
Se psis 43 37
needed served for infants wfth clear evidence of a clinically significant PDA
An emia

- DOSAGE FORMS AND STRENGTHS - 2 DOSAGE AND ADMINISTRATION To I Bleeding n

10 mg/mLaa clear sterile preservative-freesolution of the L-lysine 2.1 Recommended Dose IntraventricularHemorrhage
salt of ibuprofen in a 2 mL single-use Vial A course of therapy Is three doses of NeoProfen administered Grades1/2 15 13
inavenously (administrationvia an umbilI arterial line has not been Intravenicular Hemorrhage
CONTRAINDICATIONS evaluated) initial dose of 10 mg per kilogram is followed by two
NeoPr n is contraindicated in preterm infants Grades3/4 15 10
doses of 5 mg per kilogram eaChafter 24 and 48 hou.Al l doses ler Bleeding 6 13
With proven or suspected infection that is untreated should be S on birth weigh!. If anuria or marked oliguria (urinary Intravenbicular Hemorrha
With congenital heart disease in whom patency of the PDA is oulp <0.6 mlJ1< g10 is evident at the scheduled time of the second
necessary for satisfactory pulmonary or systemic blood flow
With impaired ren function

r third dose of NeoProfenno additional dosage should be given
until laboratory studies indicate that renal function has retumed to Ap
I Grades
nea
n
m
24

With thrombocytopeniacoagulation defects or who are bleeding normal. If the ductus arteriosus closes or is significantly reduced in Gastrointestinal Di sorders
With or who are suspected of having necrotizing enterocol IS size after completi of the first course of NProf no fuer doses non-Necrotizing Er rocol s n 18
are necessary. I~during continued medical management the ductus Total Renal Events** 21
- WARNINGS AND PRECAUTIONS arteriosus fails tojclose or reopensthen a second course of NeoProfen 15
RenalFailu 3
NeoProfen has not been assessed for neurodevelopmentaloutcome alternative phamjacological ther or su be nece. 4

and growth Re Insufficien Impaimlent 6 4

2.2 Di rections for Use UrineDutp R uced 3
NeoProfen may alter the usual signs of Infection F0 intr
aveno 0
q
sadmin i s a
on
onE BIxl CreatinineIncrea d 3
raatio
'
NeoProfen can inhibit platelet aggregationand has been shown to s
hou1dbei nscdv l
sualI
y
yt 0rpa la
t e e ddi 10
np
H0
BI UreaIncreased
prolong bleeding time in normal adult subjects toadmi nlisation whenever sol ion and ntainer pemnit

with He
..... ...
maturia h
 prolong bleeding time in normalult subjects to administration Wheneversolution and coniner permit. WIth He matuna

Ibuprofen has been shown to displace bilirubin from albumin binding-

sites
ForadministratiorlNeoProfenshould be diluted to an appropriatevolume
with dextrose or line. rofen should be prepared for infusion and
BIJd Urea Increa d

Respiratory In ction
7
19
4
13
NeoProfen should be administered carelI
y to avoid extravascular administered wittjjn 30 mlnu of preparation and infused continuously Skin Les ionllrr " 16 6
injection or leakage over a period of 15 minutes. The drug should be administered e Hypogly mia 12 6
IV po that is ne~est the inseon site. After the first withdrawal from
ADVERSE REACTIONS the vialy solution remaining must be discarded bause NProfen Hypocal mia 12 9
Most common adverse reactions (;;::10%) a sepsis anem contains no preservative. Respiratory Failure 10 4
intraventricular bleeding apnea gastrointesqnal disorde impaired Since NeoP is potentially irritating to tissuesit should be Urinary Tract In ction 9 4
renal function respiratory infection skin lesions hypoglycem administered carelI y to avoid extravasation. Adrenal Insufficiency 7
hypocalcem respiratory faBu (6) NProfen should not be simultaneously administered in the same Hype ma mia 7 4
To repo SUSPECTED ADVERSE REACTIONS contact
Recordati Rare Di
FDA at 1-800-FDA-1088
seases Inc. at 1-888-575-8344
or www .f da.gov/medwatch.
or
intravenous line with To Parenteral Nutrition .Ifnecess TPN
should interrupted for a 15-minute period prior to and after drug
administration. Line patency should be main ined by using dexase
Edema
Atel sis
4
4

or saline. ~ Within 30 days of therapy with an event rate greater on NeoProfen
DRUG INTERACTIONS than on placeboand greater than 2 events on NeoProfen.
Drug interactions in neonates have not been assessed. 3 DOSAGE FORMS AND STRENGTHS
10 mg/ mL as a dear s e preservative- soluon of the Lsine salt ~*A given su ect may have expenenced more than one specific event
Se e 17 for PATIENT COUNSELING INFORMATION within these adverse event ories. Only the most severe grade of
of ibuprofenin a 2 mL single-use al
Revised: 0212013 | unt for a given subject.
4 CONTRAINDICATIONS
FULL PRESCRIBING INFORMATION: CONTENTS* NeoProfen is contraindicated in: 6.2 Renal Function
1 INDICATIONS AND USAGE Preterm infants with proven or suspected infection that is untreat Co mpared to place ere was a small decrease in urinary output in
the ibuprofen group on days 2-6 of I with a compensatory increase
2 DOSAGE AND ADMINISTRATION Preterm infants with congenital heart disease in whom patency of the in urine output on day 9. In other studies adverse events classified as
2.1 Recommended Dos PDA is necessary for satisfactory pulmonary or systemic bld flow renal insufficiency including oligu elevated BUNelevat creatinine
(e.g.pulmonary atres.severe tealogy of Fali severe coarctation or renal ilure we in ibuprofen treated infants.
2.2 Directions for U e of the aorta);
3 DOSAGE FORMS AND STRENGTHS 6.3 Additional Adverse Events
Preterm infants who are bleedingespecially those with active
intracranial hemorrhage or gasointestinal bleeding; Th e adverse events repo ed in the multicenter s dy and of unknown
4 CONTRAINDICATIONS association include tachycardia cardiac failure abdominal distension
5 WARNINGS AND PRECAUTIONS Preterm infants with thrombocytopenia; gassophageal reflux gastritis ile inguinal hem ilion
5.1 General Preterm infants with agulation defects; site reactions cholestasis various infections feeding problems
5.2 Infection Preterm infants with or who are suspected of having necrotizing convulsionsjaundice hypotensionand various laboratory abnormalities
enterocolitis; including neutroper thrombocytopeniaand hyperglycemia.
6.4 Post-marketing Ex perience pulmonary edemaincreasedcardiac silhouetteor systoliCmurmur - or 17.5 Adminis on
The following adverse reactions have been identified from spontaneous hemodynamically significant ductus as determined by a neonatologiSt. Patients' caregivers should be informed at the infa skin and
post-marketin repor published literature: gastrointestinal One hundred and thirty-six premature infants received either placebo tissues will be monitored as leakage from administration may be
pe ration and necrotizing enterocolitis. Because these reactions are or NeoProfen (10 mglkg on the first dose and 5 mgat 24 and 48 Irrting to tissue
reported voluntarily from a popu on of uncein sizeit is not always hours). Mean birth age was 1.5 days (range: 4.6-73.0 hours)mean
possible to liably estimate their frequency or establish a causal gestational age was 26 weeks (range: 23-30 weeks)and mean Manufactured by: AAIPharmaServices
relationship to drug exposure. weight was 798 g (range: 530-1015 g). All infants had a documented CharlestonSC 29405 U.S.A
PDA with evidence of ductal shunng. Asshown in Table 2 25% of
7 DRUG INTERACTIONS For: Recordati Rare DiseasesInc.
infants on NeoProfenrequired rescue therapy versus 48% of infants on
Drug interactions of NeoProfen in neonates have not been assessed. placebo (p =0.003 from logisc regression conoiling for si) LebanonNJ 08833 U.S.A.
10 OVERDOSAGE Table 2. Summary of Efficacy Results n (%) RECORDATI
e following signs and symptoms havecurred in individuals NeoProfen Placebo
E: RARE DISEASES
GROUP
(not necearily in prema infants) following an overdose of oral N= N=
ibuprofen: br ing difficul coma dwsiness irregular heartbeat Tradem ~OfR ordatiRa
re DiseasesI
kidney failu low blood pressureseizuresand vomiting. Th ere a Required rescue through Re: February2013 PC-4477B
specific measures to treat ac overdosage with NeoPfen. Th e study day 14
ment should be followed for several days because gastrointestinal Total 17 (2 33 (48)
ulceration and hemorrhage may occur. By age at trea lent
11 DESCRIPTION Bi to < 24 hours 3/14 (21) 8/16 (50)
NeoProfenil!>is a clear sterile preservative-free solution of the 24-48 hours 9 /32 17(0)

L-lysine salt of ()-ibuprofen which is the active ingredient. > 48 hours 5/22 (23) 9/15 (60)
()-Ibuprofen is a nonsteroidal anti-inflammatory agent (NSAID). Ec hocardi raphi Ily proven 17 (1 32 (9
L-lysine is used to create a water -soluble drug product salt suitable PDAp or to rescue
for intravenous administration. Each mL of NeoProfen contains
17.1 mg of ibuprofen lysine (equivalent to 10 mg of ()-ibuprofen) Reasons for Rescue
in Water for Injection USP. The pH is a usted to 7.0 with sodium Hemodynamicallysignificant 14 (8 25 (7
hydroxide or hydrhloric acid. BouPnding pnnatal i
ulse 6 (35) 12 (36)
Th e structural formula is: 6 (35) 15 (4

CH
PHyLl3plfteToIf
ldcyanmfay
umErmidc
euwmr
eacordium 3 (18) 5 (1

)::0

2 (12) 3 (9)
Increased cardiac silhouette 1 ( 5 (1

1einfants requiring rcue within the first 14 daysafter the firstse

ofs dy drugno statisticallysignifint differencewas observed tween
NProfen is designated chemically as-methyl-4-(2-methyl propyl) the N n and placebo grJps for mean age at rt of first rescue
benzeneacetic acid lysine sa~. ~s molecular weight is 352 .4 8. Its .trnent(8.7 daysrange 4-15 daysfor the NeoP rofen.groupand 6.9
empirical formula is C19H32N204'It occurs as a white c ine solid daysrange 2-15 daysfor the place group).
which is soluble in water and slighy soluble in ethanol. Th e gr'ps were similar in the numr of deaths by day 14 the number
of patien a ventilator or ruiring oxygenationat day 14 and 14
12 CLINIC. PHARMACOLOGY the number of patients requiring rgicalligation of their PDA(12%)the

12.1 Mechanism of Action num rof .sesof PulmonaryHemorrhageand PulmonaryHype rtension

Th e mechanism of action through which ibuprofen causes closure of by day 14 and Bronchopulmonary Dys plasia at day 28. In addit no
a patent ductus arteriosus (P DA) in nnates is not known. In adul significant differences were noted in the incidences of St age 2 and 3
ibuprofen is an inhibitor .of prostaglandin synthesis. Necrotizing Enteroli Grades 3 and 4 Inaven cular Hemorrha
12.2 Phannacokinetics and Bioavailability Studies Periventrilar Leukomalacia and Retinopathy of Prem betwn
e pharmacokinetic da were ob in om 54 NeoProfen-treated
gnoupsas determined at 36 1 weeks adjust geson age.
premature infants included in a double-blind placebo-conlied Two supportive studies also determined that ibuprofen either
randomiz multicenter study. Infants were less than 30 weeks prophylactically (n=433 weight range: 400 165 g) or as treatment
gestational ageweighed between 500 and 1000 gand exhibited (n=210 weight range: 400-2370 )was superior to pi
asymptomatic PDA with evidence of echa iographic dumentation (or no eatment) in preventing the need for rescue therapy for a
of ducI shunting. Dosing was initially 10m g followed by 5 mg/k g symptomatic PDA.
or oucral snunun uoslng was IrlllIClIl Y Iu rrlgtKyiotl uwt:U uy '~y nIyt Ull l1 vlln...L.U. __..-;
.

at 24 and 48 hours. 16 HOW SUPPLIED/STORAGE AND HANDLING

The population average clearance and volume of di ibn values of
mmic ibuprofen for premature infants at bi were 3 ml./k gth and
H li
320 mlJl vely. Clearance inc rapid with postna NeoP 'en Obuprofenlysin ltion is disn d in clear glass single-

age average Ise of approximately0.5 ml./k gth per. da y). Inter-

use each nni 2 mL of s Ie on (N DC 55292-122-
individual variability in clearance and volume of disibution were 55% 52). The solution not buffered and ntains no pr rvatives. Each
and 14%respective.In generalthe half-life in infants is more than 10 millil 17.1 mg/ mL ()-ibuprofen L ins [uival O
times longer than in adults. mg/ mL ()-ibuprofen] dissolved Water for IectionUSP.NeoProfen
is suppli in a carton ntaining 3 single-use vi.
e meta lism and excretion of i profen in premature infants have
not en studi Storaoe and Handlin
In adultsren elimina 1 of unchang ibuprofen ants f W Sto at 20-25C (68-n;excursions permitted 15-30C (59-
10-15% of the e. The excretion of ibuprofen and me lites 8 [e USP Co ntrolled Room Temperature]. Pr otect from light
urs rapidly in urine es. App roxirnat y 80% of the Store vials in In until contents have been used.
d admin oral ve in urine as hydroxyland ca 1 17 PATIENT COUNSELING INFORMATION
me001 respective asa miJr e of njug j and unnjuga d
forms. Ibuprofen eliminated prima by meOOlismin the liver where 17.1 General
CVP2C9 mediates the 2- and 3-hydroxylations of R- and S-ibuprofen. Patie carivers should be informed that the ts of ibuprofen
Ibuprofenand its me litesare rther ugatl toa I glucuronides. on infants' neurodevelopmentalH megrowth and disese p ;ess

In neonat renal tuncn and e es assoctwith drug
m!i sm are underdeve~ at bi and su ltially incnse in
the days after bir1.
14 CLINICAL STUDIES
In a double-blindmulticenter clinical sdy prema infants of
bi weight between 500 and 1000 gless than 30 weeks post-
conceptional ageand with echardiographic evidence of a PDAwere
randomized to placebo or NeoProfen eln anptornatic
from their PDA at the time of enrollment. The primary efficacy
parameter was the need for rescue therapy Ondomethacinopen-label
ibuprofl or surger to eat a hemodynamically signifint PDA by
study day 14. 1 infant was ncu if lere was clinical evidence
of a hemynamically Significant A that was echarcliraphically
nfirmed. A hemodynamically significant PDA s defin by three of
the following five criteria - bounding pulsehyperdynamic pr ordium
with prematurity have not been assessed in long-term studies
17.2Infec on
NeoProfen may alter signs of inton. Patients should be
info d that the infant will be carefully monred for any signs of
infection.
17.3 Platelet Aggregation
Patients' caregivers should be informed that lil<eother NSAl DS
NeoProfen can inhibit clot formation therefo lllir innt will
manred for any signs of bleeding
17.4 Bilirubin Displacement
Patie car ive should be informed that the inf:bl II be
test for increased levels of to bilirubin.