ZOFRAN SUPPOSITORIES 16MG

Active substance: ONDANSETRON

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Zofran Suppositories 16mg

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
White torpedo shaped suppositories containing 16mg of ondansetron.

3.

PHARMACEUTICAL FORM
Suppositories

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Adults:
Zofran is indicated for the management of nausea and vomiting induced by
cytotoxic chemotherapy and radiotherapy.

4.2

Posology and method of administration
Adults:
The emetogenic potential of cancer treatment varies according to the doses and
combinations of chemotherapy and radiotherapy regimens used. The selection of
dose regimen should be determined by the severity of the emetogenic challenge.
Emetogenic chemotherapy and radiotherapy: Zofran can be given either by rectal,
oral (tablets or syrup), intravenous or intramuscular administration.
For rectal administration: The recommended dose of Zofran (ondansetron)
suppositories is one 16 mg suppository given 1 to 2 hours before treatment.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal
treatment with Zofran should be continued for up to 5 days after a course of

treatment. The recommended daily dose for rectal administration is one 16mg
suppository.
Highly emetogenic chemotherapy (e.g. high dose cisplatin): Zofran can be given
either by oral, rectal, intravenous or intramuscular administration.
For rectal administration: The recommended dose of Zofran (ondansetron)
suppositories is one suppository given 1 to 2 hours before treatment.
The efficacy of Zofran in highly emetogenic chemotherapy may be enhanced by the
addition of a single intravenous dose of dexamethasone sodium phosphate 20mg,
administered prior to chemotherapy.
To protect against delayed or prolonged emesis after the first 24 hours, oral or rectal
treatment with Zofran should be continued for up to 5 days after a course of
treatment. The recommended daily dose for rectal administration is one 16mg
suppository.
Paediatric Population:



CINV in children aged

6 months and adolescents

The use of Zofran Suppositories in children is not recommended. The usual
method of administration is IV followed by oral therapy (see below).
The dose for CINV can be calculated based on body surface area (BSA) or weight –
see below. In paediatric clinical studies, ondansetron was given by IV infusion diluted
in 25 to 50mL of saline or other compatible infusion fluid and infused over not less
than 15 minutes.
Weight-based dosing results in higher total daily doses compared to BSA-based
dosing (sections 4.4.).
There are no data from controlled clinical trials on the use of Zofran in the prevention
of delayed or prolonged CINV. There are no data from controlled clinical trials on the
use of Zofran for radiotherapy-induced nausea and vomiting in children.
Dosing by BSA:
Zofran should be administered immediately before chemotherapy as a single
intravenous dose of 5 mg/m2. The single intravenous dose must not exceed 8 mg.
Oral dosing can commence 12 hours later and may be continued for up to 5 days
(Table 1).
The total dose over 24 hours (given as divided doses) must not exceed adult dose of
32 mg.
Table 1: BSA-based dosing for Chemotherapy - Children aged 6 months and
adolescents



BSA

Day 1 (a,b)

Days 2-6(b)

< 0.6 m2

5 mg/m2 IV plus
2 mg syrup after 12 hours

2 mg syrup every
12 hours

≥ 0.6 m2

5 mg/m2 IV plus
4 mg syrup or tablet after

4 mg syrup or tablet
every 12 hours

12 hours
>1.2m2

5mg/m2 or 8mg IV plus
8mg syrup or tablet after
12 hours

8mg syrup or tablet every
12 hours

a The intravenous dose must not exceed 8mg.
b The total dose over 24 hours must not exceed adult dose of 32 mg
Dosing by bodyweight:
Weight-based dosing results in higher total daily doses compared to BSA-based
dosing (sections 4.4. and 5.1).
Zofran should be administered immediately before chemotherapy as a single
intravenous dose of 0.15 mg/kg. The single intravenous dose must not exceed 8 mg.
Two further intravenous doses may be given in 4-hourly intervals.
Oral dosing can commence 12 hours later and may be continued for up to 5 days
(Table 2).
The total dose over 24 hours (given as divided doses) must not exceed adult dose of
32 mg.
Table 2: Weight-based dosing for Chemotherapy - Children aged 6 months and
adolescents



Day 1 (a,b)

Days 2-6(b)

10 kg

Up to 3 doses of 0.15 mg/kg
every 4 hours

2 mg syrup
every 12 hours

> 10 kg

Up to 3 doses of 0.15 mg/kg
every 4 hours

4 mg syrup or
tablet every
12 hours

Weight

a The intravenous dose must not exceed 8mg.
b The total dose over 24 hours must not exceed adult dose of 32 mg.
Elderly:
Zofran is well tolerated by patients over 65 years. No alteration of oral dose or
frequency of administration is required.
Patients with renal impairment:
No alteration of daily dosage or frequency of dosing, or route of administration are
required.
Patients with hepatic impairment:
Clearance of Zofran is significantly reduced and serum half-life significantly
prolonged in subjects with moderate or severe impairment of hepatic function. In
such patients a total daily dose of 8mg should not be exceeded.
Patients with poor sparteine/debrisoqine metabolism:
The elimination half-life of ondansetron is not altered in subjects classified as poor
metabolisers of sparteine and debrisoquine. Consequently in such patients repeat



dosing will give drug exposure levels no different from those of the general
population. No alteration of daily dosage or frequency of dosing is required.

4.3

Contraindications
Concomitant use with apomorphine (see section 4.5).
Hypersensitivity to any component of the preparation.

4.4

Special warnings and precautions for use
Hypersensitivity reactions have been reported in patients who have exhibited
hypersensitivity to other selective 5HT3 receptor antagonists.
Respiratory events should be treated symptomatically and clinicians should pay
particular attention to them as precursors of hypersensitivity reactions.
Ondansetron prolongs the QT interval in a dose-dependent manner (see section 5.1).
In addition, post-marketing cases of Torsade de Pointes have been reported in patients
using ondansetron. Avoid ondansetron in patients with congenital long QT
syndrome. Ondansetron should be administered with caution to patients who have or
may develop prolongation of QTc, including patients with electrolyte abnormalities,
congestive heart failure, bradyarrhythmias or patients taking other medicinal products
that lead to QT prolongation or electrolyte abnormalities.
Hypokalaemia and hypomagnesaemia should be corrected prior to ondansetron
administration.
There have been post-marketing reports describing patients with serotonin syndrome
(including altered mental status, autonomic instability and neuromuscular
abnormalities) following the concomitant use of ondansetron and other serotonergic
drugs (including selective serotonin reuptake inhibitors (SSRI) and serotonin
noradrenaline reuptake inhibitors (SNRIs)). If concomitant treatment with
ondansetron and other serotonergic drugs is clinically warranted, appropriate
observation of the patient is advised.
As ondansetron is known to increase large bowel transit time, patients with signs of
subacute intestinal obstruction should be monitored following administration.
In patients with adenotonsillar surgery prevention of nausea and vomiting with
ondansetron may mask occult bleeding. Therefore, such patients should be
followed carefully after ondansetron.
Paediatric Population:
Paediatric patients receiving ondansetron with hepatotoxic chemotherapeutic agents
should be monitored closely for impaired hepatic function.

CINV: When calculating the dose on an mg/kg basis and administering three doses at
4-hour intervals, the total daily dose will be higher than if one single dose of 5mg/m2
followed by an oral dose is given. The comparative efficacy of these two different
dosing regimens has not been investigated in clinical trials. Cross-trial comparison
indicates similar efficacy for both regimens (section 5.1).

4.5

Interaction with other Medicaments and other Forms of Interaction
There is no evidence that ondansetron either induces or inhibits the
metabolism of other drugs commonly co-administered with it. Specific studies
have shown that there are no interactions when ondansetron is administered
with alcohol, temazepam, furosemide, alfentanil, tramadol, morphine,
lidocaine, thiopental or propofol.
Ondansetron is metabolised by multiple hepatic cytochrome P-450 enzymes:
CYP3A4, CYP2D6 and CYP1A2. Due to the multiplicity of metabolic
enzymes capable of metabolising ondansetron, enzyme inhibition or reduced
activity of one enzyme (e.g. CYP2D6 genetic deficiency) is normally
compensated by other enzymes and should result in little or no significant
change in overall ondansetron clearance or dose requirement.
Caution should be exercised when ondansetron is coadministered with drugs
that prolong the QT interval and/or cause electrolyte abnormalities. (see
section 4.4)
Use of ondansetron with QT prolonging drugs may result in additional QT
prolongation. Concomitant use of ondansetron with cardiotoxic drugs (e.g.
anthracyclines (such as doxorubicin, daunorubicin) or trastuzumab),
antibiotics (such as erythromycin), antifungal (such as ketoconazole),
antiarrhythmics (such as amiodarone) and beta blockers (such as atenolol or
timolol) may increase the risk of arrhythmias. (See section 4.4).
Serotonergic Drugs (e.g. SSRIs and SNRIs): There have been post-marketing
reports describing patients with serotonin syndrome (including altered mental
status, autonomic instability and neuromuscular abnormalities) following the
concomitant use of ondansetron and other serotonergic drugs (including SSRIs
and SNRIs). (See section 4.4)
Apomorphine: Based on reports of profound hypotension and loss of
consciousness when ondansetron was administered with apomorphine
hydrochloride, concomitant use with apomorphine is contraindicated.
Phenytoin, Carbamazepine and Rifampicin: In patients treated with potent
inducers of CYP3A4 (i.e. phenytoin, carbamazepine, and rifampicin), the oral
clearance of ondansetron was increased and ondansetron blood concentrations
were decreased.
Tramadol: Data from small studies indicate that ondansetron may reduce the
analgesic effect of tramadol.

4.6

Fertility, pregnancy and lactation
Pregnancy
The safety of ondansetron for use in human pregnancy has not been established.
Evaluation of experimental animal studies does not indicate direct or indirect harmful
effects with respect to the development of the embryo, or foetus, the course of
gestation and peri- and post-natal development. However as animal studies are not
always predictive of human response the use of ondansetron in pregnancy is not
recommended.
Breast-feeding
Tests have shown that ondansetron passes into the milk of lactating animals. It is
therefore recommended that mothers receiving Zofran should not breast-feed their
babies.

4.7

Effects on ability to drive and use machines
In psychomotor testing ondansetron does not impair performance nor cause sedation.
No detrimental effects on such activities are predicted from the pharmacology of
ondansetron.

4.8

Undesirable Effects
Adverse events are listed below by system organ class and frequency.
Frequencies are defined as: very common (≥1/10), common (≥1/100 and
<1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000) and
very rare (<1/10,000). Very common, common and uncommon events were
generally determined from clinical trial data. The incidence in placebo was
taken into account. Rare and very rare events were generally determined from
post-marketing spontaneous data.
The following frequencies are estimated at the standard recommended doses
of ondansetron The adverse event profiles in children and adolescents were
comparable to that seen in adults.
Immune system disorders
Rare:
Immediate hypersensitivity reactions sometimes severe,
including anaphylaxis.
Nervous system disorders
Very common: Headache.
Uncommon: Seizures, movement disorders (including extrapyramidal
reactions such as dystonic reactions, oculogyric crisis and.
Dyskinesia) (1)

Rare:

Dizziness during rapid IV administration.

Eye disorders
Rare:
Transient visual disturbances (e.g. blurred vision)
predominantly during IV administration.
Very rare:
Transient blindness predominantly during IV administration(2)
Cardiac disorders
Uncommon: Arrhythmias, chest pain with or without ST segment
depression, bradycardia.
Rare:
QTc prolongation (including Torsade de Pointes)
Vascular disorders
Common:
Sensation of warmth or flushing.
Uncommon: Hypotension.
Respiratory, thoracic and mediastinal disorders
Uncommon: Hiccups.
Gastrointestinal disorders
Common:
Constipation.
Hepatobiliary disorders
Uncommon: Asymptomatic increases in liver function tests(3)
General disorders and administration site conditions
Local burning sensation following insertion of suppositories.
1. Observed without definitive evidence of persistent clinical sequelae.
2. The majority of the blindness cases reported resolved within 20 minutes.
Most patients had received chemotherapeutic agents, which included
cisplatin. Some cases of transient blindness were reported as cortical in
origin.
3. These events were observed commonly in patients receiving chemotherapy
with cisplatin.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard.
4.9

Overdose
Symptoms and Signs
There is limited experience of ondansetron overdose. In the majority of cases,
symptoms were similar to those already reported in patients receiving recommended
doses (see section 4.8). Manifestations that have been reported include visual
disturbances, severe constipation, hypotension and a vasovagal episode with transient
second-degree AV block

Ondansetron prolongs the QT interval in a dose-dependent fashion. ECG monitoring
is recommended in cases of overdose.
Treatment
There is no specific antidote for ondansetron, therefore in all cases of suspected
overdose, symptomatic and supportive therapy should be given as appropriate. The
use of ipecacuanha to treat overdose with ondansetron is not recommended, as
patients are unlikely to respond due to the anti-emetic action of ondansetron itself.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Mechanism of Action
Ondansetron is a potent, highly selective 5HT3 receptor-antagonist. The precise mode
of action in the control of nausea and vomiting is not known. Chemotherapeutic
agents and radiotherapy may cause release of 5HT in the small intestine initiating a
vomiting reflex by activating vagal afferents via 5HT3 receptors. Ondansetron blocks
the initiation of this reflex. Activation of vagal afferents may also cause a release of
5HT in the area postrema, located on the floor of the fourth ventricle, and this may
also promote emesis through a central mechanism. Thus, the effect of ondansetron in
the management of the nausea and vomiting induced by cytotoxic chemotherapy and
radiotherapy is probably due to antagonism of 5HT3 receptors on neurons located
both in the peripheral and central nervous system.
The mechanisms of action in post-operative nausea and vomiting are not known but
there may be common pathways with cytotoxic induced nausea and vomiting.
Ondansetron does not alter plasma prolactin concentrations.
The role of ondansetron in opiate-induced emesis is not yet established.
QT Prolongation
The effect of ondansetron on the QTc interval was evaluated in a double blind,
randomized, placebo and positive (moxifloxacin) controlled, crossover study in 58
healthy adult men and women. Ondansetron doses included 8 mg and 32 mg infused
intravenously over 15 minutes. At the highest tested dose of 32 mg, the maximum
mean (upper limit of 90% CI) difference in QTcF from placebo after baselinecorrection was 19.6 (21.5) msec. At the lower tested dose of 8 mg, the maximum
mean (upper limit of 90% CI) difference in QTcF from placebo after baselinecorrection was 5.8 (7.8) msec. In this study, there were no QTcF measurements
greater than 480 msec and no QTcF prolongation was greater than 60 msec.

Paediatric population:
CINV
The efficacy of ondansetron in the control of emesis and nausea induced by cancer
chemotherapy was assessed in a double-blind randomised trial in 415 patients aged 1
to 18 years (S3AB3006). On the days of chemotherapy, patients received either
ondansetron 5 mg/m2 intravenous and ondansetron 4 mg orally after 8 to 12 hrs or

ondansetron 0.45 mg/kg intravenous and placebo orally after 8 to 12 hrs. Postchemotherapy both groups received 4 mg ondansetron syrup twice daily for 3 days.
Complete control of emesis on worst day of chemotherapy was 49% (5 mg/m2
intravenous and ondansetron 4 mg orally) and 41% (0.45 mg/kg intravenous and
placebo orally). Post-chemotherapy both groups received 4 mg ondansetron syrup
twice daily for 3 days. There was nodifference in the overall incidence or nature of
adverse events between the two
treatment groups.
A double-blind randomised placebo-controlled trial (S3AB4003) in 438 patients aged
1 to 17 years demonstrated complete control of emesis on worst day of chemotherapy
in:
• 73% of patients when ondansetron was administered intravenously at a dose of
5 mg/m2 intravenous together with 2 to 4 mg dexamethasone orally
• 71% of patients when ondansetron was administered as syrup at a dose of 8 mg
together with 2 to 4 mg dexamethasone orally on the days of chemotherapy.
Post-chemotherapy both groups received 4 mg ondansetron syrup twice daily for
2 days. There was no difference in the overall incidence or nature of
adverse events between the two treatment groups.
The efficacy of ondansetron in 75 children aged 6 to 48 months was investigated in
an open-label, non-comparative, single-arm study (S3A40320). All children received
three 0.15 mg/kg doses of intravenous ondansetron, administered 30 minutes before
the start of chemotherapy and then at 4 and 8 hours after the first dose. Complete
control of emesis was achieved in 56% of patients.
Another open-label, non-comparative, single-arm study (S3A239) investigated the
efficacy of one intravenous dose of 0.15 mg/kg ondansetron followed by two oral
ondansetron doses of 4 mg for children aged < 12 years and 8 mg for children aged
12 years (total no. of children n= 28). Complete control of emesis was achieved in
42% of patients.


5.2

Pharmacokinetic properties
Following oral administration, ondansetron is passively and completely absorbed
from the gastrointestinal tract and undergoes first pass metabolism. Peak plasma
concentrations of about 30ng/mL are attained approximately 1.5 hours after an 8mg
dose. For doses above 8mg the increase in ondansetron systemic exposure with dose
is greater than proportional; this may reflect some reduction in first pass metabolism
at higher oral doses. Mean bioavailability in healthy male subjects, following the oral
administration of a single 8 mg tablet, is approximately 55 to 60%. Bioavailability,
following oral administration, is slightly enhanced by the presence of food but
unaffected by antacids.
The disposition of ondansetron following oral, intramuscular (IM) and
intravenous(IV) dosing is similar with a terminal half life of about 3 hours and steady
state volume of distribution of about 140L. Equivalent systemic exposure is achieved
after IM and IV administration of ondansetron.
A 4mg intravenous infusion of ondansetron given over 5 minutes results in peak
plasma concentrations of about 65ng/ml. Following intramuscular administration of

ondansetron, peak plasma concentrations of about 25ng/ml are attained within 10
minutes of injection.
Following administration of ondansetron suppository, plasma ondansetron
concentrations become detectable between 15 and 60 minutes after dosing.
Concentrations rise in an essentially linear fashion, until peak concentrations of 20-30
ng/ml are attained, typically 6 hours after dosing. Plasma concentrations then fall, but
at a slower rate than observed following oral dosing due to continued absorption of
ondansetron. The absolute bioavailability of ondansetron from the suppository is
approximately 60% and is not affected by gender. The half life of the elimination
phase following suppository administration is determined by the rate of ondansetron
absorption, not systemic clearance and is approximately 6 hours. Females show a
small, clinically insignificant, increase in half-life in comparison with males.
Ondansetron is not highly protein bound (70-76%). Ondansetron is cleared from the
systemic circulation predominantly by hepatic metabolism through multiple
enzymatic pathways. Less than 5% of the absorbed dose is excreted unchanged in the
urine. The absence of the enzyme CYP2D6 (the debrisoquine polymorphism) has no
effect on ondansetron's pharmacokinetics. The pharmacokinetic properties of
ondansetron are unchanged on repeat dosing.
Special Patient Populations
Gender
Gender differences were shown in the disposition of ondansetron, with females
having a greater rate and extent of absorption following an oral dose and reduced
systemic clearance and volume of distribution (adjusted for weight).
Children and Adolescents (aged 1 month to 17 years)
In paediatric patients aged 1 to 4 months (n=19) undergoing surgery, weight
normalised clearance was approximately 30% slower than in patients aged 5 to 24
months (n=22) but comparable to the patients aged 3 to 12 years. The half-life in the
patient population aged 1 to 4 month was reported to average 6.7 hours compared to
2.9 hours for patients in the 5 to 24 month and 3 to 12 year age range. The
differences in pharmacokinetic parameters in the 1 to 4 month patient population can
be explained in part by the higher percentage of total body water in neonates and
infants and a higher volume of distribution for water soluble drugs like ondansetron.
In paediatric patients aged 3 to 12 years undergoing elective surgery with general
anaesthesia, the absolute values for both the clearance and volume of distribution of
ondansetron were reduced in comparison to values with adult patients. Both
parameters increased in a linear fashion with weight and by 12 years of age, the
values were approaching those of young adults. When clearance and volume of
distribution values were normalised by body weight, the values for these parameters
were similar between the different age group populations. Use of weight-based dosing
compensates for age-related changes and is effective in normalising systemic
exposure in paediatric patients.
Population pharmacokinetic analysis was performed on 428 subjects (cancer patients,
surgery patients and healthy volunteers) aged 1 month to 44 years following
intravenous administration of ondansetron. Based on this analysis, systemic exposure
(AUC) of ondansetron following oral or IV dosing in children and adolescents was
comparable to adults, with the exception of infants aged 1 to 4 months. Volume was

related to age and was lower in adults than in infants and children. Clearance was
related to weight but not to age with the exception of infants aged 1 to 4 months. It is
difficult to conclude whether there was an additional reduction in clearance related to
age in infants 1 to 4 months or simply inherent variability due to the low number of
subjects studied in this age group. Since patients less than 6 months of age will only
receive a single dose in PONV a decreased clearance is not likely to be clinically
relevant.
Elderly
Early Phase I studies in healthy elderly volunteers showed a slight age-related
decrease in clearance, and an increase in half-life of ondansetron. However, wide
inter-subject variability resulted in considerable overlap in pharmacokinetic
parameters between young (< 65 years of age) and elderly subjects ( 65 years of age)
and there were no overall differences in safety or efficacy observed between young
and elderly cancer patients enrolled in CINV clinical trials to support a different
dosing recommendation for the elderly.



Based on more recent ondansetron plasma concentrations and exposure-response
modelling, a greater effect on QTcF is predicted in patients 75 years of age
compared to young adults. Specific dosing information is provided for patients over
65 years of age and over 75 years of age for intravenous dosing.



Renal impairment
In patients with renal impairment (creatinine clearance 15-60 mL/min), both systemic
clearance and volume of distribution are reduced following IV administration of
ondansetron, resulting in a slight, but clinically insignificant, increase in elimination
half-life (5.4 hours). A study in patients with severe renal impairment who required
regular haemodialysis (studied between dialyses) showed ondansetron's
pharmacokinetics to be essentially unchanged following IV administration.
Hepatic impairment
Following oral, intravenous or intramuscular dosing in patients with severe hepatic
impairment, ondansetron's systemic clearance is markedly reduced with prolonged
elimination half-lives (15-32 hours) and an oral bioavailability approaching 100% due
to reduced pre-systemic metabolism. The pharmacokinetics of ondansetron following
administration as a suppository have not been evaluated in patients with hepatic
impairment.

5.3.

Pre-clinical Safety Data
No additional data of relevance.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of Excipients
Witepsol S58.

6.2.

Incompatibilities
None reported.

6.3.

Shelf-Life
3 years.

6.4.

Special Precautions for Storage
Store below 30°C.

6.5.

Nature and Content of Container
Each suppository is in an individually sealed cavity enclosed in a perforated
cardboard mount and packed into a carton.

6.6.

Instructions for Use, Handling and Disposal
Insert into the rectum.
For detailed instructions see the patient information leaflet included in every
pack.

7.

MARKETING AUTHORISATION HOLDER
Glaxo Wellcome UK Limited trading as GlaxoSmithKline UK
Stockley Park West
Uxbridge
Middlesex, UB11 1BT

8.

MARKETING AUTHORISATION NUMBER
PL 10949/0247

9.
DATE OF FIRST AUTHORISATION / RENEWAL OF THE
AUTHORISATION
16 January 1997

10

DATE OF REVISION OF THE TEXT
04/09/2014

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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