PROMIXIN 1 MILLION INTERNATIONAL UNITS (IU) POWDER FOR SOLUTION FOR INFUSION

Active substance: COLISTIMETHATE SODIUM

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PL393 Issue 5

1. What Promixin is and what it is used for
1 million International Units (IU)
Powder for Solution for Infusion
colistimethate sodium

Promixin

PACKAGE LEAFLET: INFORMATION FOR THE USER

PACKAGE LEAFLET: INFORMATION FOR THE USER

Promixin
1 million International Units (IU)
Powder for Solution for Infusion
colistimethate sodium

2. Before you are given Promixin

3. How you will be given Promixin

If you were not given Promixin when expected

Promixin contains colistimethate sodium. It is an antibiotic that
fights serious bacterial infections, especially chest infections
and infections of the urinary tract.

In certain circumstances your doctor may decide not to prescribe
Promixin.

Your treatment with Promixin has been prescribed by and will be
given to you under the supervision of a doctor or nurse.

If you think that you have missed a dose of Promixin and it is less
than 3 hours since you should have been given the dose, tell your
doctor or nurse.

Do not have Promixin and tell your doctor if:

The dose of Promixin is dependent on how ill you are, how well
your kidneys are working and your weight.

If it is more than 3 hours after the missed dose the doctor or nurse
will wait for your next dose.

The usual dose for adults and children who weigh up to 60 Kg is
50,000 to 75,000 International Units (IU) for each kilogram of body
weight each day. This will be divided into 3 equal doses and given
at 8 hourly intervals.

Stopping Promixin

Promixin is used when other more common antibiotics no longer
work or cannot be used.

l you

are allergic (hypersensitive) to the active substance in
Promixin (colistimethate sodium) or other polymyxins;
If this applies to you, tell your doctor before you are given
Promixin.

Take special care with Promixin and tell your doctor if:
l you

have or have had kidney problems;

l you

suffer from myasthenia gravis (a rare disease where your
muscles are extremely weak and get tired very quickly);

l you

suffer from porphyria (a rare metabolic disease that some
people are born with).

Read all of this leaflet carefully before you are given
this medicine
l Keep

this leaflet. You may need to read it again.

l If

you have further questions, please ask your doctor, nurse or
pharmacist.

l If

any of the side effects gets serious, or you notice any side
effects not listed in this leaflet, please tell your doctor, nurse or
pharmacist.

In this leaflet
1. What Promixin is and what it is used for
2. Before you are given Promixin
3. How you will be given Promixin

If any of these apply to you, tell your doctor.

Taking other medicines
Please tell your doctor or pharmacist if you are taking or have
recently taken any other medicines, including non-prescription
medicines. These medicines may interfere with the effects of
Promixin.
l If






you are taking any medicines that may affect your kidneys
including other antibiotics such as cephalothin sodium,
gentamicin, amikacin, netilmicin and tobramycin, please tell
your doctor. Taking Promixin at the same time as these other
medicines could increase your risk of kidney problems.

l Promixin

could prolong the effects of muscle relaxing medicines,
which may be used as part of a general anaesthetic if you have
an operation. If you need to have a general anaesthetic, tell the
anaesthetist that you are being given Promixin.

Pregnancy and breast-feeding

5. How to store Promixin

You may be given Promixin if you are pregnant or trying to get
pregnant if your doctor considers the benefits are greater than
the possible risks. It is unknown if having Promixin may harm
your unborn baby.

6. Further information

It is not recommended that you breast-feed while you are taking
this medicine as Promixin can pass into breast milk.

4. Possible side effects

Driving and using machines
Promixin may make you feel dizzy, confused or have problems
with your sight, such as blurred vision. If this happens to you,
do not drive or use any tools or machines.

The usual dose for adults and children who weigh over 60 Kg is
1-2 million International Units given every 8 hours.
Your doctor may decide you need a higher dose.

Your doctor will decide how long you should be given Promixin.
It is important that your treatment is completed as advised by your
doctor or your symptoms may get worse.
If you have any further questions on the use of this product, ask
your doctor.

If you have problems with your kidneys you will usually be given
a lower dose of Promixin fewer times a day. Your doctor will work
out the correct dose for you.
l You

will be given Promixin by a slow injection (infusion) into a
vein over 30 minutes.

l If

you have been fitted with a Totally Implantable Venous Access
Device (TIVAD) you may be given a smaller volume of Promixin
over a shorter time.

l Before

Promixin can be given it must be dissolved in sterile saline
(salt water).

l The

correct dose of Promixin will then be further diluted in a
suitable volume (usually 50 mL).

l Usually

you will be treated for at least 5 days.

If you are given too much Promixin
As a doctor or nurse will be giving you Promixin, it is unlikely that
you will receive an incorrect dose. Tell your doctor or nurse if you
have any concerns about the amount of medicine that you are
given.
The symptoms of having too much Promixin can include:
l dizziness
l slurred
l visual

and spinning sensation (vertigo)

speech

disturbance

l confusion
l mental

disturbance

l flushing
l kidney

problems

l muscle
l feeling

(reddening of the face)
weakness

as though you cannot breathe

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PL393 Issue 5

4. Possible side effects

5. How to store Promixin

6. Further information

Like all medicines, Promixin can cause side effects, although not
everybody gets them.

Keep Promixin out of the sight and reach of children.

What Promixin contains

Do not use Promixin after the expiry date which is stated on the
vial or carton. The expiry date refers to the last day of that month.

The active substance is colistimethate sodium.

Promixin can sometimes cause allergic reactions like skin rash
or red and lumpy skin rash, swollen eyelids, face, lips, mouth or
tongue, itching, difficulty breathing or swallowing. If this happens,
your Promixin treatment will be stopped immediately.
Promixin can also affect your kidneys, especially if the dose is high
or you are taking other medicines that may affect your kidneys.

Very common side effects (affecting more than
1 person in 10)
l blood

tests may show changes in the way the kidneys are
working

l headache
l tingling

or numbness around the mouth, lips and face

l itching
l muscle

weakness

Rare side effects (affecting less than 1 person
in 1,000)
l kidney

failure

Do not store above 25ºC
Promixin contains no preservatives. Once prepared, Promixin
should be used immediately.
Your doctor or nurse will dispose of any unused medicine safely.
These measures will help to protect the environment.

Each vial contains 1 million International Units (IU) of
colistimethate sodium, which weighs about 80 milligrams (mg).
There are no other ingredients.

What Promixin looks like and contents of the pack
Promixin is supplied as a powder in a glass vial. The powder must
be made into a solution for infusion.
Promixin is supplied in packs containing 10 vials.

Marketing Authorisation Holder
Profile Pharma Limited
Bicentennial Building
Southern Gate
Chichester
West Sussex
PO19 8EZ
UK
Tel: +44 (0) 800 1300 855
Fax: +44 (0) 800 1300 856
Email: info@profilepharma.com

Other side effects can include:

Manufacturer

l dizziness

Xellia Pharmaceuticals ApS
Dalslandsgade 11
DK-2300
Copenhagen S
Denmark

l difficulty

in controlling movements

l soreness

at the site of injection

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse.
This includes any possible side effects not listed in this leaflet. You
can also report side effects directly (see details below). By reporting
side effects you can help provide more information on the safety of
this medicine.
United Kingdom
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard

This medicinal product is authorised in the Member
States of the EEA under the following names:
Austria, The Netherlands, Sweden: Tadim
Germany, Denmark, Norway, United Kingdom: Promixin
This leaflet was last approved in July 2014.

PL393 Issue 5

1 million International Units (IU)
Powder for Solution for Infusion

Promixin

THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL
OR HEALTHCARE PROFESSIONALS ONLY:
Summary of Product Characteristics for

1061604 Issue 4

4.2 Posology and method of administration

THE FOLLOWING INFORMATION IS INTENDED FOR MEDICAL
OR HEALTHCARE PROFESSIONALS ONLY:
Summary of Product Characteristics for

Promixin

1 million International Units (IU)
Powder for Solution for Infusion

It is recommended that Promixin should be administered under the
supervision of physicians with appropriate experience in its use.

Promixin, 1 million International Units (IU), Powder for Solution for
Infusion.

2. Qualitative and quantitative composition
Each vial contains 1 million International Units (IU) which is
approximately equivalent to 80 mg of colistimethate sodium.

Administration is by intravenous infusion. Each dose of Promixin
can be diluted in 50 mL and administered by intravenous infusion
over 30 minutes. Patients fitted with a totally implantable venous
access device (TIVAD) may tolerate an injection of up to 2 million IU
in 10 mL given over a minimum of 5 minutes.
Solutions should be used immediately after reconstitution. For
instructions on dilution of the product before administration see
section 6.6.

The dose regimen of Promixin that is selected should take into
account factors such as the susceptibility of the pathogen(s), the
severity and type of infection, and the ideal body weight and renal
function of the patient. The duration of treatment is usually at least
5 days.
Standard dose recommendations are as follows:
Up to 60 Kg: 50,000 IU/Kg (4 mg/Kg) bodyweight, to a maximum
of 75,000 IU/Kg (6 mg/Kg), in 24 hours. The total daily dose should
be administered as three equal doses at 8 hourly intervals.
Over 60 Kg: 1-2 million IU every 8 hours. The maximum standard
dose is 6 million IU (480 mg) in 24 hours.

Powder for solution for infusion

Limited pharmacokinetic data from critically ill patients suggest
that use of a loading dose and higher than standard doses may be
appropriate (see Section 5.2). For severe infections and in critically
ill patients doses up to 9 million IU per day in divided doses, have
been reported in the literature. Clinical efficacy and safety data with
these regimens are very limited and caution is advised (see sections
4.4 and 5.2).

The powder is white to off white

Paediatric population

3. Pharmaceutical form

4. Clinical particulars

Dose recommendations are the same in adults and all paediatric
sub groups.
Renal impairment

4.1 Therapeutic indications
Promixin is indicated for treatment of the following infections caused
by susceptible aerobic Gram-negative bacteria (see section 5.1):
- Hospital acquired pneumonia (HAP)
- Complicated urinary tract infections
It is recommended that Promixin should be selected when
antibacterial agents that are commonly used to treat these
infections are not considered to be appropriate for the individual
patient and/or the causative pathogen(s) (see sections 4.4 and 5.1).
Consideration should be given to official guidance on the
appropriate use of antibacterial agents.

Degree of Renal Impairment

Method of Administration

Posology

1. Name of the medicinal product

Table 1: Suggested modification of dosage of Promixin for
adults with impaired renal function

The suggested dose recommendations in Table 1 for patients
with renal impairment are based on the standard total daily dose
of 3-6 million IU/day. For patients with renal impairment in whom
higher doses (e.g. up to 9 million IU/day) would be considered if
their renal function was normal, corresponding proportional
adjustments should be considered when calculating the dose.
Caution is advised when administering Promixin to any patient
with renal impairment due to the limited information available on
safety and appropriate dose regimens (see section 4.4).

Normal
Creatinine
76 to 100
Clearance
(% of normal)

Mild

Moderate

Severe

40 to 75

25 to 40

Less
than 25

Dose
Unit dose
(Million IU)

1.3 to 2

1 to 1.5

1

1 to 1.5

Frequency
(Times per
day)

3

2

1 or 2

Every
36 hours

Total
Daily Dose
(Million IU)

4 to 6

2 to 3

1 to 2

0.6 to 1

Hepatic impairment
It is not known whether the dose of Promixin requires adjustment in
patients with hepatic impairment and therefore caution is advised.

Colistimethate sodium is known to reduce the amount of
acetylcholine released from the pre-synaptic neuromuscular
junction and therefore should not be used in patients with
myasthenia gravis, unless in life-threatening situations.
Clostridium difficile associated diarrhoea (CDAD) has been reported
with use of nearly all antibacterial agents, and may range in severity
from mild diarrhoea to fatal colitis. Treatment with antibacterial
agents alters the normal flora of the colon leading to overgrowth
of C. difficile. Therefore, it is important to consider this diagnosis
in patients who present with diarrhoea during or subsequent to
the administration of colistimethate sodium. Discontinuation of
therapy with colistimethate sodium and the administration of
specific treatment for Clostridium difficile should be considered.
Medicinal products that inhibit peristalsis should not be given.
Use with extreme caution in patients with porphyria.

4.5 Interaction with other medicinal products and other
forms of interaction
Due to the effects of colistimethate sodium on the release of
acetylcholine, non-depolarising muscle relaxants should be used
with extreme caution in patients receiving Promixin as their effects
could be prolonged.
Concomitant use of colistimethate sodium with other medications
that are nephrotoxic or neurotoxic (eg. cephalothin sodium,
aminoglycosides, non-depolarising muscle relaxants) should only
be undertaken with the greatest caution.

Hypersensitivity to the active substance colistimethate sodium or
other polymyxins.

The potential of colistimethate sodium to affect the
pharmacokinetics of other medicinal products has not been
evaluated. Caution is recommended if colistimethate sodium is
combined with medicinal products with a narrow therapeutic index.

4.4 Special warnings and precautions for use

4.6 Fertility, pregnancy and lactation

Use with caution in patients with renal impairment as colistimethate
sodium is renally excreted.

Fertility
There are no data on the effects of colistimethate sodium on human
fertility. Effects on male and female fertility have not been evaluated
in animal studies.

4.3 Contraindications

Nephrotoxicity or neurotoxicity may occur especially if the
recommended dose is exceeded (see also Section 4.5). There are
limited safety data when colistimethate sodium is used in doses
exceeding 6 million IU/day.
Monitoring of renal function should be performed before initiating
treatment with Promixin. Monitoring of serum creatinine must
continue at regular intervals (at least daily) during therapy. Particular
caution should be exercised when administering doses greater
than 6 million IU/day. The dose of Promixin may have to be reduced
if serum creatinine concentrations rise or exceed the upper limit of
normal.
There is evidence that it is the total cumulative dose (not the daily
dose) of colistimethate sodium that may be associated with risk of
nephrotoxicity.
Do not use concomitantly with other medications with nephrotoxic
or neurotoxic effects except with the greatest caution.

Pregnancy
Safety in human pregnancy has not been established. Animal
studies are insufficient with respect to effects on reproduction.
There is evidence that colistimethate sodium crosses the placenta
and consequently there is potential for foetal toxicity if administered
during pregnancy. Hence, Promixin should only be given during
pregnancy if the benefits outweigh any potential risk.
Lactation
Colistimethate sodium is excreted in breast milk; breast feeding is
not recommended during therapy.

4.7 Effects on ability to drive and use machines
Neurotoxicity, characterised by dizziness, confusion or visual
disturbances have been reported following parenteral administration
of colistimethate sodium. If these effects occur patients should be
warned against driving or operating machinery.

4.8 Undesirable effects
The most commonly reported adverse reaction is renal function
impairment, and more rarely renal failure, usually following use of
higher than recommended doses in patients with normal renal
function, or failure to reduce the dosage in patients with renal
impairment or when used concomitantly with other nephrotoxic
antibiotics. The effect is usually reversible on discontinuation of
therapy, but rarely intervention (renal replacement therapy) may be
required.
High serum concentrations of colistimethate sodium, which may
be associated with overdosage or failure to reduce the dosage
in patients with renal impairment, have been reported to lead to
neurotoxic effects such as facial paraesthesia, muscle weakness,
vertigo, slurred speech, vasomotor instability, visual disturbances,
confusion, psychosis and apnoea. Concomitant use with either
non-depolarising muscle relaxants or antibiotics with similar
neurotoxic effects can also lead to neurotoxicity. Dose reduction of
colistimethate sodium may relieve symptoms.
Hypersensitivity reactions such as skin rash and angioedema have
been known to occur. In the event such reactions occur, treatment
with colistimethate sodium should be withdrawn.
Adverse reactions are tabulated below by system organ class
and frequency. Frequencies are defined as very common (≥1/10):
common (≥1/100 to <1/10): uncommon (≥1/1,000 to <1/100):
rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000), not known
(cannot be estimated from the available data).
Body System

Frequency

Reported adverse reaction

Immune system
disorders

Not known

Hypersensitivity reactions
such as skin rash and
angioedema

Nervous system
disorders

Very Common

Neurotoxicity such as,
facial, mouth and peri-oral
paraesthesia, headache, and
muscle weakness

Not known

Dizziness
Ataxia

Skin and
subcutaneous
tissue disorders

Very Common

Pruritus

Renal and urinary
disorders

Very Common

Renal impairment
demonstrated by increased
blood creatinine and / or urea
and / or decreased creatinine
renal clearance

Rare

Renal failure

General disorders Not known
and administration
site conditions

Injection site reaction

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1061604 Issue 4

4.8 Undesirable effects (continued..)

Mechanisms of resistance

Reporting of suspected adverse reactions

Acquired resistance to colistimethate sodium in Pseudomonas
aeruginosa appears to be related to alterations in the bacterial
outer membrane. In-vitro studies with Salmonella and E. coli have
shown that resistance may occur due to modification of the cell
wall lipopolysaccharide phosphate groups. Modification is achieved
by substitution of the phosphate groups with ethanolamine or
aminoarabinose. Proteus mirabilis, Burkholderia cepacia and
other naturally resistant Gram-negative bacteria, show complete
substitution of their lipopolysaccharide groups.

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;
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard

Overdosage may cause renal insufficiency, renal failure, apnoea,
muscle weakness, vertigo, slurred speech, vasomotor instability,
visual disturbances, confusion and psychosis.

Polymyxins including colistimethate sodium differ in their mechanism
of action compared with other antibiotics and there is evidence to
show that Gram-negative bacteria resistant to other antibiotics may
be susceptible to colistimethate sodium. There is no co-resistance
between polymyxins and other groups of antibiotics.

No antidote is available.

Susceptibility

Management of overdose is by means of supportive treatment
and measures designed to increase clearance of colistimethate
sodium such as inducing an osmotic diuresis with mannitol,
peritoneal dialysis or prolonged haemodialysis.

The prevalence of acquired resistance may vary geographically and
with time for selected species and local information on resistance is
desirable, particularly when treating severe infections. Expert advice
should be sought when the local prevalence of resistance is such
that the utility of the agent, in at least some types of infections, is
questionable.

4.9 Overdose

5. Pharmacological properties

Commonly susceptible species

the volume of distribution in critically ill patients, may lead to a delay
in reaching effective plasma concentrations. Therefore the use of
an initial loading dose of up to 9 million IU has been suggested,
especially in critically ill patients.

6. Pharmaceutical particulars

7. Marketing authorisation holder

6.1 List of excipients

In critically ill patients given colistimethate sodium 2 million IU and
3 million IU three times a day intravenously, peak colistin plasma
concentrations of 2.21 and 2.93 mg/L, respectively, were observed.

None

Profile Pharma Limited
Bicentennial Building
Southern Gate
Chichester
West Sussex
PO19 8EZ
United Kingdom

Biotransformation
Colistimethate sodium undergoes conversion to polymyxin E1
and polymyxin E2 (colistin) in vivo. It has been estimated that
approximately 30% of the colistimethate sodium is converted to
colistin.
Elimination
Colistimethate sodium is primarily excreted unchanged in the urine
where the hydrolysis to the active moiety continues. Following
intravenous administration 62% of a dose is recovered in the urine
within 8 hours.
Colistin is excreted by the non-renal route.
The half-life of colistin following administration of colistimethate
sodium in healthy volunteers and in patients with cystic fibrosis
has been reported to be 3 hours and 4.2 hours respectively. The
half-life of colistin following administration of colistimethate sodium
has been reported to increase when administered to critically
ill patients compared to healthy volunteers and mean half life is
estimated to range from approximately 5.9 hours to 7.4 hours
following intravenous administration to critically ill patients.

5.1 Pharmacodynamic properties

Acinetobacter species

Pharmacotherapeutic group: other antibacterials, Polymyxins

Klebsiella species

ATC code: J01XB01

Pseudomonas aeruginosa

General properties

Species for which acquired resistance may be a problem

Mode of action

Stenotrophomonas maltophilia

In patients with renal impairment, colistimethate sodium excretion
is reduced and a higher proportion may be converted to colistin,
leading to increased plasma colistin concentrations.

The polymyxin antibiotics are surface active agents and act by
binding to and changing the permeability of bacterial cell membrane
causing bacterial cell death. Polymyxins are bactericidal against
Gram-negative bacteria with a hydrophobic outer membrane.

Achromobacter xylosoxidans

5.3 Preclinical safety data

Inherently resistant organisms

Animal studies are insufficient with respect to effects on
reproduction.

Proteus spp

PK/PD relationship
Polymyxins have been reported to have a concentration-dependent
bactericidal effect on susceptible bacteria.

Providencia spp
Serratia spp

5.2 Pharmacokinetic properties

EUCAST Breakpoints
Susceptible (S)

Resistant (R) a

Acinetobacter S≤2

R>2 mg/L

Enterobacteriaceae S≤2

R>2 mg/L

Pseudomonas Spp S≤4

R>4 mg/L

Breakpoints apply to dosage of 2-3 million IU x 3. A loading dose (9 million IU)
may be needed.
a

Burkholderia cepacia and related species

Absorption
Absorption of colistimethate sodium from the gastrointestinal tract
does not occur to any appreciable extent in the normal individual.
Distribution
The volume of distribution of colistin following administration of
colistimethate sodium in healthy volunteers and in patients with
cystic fibrosis has been reported to be 12.4L and 20.4L respectively.
In comparison the volume of distribution for colistin following
administration of colistimethate sodium has been shown to be
between 90.6 L and 139.9 L in critically ill patients. The increase in

Data on potential genotoxicity are limited and carcinogenicity
data for colistimethate sodium are lacking. Colistimethate sodium
has been shown to induce chromosomal aberrations in human
lymphocytes, in vitro. This effect may be related to a reduction in
mitotic index, which was also observed.

6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal
products except those mentioned in section 6.6.

6.3 Shelf life
Unopened:
Two years
After reconstitution:
Chemical and physical in-use stability has been demonstrated for
up to 8 hours at room temperature.
From a microbiological point of view solutions should be used
immediately. If not used immediately in-use storage times and
conditions prior to use are the responsibility of the user and
would normally not be longer than 24 hours at 2 to 8ºC, unless
reconstitution/dilution has taken place in controlled and validated
aseptic conditions.

6.4 Special precautions for storage
Do not store above 25ºC

8. Marketing authorisation number(s)
PL 19419/0002

9. Date of first authorisation/renewal of the

authorisation
Date of first authorisation: 24th June 2003
Date of latest renewal: 13th March 2009

10. Date of revision of the text
10 July 2014

For storage conditions of the reconstituted/diluted product see
section 6.3.

6.5 Nature and contents of container
The product is supplied in clear type I glass vials sealed with a
siliconised chlorobutyl type I rubber stopper and protected by a
20 mm aluminium tear-off cap incorporating a red flip-up central
plastic top. The product is supplied in pack sizes of 10 vials.

11. Legal category
POM

6.6 Special precautions for disposal and other handling
For single use only.
Promixin must be reconstituted, under aseptic conditions, with
sodium chloride solution 9 mg/mL (0.9%) to produce a clear
colourless to pale yellow solution. Following reconstitution, the
solution should be diluted to a suitable volume for infusion over
30 minutes with sodium chloride solution 9 mg/mL (0.9%) for
infusion. The solution should be inspected visually for particulate
matter and discoloration prior to administration. The solution should
only be used if the solution is clear and free from particles.
Solutions should be used immediately after reconstitution (see
section 4.2).
Discard any unused solution. Waste material should be disposed
of in accordance with local requirements.
1061604 Issue 4

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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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