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

Active substance: COLISTIMETHATE SODIUM

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In this leaflet
1. What Promixin is and what
it is used for

PACKAGE LEAFLET:
INFORMATION FOR THE USER

Promixin

®

1 million International Units (IU)

2. Before you are given
Promixin
3. How you will be given
Promixin

Powder for Solution for Infusion
colistimethate sodium

Read all of this leaflet
carefully before you are
given this medicine
• Keep this leaflet. You may need
to read it again.
• If you have further questions,
please ask your doctor, nurse
or pharmacist.
• 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.

4. Possible side effects
5. How to store Promixin
6. Further information

1. WHAT PROMIXIN IS
AND WHAT IT IS
USED FOR
Promixin contains colistimethate
sodium. It is an antibiotic that
fights serious bacterial
infections, especially chest
infections and infections of the
urinary tract.
Promixin is used when other
more common antibiotics no
longer work or cannot be used.

2. BEFORE YOU ARE
GIVEN PROMIXIN
In certain circumstances your
doctor may decide not to
prescribe Promixin.

Do not have Promixin and
tell your doctor if:
• 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:
• you have or have had kidney
problems;
• you suffer from myasthenia
gravis (a rare disease where
your muscles are extremely
weak and get tired very quickly);
• you suffer from porphyria
(a rare metabolic disease that
some people are born with).
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 nonprescription medicines. These
medicines may interfere with
the effects of Promixin.
• 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.
• 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 breastfeeding
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.
It is not recommended that you
breast-feed while you are taking
this medicine as Promixin can
pass into breast milk.

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.

3. HOW YOU WILL BE
GIVEN PROMIXIN
Your treatment with Promixin
has been prescribed by and will
be given to you under the
supervision of a doctor or nurse.
The dose of Promixin is
dependent on how ill you are,
how well your kidneys are
working and your weight.
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.
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.

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PL393 Issue 4

3. HOW YOU WILL BE
GIVEN PROMIXIN
continued...
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.
• You will be given Promixin by a
slow injection (infusion) into
a vein over 30 minutes.
• 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.
• Before Promixin can be given
it must be dissolved in sterile
saline (salt water).
• The correct dose of Promixin
will then be further diluted in a
suitable volume (usually 50 mL).
• 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:
• dizziness and spinning
sensation (vertigo)
• slurred speech
• visual disturbance
• confusion
• mental disturbance

Stopping Promixin
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.

• muscle weakness
• feeling as though you cannot
breathe

If you were not given
Promixin when expected
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.
If it is more than 3 hours after
the missed dose the doctor or
nurse will wait for your next
dose.

• blood tests may show changes
in the way the kidneys are
working
• headache
• tingling or numbness around
the mouth, lips and face
• itching

4. POSSIBLE SIDE
EFFECTS

• flushing (reddening of the face)
• kidney problems

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

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

• muscle weakness

Rare side effects (affecting
less than 1 person in 1 000)
• kidney failure

Other side effects can
include:
• dizziness
• difficulty in controlling
movements
• soreness at the site of injection
If any of the side effects gets
serious, or if you notice any side
effects not listed in this leaflet,
please tell your doctor, nurse or
pharmacist.

5. HOW TO STORE
PROMIXIN
Keep Promixin out of the reach
and sight of children.
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.
Promixin does not require any
special storage conditions.
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.

6. FURTHER
INFORMATION
What Promixin contains
The active substance is
colistimethate sodium.
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
Chichester Business Park
City Fields Way
Tangmere
Chichester
West Sussex
PO20 2FT
UK
Tel:
Fax:
Email:

+44 (0) 800 1300 855
+44 (0) 800 1300 856
info@profilepharma.com

Manufacturer
Xellia Pharmaceuticals ApS
Dalslandsgade 11
DK-2300
Copenhagen S
Denmark
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
August 2011

PL393 Issue 4

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

1. NAME OF THE
MEDICINAL PRODUCT
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.

3. PHARMACEUTICAL
FORM
Powder for solution for infusion
The powder is white to off white

4. CLINICAL
PARTICULARS
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.

4.2 Posology and method
of administration
It is recommended that Promixin
should be administered under the
supervision of physicians with
appropriate experience in its use.
Method of Administration
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.

Table 1: Suggested modification of dosage of Promixin for adults with impaired renal function
Degree of Renal Impairment
Normal
Creatinine Clearance
(% of normal)

Mild

Moderate

Severe

76 to 100

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

Posology
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:

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).

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.

Paediatric population

Over 60 Kg: 1-2 million IU every
8 hours. The maximum standard
dose is 6 million IU (480 mg) in
24 hours.

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

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

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

4.3 Contraindications
Hypersensitivity to the active
substance colistimethate sodium
or other polymyxins.

4.4 Special warnings and
precautions for use
Use with caution in patients with
renal impairment as colistimethate
sodium is renally excreted.

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.
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.
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.

4.6 Fertility, pregnancy and
lactation
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.
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).

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1061604 Issue 3

Body System
Immune system disorders
Nervous system disorders

Reported
adverse reaction

Frequency
Not known
Very Common

Hypersensitivity reactions such as
skin rash and angioedema
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
General disorders and
administration site conditions

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

Renal failure

Not known

Injection site reaction

5. PHARMACOLOGICAL
PROPERTIES
5.1 Pharmacodynamic
properties
Pharmacotherapeutic group:
other antibacterials, Polymyxins

No antidote is available.

ATC code: J01XB01

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.

General properties
Mode of action
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.

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

EUCAST Breakpoints
Acinetobacter
Enterobacteriaceae
Pseudomonas Spp

Susceptible (S) Resistant (R)a
S≤2 R>2 mg/L
S≤2 R>2 mg/L
S≤4 R>4 mg/L

a

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

Mechanisms of resistance
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.
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.
Susceptibility
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.

Commonly susceptible species
Acinetobacter species
Klebsiella species
Pseudomonas aeruginosa
Species for which acquired
resistance may be a problem
Stenotrophomonas maltophilia
Achromobacter xylosoxidans
Inherently resistant organisms
Burkholderia cepacia and related
species
Proteus spp
Providencia spp
Serratia spp

5.2 Pharmacokinetic properties
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 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.
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.
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.
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.

5.3 Preclinical safety data
Animal studies are insufficient with
respect to effects on reproduction.
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. PHARMACEUTICAL
PARTICULARS
6.1 List of excipients
None

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
No special precautions for storage.
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.

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.

7. MARKETING
AUTHORISATION
HOLDER
Profile Pharma Limited
Chichester Business Park
City Fields Way
Tangmere
Chichester
West Sussex
PO20 2FT
United Kingdom

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
30th August 2011

11. LEGAL CATEGORY
POM

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 3

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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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