Download Drug-induced oedema, Trimovate® alternatives and

Ask the Pharmacist
Drug-induced oedema,
Trimovate® alternatives
and tacrilomus
Rod Tucker, a pharmacist with a special
interest in dermatology, answers more
questions submitted by DN readers. If
you have a burning question that
you’d like to see answered in a
future issue, please email it to
[email protected] entitling
your email: Ask the Pharmacist.
Q.
Which drugs can contribute to leg oedema and why?
A.
Water accounts for nearly 60% of total
body weight and is contained either
within cells (intracellular) or between
cells (extracellular).The extracellular
compartment consists of the intravascular
plasma volume and interstitial fluid, ie the
fluid that surrounds cells in a tissue.The
interstitial fluid is a source of nutrients
and oxygen for cells as well as a means of
removal of metabolic waste products and
carbon dioxide and this exchange occurs
via the capillary network. Nutrients and
oxygen are replenished from the arterial
blood supply and waste products removed
into the venous system.To prevent a buildup of interstitial fluid any excess is drained
away through the lymphatic system.
The volume of interstitial fluid
is maintained by the balance of two
opposing forces, which dictate whether
fluid moves into the interstitium or back
into the plasma: the hydrostatic (or fluid
pressure) generated from blood entering
the capillary network and the osmotic (or
oncotic) pressure of the plasma generated
by the presence of proteins.The direction
of flow depends on the difference
between these two pressures so that:
direction of flow = hydrostatic pressure
– oncotic pressure.
If this difference is positive, fluid moves
into the interstitium; if negative, fluid
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moves from the interstitium back into the
capillaries.
At the arterial or pre-capillary end,
the hydrostatic pressure is greater than
the oncotic pressure of the plasma and
therefore fluid moves into the interstitium.
Conversely, at the venous or post-capillary
end, the hydrostatic pressure is less than
the oncotic pressure and thus fluid moves
back into the capillaries.
The term ‘oedema’ refers to an
accumulation of fluid in the interstitium
and can occur through one of four
mechanisms:
1 Reduced outflow due to blockage of
the lymphatic system
2 Increased capillary hydrostatic pressure
3 Reduced plasma oncotic pressure
4 Increased capillary wall permeability.
Several conditions can lead to oedema.
Lymphoedema affects drainage (1),
venous congestion caused by congestive
heart failure and hypertension increases
hydrostatic pressure (2), nephrotic
syndrome and cirrhosis decrease the
protein content of the plasma (3), and
finally allergic reactions or infections
increase capillary wall permeability (4).
The increased fluid in the interstitium
reduces the volume of fluid circulating
within the intravascular network and this
activates the renin-angiotensin-aldosterone
(RAA) system which promotes sodium
and water retention to maintain plasma
volume, thus exacerbating the problem of
fluid overload.
Which drugs cause peripheral oedema?
Peripheral oedema is characterised by
swelling of the ankles and/or lower leg and
can be caused by a number of medical
conditions (Cho, Atwood, 2002). However,
it can be induced by several commonly
prescribed medicines, including:
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8 Calcium channel blockers (CCBs), eg
amlodipine
8 Non-steroidal anti-inflammatory drugs
(NSAIDs), eg diclofenac
8 Corticosteroids, eg prednisolone, oral
contraceptives.
Other classes of drugs that are
known to cause oedema and the possible
mechanisms involved are listed in Table 1.
How do drugs induce peripheral oedema?
The mechanism through which CCBs
cause peripheral oedema is due to a
reduction in arterial blood pressure that
is not matched in the venous system.
Consequently, there is greater hydrostatic
pressure in the pre-capillary network thus
forcing more fluid into the interstitium.
NSAID drugs cause oedema as a
consequence of their mode of action.
By inhibiting cyclooxygenase enzymes
(COX-1 and COX-2) this leads to an
inhibition of a number of prostaglandins,
some of which serve to maintain kidney
function. Without these prostaglandins,
glomerular filtration is reduced and this
triggers retention of sodium and water
(via the RAA system), which increases
blood pressure and subsequently arteriolar
hydrostatic pressure leading to oedema.
In fact, a second potential problem when
using NSAIDs is the risk of hypertension.
Corticosteroids cause oedema
because of their chemical similarity to
aldosterone, which is part of the RAA
system.These drugs can therefore
stimulate the aldosterone receptor leading
to increased fluid retention and oedema.
What can be done about drug-induced
peripheral oedema?
Health professionals should review a
patient’s medicine if peripheral oedema
develops to rule out a possible drug cause.
If a medicine known to cause the problem
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ask the pharmacist
is being taken, stopping or changing the
treatment will usually resolve the problem
and this is a more appropriate course of
action than use of diuretics.
References
Cho S, Atwood JE (2002) Peripheral edema.
Am J Med 113(7): 580-86
Q.
What are the alternatives for Trimovate® cream?
A.
Pharmacies are currently experiencing
supply problems with Trimovate® cream,
a combination product that contains
clobetasone, oxytetracycline and nystatin.
The indications for Trimovate® cream
include “the treatment and management
of steroid responsive dermatoses where
candidal or bacterial infection is present,
suspected or likely to occur…” … “these
include infected eczemas, intertrigo, napkin
rash, anogenital pruritus and seborrhoeic
dermatitis.” (eMC, 2007.)
In pursuit of an alternative product, it
is worth reviewing the management of
these conditions to determine whether
Trimovate® can be easily replaced.
Infected eczema
Flares of atopic eczema require the use
of topical steroids and the skin can often
become infected with staphylococcus
aureus. However, a systematic review
found that there was no convincing
evidence that addition of antibacterial
treatment led to improvements above
those from using a topical steroid alone
(Birnie et al, 2008). Nevertheless, in clinical
practice topical antibacterial-steroid
combination treatments are widely used
and appear to be effective. If Trimovate®
cream is prescribed to treat localised
infected eczema, suitable alternatives
include Betnovate® C or Fucibet® (PCDS,
2014).
Intertrigo
This is an inflammatory reaction in body
folds and is caused by a combination
of factors such as heat, friction and
maceration of skin. Infection normally
occurs with candida yeasts but coexistent bacterial infection may be
present. In a recent systematic review of
the treatments for intertrigo in adults, it
was difficult to make recommendations
about the relative effectiveness of the
different interventions. With respect
to combination products (ie, steroidantibiotic-antifungal or even antiseptic
agents), the reviewers commented that
“although the study authors (of included
studies) claimed the combinations
worked, no firm conclusions about
any of the combinations can be made
due to weak research designs and the
small sample sizes” (Mistiaen, van HalmWalters, 2010). Nevertheless, the absence
of evidence from clinical studies does
not mean that Trimovate® is ineffective.
In practice the cream does work but the
lack of comparative studies simply means
that we don’t know if it works any better
than the alternatives.
If Trimovate® cream is prescribed for
intertrigo, alternatives will include single
agent antifungals, topical steroids or topical
immunomodulators (Selden, 2012).
Table 1.
Drugs that can cause peripheral oedema and possible mode of action.
Drug class
Mechanism
Antipsychotics, eg
risperidone, olanzapine
Unknown but because these drugs cause vasodilatation, it is
possible that this increases hydrostatic pressure in the pre-capillary
network.
Thiazolidinediones, eg
pioglitazone, rosiglitazone
Unknown but possibly related to increased blood volume and
hence hydrostatic pressure.
Vasodilators (antihypertensive drugs), eg
minoxidil
Vasodilator effect leading to activation of the RAA system leading
to sodium/water retention. In addition, arteriolar dilatation increases
hydrostatic pressure.
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50-52 Ask the Pharm C.indd 51
Napkin rash
Nappy rash is an irritant contact dermatitis
confined to the nappy area often
colonised with candida albicans, though
if not treated further colonisation with
bacteria such as staph aureus can occur.
If Trimovate® cream is prescribed for
napkin rash, use topical imidazoles; if signs
of bacterial infection are present, treat
with oral flucloxacillin (or erythromycin or
clarithromycin if allergic to penicillin) (NICE
CKS, 2013).
Anogenital pruritus
Irritation around the anus or perianal area
is a common complaint that causes a great
deal of discomfort for patients.There are
several potential common causes such as
faecal soiling as well as allergic or irritant
dermatitis, psoriasis and bacterial or fungal
infections.
If Trimovate® cream is prescribed for
anogenital pruritus, use topical steroids
alone, imidazoles if a fungal infection
is suspected, mupirocin or fusidic acid
topically where bacterial infection is
present/suspected and oral antibiotics if it
is a long-term problem (Siddiqi et al, 2008).
Seborrhoeic dermatitis
Seborrheoic dermatitis is an inflammatory
condition affecting the scalp, face and
body in areas with a high number
of sebaceous glands. The Primary
Care Dermatology Society actually
advises against the use of products
such as Daktacort® (miconazole and
hydrocortisone) or Trimovate® because
this might lead to overuse of topical
steroids on the face (PCDS, 2013).
If Trimovate® cream is prescribed
for seborrhoeic dermatitis, use topical
imidazoles, although topical steroids
can be used short-term to help settle
inflammation (NICE CKS, 2013).
Conclusion
Suitable alternatives to Trimovate®
are available to manage the licensed
indications. Whether Trimovate® is more
effective than these alternatives needs
further research. In the meantime, clinical
experience will inform on whether
the potential replacements provide a
satisfactory resolution of symptoms.
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References
Birnie A, Bath-Hextall F, Ravenscroft J,
Williams HC (2008) Interventions to
reduce Staphylococcus aureus in the
management of atopic eczema. Coch Rev 3.
Art. no: CD003871. DOI: 10.1002/14651858.
CD003871.pub2
eMC (2007) Summary of Product
Characteristics Trimovate cream. Available at:
www.medicines.org.uk/emc/medicine/13574/
SPC/Trimovate/#INDICATIONS
Mistiaen P, van Halm-Walters M (2010)
Prevention and treatment of intertrigo in large
skin folds of adults: a systematic review. BMC
Nurs 9:12
NICE CKS (2013) Nappy rash.
Clinical Knowledge Summaries.
Available at: cks.nice.org.uk/nappyrash#!scenariorecommendation:2
NICE CKS (2013) Seborrheoic dermatitis.
Clinical Knowledge Summaries.
Available at: cks.nice.org.uk/seborrhoeicdermatitis#!topicsummary
PCDS (2013) Eczema: atopic eczema. Primary
Care Dermatology Society. Available at:
www.pcds.org.uk/clinical-guidance/atopiceczema#management
PCDS (2013) Seborrhoeic dermatitis. Primary
Care Dermatology Society. Available at:
www.pcds.org.uk/clinical-guidance/
seborrhoeic-eczema#management
Selden ST (2012) Intertrigo. Medscape.
Available at: emedicine.medscape.com/
article/1087691-overview
Siddiqi S, Vijay V, Ward M, Warren S (2008)
Pruritus Ani. Ann R Coll Surg Engl 90(6):
457-463
Q.
Can children prescribed topical tacrolimus receive
live vaccinations?
A.
Tacrolimus was isolated in 1984 from a
Japanese soil bacterium and introduced in
1989 as an oral immunosuppressive agent
to prevent rejection of transplant organs.
The precise mechanism through which
tacrolimus causes immunosuppression is
unclear but thought to be due to inhibition
of T-lymphocyte activation. Patients who
are immunocompromised either because
of specific drug treatment or for medical
reasons have an increased risk of infection
because they are unable to mount a
sufficient response to immunisation.
These patients should therefore avoid live
52
vaccines as this allows the virus to replicate
and in some instances can induce infection.
The manufacturer of oral tacrolimus
(Adoport®) advises against the use of live
attenuated vaccines.
found that treatment did not affect
seropositive responses to vaccination
against tetanus, diphtheria, measles or
rubella (Papp et al, 2005).
In 2000, a topical formulation of
tacrolimus was developed for the
treatment of atopic eczema. Due to the
risks associated with the oral formulation,
concerns have been expressed that the
topical preparation might also lead to
immunosuppression, especially in children,
who receive live vaccines such as the
MMR (measles, mumps and rubella) and
oral polio. Does this mean that children
prescribed topical tacrolimus cannot be
given live vaccinations?
Although the SPC for Protopic® does
not provide any specific guidance on the
administration of live vaccines in relation to
use of the product, the available evidence
would appear to suggest that topical
tacrolimus does not affect the immune
response to live vaccination. While
there are no data available for the use
of tacrolimus in conjunction with either
MMR or polio, it seems reasonable to
assume, given the current evidence, that
topical immunomodulators are unlikely
to impair the body’s ability to produce
sufficient antibodies in response to the use
of live vaccines. Nonetheless, the decision
whether or not to vaccinate remains a
clinical one and should be based on the
immune status of the individual patient.
According to the SPC for Protopic®
the elimination half-life after repeated
application is 65 hours in children (eMC,
2013). Consequently, parents who wish
to stop using the drug before vaccination
should wait at least 3 days to be sure that
the drug has cleared from the body.
Clinical evidence
For tacrolimus to cause immunosuppression, the drug needs to reach
a sufficient concentration in the blood
stream. In a study exploring repeated
application of tacrolimus ointment in
children aged between 6 and 12, plasma
levels of tacrolimus reached only 3% of
those obtained from oral administration
in liver transplant patients (Harper et al,
2005).Therefore, plasma levels remain low
after topical application which suggests that
it would be safe to administer live vaccines
to children. Nevertheless, this study did
not consider the more important question
of whether antibody production was
impaired after the use of live vaccines in
conjunction with topical tacrolimus.Two
specific studies were designed to address
this specific question.
In the first study, 23 children
prescribed topical tacrolimus for 7 weeks
were vaccinated with pneumococcal
polysaccharide vaccine during treatment. It
was observed that all children developed
protected antibody responses (Stiehm
et al, 2005) suggesting that the effect
of the drug is limited to the skin. In the
second study, children aged between 2
and 11 years were prescribed tacrolimus
ointment 0.03% and vaccinated against
meningococcal serogroup C disease
and the authors found that 99.1% of
children developed sufficient antibody
titre (Hofman et al, 2006). Furthermore,
in a two-year study in children
prescribed pimecrolimus (another topical
immunomodulator for eczema) it was
Dermatological Nursing, 2014, Vol 13, No 1
50-52 Ask the Pharm C.indd 52
Bottom line
References
eMC (2013) Protopic® Summary of Product
Characteristics. Available at: www.medicines.
org.uk/emc/medicine/8884/SPC/Protopic+0.03+
+ointment/#PHARMACOKINETIC_PROPS
Harper J, Smith C, Rubins A, et al (2005) A
multicenter study of the pharmacokinetics of
tacrolimus ointment after first and repeated
application to children with atopic dermatitis. J
Invest Dermatol 124(4): 695-699
Hofman T, Cranswick N, Kuna P, et al
(2006) Tacrolimus ointment does not affect
the immediate response to vaccination, the
generation of immune memory, or humoral
and cell-mediated immunity in children. Arch
Dis Child 91(11): 905-910
Papp K (2005) Long-term treatment of atopic
dermatitis with pimecrolimus cream 1% in
infants does not interfere with the development
of protective antibodies after vaccination. J Am
Acad Dermatol 52(2): 247-53
Stiehm E, Roberts R, Kaplan M, et al (2005)
Pneumococcal seroconversion after vaccination
for children with atopic dermatitis treated with
tacrolimus ointment. J Am Acad Dermatol 53(2
suppl 2): S206-13 DN
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