East & South East England Specialist Pharmacy Services
East of England, London, South Central & South East Coast
East Anglia Medicines Information Service
Medicine Review
Medicine / Trade name
Manufacturer
Indication
Document status
Traffic light decision
Prescribers rating
Mechanism of action
Dosage
Treatment alternatives
Place in therapy
Imiquimod 3.75% cream (Zyclara®) for actinic keratitis
Meda
Zyclara® is indicated for the topical treatment of clinically typical,
nonhyperkeratotic, nonhypertrophic, visible or palpable actinic
keratosis (AK) of the full face or balding scalp in immunocompetent
adults when other topical treatment options are contraindicated or less
appropriate. (1)
Reviewed at Suffolk CCGs D&T Committee meeting 18 November
2014 and CPG 8 December 2014
Double red – no prescribing
TBC
Imiquimod is an immune response modifier. It is the lead compound of
the imidazoline family. In animal models imiquimod is effective against
viral infections and acts as an antitumour agent principally by inducing
release of alpha interferon and other cytokines. Increases in systemic
levels of alpha interferon and other cytokines following topical
application of imiquimod were also observed in human data. (1)
Apply to lesion on face or balding scalp at bedtime for 2 weeks
(maximum 2 sachets daily); repeat course after a 2-week treatmentfree interval; assess response 8 weeks after second course.
Zyclara should be rubbed in and allowed to stay on the treated area for
8 hours, then washed off with mild soap and water. (1)
 Cryotherapy
 Photodynamic therapy
 Efudix ® cream (5-FU)
 Actikerall ® solution (5-FU and salicylic acid)
 Aldara ® cream (5% imiquimod)
 Picato ® gel (ingenol mebutate, as 150 µg/g or 500 µg/g)
 Solaraze ® gel (3% diclofenac in sodium hyaluronate)
The Primary Care Dermatology Society with the British Association of
Dermatologists (BAD) has produced a flow chart for the management
of AK. (2) This is available via the following link
http://www.pcds.org.uk/p/other-guidelines
The relevant steps in therapy are summarised below:
Step 3: Lesion specific treatment i.e. a few lesions or larger
numbers that are widely distributed (i.e. dotted around the face,
scalp and hands etc.)
Treat the individual lesions and not the normal surrounding skin.
Cryotherapy - a single freeze-thaw cycle of approximately ten
seconds (avoid the gaiter area of the legs due to risk of leg ulceration).
Efudix ® cream (5-FU) - apply every night for four weeks. Wash hands
thoroughly after application. Leave treated areas uncovered and wash
the following morning. Patients should be advised to expect a relatively
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
mild degree of redness and discomfort during the treatment period.
Actikerall ® solution is a new treatment combining 5-FU with salicylic
acid. It is licensed for treating moderately thick hyperkeratotic AK. It
should be used once a day for 6-12 weeks.
Step 4: field change
Field change refers to areas of skin that have multiple AK associated
with a background of erythema, telangiectasia and other changes seen
in sun-damaged skin. These areas are probably more at risk of
developing SCC, especially if left untreated and, as such, it is
recommended that they should be treated more vigorously. As such,
the treatments should be applied to the whole area of field change and
not just the individual lesions.
As when treating other patients with actinic keratoses the primary aim
of treatment is to reduce the total number of lesions that the patient
has at any one time, the fewer lesions a patient has the less risk they
have for developing an SCC. Treatment courses will need to be
repeated from time to time. Note that all field based treatments will
elicit local skin responses, which are expected as part of the treatment.
The length of time a patient has to endure local skin responses varies
widely between the treatments referred to below, and this needs to be
discussed with the patient to aid them with the decision making.
For smaller areas of field change (e.g. an area the size of a palm or
most of the forehead) consider the following treatments, which are
listed alphabetically:
Aldara ® cream (5% imiquimod) Use three nights a week e.g.
Monday, Wednesday and Friday for four weeks. Apply overnight and
wash off the following morning. After four weeks stop the treatment and
consider the use of a mild topical steroid e.g. 1% Hydrocortisone or
Eumovate ® cream BD for two to four weeks to help settle down any
inflammation. Follow up three months after the treatment was started,
repeat the treatment if needed.
Advantages - generally very effective in terms of clearance, and
cosmetic appearance once inflammation resolved.
Disadvantages - patients should be warned to expect marked
erythema with crusting of the skin. Timing of the treatment is important
and is best avoided during holidays and important social occasions.
Some patients develop flu-like symptoms during treatment.
Efudix ® cream (5-FU) Used once a day for four weeks. Apply thinly in
an evening with a gloved finger; alternatively wash the finger after
application. The treated area should be washed the following morning.
After four weeks stop the treatment and consider the use of a mild
topical steroid e.g. 1% Hydrocortisone or Eumovate ® cream BD for
two to four weeks to help settle down any inflammation. Follow up
three months after the treatment was started.
Advantages and disadvantages similar to with Aldara ®, although
patients do not develop flu-like symptoms.
Picato ® gel (ingenol mebutate, as 150 µg/g or 500 µg/g)
Advantages - similar outcomes to the above, but in addition a very
short treatment period and recovery phase when compared to the
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
other topical treatments
For the face and scalp - apply the 150 µg/g formula for 3 consecutive
days only.
For the trunk and extremities - apply the 500 µg/g formula for 2
consecutive days only.
Photodynamic therapy
This is provided by some dermatology departments and occasionally
GPwSI clinics. A single treatment often provides an effective treatment
for an area of field change. The skin settles down within a few days of
treatment. Cosmetic outcomes are good.
For larger areas of field change consider the following treatments
(listed alphabetically):
Solaraze ® gel (3% diclofenac in sodium hyaluronate) Use twice a day
for 12 weeks. Review patient four weeks after treatment has finished to
assess the response.
Advantages - generally well-tolerated and so can be used on any sized
area.
Disadvantages - most dermatologists view Solaraze as a milder
treatment, which may not be as effective as some of the other
treatments and so is best used where the AK are thin. Once treatment
is complete any remaining AK can then be managed with the
treatments referred to in step three above.
Future alternatives
Evidence for use
Cautions
Drug Interactions
Side effects
Zyclara ® cream (3.75% imiquimod cream)
Apply once daily for two 2-week treatment cycles separated by a 2week treatment-free period. Adverse effects less than when using
Aldara ® cream (5% imiquimod).
None known
The efficacy of Zyclara was studied in two double-blind, randomized,
vehicle-controlled clinical studies. Patients had 5-20 typical visible or
palpable AK lesions in an area that exceeded 25 cm 2 on either the
face or balding scalp. 319 subjects with AK were treated with up to 2
sachets once daily of imiquimod 3.75% cream or a matching vehicle
cream for two 2-week treatment cycles separated by a 2-week notreatment cycle. For the combined trials the complete clearance rate of
the full face or balding scalp under imiquimod 3.75% cream was 35.6%
(57/160 patients, CI 28.2%, 43.6 %) under vehicle 6.3% (10/159
patients, CI 3.1%, 11.3%) at the 8-week post-treatment visit. No overall
differences in safety or effectiveness were observed between patients
65 years or older and the younger patients. Squamous cell carcinoma
(SCC) was reported in 1.3% (2/160) of patients treated with imiquimod,
in 0.6% (1/159) treated with vehicle. This difference was not
statistically significant.
In a follow-up study where initially cleared patients with imiquimod
were followed for at least 14 months without any further AK-treatment,
40.5% of the patients showed sustained complete clearance of the
whole treatment area (either full face or scalp) There are no data on
long-term clearance beyond that. (1)
See SPC available via www.medicines.org.uk
No new safety concerns were identified in the clinical trials.
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
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NNT/NNH
Costs
Costs of alternatives
BNF 67
Potential number of
patients per 100,000
population
Points for consideration
Excipients include benzyl alcohol, cetyl alcohol, hydroxybenzoates
(parabens), polysorbate 60, stearyl alcohol.
Not calculated.
28-sachet pack = £113.00
Drug
Solaraze ® gel
Aldara ® cream
Efudix ® cream
Picato ® gel
Cost
50g £38.30, 100g £76.60
12 sachet pack £48.60
40g £32.90
3 x 0.47g single use tubes £65 (150 mcg strength)
2 x 0.47g single use tubes £65 (500 mcg strength)
NICE estimates that over 23% of the UK population aged 60 and
above have AK. Although the risk of an AK transforming into a
squamous cell carcinoma (SCC) is very low, this risk increases over
time and with larger numbers of lesions. The presence of AK is
associated with a 14% risk of developing an SCC within five years.
http://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn.-solarkeratosis
-Zyclara ® cream (3.75% imiquimod cream) is
recommended at stage 4 AK, when there is a large area of field
change.
-Fewer adverse effects are seen than when using Aldara ® cream (5%
imiquimod).
-Zyclara® is not on the IESCCG/IHT joint dermatology formulary.
The options for photodamage on this formulary are as follows:
Diclofenac 3% gel for diffuse chronic sun damage/mild scaling
Actikerall® solution (fluorouracil + salicylic acid) For hyperkeratotic
actinic keratosis.
Fluorouracil 5% cream (Efudix®) for Bowen’s disease or on the advice
of secondary care.
Salicylic acid 2% ointment Only on advice from secondary
Imiquimod 5% cream (Aldara®) secondary care use only.
Decisions sought from
other bodies
Decision review date
WSCCG does not have a joint dermatology formulary with the WSH.
NICE not considered
SMC – rejected
Cambridgeshire and Peterborough CCG – TBC
Norfolk TAG – TBC
NICE – TBC
AWMSG - TBC
2 years following decision or unless superseded by NICE guidance or
substantial and significant new evidence becomes available.
References
1. Zyclara® Summary of Product Characteristics available via www.medicines.org.uk
2. http://www.pcds.org.uk/clinical-guidance/actinic-keratosis-syn.-solar-keratosis
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
Comments
Khalid Mahmood (IHT)
I agree that Zyclara does have a role for field treatment of chronic actinic damage/actinic keratoses
especially where the area treated is more than 25cm2. For larger areas this shall be cost effective
compared with Aldara because of the larger area covered by Zyclara sachet.
It shall be worth considering addition of Picato for field treatment of smaller areas up to 25cm2
especially because of the advantage of short 2-3 day course with better compliance and early
recovery time which matters a lot for the lesions on face.
I feel GPs who are familiar with the products and are confident in prescribing should be allowed to
prescribe provided they choose the right type of lesions.
best regards
Dr Mahmood
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications
For many years scientists have recognised two types of research:
 Primary: original studies, based on observation or experimentation on subjects.
 Secondary: reviews of published research, drawing together the findings of two or more primary studies.
In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and
closer to objective truth it is assumed to be. The orthodox hierarchy looks something like thisRank: Methodology
Description
1
Systematic review: review of a body of data that uses explicit methods to locate
primary studies, and explicit criteria to assess their quality.
Meta-analysis: A statistical analysis that combines or integrates the results of
several independent clinical trials considered by the analyst to be "combinable"
usually to the level of re-analysing the original data, also sometimes called:
pooling, quantitative synthesis.
Both are sometimes called "overviews."
2
Systematic reviews and meta-analyses
Randomised controlled trials
Individuals are randomly allocated to a control group and a group who receive
(finer distinctions may be drawn within
a specific intervention. Otherwise the two groups are identical for any
this group based on statistical parameters significant variables. They are followed up for specific end points.
like the confidence intervals)
3
Cohort studies
Groups of people are selected on the basis of their exposure to a particular
agent and followed up for specific outcomes.
4
Case-control studies
"Cases" with the condition are matched with "controls" without, and a
retrospective analysis used to look for differences between the two groups.
5
Cross sectional surveys
Survey or interview of a sample of the population of interest at one point in time
6
Case reports.
A report based on a single patient or subject; sometimes collected together into
a short series
7
Expert opinion
A consensus of experience from the good and the great.
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
8
Anecdotal
Something a bloke told you after a meeting or in the bar.
Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008
To Decide if a Medication Is To Be Used In Suffolk
Criterion to be measured
Quality of evidence in the papers reviewed
Magnitude of effect inferred from trials reviewed
Are trial end-points surrogate markers or clinical outcomes?
Clinical usefulness of trial end-points
Known Side Effect Profile
Known Interactions
Concern re Possible Side Effects Not Yet Uncovered
Balance of Benefit To Harm (side effects toxicity interactions etc)
NNT
Comparison Of Effectiveness With Other Medicines In Use For
The Same Condition
Severity of Condition to be Treated
Novel drug or member of existing class
Uptake (estimated proportion of people with this condition likely
to be prescribed the medication under consideration – maximum
and minimum uptake)
Is the drug to be used in Suffolk?
Tends to poor
5
Low
Low
4
Medium
3
Medium
Medium
2
Tends to good
1
High
High
Low
High
High
High
Poor
High
Poor
Medium
Medium
Medium
Medium
Medium
Medium
Medium
High
Low
Low
Low
Good
Low
Good
Severe
Medium
Trivial
Prescriber’s Rating Definitions
1. Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available.
2. A real advance - The product is an important therapeutic innovation but has certain limitations.
3. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice.
4. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare
circumstances.
5. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug
are available.
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes
6. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities
offered by previous products available. In most cases these are “me-too” products.
7. Not acceptable - Product without evident benefit over others but with potential or real disadvantages.
(With acknowledgement to Prescrire)
To Decide Where A Medication Is To Be Used In Suffolk
Criterion
Skills of the
prescriber
Therapy
Experience Of The Condition
Red
4
Specific
Amber
3
Specific
Green
2
Specific
Blue
1
General
Diagnosis
Monitoring Progress Of Treatment
Specific
Difficult
Specific
Specific
Specific
General
General
General
Patient Selection
Initiation Of Treatment
Dose Titration
Monitoring Of Side Effects
Method Of Administration
Discontinuation Of Treatment
Difficult
Difficult
Difficult
Complex
Complex
Complex
Specific
Difficult
Specific
Easy
Normal
Complex
Specific
Easy
Easy
Easy
Normal
Easy
Easy
Easy
Easy
Easy
Normal
Easy
References
Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174
Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Tru
Review prepared by Sarah Cavanagh, East Anglia Medicines Information Service
May be freely copied by NHS agencies
Not to be used for promotional purposes