MINUTES OF THE 80th MEETING OF THE
THERAPEUTIC ADVISORY SERVICE
Held on Tuesday 13 December 2005
Present:
Dr I Squire – Chair
Mr M Qualie
Miss A Medcalf
Mrs R Broughton
Mr D Harris
Dr J Thompson
Dr O Uprichard
Dr P Topham
Dr A Elias-Jones
Dr R O’Brian
Dr V Riley
Shailesh Panchmatia
Apologies:
Mrs S Khalid, Dr A Wilson, Mr J Prydal, Dr S Bukhari,
Mr G Hall, Ms C Clarke
1. Minutes of last Meeting
Minutes approved with the exception that Professor A Watson is a Consultant
Nephrologist not a Neurologist
2. Matters Arising
2.1 Levosimendan – No policy has been received as per request from Dr
Nichani. IS informed the Group that he had recently seen two studies,
reported at an American Heart Failure Meeting, which showed negative
outcomes when levosimendan was used in heart failure patients. It was
agreed that IS should write to Dr Nichani highlighting the results of the
two papers and to seek further clarification regarding his intention to
prescribe levosimendan in paediatric patients.
Action: IS to write to Dr Nichani
2.2 Flunarazine – no further information available. DH agreed to chase
other Trusts regarding any policies they have for the prescribing of
flunarazine. If no such policies exist then this request will not be
supported.
Action: DH to investigate whether any policies exist
2.3 Botulinim toxin – MQ informed the Group that he had received further
information from Mr Thomas regarding this products place in treating anal
fissures. He confirmed that it would only be used after other conventional
treatments have failed. Request therefore approved.
ACTION: MQ to inform the Clinical Director
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2.4 Chendeoxycholic acid - MQ informed the Group that he had spoken to
Dr Lawden regarding his request. Dr Lawden confirmed that trials had
only shown chendeoxycholic acid to have any benefit and that the UK
licensed product ursodeoxycholic acid had shown no benefit. This being
the case and following agreement at the previous TAS meeting MQ had
requested approval from Dr Nichol for this product to be available in the
medical directorate. This had been sanctioned.
2.5 Duloxetine – No further correspondence has been received regarding
this product.
3. Requests from EGOC
No requests have been received from EGOC
4. New Product Requests
4.1 Staloral® sublingual solution of allergen extracts for specific
immunotherapy (SIT) in severe allergic hay fever
Requested by: Dr D Luyt (Paediatrics), Dr A Croom (Respiratory Consultant)
Information supplied:
Indicated in patients whose hay fever (usually grass pollen) is not controlled by
standard treatment (antihistamines, intranasal steroids) at maximum dose.
Shown to add symptom control in this situation
References cited:
Allergy 1994; 49: 309-313
Allergy 1998: 53: 493-498
Allergy 1999; 54: 819-828
Background information
A preparation of timothy grass pollen administered subcutaneously has been
used in the past (initially as part of a clinical trial) but this product is no longer
available due to safety concerns (reports of severe hypersensitivity/anaphylactic
reactions).
Literature review
Staloral® is an allergen product manufactured by Stallergenes that is available in
several European countries. It contains standardised five-grass-pollen extract
(orchard grass, meadow grass, ryegrass, sweet vernal grass and timothy grass
pollens) the biologic activity of which is expressed as the index of reactivity (IR).
1
Allergen products are used diagnostically in skin tests and provocation tests to
confirm the cause of a suspected hypersensitivity reaction. They are also used
for allergen immunotherapy in certain patients with hypersensitivity reactions,
particularly to insect venoms, pollens, or house-dust mite. Allergen
immunotherapy (desensitisation or hyposensitisation) is the administration of
gradually increasing quantities of allergen extract in a vaccine to reduce the
effects of subsequent exposure to the allergen. Such therapy generally given by
subcutaneous route has become less popular following reports of severe and
fatal anaphylactic reactions and should only be carried out in specialist centres.
Interest in alternative routes of administration e.g. oral, nasal, sublingual, and
bronchial is growing. Allergen immunotherapy is thought to be more effective in
children than adults. It has been suggested that its use in children with allergic
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rhinoconjunctivitis may also prevent the development of asthma. Allergen
immunotherapy for seasonal allergic rhinitis and conjunctivitis triggered by
pollen has generally been reserved for severely affected patients when antiallergic drugs have failed. 2
A literature search confirmed that the references cited by Dr Luyt represent a
significant proportion of the clinical evidence supporting the use of sublingual
immunotherapy (SLIT) in pollen allergy. All 3 studies used a standardised
allergen preparation supplied by Stallergenes and included some children:
In the earliest of the 3 studies, Sabbah et al randomly assigned 58 patients (age
range 13-51) with a history of hay fever to receive either SLIT or a matched
placebo for 17 weeks. 3 Efficacy was assessed on the basis of clinical
symptoms and on the use of authorised rescue treatments (including sodium
cromoglycate
drops,
terfenadine
and
betamethasone
plus
dexchlorpheniramine). The actively treated patients had significantly (P<0.05 to
P<0.01) fewer symptoms of rhinitis and conjunctivitis during the pollen season
compared with the placebo group. Use of sodium cromoglycate drops and of
betamethasone plus dexchlorpheniramine was significantly less in the
desensitized group (P<0.01) and side effects were reported as negligible.
A similar study included 136 patients (mean age: 27 ± 10 years; range 8-55
years) with grass-pollen rhinitis with or without mild asthma. 4 Patients received
either placebo or SLIT with a standardised grass-pollen extract administered
daily with increasing doses up to 300IR (index of reactivity). During the grasspollen season, patients were instructed to use medications as required and to
visit their doctors in case of asthma. Symptom-medications scores were
assessed, and serum-specific IgG4 was measured before and at the end of
SLIT. In the SLIT group, drug use dropped significantly throughout the pollen
season (P<0.02). At the peak, betamethasone consumption was significantly
reduced in the SLIT group (P<0.02). Only one patient in the SLIT group had an
asthma attack compared to eight patients in the placebo group (P<0.02). IgG4
levels increased significantly in the SLIT group (P<0.001). Side effects were
comparable in both groups.
The aim of the third randomised controlled study was to evaluate the efficacy
and safety of SLIT, initially given as drops, and then as tablets. A total of 126
patients (including 17 children) with grass-pollen seasonal rhinitis were included.
5
During the progression of doses phase, a five-grass extract was given as
sublingual drops from 1-100IR/ml. Once the 100IR dose was reached, the drops
were replaced by a single 100IR sublingual tablet per day. Throughout the
grass-pollen season, patients in the active treatment group had significantly
lower (P<0.05) total conjunctivitis and ocular redness scores. Rhinitis symptoms
were not significantly different between the two groups. Patients given the active
treatment were significantly (P<0.02) less likely to have asthma symptoms. The
global medication score showed no significant difference between the two
groups. A highly significant difference in favour of the active treatment group
was seen in inhaled salbutamol use (P<0.01). The overall safety profile of the
active treatment (drops or tablets) was reported as good.
Comparative data versus subcutaneous immunotherapy is extremely limited
with a single study identified by the literature search. 6 This study compared the
efficacy of the same biologically standardised grass pollen extract administered
by injection or the sublingual route, in 20 patients followed for two pollen
seasons. Both therapies were administered for 12 months according to a
double-blind plan; at the end of the trial the cumulative dosage of the sublingual
therapy was 2.4 times higher than that of the injective therapy. Data about skin
reactivity, symptoms and drugs scores during the pollen season, as well as total
specific IgG and specific IgG4, during and after the trial, were obtained.
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Sublingual and injected therapies were found to be equally effective according
to subjective clinical parameters, with a statistically highly significant reduction of
symptoms and drug use (P=0.002 for symptoms and drugs in SLIT-treated
patients; P=0.002 for symptoms and P=0.0039 for drugs in patients given
injections). On the other hand, objective parameters (total specific IgG, specific
IgG4, skin reactivity) changed only in patients treated with active injective
therapy, with P<0.001, P<0.001 and P=0.021, respectively. The authors
concluded that discrepancies observed could be as a consequence of different
mechanisms of action or due to the lack of close relationships between the
clinical and the objective parameters that were considered.
More recently there have been a couple of studies carried out specifically in
children, one open-label comparison versus standard symptomatic treatments 7
and another double blind placebo controlled trial. 8
The open-label 3-year study (n=113) sought to determine whether sublingual
immunotherapy (SLIT) is effective in reducing symptoms and the development
of asthma in children with hay fever. 7 The actively treated children used less
medication in the second and third years of therapy, and their symptom scores
tended to be lower. From the second year of immunotherapy, subjective
evaluation of overall allergy symptoms was favorable in the actively treated
children. Development of asthma after 3 years was 3.8 times more frequent
(95% confidence limits, 1.5-10.0) in the control subjects. The authors concluded
that SLIT improves seasonal allergic rhinitis symptoms and reduces the
development of seasonal asthma in children with hay fever.
The most recent paediatric study also looked at hay fever and asthma
symptoms. 161 children with seasonal rhinoconjunctivitis (including 68 with
asthma symptoms) were treated with SLIT on a daily basis. 8 After 1 year all
children were given treatment for another 2 years in an open-controlled setting.
Symptom scores and medication were assessed during the pollen seasons with
structured interviews. Daily diary cards documented applied allergen dosage,
compliance, and side effects. Primary endpoint was a clinical index (CI)
combining symptom scores with medication index. Titrated skin prick tests
(SPT) and specific antibody measurements were performed each year.
Allergen-specific IgE- and IgG-subclass antibodies increased significantly in
patients treated with SLIT indicating an activation of the immune response
induced by the locally applied grass pollen extract. SPT reactivity did not
change during therapy. After 1 year of SLIT in the original design there was no
significant difference in the CI between treatment and placebo. However,
subgroup analysis in a repeated measures model revealed that patients with
SLIT and severe symptoms before the beginning of treatment (CI > mean/ >
1.51) showed a significant improvement of clinical symptoms after 3 years. SLIT
was accompanied by a significant placebo effect and efficacy of treatment could
only be seen in children with severe clinical symptoms.
Current costs per 6 month course of treatment = £358.20 (excluding VAT and
postage & packing).
1.
2.
3.
4.
5.
6.
7.
8.
References:
Allergy 1999; 54: 819-828
Sweetman S C. Martindale The Complete Drug Reference 33rd edition. London.
Pharmaceutical Press. 2002
Allergy 1994; 49: 309-313
Allergy 1998; 53 (5): 493-498
Allergy 1999; 54 (8): 819-828)
Clinical and experimental allergy 1996; 26 (11): 1253-1261
Journal of Allergy and Clinical Immunology 2004; 114 (4): 851-857
Allergy 2004; 59 (5): 498-504
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Dr Luyt attended the meeting to support his request. He informed the Group
that he had had some great successes using subcutaneous immunotherapy for
patients with allergies. However the products are not currently licensed in the
UK and are much more likely to cause an anaphylactic reaction in individual
patients compared to SLIT. He advised that he would generally exclude
patients with asthmas and agreed that this product should only be prescribed
through specialist allergy clinics. IS thanked Dr Luyt for attendance. MQ
informed members that he had also received support for the product from Mr
Banerjee, ENT consultant surgeon. Following discussion the use of staloral®
within paediatrics was approved for use within the specialist allergy clinic as
suggested by Dr Luyt. With regard to the request from the adult physicians, the
product was supported but members felt that this should also be restricted to the
specialist allergy clinic. Staloral® has been allocated as red for traffic light
purposes.
ACTION: MQ to inform Clinical Directors
4.2 Restylate® - This product had been requested by Mr Henderson to bulk
out an indentation in a patients lip. This is a hyaluronic acid product and
is classed as a medical device. Members of the Group felt that as it is
not classed as a drug, the request should be deferred to NIPAG.
ACTION: MQ to inform Mr Henderson re decision
4.3 Triptorelin for advanced prostate cancer
Requested by: Mr Tim Terry, Mr Paul Butterworth and Mr Roger Kockelbergh
(Urology)
Information supplied: Equal efficacy to Zoladex® /Prostap® but cheaper
Reference cited: Nil
Literature review
Decapeptyl® SR is available in two presentations in the UK; Decapeptyl® SR
3mg for intramuscular injection every 28 days and Decapeptyl® SR 11.25mg for
intramuscular injection every 3 months. Decapeptyl® SR 3mg is licensed for the
treatment of advanced prostate cancer, endometriosis and uterine fibroids prior
to surgery or when surgery is not appropriate. Decapeptyl® SR 11.25mg is
licensed for the treatment of advanced prostate cancer and for the treatment of
endometriosis. The 3-monthly formulation has been shown to be
pharmacologically equivalent to 3 separate monthly injections. 1
A comprehensive literature search identified 2 comparisons with leuprorelin but
none with goserelin. In both studies the objective was to compare the efficacy of
monthly injections of triptorelin or leuprorelin to induce and maintain castrate
levels of serum testosterone in men with advanced prostate cancer.
In the larger study, men with advanced prostate cancer were randomised to
receive triptorelin 3.75mg or leuprorelin 7.5mg by intramuscular injection every
28 days for 9 injections. 2 Primary endpoints were the percentages of men
whose serum testosterone concentrations declined to and were maintained at or
below castrate levels (≤ 1.735 nmol/L or ≤ 500ng/L) during 9 months (253 days)
of treatment. Secondary endpoints were luteinising hormone levels, bone pain,
prostate specific antigen (PSA) levels, quality of life, testosterone
pharmacodynamics, survival and safety variables. A total of 284 men received
either triptorelin (n=140) or leuprorelin (n=144). The percentage of men with
castrate levels of serum testosterone was lower at 29 days for the triptorelin
group compared with the leuprorelin group (91.2% vs. 99.3%), but equivalent at
57 days (97.7% vs. 97.1%). The mean (98.8% vs. 97.3%) and cumulative
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(96.2% vs. 91.2%) castration maintenance rates between 29 and 253 days were
equivalent between the treatment groups. Secondary endpoints were equivalent
between treatment groups except for the 9-month survival rate, which was
significantly higher for triptorelin than for leuprorelin (97% vs. 90.5%; P = 0.033).
Both treatments were well tolerated. In conclusion, triptorelin reduced
testosterone concentrations less rapidly but maintained castration as effectively
as leuprorelin. There was no evidence that the slower onset of castration
caused deleterious effects.
The smaller study included 68 patients with metastatic prostate cancer that were
randomised to either subcutaneous leuprorelin 3.75mg (n=36) or intramuscular
triptorelin 3.75mg (n=32). 3 Patients received nilutamide as flare-up prevention.
Plasma testosterone, luteinising hormone and serum PSA levels were evaluated
after 1, 3 and 6 months with the main outcome measure being the proportion of
patients with testosterone level ≤ 0.5 ng/ml. The percentages of patients with
testosterone ≤ 0.5 ng/ml were not significantly different between the 2 groups
and were equal to 100% and 90%, 97% and 100% and 100% and 96% at the 3
study times, for leuprorelin and triptorelin respectively. The difference was
significant at 1 month on complementary analysis at the limit of testosterone <
0.3 ng/ml (86% with leuprorelin vs. 60% with triptorelin; p = 0.02) and for mean
plasma testosterone (0.16 ± 0.1 ng/ml vs. 0.33 ± 0.44 ng/ml respectively; p =
0.02). The clinical subjective efficacy was not significantly different. The authors
concluded that both treatments were effective although plasma testosterone fell
more rapidly with leuprorelin. Overall safety was satisfactory but it was not
possible to draw a conclusion about the clinical or survival benefits.
References:
1. Hormone Research 2004; 62: 252-258
2. BJU Int 2003; (92 (3): 226-31
3. Prog Urol 1997; 7 (6): 984-95
Discussion took place around this request re long term outcome data
verses the existing products currently used in prostrate cancer. There is
no long-term outcome data available for triptorelin. AM agreed to review
the long-term data available for both goserelin and leuprorelin to see if
there is any specific data available. If long-term data is available the
Group felt that the requesting Consultants should be asked to confirm
whether they would like to pursue this request given the lack of end-point
data.
ACTION: AM to review long term for goserelin and leuprorelin
4.4 Co-diovan® for hypertension
Requested by: Dr Ian Hudson (Cardiology)
Information supplied:
This has the advantage of being a flexible form of monotherapy in patients who
require more than one agent to control blood pressure
The combination would be well tolerated, and clinical trials support this
I understand that the cost is the same as Valsartan monotherapy, although this
would need to be confirmed with Novartis.
References cited:
J Hum Hypert 1998; 12: 861-866
Blood Pressure 2003; 12 (Suppl 1): 36-43
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Literature review
A comprehensive review by Wellington and Faulds 1 summarises the clinical
evidence for the fixed dose combination of valsartan and hydrochlorothiazide in
hypertension. In all studies, the primary endpoint was the mean reduction from
baseline in trough sitting diastolic blood pressure (DBP) with sitting systolic
blood pressure (SBP) also reported in some studies. The combination has been
evaluated in clinical trials lasting from 8 weeks to 3 years. A dose-response
study (n=871) showed that the combination of valsartan 80mg or 160mg with
hydrochlorothiazide 12.5mg or 25mg once daily was significantly more effective
than either drug alone at reducing blood pressure (BP). 2 The greatest
reductions in BP were seen in the valsartan 80mg plus hydrochlorothiazide
25mg and 160mg plus 25mg groups (mean reductions in systolic/diastolic BP of
21.1/15.7 and 22.5/15.3mm Hg). Mean reductions in SBP/DBP for patients who
received valsartan 80mg plus hydrochlorothiazide 12.5mg or 160mg plus
12.5mg were 16.5/11.8 and 17.8/13.5mm Hg.
Valsartan plus hydrochlorothiazide was also effective at reducing BP in patients
who did not respond to monotherapy with either valsartan or
hydrochlorothiazide. Patients were deemed to be nonresponders if sitting DBP
was ≥ 95mm Hg and ≤ 115mm Hg after 4 weeks on monotherapy. Among
nonresponders to monotherapy with valsartan 80mg, SBP/DBP reductions in
patients who received valsartan 80mg in combination with hydrochlorothiazide
12.5mg (9.8/8.2mm Hg) or 25mg (16.0/10.8mm Hg) were significantly greater
than those seen in patients who received monotherapy with valsartan 80mg
(3.9/5.1mm Hg) or 160mg (6.5/6.2mm Hg). Similarly nonresponders to
hydrochlorothiazide 12.5mg achieved significantly better BP control with fixed
dose valsartan/hydrochlorothiazide 80/12.5mg (14.9/11.2mm Hg) than with
hydrochlorothiazide 12.5mg (5.2/2.9mm Hg) or 25mg (6.8/5.7mm Hg).
Effective BP control was maintained with valsartan plus hydrochlorothiazide in
long-term open label studies, with BP reductions observed after 3 months of
treatment being similar to those seen after 1, 2 or 3 years. Reductions from
baseline in SDP/DBP after 3 years treatment with valsartan 80mg plus
hydrochlorothiazide 12.5mg or 25mg were 11.7/12.5 and 16.4/12.6mm Hg.
Fixed-dose valsartan/hydrochlorothiazide 80/12.5mg showed similar BP
reductions to amlodipine 10mg (in patients who did not respond to valsartan
80mg or amlodipine 5mg respectively), and valsartan 80mg plus benazepril
10mg
in
patients
not
responding
to
valsartan
80mg.
Both
valsartan/hydrochlorothiazide and amlodipine provided effective 24-hour
ambulatory SBP/DBP control, with trough-to-peak ratios of 0.61/0.57 and
0.56/0.56.
The combination of valsartan with hydrochlorothiazide is generally well
tolerated. The most common adverse events occurring in clinical trials were
headache, dizziness and fatigue but the incidence of the events was not
significantly different to that in placebo recipients. Hypokalaemia occurred in
approximately 4.5% of patients who received valsartan plus hydrochlorothiazide.
Reference
1. Drugs 2002; 62 (13): 1983-2005
2. J Hum Hypertens 1998; 12 (12): 861-6
Concerns were raised regarding this request as to whether patients who
are currently taking ACEI’s might be switched to this combination if a
thiazide diuretic needs adding to therapy. This would have major cost
implications and it was felt that if this product was used at all it should
only be available for those patients who require fixed doses of an ARB
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plus a thiazide. It was suggested that IS should write to Professor
Williams and Professor Thurston to seek their views on the place of this
combination product in therapy.
Action: IS to write to Prof Williams & Thurston
4.5 Infliximab for Behcets disease refractory to conventional immunosuppressive therapy
Requested by: Dr Michael Duddridge (Clinical Immunology/Medicine)
Information supplied:
New therapy for patients with severe Behcet’s disease refractory to conventional
immunosuppressive therapy
Efficacy of infliximab usually becomes apparent within days or weeks of
commencement of therapy
Recognised risk of infection and recurrent mycobacterial disease in those with a
past history of tuberculosis – patients screened with chest x-ray and Mantoux
testing
References cited:
Ann Rheum Dis 2004; 63 (suppl II): ii79-ii83
Ann Rheum Dis 2002; 61: ii51-ii53
J Rheumatol 2004; 63: 744-745
Rheumatology 2001; 40: 473-474
The Journal of Rheumatology 2004; 31: 1241-1243
J Rheumatol 2005; 32: 98-105
Rheumatology 2002; 41: 1213
Literature review
Behcet’s disease is a multisystemic, chronic relapsing inflammatory disease.
Recurrent mucocutaneous lesions may be the only symptoms in mild cases, but
articular, ocular, vascular, and/or gastrointestinal and central nervous system
involvement may occur in most of the patients. Ocular disease is the most
frequent cause of morbidity leading to blindness is 25% of those affected. 1
Drugs currently being used for Behcet’s disease include colchicine, dapsone,
corticosteroids and other drugs, which affect the immune system including
azathioprine, mycophenolate, ciclosporin and tacrolimus. Infliximab is a cytokine
inhibitor that inhibits the activity of tumour necrosis factor (TNF). It is licensed in
the UK for the treatment of rheumatoid arthritis, Crohn’s disease, ankylosing
spondylitis, psoriatic arthritis and psoriasis. 2
There is increasing interest in using infliximab in Behcet’s disease as symptoms
are thought to be mediated by a variety of cytokines including TNFα. To date
there do not appear to have been any randomised controlled trials but
numerous case reports have been published. Most patients were treated
primarily for ocular disease although patients with gastrointestinal, vascular,
articular, and mucocutaneous lesions and central nervous system involvement
have also been treated. This review will focus on the larger therapeutic studies
in ocular disease.
Ohno et al conducted an open label trial of infliximab in 13 patients with
Behcet’s disease accompanied by refractory uveoretinitis. 3 Following a 14-week
observation period, infliximab was administered 4 times at weeks 0, 2, 6 and 10
at doses of either 5 or 10mg/kg by intravenous infusion. The primary efficacy
endpoint was frequency of ocular attacks with visual acuity and extraocular
symptoms as secondary endpoints. During the 14-week observation period, the
mean number of ocular attacks was 3.96 times for the group that went on to
have 5mg/kg and 3.79 times for the group that went on to have 10mg/kg.
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Following treatment the mean number of ocular attacks decreased to 0.98 times
and 0.16 times respectively. One patient in the 10mg/kg group went on to
develop tuberculosis.
In the largest case series published to date, Sfikakis et al reported on 25
patients with acute sight-threatening ocular inflammation who were treated with
a single infliximab infusion at the immediate onset of relapse. 4 The primary
outcome measure was time to complete suppression of ocular inflammation.
They also reported on 15 of these patients who had experienced at least one
additional relapse while taking immunosuppressive therapy in the 32-week
period before infliximab administration. These patients were enrolled in a
subsequent 32-week protocol of continuous infliximab therapy. The primary
outcome measures were a possible decrease in the frequency of relapses and
final visual acuity. Consecutive patients with relapsing posterior eye segment
inflammation were assessed at baseline and at 1, 7, 14 and 28 days after
treatment. Infliximab at a dose of 5mg/kg was given intravenously, either alone
or in addition to previous immunosuppressive treatment. In 24 of 25 patients,
acute ocular inflammation was rapidly controlled starting one day after
treatment. Complete response of vitritis and retinitis was achieved at day 7 in
68% and 44% of patients respectively, and in 100% of patients at day 28.
Retinal vasculitis resolved in 6% of patients by day 7, 61% of patients by day 14
and 94% of patients by day 28. Cystoid macular oedema, the most resistant
manifestation, resolved in 90% of patients by day 28. Visual acuity improved
markedly in all patients and no relapses were observed within the 28 days.
The 15 patients who were enrolled in the 32-week protocol received additional
infusions at day 28 and at weeks 8, 16 and 24. In this group of patients
complete remission was observed in 60%. Concomitant immunosuppressive
therapy was substantially reduced and there were no major adverse effects
requiring withdrawal of infliximab.
Lindstedt et al described the effect of infliximab in a case series of 13 patients
with serious sight threatening uveitis including 6 with Behcet’s disease. 5
Patients were treated with 200mg (approximately 3mg/kg) infliximab infusion
which was repeated according to clinical response. Onset and course of ocular
inflammation, inflammatory signs, and visual acuity were assessed. Infliximab
treatment resulted in effective suppression of ocular inflammation in all patients.
In patients with non-Behcet’s disease uveitis visual acuity in 6 out of 8 patients
improved or was stable. In patients with Behcet’s disease visual acuity in 5 out
of 6 patients improved or was stable.
Another open-label study evaluated the long-term efficacy and safety of
infliximab as a treatment for non-infectious posterior uveitis. 6 Seven patients
refractory to conventional treatment regimens with corticosteroids and at least
one immunosuppressive agent were included. Each patient received three
intravenous doses of 5mg/kg of infliximab administered at weeks 0, 2 and 6.
Infusion was repeated in patients that experienced a relapse of uveitis after
initial remission. Improvement was defined as improvement of visual acuity or
disappearance of retinal exudates and/or haemorrhages, decreased macular
oedema and/or visual opacities. All patients were followed up for 36 months.
Five patients with Behcet’s disease and one with sarcoidosis showed a
significant improvement after the first dose of infliximab. One patient with
chronic idiopathic multifocal choroiditis withdrew from the study due to lack of
effect. At the end of follow up, one eye had lost one line of vision and three eyes
showed improved vision. All eyes had improved in terms of signs of
inflammation and no adverse events were observed.
A Turkish study 7 investigated the effect of infliximab on the frequency of uveitis
attacks and the visual prognosis in male patients with Behcet’s disease resistant
to combination therapy with corticosteroids, azathioprine and ciclosporin. 13
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patients who had experienced at least 2 attacks of posterior uveitis/panuveitis or
retinal vasculitis during the previous 6 months were enrolled. Infliximab infusions
(5mg/kg) were administered at weeks 0, 2, 6 and 14. Weeks 0-22 were defined
as the infusion period and weeks 23-54 were defined as the observation period.
Patients continued to receive azathioprine and corticosteroids, but ciclosporin
was discontinued after the screening visit. The primary outcome measures were
the absence of uveitis attacks during the infusion period (remission) and the
absence of uveitis attacks throughout the study period (sustained remission).
The study group had experienced 32 uveitis attacks involving the posterior
segment during the 6 months prior to the study. During the infusion period, 4
patients (30.8%) remained attack free and 9 patients had a total of 13 uveitis
attacks. 10 of these attacks (76.9%) occurred at either week 14 or week 22.
One of the patients fulfilled the definition of sustained remission and the
remaining 12 patients had a total of 36 uveitis attacks during the observation
period. The mean number of uveitis attacks and daily corticosteroids doses
were significantly lower during the infusion period than prior to the study or
during the observation period. Although visual acuity improved following
infliximab infusion, this effect was not preserved until week 54. None of the
patients experienced a serious adverse event.
Current drug costs
BNF price for infliximab (Remicade®) 100mg vial = £419.62 (ex. VAT)
UHL NHS Trust price of infliximab 100mg vial = £437.38 (inclusive of VAT)
Induction treatment regimen is 5mg/kg at 0 weeks, +2 weeks and +8 weeks
Maintenance treatment regimen is 5mg/kg every 6-8 weeks thereafter
Typical first year cost (for individual weighing 80kg and maintenance therapy
every 8 weeks) = 400mg x 8.5 doses pa = £14,870.92 (pharmaceutical cost)
Typical subsequent year costs (for individual weighing 80kg with therapy every
8 weeks) = 400mg x 6.5 doses pa = £11,371.88 pa (pharmaceutical cost)
References:
1. Ann Rheum Dis 2002; 61: ii51-ii53
2. October 2005. Remicade – Summary of Product Characteristics [on-line].
Schering Plough Ltd. Available from: http://www.medicines.org.uk [accessed
8th December 2005]
3. J Rheumatol 2004; 31: 1362-1368
4. Annals of Internal Medicine 2004; 140 (5): 404-406
5. Br J Ophthalmol 2005; 89: 533-536
6. Eye 2005; 19 (8): 841-845
7. Arthritis and Rheumatism 2005; 52 (8): 2478-2484
Following discussion this product was approved for use. It will be classed
as red for traffic light purposes.
ACTION: MQ to inform Clinical Director re decision
4.6 Peppermint oil enema for spasm during colonoscopy
Requested by: Dr Rathbone (Gastroenterologist)
Information supplied:
Spasm is a problem in many patients at colonoscopy
Our only treatment is IV Buscopan®
Other units use topical peppermint oil to give a rapid local effect without any of
the systemic side effects of Buscopan®
Reference cited: Nil
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Literature review
Peppermint oil is known to act as an antispasmodic by a direct relaxant effect on
gastro-intestinal smooth muscle and is widely used in capsule form in the
management of irritable bowel syndrome and diverticular disease. 1
A comprehensive literature search identified a few reports of peppermint oil
being administered during colonoscopy or with barium enema:
In 1982 in a letter to the Lancet 2, Leicester and Hunt described how they
injected peppermint oil BP along the biopsy channel of the colonoscope in 20
patients. They reported that in every case colonic spasm was relieved within 30
seconds allowing easier passage of the instrument or assisting polypectomy.
They subsequently replaced the neat oil with a diluted peppermint oil
suspension as the oil was found to be irritant to the eyes.
A later study also evaluated the intracolonic administration of peppermint oil
during colonoscopy. 3 In this study, the treatment group consisted of 409
patients who were given approximately 200ml of a solution containing 8ml of
peppermint oil and 0.2ml of Tween 80 per 1 litre of water with 0.04% indigo
carmine. The solution was administered using a hand pump attached to the
accessory channel of the colonoscope. There were 36 patients in the control
group who were given the solution without peppermint oil. Changes in patient
posture were made to distribute the solution. A satisfactory spasmolytic effect
was observed in 88.5% of the treated patients compared with 33.3% of the
control group (p < 0.0001). No adverse effects were observed. The mean time
to onset was 21.6 ± 15.0 seconds, and the effect continued for at least 20
minutes. Efficacy was reported to be significantly lower in patients with irritable
bowel syndrome (p < 0.0001).
In addition to these 2 reports, there have been 2 published studies in which
peppermint oil was added to barium sulphate suspension to relieve colonic
muscle spasm during barium enema examination:
In one of these studies, 141 patients were randomised either to a control group
who received peppermint oil mixed with the barium. 4 The authors reported that
no residual spasm was evident in a significant proportion of the treated group
(60%) compared with the control group (35%) (p < 0.001). The patients’
acceptability of the procedure was good and there were no adverse effects on
the overall quality of the examination.
The other study is the only one that actually compared the effect of peppermint
oil with that of Buscopan. A total of 383 patients due to undergo double contrast
barium enema (DCBE) were assigned to one of four groups: peppermint in
barium (n=91), peppermint in tube (n=90), Buscopan (n=105), or no treatment
(n=97). 5 After a screening sigmoidoscopy, the DCBEs were performed using air
as a distending gas. In the Buscopan group, 20mg Buscopan was given by
intramuscular injection at the start of the examination. The peppermint oil
groups received 30ml of a peppermint oil preparation either mixed in the barium
solution or included in the enema tube. The presence of spasm on a series of
spot films was evaluated without information about the type of spasmolytic
agent i.e blinded. The percentage of patients with absence of spasm in the
entire colon on the series of spot films was no treatment 13.4%, Buscopan
38.1%, peppermint in tube 41.8% and peppermint in barium 37.8%. The rate of
patients with non-spasm examination was significantly higher in the groups
using peppermint oil or Buscopan than in the no-treatment group (p < 0.0005).
Peppermint oil was found to have the same spasmolytic effect as the systemic
administration of Buscopan in the traverse and descending colon and appeared
to have a stronger effect in the caecum and ascending colon (p < 0.005). There
was no advantage to placing peppermint oil in the enema tube over mixing it
with the barium solution. Peppermint oil did not impair image quality. The
authors concluded that barium solution mixed with peppermint oil was safe and
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effective for the elimination of colonic spasm during DCBE and could be used
instead of Buscopan.
Current cost
Made to order as an unlicensed special from Preston Pharmaceuticals
500ml = £21.17
References:
1. British National Formulary No 50. September 2005
2. Lancet 1982; 2: 989
3. Gastrointestinal Endoscopy 2001; 53 (2): 172-177
4. British Journal of Radiology 1995; 68 (812): 841-843
5. Clinical Radiology 2003; 58: 301-5
As this is an unlicensed product and there may be potential for cost
implications it was agreed that this request should be deferred until
pricing of the product could be checked. It was suggested in the request
that 60 ml syringes are available, however only have price for 500ml
bottle. While it is clear that 500mls would not be required for each
endoscopy it is not clear whether the solution might need to be discarded
after a certain length of time. MQ agreed to check potential costs of
using peppermint oil enemas for the next meeting.
ACTION: MQ to check costs
4.7 Fosavance® for primary and secondary prevention of ospeoporotic
induced fractures
Requested by: Dr Iqbal (Consultant in Metabolic Medicine)
Information supplied:
Postmenopausal osteoporotics being treated with bisphosphonates should all
receive Vit D + calcium supplements. (As per major bisphosphonate
osteoporotic trials). Compliance in this area has been shown to be poor.
Fosavance® provides bisphosphonate + Vit D in single tablet. Calcium input
may be achievable by diet – not possible with Vit D.
To replace fosamax® weekly
Reference cited: Nil
Fosavance® is a combination product containing alendronic acid 70mg
and vitamin D 2,800iu. The alendronic acid content is equivalent to
fosamax® once weekly and the vitamin D content matches the weekly
intake of one tablet of Calcichew D3 Forte®.
Following discussion members were not convinced that this would aid in
compliance, nor that it might negate to the need to still use calcium
tablets over and above that consumed in the patient’s dietary intake. MQ
also advised the Group that alendronate once weekly is now generic and
UHL can purchase this product at around £4.50 a month verses £24 for
fosavance®. Due to the high cost implications if this drug was approved
the request was not supported.
ACTION: IS to inform the requestor re decision
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4.8 Ibandronic acid for osteoporosis in postmenopausal women
Requested by: Dr Iqbal (Consultant in Metabolic Medicine)
Information supplied:
Many people will find the monthly regimen easier because of the known GI
intolerance with bisphosphonates.
Reference cited: Nil
Literature review
Ibandronate (ibandronic acid) once monthly (Bonviva® 150mg) has received a
positive opinion on granting a marketing authorisation from the European
Medicines Evaluation agency in June 2005.
The licensed indication for ibandronate once monthly will be the treatment of
osteoporosis in postmenopausal women, in order to reduce the risk of vertebral
fractures.
Ibandronate is a third generation bisphosphonate, which inhibits bone resorption
in human and animal studies. The Monthly Oral iBandronate in ladies Study
(MOBILE) is a two-year phase III double blind, active comparator trial. The oneyear results were published at the American Society for Bone and Mineral
Research (ASBMR) 26th annual meeting in October 2004.
One-year results from MOBILE showed that once monthly regimens of oral
ibandronate were as effective as 2.5mg once daily oral ibandronate with similar
tolerability in the treatment of postmenopausal osteoporosis. The MOBILE study
did not assess the effect of once monthly ibandronate on fracture rate or risk.
There are no human studies to date which compare once monthly ibandronate
with other bisphosphonates. In animal studies, oral ibandronate was more
potent than oral etidronate, clodronate, pamidronate and alendronate, however
it was comparable in potency to risedronate.
The main adverse effects of ibandronate in clinical trials were similar to other
bisphosphonates and included dyspepsia, diarrhoea, myalgia, arthralgia and
non-specific rash. Uncommon adverse effects included dysphagia, vomiting,
gastritis, oesophagitis, including oesophageal ulcerations and strictures,
headache, dizziness, flu syndrome, fatigue and back pain.
The London New Drugs Group inj their review of the product concluded that
more data is required regarding the once monthly dosing regimen and its affect
on compliance in clinical practice. Ibandronate may be an alternative in patients
who find the current weekly or daily regimens inconvenient.
Members raised concerned that there was lack of hard end point data
regarding reduction in fractures with the monthly preparation. They
where also not convinced that a once monthly preparation would
necessarily increase compliance. Members therefore agreed that this
product should not be supported within UHL until long term fracture data
is available.
ACTION: IS to inform requestor re decision
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4.9 Fulvestrant for 4th line hormone treatment of metastatic breast
cancer
Requested by: Dr Mulatero (Medical Oncologist)
Information supplied:
The response rate to fulvestrant in patients with oestrogen and progesterone
sensitive tumours as fourth line hormonal therapy lies between 27 and 46 %.
The side effect profile is acceptable1.
No alternative hormonal therapy is currently available in this setting.
Reference cited: Nil
Fulvestrant ('Faslodex'): Clinical experience from the Compassionate Use
Programme Steger, G. G. et al. Cancer Treat Rev. 2005. 31 Suppl 2. S10-6.
The supporting clinical paper cited by Dr Mulatero showed a high
response rate for fulvestrant when used as a third/forth line agent. It was
agreed however that before supporting this request the views of the
cancer network should be sought. MQ agreed to chase
ACTION: MQ to seek cancer network views
5. Any Other Business
5.1 Tiatropium - MQ informed the Group that he had received a request for
tiatropium from Dr Patel, a Consultant in Intregrated Medicine. He
reminded the Group that this drug had been approved for use by
Respiratory Specialists and asked whether members felt that access
should be expanded to other specialities. It was agreed that the
Respiratory Prescribing Group be asked for their opinion.
ACTION: MQ to write to Susan Carr to seek advice
5.2 Botulinum toxin - A request for botulinum toxin to treat bladder instability
has been received by NIPAG. Dr Blanshard (Chair) has asked whether
TAS should review this request. Members agreed a review by TAS would
be required.
ACTION: MQ to inform Dr Blanshard and to ask requestor to
complete a new product form
6. Date & Time of next Meeting
24 January 2006, 4 p.m. Venue Room 105, LRI
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