Microsoft word - 77 tas minutes - 15-08-05.doc

Held on Tuesday 15 August 2005

1. Minutes of last Meeting

2. Matters Arising

2.1 Ciclesonide – AM had looked for further information on the FDA Website
as requested at the last TAS meeting. It was reported that no further information was available regarding this drug. MQ reported that the Directorate have approved the use of the drug as per TAS recommendations i.e. second line to beclomethasone in patients intolerant to side effects. 2.2 Sunsense Ultra – MQ reported that he had received an e-mail from Dr
Burd re this request. In his e-mail Dr Burd clarified that he had requested this product for those patients who have a photosensitive disorder with wide spread dysplastic lesions and or a history of skin cancer. Of particular risk are groups such as organ transplant recipients or those on long term immunosuppressants. While Dr Burd agreed that it could replace one of the existing products he also felt that a wider range would allow better patient choice and compliance. Following discussion the request was supported for the indications outlined by Dr Burd. In addition Dr Burd had also suggested that a dermatologist should attend TAS bearing in mind the wide range of products that are requested by the speciality. This suggestion was supported. This product has been classed as green. ACTION: MQ to write to Clinical Director re request and to Dr Burd
re attendance at TAS

2.3 Methylaminolevulinate for PDT – MQ advised the Group that he had
received correspondence from Dr Burd regarding this request, which had been submitted in June of last year. Dr Burd had sought information re the status of this request and MQ had replied stating that TAS were C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc waiting for a response re whether photo lamps were available and that the infrastructure was available to use this product. In his reply Dr Burd had confirmed that such lamps where already available and that indeed given that this could be a nurse led service there may be direct cost savings in terms of Doctors time. Following further discussion this request was supported. This product has been classed as red. ACTION: MQ to write to Clinical Director re request
2.4 Solifenacin – This request from Mr Terry had been discussed at the
meeting in February and had not been supported based on lack of evidence re the superiority of the product compared with tolterodine Further to this submission a second submission had now been received from Mr Mayne for the treatment of urge incontinence in patients with over active bladder syndrome. In his request Mr Mayne had suggested that a comparative trial with tolterodine had shown superior efficacy with solifenacin. On reviewing this trial, which was double blind placebo controlled, the evidence suggested that there was a slight superiority for solifenacin over tolterodine. It was therefore agreed that solifenacin should be made available as an alternative to tolterodine XL in patients with bladder instability.
MQ to inform Clinical Directors of obstetrics and gynaecology
2.5 Vardenafil – IL requested that this product be made available to the
Diabetologists who run an andrology clinic. MQ agreed to write to the Clinical Director for the Medical Directorate to seek approval for this drug within the Directorate. ACTION: MQ to write to Clinical Director
3. Requests from EGOC
3.1 Interferon gamma 1b
Requested by: Dr M Duddridge (Clinical Immunology)
Information supplied:
• New therapy should reduce period of standard antituberculous therapy from
long-term to period of 15 to 18 months after start of interferon gamma. • Type 1 cytokine deficiency is a very rare disorder – 3 potential patients identified for therapy. Thereafter max. anticipated 2 per annum. • High Cost Therapy cases of need submitted. • There are no alternative first-line treatments for these primary immunodeficiency states affecting the interleukin-12/interferon-gamma pathway of monocyte/macrophage activation (important in mycobacterial immunity) with either (i) atypical mycobacterial infection unresponsive to standard therapy, or (ii) metastatic M. tuberculosis infection unresponsive to standard therapy. Without treatment with interferon-gamma these patients C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc essentially require life long antituberculous therapy with significant risk of respiratory or other morbidity/death. References cited:
• TRIC (Trent Immunodeficiency Consortium) guideline 36.01 “Type I
cytokine deficiency” available at • Microbes Infect 2000; 2 (13): 1567-78 • Immuno Rev 2005; 203 (1): 38-47 • N Engl J Med 1994; 330 (19): 1348-55 • J Clin Invest 1998; 102 (12): 2035-40 Additional background information from Dr Duddridge Interferon gamma-1b has been used off-label in the management of deficiency of the interleukin-12/interferon gamma pathway with recurrent/persistent mycobacterial infection. In these very rare primary immunodeficiencies interferon gamma-1b has been used as a first-line treatment (alongside standard anti-tuberculous drugs) throughout the UK, North America and in Europe. It has previously been used in UHL to treat a young child as recommended by a recognised national paediatric expert. The interleukin-12/interferon gamma pathway of monocyte macrophage activation is pivotal in the control of mycobacterial infection and immunity. Genetic defects of this pathway or low production on interferon gamma result in very rare cases of primary immunodeficiency with particular susceptibility to either atypical mycobacterial infection or metastatic Mycobacterium tuberculosis infection. These infections are persistent/recurrent and are unresponsive to standard anti-tuberculous therapy. Treatment of these patients with interferon-gamma for one year has the potential to: • Cure mycobacterial infection and withdraw anti-TB therapy 6 months later • Reduce/prevent the risk of further progressive CNS, bone or lung disease The only alternative is life-long continuation of anti-TB therapy without the prospect of cure and with the likelihood of progressive disseminated mycobacterial infection, including: • CNS disease and its associated morbidity/mortality • Osteomyelitis and soft tissue infection with its associated morbidity • Progressive bronchiectasis with increasing respiratory morbidity (including respiratory failure) and premature death • Poor quality of life – including weight loss and increasing fatigue. Both Professor Nicholson and his colleagues in the Infectious Diseases Unit, Leicester Royal Infirmary and Dr G Woltmann, Consultant Respiratory Physician, Glenfield Hospital, Leicester are supportive of this application. These 2 teams and the Children’s Hospital, Leicester Royal Infirmary are the likely source of referral of cases of mycobacterial infection unresponsive to standard anti-tuberculous therapy for further evaluation to exclude primary immunodeficiency of the interleukin-12/interferon-gamma pathway. Following discussion this request was approved. However concerns where raised re the potential for this drug to be overly prescribed. TAS C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc members agreed interferon gamma 1b should only be available on the agreement of two Consultants one of which should be the treating physician the second of which should be a Consultant Immunologist. It was also agreed that prescribing should follow the guidelines produced by the Trent Immunodeficiency Consortium. This has been classed as red.
ACTION: MQ to write to Clinical Director re decision

3.2 Growth hormone – Dr Declan Cody had requested the use of growth
hormone for two specific growth hormone deficiency states namely Noonans Syndrome and SGA. Neither of these disease states are mentioned in the NICE guidance for the use of growth hormone which mainly covers Turners syndrome which largely effects the female population. Noonans Syndrome - the male equivalent of Turners, is quite a rare condition - only one or two patients will present per year. None of the growth hormone products are currently licensed for Noonans and would be unlikely to become licensed due to its rare occurrence. Three of the five growth hormones currently available are licensed for SGA. This is likely to be considered by NICE in the future. Following discussion the request to support the use of growth hormone for the conditions stated was supported. This has been classed as red. ACTION: MQ to inform ECOG of the decision
4. New Product Requests

4.1 Strontium for secondary prevention of osteoporotic fractures

Requested by: Dr Sheldon (supported by Dr Iqbal and Dr Reid)
Information supplied:
• Less irritant to oesophagus
• Stimulates new bone formation
Reference cited: Nil
Strontium ranelate (Protelos, 2g granules for oral suspension) was licensed in the UK in November 2004 for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. Two Phase III studies have been carried out: The SOTI study tested the safety of strontium ranelate and its efficacy in preventing vertebral fractures in postmenopausal women. The TROPOS study evaluated the efficacy of strontium ranelate in preventing non-vertebral fractures in postmenopausal women. Both the TROPOS and SOTI studies compared 2g strontium ranelate/day to placebo, over a three year period. Only the SOTI study has been fully published. Results showed a significant reduction in new vertebral and symptomatic fractures with strontium ranelate treatment compared to placebo and significant C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc increases in bone mineral density, at the end of the three year treatment period. Compliance was good – 83% in the strontium ranelate group and 85% in the placebo group after 3 years. Data from the TROPOS study shows that the use of strontium ranelate over a three year period significantly reduces the risk of nonvertebral fractures (including hip fractures) in postmenopausal women, compared to placebo. Strontium ranelate increases bone formation and decreases bone resorption, which has been shown in the trial results as measured by serum biochemical markers. Data from these two studies were pooled for analysis and supports the efficacy claims that strontium ranelate reduces the risk of new fractures in postmenopausal women with osteoporosis with or without prevalent vertebral fractures. Pooled data demonstrates a risk reduction in new vertebral and non-vertebral fractures of over 30% in patients aged over 80 years. No other anti-osteoporotic treatment has demonstrated non-vertebral fracture efficacy in this age group. The absorption of strontium ranelate is affected by food and milk/derivatives. The suspension should ideally be given at bedtime, at least two hours after these products. The cost of one months treatment with strontium ranelate is comparable to that of bisphosphonates and raloxifene. References 1. Meunier PJ, Roux C, Seeman E, Ortolani S, Badurski JE, Spector TD et al. The effects of strontium ranelate on the risk of vertebral fractures in women with postmenopausal osteoporosis. N Engl J Med 2004; 350:459-468. 2. Rizzoli R, Reginster JY, Diaz-Curiel M, Ortolani S, Benhamou C, Compston.J. et al. Patients at high risk of hip fracture benefit from treatment with strontium ranelate. Abstract OC39. IOF World Congress on Osteoporosis, Rio de Janeiro, Brazil, May 14th-18th: 2004 3. Servier Laboratories Ltd. Detailed summary of the TROPOS Study. 2004. 6- 4. Summary of product characteristics. Protelos (Strontium ranelate 2g granules). Les Laboratoires Servier 2004 Following discussion this request was supported as a second line therapy
for patients who are intolerant of bisphosphonates. This decision would
be reviewed subject to the guidance produced by NICE in 2006. It was
also agreed that current NICE guidance for the secondary prevention of
osteoporotic fractures should be followed when initiating strontium
therapy. Strontium has been classed as green for traffic light purposes.

4.2 Levosimendan for the treatment of heart failure
Requested by: Dr Nichani (Paediatric Intensivist) for use in approx. 12 patients
per year
Information supplied:
• Different mechanism of action ie calcium sensitiser
Reference cited: Nil
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc Levosimendan is a pyridazinone-dinitrile derivative, the active isomer of simandan. It is an inotropic/vasodilator that increases the sensitivity of myocardial contractile proteins to calcium.1,2 Two investigations have compared the effects of levosimendan with placebo therapy in patients with heart failure. In the RUSSLAN study (unpublished): randomised / double blind study 503 patiens with LVF who had had an acute MI within the last 5 days received either placebo or levosimendan at various bolus (6-24ug/kg) and continuous (0.1-0.4 ug/kg/min) infusion rates for a total of 6 hrs treatment. In this study treatment significantly reduced the combined risk of death and worsening heart failure (4.0%(L) vs. 8.8%(P) p=0.044) during first 24 hours and there was a significant reduction in all cause mortality at 14 days (11.4% (L) vs. 19.6%(P) p=0.023). There was improvement in symptom scores for fatigue and dyspnoea on treatment. Higher doses (above 0.2ug/kg/min) were associated with a higher incidence of hypotension and ischeamia (4) In the second study, a multicentre, double blind, placebo-controlled study in 146 patients with NYHA class III or IV heart failure, patients received either levosimendan (n=96) or placebo (n=46) for six hours. The test group received a 6ug/kg loading and then a 0.1ug/kg/min infusion increasing at hourly intervals to 0.4ug/kg/min if tolerated with, unlike other studies, repeated loading at each stage. Haemodynamic and clinical measurements were taken between 0-6 hrs and at 6 hours the trial was unblended. Here placebo patients received conventional therapy and levosimendan patients continued. In this trial 70% of patients received the high dose (0.4ug/kg/min) therapy. However stroke volume (SV) increased significantly at all doses compared to placebo, in a dose dependant manner. At six hours 56% of the levosimendan and only 4% of the placebo group had an increase>25% in SV. Cardiac index (CI) increased significantly at all infusion rates and pulmonary capillary wedge pressure (PCWP) decreased significantly at all infusion rates in a dose dependent manner [PCWP decreases>25% in 43%(L) vs. 15% of (P) (p=0.001)]. There were also significant decreases in systemic vascular resistance (SVR) and pulmonary arterial pressure (PAP) at all doses. At higher does (>0.2ug/kg/min) however there were significant increases in heart rate (HR). this study also found improvement in fatigue and dyspnoea scores as measured by patient and physician although the haemodynamic response could have led to inadvertent unblinding and therefore bias (5). The LIDO study (unpublished) a multicentre, double blind, parallel group, randomised study in 203 patients with severe heart failure compard levosimendan with dobutamine. Patients were given either bolus dose of levosimendan (24ug/kg) followed by infusion at 0.1mcg/kg/min, increasing to 0.2mcg/kg/min if cardiac index not increased by>30% in 2 hours, or dobutamine 5mcg/kg/min, increasing to 10ug/kg.min if no adequate increase in cardiac index. At 24 hours 28% of levosimendan group had met primary endpoint (improved CI>30% and decreased PCWP>25%) compared with 15%of dobutamine group (p=0.02). Levosimendan group had greater improvement in clinical symptoms, less chest pain, fatigue, and dyspnoea. At 180 days levosimendan group had significantly lower risk of death (6). In a study a double blind, placebo controlled, randomised mutilcentre, parallel group study in 151 patients. Patients received variable loading doses (3.0- C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc 36ug/kg) and variable maintenance (0.05-06mcg/kg/min) compared with open label dobutamine (6mcg/kg/min) or placebo. Primary endpoint was to meet one of the following: a)>15% increase in SV at 23-24 h, b) >25% decrease in PCWP at 23-24 h, c)>40% increase in CO (with <20% change in HR) or d) a >50% in PCWP in two consecutive readings. This trial found no significant difference in overall response rate with levosimendan over dobutamine, but both were significantly better than placebo. All doses gave significantly greater falls in PCWP with levosimendan than dobutamine but no difference in SV. Significantly greater increases in CO at levosimendan doses of 0.4 and 0.6 mcg/kg/min probably due to increased HR (3). The main side effects reported with levosimendan are hypotension, reflex tachycardia, headache, vertigo, pain on injection and hypokalaemia. No drug interactions have yet been reported.(1) In conclusion, levosimendan is a new calcium sensitising agent for use in the short-term treatment of acute heart failure. It is an inotropic/ vasodilator that increases the sensitivity of myocardial contractile proteins to calcium. To date levosimendan appears to be at least as effective as dobutamine, but further studies are required to fully understand its place in therapy. It is currently UNLICENSED. References 1. Micromedix Vol 107 disc b monograph for Levosimendan 2. Calcium sensitisation – a new approach to the treatment of acute heart failure. Data from Orion Pharma, Leat house, Newbury 3. Markku, S et al. Haemodynamic and Neurohumoral effects of Continuous Infusion of Levosimendan in Patients with Congestive Heart failure. Jn am Coll Card. 2000; 36(6) p1203-12 4. Levosimendan: the RUSSLan study. Unpublished date from Orion Pharma 5. Slawsky, M et al. Acute Hemodynamic and Clinical Effects of Levosimendan in Patients with Severe Heart Failure. Circulation 2000; 102 p 2222-2227 6. Levosimendan: The LIDO study. Data from Orion Pharma Concerns were raised regarding this request primarily due to lack of
evidence of use in paediatric patients. Following discussion it was
agreed that IS should write to Dr Nichani requesting further information
including the submission of a protocol/guideline/criteria for the use of this
drug. It was also suggested at this stage it may be considered for a multi
centre clinical trial in paediatrics. Request is therefore pending until
further information is supplied.
ACTION: IS to write to Dr Nichani for further information

4.3 Femseven Conti Patch for HRT

Requested by: Mrs Oppenheimer (Obs/Gynae)
Information supplied:
• I wish to prescribe this treatment for a young woman with Swyer Syndrome
who has recently undergone gonadectomy and now requires HRT. • Initial treatment in such a rare condition needs to be hospital-based and once • I understand there is a requirement within the Directorate for continuous C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc Reference cited: Nil

Background information
This is a retrospective request for a young woman with Swyer’s syndrome that
has recently had her ovaries removed. She has an intact uterus and therefore
requires combined HRT to prevent menopausal symptoms and reduce the risk
of osteoporosis. Transdermal patches have been requested to aid concordance,
as this treatment will be required long-term due to her young age. At present
UHL pharmacies do not routinely stock any continuous combined HRT
preparations. Although this request is for an individual patient it would be useful
to have an oral and transdermal preparation available for initiation by UHL
consultants. The Recommended Drugs List for General Practice (April 2003)
based on the August 2002 version of the Leicestershire Prescribing Guide
includes 2 recommended tablet formulations i.e. Elleste Duet Conti and
Premique. It is therefore also proposed that Elleste Duet Conti be added to the
UHL formulary as the preferred oral preparation.

Literature review
Dr G Swyer first described Swyer’s syndrome in the 1950s. It belongs to a group
of conditions known as gonadal dysgenesis. It is a chance occurrence where
the testes or ovaries do not develop in the usual way during early pregnancy
and does not run in families. Girls with Swyer’s syndrome have XY (usual male)
genes but the Y chromosome and gonads do not function in the usual way.
They are usually born with a uterus and vagina but the ovaries are
underdeveloped. Swyer’s syndrome is usually diagnosed at puberty when not all
the usual changes occur. Swyer’s syndrome is usually managed with hormone
replacement therapy (HRT), which allows the breasts and normal female body
shape to develop. HRT also helps to prevent osteoporosis in later life. There is a
30% chance of some gonadal cancers, so the gonads are usually removed
(before puberty). Women with Swyer’s syndrome are infertile, as the original
gonads do not contain eggs. However, it may be possible for donor eggs to be
used to create a pregnancy that can be maintained with hormonal treatment. 1
The evidence for using combined HRT (with oestrogen and progestogens) to
prevent or treat menopausal symptoms in women with an intact uterus is well
established. One systematic review and subsequent randomised controlled
trials found that oestrogen plus progestogens improved vasomotor symptoms,
urogenital symptoms and psychological symptoms in the short-term compared
with placebo. However, important adverse effects include increased risk of
breast cancer and venous thromboembolic disease (attributed to oestrogens). 2
Long-term use of HRT (> 5 years) is no longer recommended to prevent
osteoporosis because there is evidence of an increase in the overall risk of
adverse cardiovascular events in older women. One systematic review (18
RCTs, 5247 women) found significant reductions in the incidence of endometrial
hyperplasia when women receiving oestrogen were given progestogens either
cyclically or continuously, with combined HRT having the greatest effect at 36
months (RR for continuous combined HRT vs. oestrogen only HRT 0.17, 95%
CI 0.02-1.26). 2
1. Anon. Swyer’s Syndrome Fact sheet [on-line]. Available at: [accessed 29th July 2005]. C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc 2. June 2005. Tovey D (Ed). Clinical Evidence No. 13 [on-line]. Available at: [accessed 29th July 2005]. Following discussion this request was approved. Members also agreed
that an oral combination HRT should be made available for use within
UHL. Following discussion it was felt that elleste-combi should be made
available. Both these drugs will be classed as green for traffic light
purposes. It was also agreed that premique should no longer be stocked
within UHL.
ACTION: MQ to write to Clinical Director re decision

4.4 Lanreotide autogel for intractable diarrhoea
Requested by: Mr Dennison for use in approx. 6 patients per year
Information supplied:
• Essentially longer acting version of the only product found to control the
• Some
Reference cited: Nil
This product currently has approval in UHL for acromegaly and reducing
intractable diarrhoea in neuroendocrine tumours. The request is for an
unlicensed indication although lanreotide and octrotide are often used in
short bowel syndrome patients to reduce secretions. The autogel
presentation allows fewer injections (half as many) and as it is pre-filled
may allow some patients to self treat at home. Several studies have
suggested that lanreotide/octreotide can reduce intractable diarrhoea
regardless of aetiology. This request refers to a particular patient who has
already responded well to i/m lanreotide treatment.
Following discussion this request was approved. However MQ pointed
out that while Lanreotide autogel had advantages over i/m lanreotide, this
latter product had never actually been approved for reducing severe
diarrhoea. Members agreed therefore that when writing to the Clinical
Director it should be pointed out that this drug has not been approved for
this indication and to seek guidance on whether the Clinical Director
wished this to be processed further. It has been classed as red for this
ACTION: MQ to write to Clinical Director re decision

4.5 Bicavera for peritoneal dialysis in paediatric patients requiring
lactate free bags
Requested by: Dr D Luyt (Paediatrician)
Information supplied:
• To be used in paediatrics and cardio-respiratory
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc • Peritoneal dialysis tends to be used in neonates as very effective and at present have problems with CVVH in neonates • Neonates on PICU tend to be critically unwell with high lactate and metabolic acidosis. Dianeal is high lactate and Physioneal is still “high lactate”. • BicaVera far superior as no lactate and as it is bicarbonate based it should be • NB Should also be more cost effective • For use in neonates and paeds across Directorates but mainly at Glenfield.
Reference cited: Nil
Related abstracts
Adv Perit Dial. 1997;13:179-82. Advantages of HCO3 solution with low sodium concentration over standard lactate solutions for acute peritoneal dialysis. Vande Walle J, Raes A, Castillo D, Lutz-Dettinger N, Dejaegher A. The aim of this study was to identify the advantages of a bicarbonate solution with a low sodium concentration. Twelve children (3 days-6 years) with acute renal failure (ARF), positive fluid balance, and lactate acidosis (> 40 mg/dL) were treated by automated peritoneal dialysis (APD) with frequent exchanges of small fill volumes of a hypertonic solution. For Day 1 we used PD1/PD4 Dianeal (3.86%) (Baxter). After 24 hours we switched to a HCO3 solution: 38 mmol/L, Na 128 mmol/L. As the control group, we studied retrospectively the last 12 children of the previous period who were treated with APD. The age distribution was 4 days to 4 years. No significant differences were found between the groups for serum creatinine, blood urea nitrogen, and fluid overload (Day 1 to Day 4). Although the values for lactate and Na were not different before the start of the study (Day 1) and after 24 hours of Dianeal (Day 2), they were significantly lower in the study group on Day 4 [HCO3 53 (23-83), Na 148 (137-136) mEq/L] than in the control group [lactate 148 (137-156), Na 154 (142-165) mEq/L]. A low sodium concentration results in higher sodium extraction, which is important for patients with fluid overload. Low sodium concentrations in APD are needed because the peritoneal membrane "sieves" the sodium during short dwells. HCO3 dialysis is a logical choice for patients with lactate acidosis, resulting in a significant lower serum lactate and increase of BE after 48 hours of treatment. J Pediatr. 1977 Jul;91(1):101-5 Neonatal lactic acidosis and renal failure: the role of peritoneal dialysis. Nash MA, Russo JC. Lactic acidosis accompanied by acute renal failure in the newborn period was studied in two infants with circulatory insufficiency and hypoxia. Peritoneal dialysis was necessitated by anuria and serum potassium concentrations of 12.0 and 8.9 mEq/1. Plasma lactate concentration was 35 and 50 mM/1 and blood pH 7.23 and 7.18, respectively, at the time dialysis was instituted. Because of the uncontrollable anaerobic metabolism in these two patients, and the attendant inability to metabolize lactate, the use of commercial lactate-containing dialysates as a source of base was shown to be ineffective in correcting the acidosis and hypothesized to cause a worsening of metabolic acidosis due to a loss of bicarbonate from extracellular fluid into dialysate. C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc Stabilization or improvement in the metabolic acidosis occurred with the
utilization of a dilaysate containing bicarbonate with a gradient favoring
movement of bicarbonate into, and lactate out of, extracellular fluid.

While this appears to be the only product available for paediatrics that is
lactic free concerns where raised as to whether other centres are using
this product. AEJ suggested that the regional neurology service be
contacted re any evidence for use. MQ agreed to contact the HoS.
ACTION: MQ to contact Head of the Regional Nephrology Service
4.6 Flunarazine capsules for alternating hemiplegia of childhood
(refractory epilepsy)
Requested by: Dr Jay Gosalakkal (Paediatric Neurologist)
Information supplied:
• Maintenance dose 5-10mg daily
• Only specific treatment for alternating hemiplegia • For use in specialty only
References cited:
- Behrman, Kliegman & Jenson. Nelson Textbook of Pediatrics. 16th edition.
- Anon. Flunarizine DrugDex evaluation [on-line]. - Available from: [accessed 29th June 2005] Literature review Alternating hemiplegia of childhood is occasionally associated with migraine, but in most cases the cause is unknown. 1 It develops in infants between 2 and 18 months of age and is characterised by intermittent episodes of hemiplegia alternating from one side of the body to the other. Rarely, both sides are involved during an attack. Choreoathetosis and dystonic movements are commonly observed in the hemiparetic extremity. Symptoms spontaneously regress with sleep but recur with wakening. The hemiplegia persists for minutes to weeks and resolves spontaneously. The condition has a poor prognosis with progressive mental retardation and developmental problems. Results of neuroimaging and metabolic studies are predictive. Flunarizine (a selective calcium-entry blocker) is not licensed for this indication in children, but there is some evidence supporting it. The pivotal studies were carried in the 1980s and 1990s. The first study established the dose range of 5-10mg daily. 2 The main efficacy study carried out by Silver and Andermann was published in 1993. They used flunarizine in 10 patients with alternating hemiplegia. The duration of attack was reduced by up to 85% in 7 out of 9 patients but was unaffected in 2 when treated with flunarizine 5 to 25mg daily. Reduced frequency of attack (average 55%) was noted by 3 patients, while one had increased frequency. The authors concluded that the effect of flunarizine on the long-term course of this condition at that time was uncertain. 3 A more recent study in 44 patients with alternating hemiplegia of childhood whose presenting signs included abnormal ocular movements 65%, dystonia 60% and hemiplegia in 32%. 4 Patients with an early onset of the disorder and early appearance of hemiplegic spells faired poorest developmentally. Developmental delay was present in 91%, ataxia in 68%, choreoathetosis in 50%, and seizures in 18%. Laboratory investigations suggested mitochondrial abnormalities and cerebrovascular dysfunction in several patients. Numerous therapies were found to be ineffective. Flunarizine reduced the duration, severity C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc and frequency of attacks in 78%. Patients that received flunarizine did not differ developmentally from those who did not. The authors concluded that their data suggest that flunarizine does not adversely affect and may favourably influence the outcome in patients with alternating hemiplegia of childhood. In addition, the occurrence of autosomal-dominant cases of the syndrome, although rare, suggests that genetic factors may be important. Sasaki et al followed up 28 patients with alternating hemiplegia by sending out a questionnaire. 5 All patients had received flunarizine. In 18 of the 28 patients, flunarizine reduced the severity, duration, or frequency of hemiplegic attacks. No other drug was more effective than flunarizine. Some patients in whom flunarizine was not effective were in a poor condition e.g. they had dementia or were ventilator assisted. Flunarizine had not only a short-term effect but in the long-term improved motor and interlectual development in some patients with alternating hemiplegia of childhood. Current cost for 28 days supply (inc. VAT) * 5-10mg daily = £11.38-£22.77 * Information supplied by Customer Services at IDIS World Medicines (minimum order value £30.00) on 15th August 2005 References: 1. Behrman, Kliegman & Jenson. Nelson Textbook of Pediatrics. 16th edition. 2. Caers et al. Clinical Neuropharmacology 1987; 10 (2): 162-168 3. Silver k & Andermann F. Neurology 1993; 43: 36-41 4. Pediatric Neurology 2000; 23 (2): 134-141 5. Brain and Development 2201; 23 (5): 303-305 Following discussion members felt that further information was required before this product was approved. In particular it was felt that other specialist centres should be contacted to seek further guidance on its place in the therapy. AM agreed to contact colleagues around the UK to ascertain whether this product is available. Request deferred until the next meeting. ACTION: AM to contact colleagues re this request

4.7 Botulinum toxin for recurrent anal fissures

Requested by: Mr Thomas (Consultant Surgeon) for use in approx. 4-6 patients
per year
Information supplied:
• If used it may prevent this patient from having a lateral sphinctectomy, which
may cause permanent damage to sphincter. Reference cited: Nil
Literature Review
Currently, the basis for management of chronic anal fissure is reduction in anal
sphincter tone either by surgical sphincterectomy or, more recently, by use of
drugs. Aims of treatment are to relieve the symptoms of pain, anal bleeding and
irritation, heal the fissure and minimize adverse effects of treatment (2).
Principal outcome measures are persistence of the fissure (measured by
persistence of anal pain) and post treatment minor incontinence. The distinction
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc between persistence and recurrence is difficult to make, since the condition typically waxes and wanes (3). In January 2003, the American Gastroenterology Association (AGA) issued a medical position statement on the diagnosis and care of patients with anal fissure (4). This concludes that topical therapy and botulinum toxin injection are acceptable options for the management of anal fissure – “even if not entirely proven”. Because of low morbidity profiles, they may be considered as first line treatment and not just salvage treatment for failed conservative care. This position statement is based on an accompanying technical review by the AGA (5). A similar conclusion was reached by the authors of a Cochrane review (3) : “Medical therapy for chronic anal fissure, acute fissure and fissure in children may be applied with a chance of care that is only marginally better than placebo…. and might be used in individuals wanting to avoid surgical therapy”. Current advice from PRODIGY is that topical GTN (see 5.9 below) is recommended as first-line for the treatment of chronic anal fissure in adults (1). Use of botulinum toxin for chronic anal fissure has been reviewed in Clinical Evidence [2] and by Lindsey et al (6). It has potential advantages over other medical treatments as it is given by a single injection into the internal sphincter and appears to be well tolerated. Botulinum toxin produces a constant reduction in maximum resting pressure that is sustained over 2-3 months which should lead to improved healing. Side effects such as short-term minor incontinence and urgency are infrequent and transient (6). Randomised controlled trials have found higher rates of fissure healing with botulinum toxin versus placebo and versus topical GTN. One study demonstrated improved healing rates when injection of botulinum toxin was followed by use of topical isosorbide dinitrate when compared to injection alone (7). However, use of BT has not been consistently effective, with one study showing no difference from placebo when a single dose was used (8). The mechanism of action of BT and its optimal dose and injection site have been the subject of debate (6). A recent study has shown that, taking into account a conversion for biological potency, there was no difference in efficacy and tolerability between two preparations of serotype A, Botox and Dysport (9). Limited data suggest that healing rates are lower in GTN-resistant fissures (6,10). References 1.PRODIGY guidance – anal fissure (revised April 2005) accessed 25.5.05 2. Anal fissure: In Clinical Evidence No 13 April 2005. BMJ Publishing Group . 3. Nelson R. Non surgical therapy for anal fissure The Cochrane Database of Systematic Reviews 2003 Issue 4 John Wiley & Sons. ,accessed 31.3.05 4. American Gastroenterological Association. Medical position statement: Diagnosis and care of patients with anal fissure. Gastroenterology 2003;124:233-234 5. Madoff R D and Fleshman J W for American Gastroenterological Association. AGA technical review on the diagnosis and care of patients with anal fissure. Gastroenterology 2003;124:235-245 6. Lindsey I et al. Chronic anal fissure. Br.J.Surg. 2004;91:270-279 7. Lysy J et al. Topical nitrates potentiate the effect of botulinum toxin into treatment of patients with refractory anal fissure. Gut.2001;48:221-224 8. Siproudhis L et al. Lack of efficacy of botulinum toxin for chronic anal fissure. C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc 9. Brisinda G et al. Botulinum neurotoxin to treat chronic anal fissure: results of a randomised “Botox vs Dysport” controlled trial. 10. Lindsey I et al. Botulinum toxin as second-line therapy for chronic anal fissure failing 0.2 per cent glyceryl trinitrate. Dis. Colon Rectum 2003;46:361-366 Following discussion it was felt that Mr Thomas should be contacted re what other products had been tried in this patient before approval be made. EAS suggested that botox might already have beenused for this indication and MQ agreed to investigate this. It was therefore recommended that an algorithm for the treatment of anal fishes be requested from Mr Thomas and Mr Jameson (see below for GTN ointment) before approval be made for this product. Therefore request deferred. ACTION: MQ to contact Mr Thomas re other products tried, MQ to
write to Mr Thomas and Mr Jameson re potential algorithm

4.8 Sodium oxybate oral solution for narcolepsy

Requested by:
Dr C D Hanning (Sleep Medicine)
Information supplied:
Better control over daytime sleepiness and cataplexy
References cited: Nil
Literature Review
Sodium oxybate also known as gamma hydroxybutyrate (GHB) is a central
nervous system depressant that is licensed in the US for cataplexy associated
with narcolepsy 1. It is available in the form of an oral solution containing 0.5g/ml
with the brand name Xyrem® (Orphan Medical). Distribution is tightly regulated
because of the significant potential for abuse and adverse nervous system
effects including respiratory depression and death. For adults with cataplexy
associated with narcolepsy, the recommended starting dose is 4.5g (9ml) daily
orally in 2 equal doses of 2.25g taken at bedtime (while in bed) and then 2.5 to 4
hours later. The dose may be increased to a maximum of 9g/day in two-weekly
increments of 1.5g daily. In clinical trials 80-85% of patients continued to receive
stimulant medication during daytime. Comparisons with other treatments for
narcolepsy have not been published.
Following the publication of several small studies in the 1980s and 1990s 2-5, the
product licence for Xyrem® was granted on the basis of data from 2 randomised,
double-blind placebo-controlled trials:
The first study enrolled 136 narcoleptic patients with moderate to severe
cataplexy (3-249 attacks per week, median 21) 6. After discontinuation of
treatments for cataplexy, the patients underwent a washout period before being
assigned to sodium oxybate (3, 6, or 9 grams) or placebo, administered in equal
divided doses at bedtime and 2.5 to 4 hours later, for 4 weeks. Stable doses of
stimulants were permitted. The one patient with 249 attacks per week (who was
receiving the 6g dose) had an aberrant response to sodium oxybate, with an
increase in attacks over the 4-week study. Excluding his data from analysis, the
weekly frequency of cataplexy decreased with the 6g and 9g doses when
compared to placebo (p=0.0529 and p=0.0008, respectively). Daytime
sleepiness, as assessed by Epworth Sleepiness Scale (ESS) improved in all
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc groups in a dose-related manner, reaching statistical significance (p=0.0001) in
the 9g dose group when compared to placebo. There were significant
decreases in the number of inadvertent naps/sleep attacks at both the 6g and
9g doses (p=0.0497 and p=0.0122, respectively) and in nocturnal awakenings at
the 9g dose (p=0.0035). The most common adverse events were nausea,
vomiting, dizziness, and enuresis. One patient experienced a serious adverse
event in the form of an acute confusional state. During the 3-5 day washout
period at the end of the trial, the number of cataplexy attacks increased in each
treatment group.
The second study was designed to assess the longer-term safety of sodium
oxybate and the effect of withdrawing treatment 7. 55 narcoleptic patients that
had been taking sodium oxybate (3-9g per night) for 7-44 months (mean 21
months) were randomised to placebo (n=29) or continued treatment (n=26) for 2
weeks. The primary efficacy measure was the frequency of cataplexy attacks.
Patients randomised to placebo experienced a significant increase in cataplexy
attacks (P<0.001) compared with those that continued to receive sodium
oxybate. Symptoms of anxiety, dizziness, insomnia and somnolence reported in
patients receiving placebo were considered to be consistent with the returning
symptoms of narcolepsy.
In addition a comprehensive literature search identified the following open label
extension study.8 118 narcolepsy patients that were included in the original 4-
week study took sodium oxybate 3, 4.5, 6, 7.5, or 9 grams nightly, on the same
schedule. Sodium oxybate produced overall improvements in narcolepsy
symptoms that were significant after 4 weeks and maximal after 8 weeks.
Reported improvements included a significant decrease in frequency of
cataplexy attacks (p<0.001); diminished daytime sleepiness (p<0.001); and
patient descriptions of nocturnal sleep quality, level of alertness, and ability to
concentrate (p<0.001 for each). The most common adverse events were
headache, nausea, viral infection, dizziness, pain, enuresis, and somnolence.
Cost (inc. VAT)
Sodium oxybate 0.5g/ml oral solution (pack size 180ml) = £194.00 9
Note: This represents approximately 2 weeks treatment at a dose of 6g (12ml)
each night
1. Anon. Sodium oxybate (DrugDex evaluation). In: Hutchinson T A & Shahan D
R (Eds). DrugDex System. Micromedex, Greenwood Village, Colorado. (Expires end 06/04, volume 120). 2. Canadian Journal of Neurological Sciences 1979; 6 (1): 1-6 3. Journal of Clinical Psychiatry 1985; 46 (6): 222-5 4. Biological Psychiatry 1989; 26 (4): 331-43 5. Sleep 1990; 13 (6): 479-90 6. Sleep 2002; 25 (1): 42-49 7. Journal of Toxicology and Clinical Toxicology 2003; 41 (2): 131-5 8. Sleep 2003; 26 (1): 31-5 9. IDIS World Medicines. Karen, Customer Services. 25th March 2004 [personal MQ reminded members that this product had been reviewed in May of last year for patients who had undergone a clinical trial and had been successfully treated. It had been made available for compassionate use for those patients and it was agreed at that time that the request should C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc be supported. This new request has been submitted for naïve patients who have failed other treatments such as modafinil and venlafaxine. AM pointed out that venlafaxine is in fact not licensed for this indication nor has been given TAS approval for this indication. AM also pointed out that sodium oxybate is currently in the 90 day assessment period for licensing approval. Following further discussion members felt that this request should be deferred until the product has been licensed. However if Dr Hanning wished to attend the next meeting to seek earlier approval then he could do so. The request was therefore deferred. ACTION: IS to write to Dr Hanning re decision and potential invite to
next meeting

4.9 Glyceryl trinitrate ointment for anal fissures

Requested by: Mr Jameson (Consultant Surgeon)
Information supplied:
• Better shelf life than unlicensed product
• Metered dosage
Reference cited: Nil
Literature Review
See 5.7 above. In addition:
Nitric oxide has been shown to be an important transmitter in the human internal
anal sphincter and mediates smooth muscle relaxation (1). First reports of the
use of topical GTN appeared in 1992 and 1993 where a reduction in anal canal
pressure was demonstrated in normal (2) and constipated patients (3). Effects
of topical GTN in anal fissure have been reviewed in Clinical Evidence (2 – in
5.7 above) and in a Cochrane Systematic Review (3 – in 5.7 above). Other
recent reviews have included topical GTN amongst a range of non-surgical
treatments for chronic anal fissures (4,5).
Two randomized, placebo-controlled studies involving 80 (6) and 70 (7) patients
with chronic anal fissure treated with topical GTN 0.2% two and three times daily
respectively for 8 weeks found significant healing in the treatment groups versus
placebo. Furthermore, Kennedy et al (8) noted a significant reduction in pain
score after 4 weeks treatment with 0.2% topical GTN in a group of 43 patients
(p=0.001) and a significant reduction in fissure grade (p=0.0001). A total of 46%
of fissures healed with GTN compared with 16% with placebo (p=0.001). Long-
term follow up after a mean of 28 months showed long-term healing in 59% of
chronic anal fissures and significant improvement in pain.
In contrast, Altomare et al (9) failed to demonstrate any significant difference in
healing between patients with chronic anal fissure treated for 4 weeks with 0.2%
GTN ointment twice daily and those given placebo.
A recent multicentre, randomized, double-blind study has attempted to
determine the optimum dose regimen for GTN ointment for chronic anal fissures
(10). 300 patients were randomized to receive 0, 0.1, 0.2 or 0.4% GTN ointment
applied either twice or three times a day for up to 8 weeks. There were no
significant differences in fissure healing among any of the treatment groups. All
groups, including placebo, had a healing rate of approximately 50%. The
highest strength GTN ointment gave a significant decrease in average pain
intensity compared with placebo (10).
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc Two open studies have used GTN ointment 0.5% (11,12). Symptomatic relief
was seen within 2 days in most cases and within a week in 18 patients in one
study (11). Twelve of 14 patients had complete healing. In the second study
(12), 73% of the 45 patients healed within 6 weeks. 84% experienced
headache and there was an 11% incidence of headache-related non-
compliance. No difference in healing rates was noted in a comparative study of
0.2% GTN ointment and a 10mg GTN patch (13). In contrast, a later study (14)
in 89 outpatients showed that application of a GTN patch (Nitroderm TTS5)
applied for 12 hours a day produced complete resolution of symptoms in 38/52
patients vs 24/37 given GTN 0.2% ointment at 6 weeks but relapse by 12 weeks
was seen in 7/48 in the patch group versus 3 of 34 in the ointment group. Four
patients in the treatment group and 3 in the control group declined further
treatment after 6 weeks.
Rectogesic 0.4% rectal ointment was approved in the UK in September 2004 for
pain associated with chronic anal fissure. The 0.4% formulation was selected to
deliver the same amount of active drug as used in the majority of clinical trials,
but in a smaller volume for patient convenience. The product was developed by
Cellegy and is licensed to Strakan who are responsible for sales, marketing and
distribution. It was launched in May 2005 (15). There are no other products with
a UK licence for this indication.
1. O’Kelly T J et al. Nerve mediated relaxation of the human internal anal
sphincter: the role of nitric oxide. Gut 1993;34:689-693 2. Guillemot F et al. Nitroglycerin in situ reduces upper anal canal pressure. 3. Guillemot F et al. Action of in situ nitroglycerin on upper anal canal pressure of patients with terminal constipation. A pilot study. Dig.Dis.Rectum 1993;36:372-376 4. Jones O M et al. The physiology, pharmacology and therapeutic manipulation of the internal anal sphincter. Can.J.Gastroenterol. 2002;16(4):249-257 5. Brown S R et al. The management of persistent and recurrent chronic anal 6. Lund J N and Scholefield J H. A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in the treatment of anal fissure. Lancet 1997;349:11-14 7. Carapeti E A et al. Randomised controlled trial shows that glyceryl trinitrate heals anal fissures, higher doses are not more effective and there is a high recurrence rate. Gut 1999;44:727-730 Glyceryl trinitrate ointment for the treatment of chronic anal fissure results of a placebo-controlled trial and long term follow up. Dis.Colon Rectum 1999;42:1000-1006 Glyceryl trinitrate for chronic anal fissure-healing or headache? Results of a multicenter, randomised, placebo-controlled, double-blind trial. Dis.Colon Rectum 2000;43:174-179 10. Bailey H R et al. A study to determine the nitroglycerin ointment dose and dosing interval that best promote the healing of chronic anal fissures. Dis.Colon Rectum 2002;45(9):1192-1199 11. Ward D I et al. Cut or paste? The use of glyceryl trinitrate paste in the treatment of acute and chronic anal fissure. Aust.N.Z.J-Surg.2000;70(1):19-21 12. Palazzo F F et al. Glyceryl trinitrate treatment of chronic fissure in ano: one year’s experience with 0.5% GTN paste. J.Roy.Coll.Surg.Edin.2000;45(3):168-170 C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc 13. Zuberi BG F et al. A randomised trial of glyceryl trinitrate ointment and nitroglycerin patch in healing of anal fissures. Int.J.Colorectal Dis.2000;15(4):243-45 14. Colak T et al . A randomised study comparing transdermal treatment and local application of glyceryl trinitrate ointment in the management of chronic anal fissure. Eur.J.Surg.2003;Suppl 588:18-22 15. Rectogesic 0.4% Rectal Ointment Summary of Product Characteristics per electronic Medicines Compendium 6.06.05 AM advised that under normal circumstances the norm would be to use the licensed product over an unlicensed product due to the low potential for litigation following misuse. While the licensed version has a higher concentration than the currently stocked unlicensed GTN ointment it was pointed out that the same dose would be received due to the difference in application. The request was therefore supported. Its use would be second line following lidocaine gel. It was also agreed that Diltiazem should still be available for those patients unable to tolerate GTN ointment. This decision would also depend on any algorithm produced by Mr Thomas (and Mr Jameson) see botulinum toxin above) ACTION: MQ to inform Directorate Lead Pharmacist re decision.
DLP’s to inform where appropriate Clincial Directors of the
availability of the new concentration of GTN ointment.

5. Any Other Business
MQ asked members of TAS whether they would be happy for information
regarding membership of the Group to be placed on the TAS website. This
would include names of members plus some additional information re clinical
background. Members where happy for this to occur with the proviso that a
further statement be added regarding access to members from e.g.
pharmaceutical representatives.

ACTION: MQ to write to members to seek paragraph re clinical
background etc

6. Date & Time of next Meeting
C:\Documents and Settings\Sue\Local Settings\Temporary Internet Files\Content.IE5\BU4RZPC1\77 TAS minutes - 15-08-05.doc


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