PRIMARY CARE BRIEFING GLUSARTEL (GLUCOSAMINE SULPHATE)

Transcription

1 Summary This Primary Care Briefing informs healthcare professionals of a new preparation of glucosamine sulphate, Glusartel, licensed for the relief of symptoms in mild to moderate osteoarthritis of the knee and presented as a preparation of 1500 mg ( 1178 mg glucosamine) as a powder for oral solution 1. A number of high-quality systematic reviews, including publications by NICE and Cochrane, have previously assessed the role of glucosamine both as the hydrochloride and sulphate salts. Their work has suggested some moderate benefits associated with glucosamine sulphate but with an evolving trend toward demonstration of lesser overall effectiveness than previously thought. A recent meta-analysis in the BMJ concluded that glucosamine and chondroitin do not significantly improve joint pain, although the effects of glucosamine sulphate were not analysed separately. The manufacturers state that since current reimbursable prices for unlicensed glucosamine sulphate exceed those of Glusartel, significant cost savings could be realised were their product adopted. They also state that since Glusartel is a licensed product its quality can be guaranteed in comparison with alternatives. However, although published prior to the availability of Glusartel, neither the 2008 NICE guidance nor a 2009 Health Technology Assessment identified glucosamine as a cost-effective intervention for the NHS, with NICE recommending patients purchase their own glucosamine sulphate 1500 mg daily as a food supplement should they wish to trial it. This approach is re-iterated in the recent BMJ article which suggests health systems should not be expected to cover the cost of this intervention (although no new economic data is presented and the study does not consider the NHS specifically). It is conceivable that for some PCTs Glusartel may offer a possibility to reduce the cost of prescribing for glucosamine sulphate; however, such prescribing on the NHS continues to be out-of-step with NICE and other guidance that suggests patients should meet the cost of trialling therapies. A brief digest of the evidence available is presented below together with an outline of figures we understand the manufacturing is distributing to PCTs suggesting cost benefits. Prescribing information is also included. A brief update on the evidence NICE guidance 2 London New Drugs Group October 2010 PRIMARY CARE BRIEFING GLUSARTEL (GLUCOSAMINE SULPHATE) The National Collaborating Centre (NCC) published clinical guidelines on osteoarthritis on behalf of NICE in Part of their work considered the role of neutraceuticals including glucosamine and chondroitin. With reference to glucosamine they considered a single meta-analysis (the Cochrane review discussed below) and 2 additional RCTs. The identified that studies in the area are heterogeneous in terms of the site of osteoarthritis (OA), the presentation of glucosamine as hydrochloride or sulphate, the choice of comparator, the method and dose of administration, trial size and length, and the method used to measure outcome. The NCC considered the various outcomes separately and report symptomatic effects such pain, stiffness, and function; as well as outcomes including structural modification, global assessment, quality of life, and adverse effects. It is quite striking that for the vast majority of outcomes presented the effect of glucosamine was statistically insignificant against any comparator. It is, however, the case that for those studies in which statistical significance was reached, glucosamine sulphate (as opposed to hydrochloride) was the active intervention. Given the generally poor evidence base identified the conclusions of NICE are unsurprising: they do not recommend glucosamine for use within the NHS. With reference to glucosamine sulphate, NICE considered that a small benefit over placebo is possible for the symptomatic treatment of knee OA only. However, at the time the guidance was written glucosamine sulphate was unlicensed, and the evidence determined to be of insufficient strength to recommend prescribing on the NHS regardless of a limited expectation of potential harm. In addition, NICE considered studies measuring joint-space narrowing to be of questionable value in determining whether glucosamine has longer term structural modification and progression benefits. With reference to cost effectiveness, NICE considered that only glucosamine sulphate could potentially be cost effective, but that a wide range of incremental cost-effectiveness ratios (ICERs) were reported and that the poorest estimates of efficacy would take it beyond the threshold of affordability in the NHS. As a way forward, NICE recommend that patients wishing to trial glucosamine should be advised that potential benefits identified in early research are purely related to a reduction of pain (for some people and to only mild or modest degree), and that those occurred with glucosamine sulphate 1500 mg daily. They suggest that patients

2 use an over-the-counter trial of therapy, evaluating their pain before starting glucosamine and reviewing the benefits after three months. Health Technology Assessment 3 An extensive and recent health technology assessment is available evaluating the clinical and economic considerations of glucosamine use in OA. The full review is available at: The review identified 5 systematic reviews, 1 guideline, and also separately assessed another 8 clinical trials. The HTA recognises the statistical significance of the findings for glucosamine, but questions the clinical significance of the findings of both previous reviews and guidelines and the 8 clinical trials independently assessed. The HTA recognises the potential superiority of glucosamine sulphate against other glucosamine salts, but suggests limited clinical significance for the differences. In summary the HTA authors conclude in their Executive Summary: There was evidence that glucosamine sulphate shows some clinical effectiveness in the treatment of OA of the knee. No trial data came from the UK, and in the absence of good UK data about the current referral practice, management and surgical rate, caution should be exercised in generalising these data to the UK health-care setting. Cost-effectiveness was not conclusively demonstrated, with substantial uncertainty related to the magnitude and duration of QoL gain following treatment. There was evidence from biological studies to support the potential clinical impact of glucosamine sulphate. For other preparations, the evidence base was less consistent (chondroitin) or absent (glucosamine hydrochloride). Cochrane review: Glucosamine therapy for treating osteoarthritis 4 This review considered RCTs evaluating the safety and effectiveness of glucosamine in osteoarthritis both placebo and comparative studies were included although trials involving combination preparations (e.g. those with chondroitin) were excluded, studies were of either single or double blinded design and included patients with OA at any body site excluding the temporomandibular joint. Outcome measures considered included pain (assessed using a variety of scales), range of motion, functional assessment, and global assessment. For the most recent update the review considered the literature up to January 2008 for glucosamine sulphate (GS) and glucosamine hydrochloride (GH). 25 trials were included all of which had a double-blind randomised parallel group design, but with wide variation in trial duration from 3 weeks to 3 years (mean 25.5 weeks). The trials represented a total of 4963 patients of whom 1905 received glucosamine and 3058 comparator (either placebo or active). The trials were quite heterogeneous in the choice of comparator, the method of administration of glucosamine, and the type and site of OA evaluated. Fourteen of the 25 trials investigating GS use alone had some link to the product s manufacturer, Rotta Pharm. For the GS studies alone the pooled data showed the following. For pain reduction pooled data from 8 RCTs showed an effect in favour of glucosamine (standardised mean difference (SMD) -1.11, (95% CI to )). For Lequesne index scores (a composite marker of 3 categories related to OA severity) pooled data from 5 RCTs showed effects in favour of GS (SMD (95% CI to -0.12)). And for a reduction in WOMAC score (the Western Ontario and McMaster Universities Arthritis Index) pooled data from 3 RCTs showed effects in favour of GS also (SMD (95% CI to -0.01)). Considering pooled results from the GS sub-group against the main findings of the review, the results are analogous in that statistically significant improvements in favour of glucosamine where found for a similar variety of outcomes regardless of preparation. It is worth noting, however, that whilst pooled outcome results that included both GH and GS did suggest benefit, 7 RCTs failed to show effects of glucosamine above placebo. In addition, the only head-to-head study of GS vs GH included failed to show superiority of the former. In essence then whilst there is evidence suggesting glucosamine is beneficial it is conflicting and evolving with an apparent trend towards a demonstration of decreased effectiveness than previously supposed. The Cochrane authors note this evolving evidence base. They discuss that when the 2005 review was undertaken with 20 studies and 2570 participants, GS produced a 28% benefit from baseline in pain reduction and a 21% increase in function (as measured using the Lequesne index), but that inclusion of more recent data in the 2008 update has reduced the percentage benefits associated with GS to 22% for pain reduction and 11% for an increase in function with overall benefits for WOMAC scores no longer present for pooled GS and GH data. Drugs and Therapeutics bulletin 5 The DTB bulletin presents a previous version of the Cochrane review discussed above (the 2005 update). In addition the bulletin presents another systematic review published in the Annals of Pharmacotherapy that

3 pooled data from 2 RCTs, a meta-analysis that pooled data from 15 RCTs, and 2 further randomised controlled trials. With reference to the larger meta-analysis included in the DTB review, the pooled effect size for all types of glucosamine was 0.35 (95% CI 0.14 to 0.56), rising to 0.44 (95% CI 0.18 to 0.70) for glucosamine sulphate, and falling to 0.06 (95% CI to +0.20) for the hydrochloride salt. The authors concluding that even for glucosamine sulphate enough heterogeneity existed between the studies that no definitive conclusion about efficacy was possible. The DTB bulletin also discusses the NICE guidance in the area and they conclude in a similar vein to NICE: recommending that glucosamine hydrochloride should not be prescribed on the NHS and that glucosamine sulphate at a dose of mg daily may provide modest pain relief in knee osteoarthritis but that its use on the NHS is precluded by limited data on cost effectiveness. They recommend that patients wishing to trial glucosamine sulphate should be advised to purchase it as a food supplement. New Product Review Pack: Glusartel, HFA Healthcare Limited 6 The manufacturer has produced an extensive (53 page) review pack supporting their product, which we understand is being circulated to PCTs. Six key studies are presented in making the case for the efficacy of glucosamine sulphate, 2 of which were included in the Cochrane review discussed above. For the 4 studies not previously discussed, 2 were short (4 week) trials assessing investigator defined endpoints only these studies are unlikely to add significantly to the evidence already presented by Cochrane and others. The 2 other trials were longer term 3-year studies, designed to assess effects on joint progression in knee OA. These studies suggested benefit for glucosamine for some patients over a longer time frame in reducing pain in OA, as well as reporting changes in joint structure and progression. However, both studies reported effects on joint-space narrowing as their endpoint for structural changes, and as previously discussed NICE consider this endpoint of questionable value. An analysis is also presented that assessed the incidence of total knee replacement for patients previously enrolled in glucosamine studies. The findings suggested glucosamine sulphate to be associated with a potentially decreasing the incidence of total knee replacement; however, this was a retrospective uncontrolled analysis open to confounding and its results at best exploratory at this point. BMJ meta-analysis 7 This systematic review and network meta-analysis included data from 10 trials with a total of 3803 participants in which glucosamine, chondroitin, or a combination of both were compared with placebo. Pre-specified study selection criteria and outcome measurement criteria were included, with primary outcome being absolute pain intensity reported at a number of time windows within each study. Secondary outcomes included changes in the minimum radiographic joint space. Meta-analysis of the results was undertaken using a random-effects model at the level of trials and time points. The characteristics of included studies were 5 trials (1104 patients) in which glucosamine sulphate was compared with placebo; 1 trial (205 patients) in which varying glucosamine sulphate and hydrochloride preparations were used; 3 trials (1229 patients) that compared chondroitin sulphate with placebo; and 1 trial (1265 patients) that compared glucosamine hydrochloride, chondroitin sulphate, and their combination with placebo. Eight of the 10 trials included patients with OA of the knee only, 1 studied patients with OA of the hip only, and 1 studied patients with OA of either. The meta-analysis authors present pooled estimates for all trials (i.e. both those with and without glucosamine sulphate) of the effect on pain of the difference in means on a 10 cm visual analogue scale (VAS). They considered that products were clinically equivalent at any time point where the difference in mean 10 cm VAS was -1 to 1. For all time points and for all sub-analyses (including that in which glucosamine sulphate only trials were considered) a clinically significant effect was not seen of any intervention over placebo. Subsequent criticism of the BMJ meta-analysis has most notably surrounded the diluting effect of pooling data from glucosamine hydrochloride and glucosamine sulphate studies 8. The significant heterogeneity of the 7 included studies (I 2 = 63%) compares with nil heterogeneity (I 2 = 0%) when the 3 GS only studies are analysed 8. For a separate analysis following the same principles as the original study but including only the 3 GS studies, a small to moderate effect size of 0.34 (95% CI ) for the various pain endpoints was determined 8. The cost and apparent marketing strategy for Glusartel Our understanding is that the manufacturer, HFA Healthcare, is marketing Glusartel as a replacement to unlicensed glucosamine products where those are currently prescribed and reimbursed on the NHS. Their marketing appears based on the following:

4 HFA placed a freedom of information request regarding glucosamine use overall during This did not identify any NHS Alateris (glucosamine hydrochloride) prescribing, but identified a total NHS spend on glucosamine sulphate products of 25.5 million. Of this spend 81% ( 20.7 million) was for 5 specific presentations with individual reimbursement costs ranging from to per month of treatment. HFA suggest that significant savings of 10.4 million for England could be realised were Glusartel to be prescribed as an alternative to these products. In addition to their case for switching prescribing to Glusartel for symptomatic relief, they suggest savings to the cost of total knee replacement surgery based on the results of a single retrospective study in the area. Such cost-avoidance seems exceptionally unlikely: the evidence base is inconclusive in determining the effectiveness of glucosamine in preventing osteoarthritis progression and the drug has marketing authorisation for symptomatic use only. The basic NHS list price for Glusartel is (identical to that of Alateris ). HFA s assumption is that prescribing glucosamine sulphate on the NHS is appropriate and should continue albeit with a switch to Glusartel. HFA assert that the place in therapy for their product is in conjunction with paracetamol, as part of a strategy to avoid NSAID exposure in OA. As the literature summarised above suggests, the case for the clinical efficacy of glucosamine is conflicting. HFA cite a Canadian paper 9 that investigated the quality of a variety of over-the-counter glucosamine products and found considerable variation. Potential variation in the constituents of over-the-counter glucosamine products in the UK has not, however, been investigated. Prescribing information What is Glusartel? Glusartel is a preparation of glucosamine sulphate 1500 mg ( 1178 mg glucosamine); it is presented as a powder for oral solution 1. What is Glusartel licensed for? Glusartel is licensed for the relief of symptoms in mild to moderate osteoarthritis of the knee 1. How is Glusartel given? The contents of one sachet should be dissolved in at least 250mL of water and taken once daily 1. What needs to be monitored? The main response should be a decrease in pain severity which may take a number of weeks to occur; if an improvement in pain has not occurred after 2 3 months re-evaluate treatment 1. The summary of medicinal product characteristics (SmPC) suggests glucosamine has an effect on glycaemic control and that blood glucose levels and insulin requirements should be monitored routinely in diabetic patients 1. However, the evidence base supporting this recommendation is comparatively sparse and conflicting, with most clinical trials not suggesting a significant change in blood glucose levels In the absence of robust data the recommendation to monitor seems reasonable, although it seems unlikely that additional monitoring to that routinely undertaken already for diabetic patients would be necessary. No other routine monitoring is necessary. Does glucosamine interact with other medicinal products? The SmPC reports the possibility of glucosamine increasing the INR for patients taking concomitant coumarin anticoagulants, and that patients should be monitored closely when initiating or ending glucosamine therapy 1. The evidence suggesting this interaction appears limited to relatively few case reports describing increased INR, with a single contradictory report describing a decrease Given that glucosamine is likely to be taken in a cohort of elderly patients a number of whom might also be expected to have been prescribed warfarin, the small number of case reports may indicate that any interaction between glucosamine and coumarin anticoagulants is rare. Even so, close monitoring of INR for patients taking warfarin and for whom glucosamine is either initiated or discontinued seems prudent. The SmPC also reports that absorption and serum concentrations of tetracyclines may be increased following concomitant use although the manufacturers suggest limited clinical significance 1. This interaction is not reported in various standard texts and the SmPC statement is in fact based on 2 fifty-year old poorly designed pharmacokinetic studies Use of one drug should not preclude use of the other and no action need be taken should the 2 drugs be administered concomitantly.

5 What are the side effects of glucosamine sulphate? Mild gastrointestinal disturbance, headache, and fatigue are the most common side effects A single report exists of exacerbated asthma symptoms following initiation of glucosamine with subsequent improvement following withdrawal of the drug 1. Are there any contraindications? Glucosamine must not be given to patients who are allergic to shellfish, as the active ingredient is obtained from shellfish 1. References: 1 Summary of Product Characteristics, Glusartel (glucosamine sulphate) powder for oral solution. April 2010, Rottapharm Ltd. 2 National Collaborating Centre for Chronic Conditions. Osteoarthritis: national clinical guideline for care and management in adults. London: Royal College of Physicians, available at: 3 Black C, Clar C, Henderson R et al. The clinical effectiveness of glucosamine and chondroitin supplements in slowing or arresting progression of osteoarthritis of the knee: a systematic review and economic analysis. Health Technol Asess 2009; 13 (52): Available at: 4 Towheed T, Maxwell L, Anastassiades TP et al. Glucosamine therapy for treating osteoarthritis. Cochrane Database of Systematic Reviews 2005; Issue 2 5 Glucosamine for knee osteoarthritis what s new? DTB 2008; 46: New Product Review: Glucosamine Sulphate Sodium Chloride (Glusartel ). A licensed prescription-only oral treatment for the relief of symptoms in mild to moderate osteoarthritis of the knee. HFA Healthcare, April Wandel S, Juni P, Tendal B et al. Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip and knee: network meta-analysis. BMJ 2010; 341: c Reginster JY, Altman RD, Hochberg MC. Prescription glucosamine sulphate is effective in knee osteoarthritis. BMJ rapid responses, 30th September Russell AS, Aghazadeh-Habashi A, Jamali F. Active Ingredient Consistency of Commercially Available Glucosamine Sulfate Products. J Rheumatol 2002; 29: "Glucosamine" in Drugdex System. Thomson Reuters (Healthcare) Inc. (accessed 16 th August 2010) 11 Glucosamine monograph. Sweetman SC (ed), Martindale: The Complete Drug Reference. [online] London: Pharmaceutical Press < (accessed on 16 th August 2010) 12 Glucosamine monograph. Baxter K (ed), Stockley s Drug Interactions. [online] London: Pharmaceutical Press < (accessed on 16 th August 2010) 13 Gittinger WC, Weiner H. The activation by glucosamine of the absorption of tetracycline into the systemic circulation. Pfizer Laboratories, Brooklyn, NY, Tubaro E, Raffadoni E. Influenza della glucosamina sull assorbimento della tetraciclina. Boll. Chim. Farm. 1958; 97: [English abstract only]