Scottish Medicines Consortium diclofenac 1% gel patches (Voltarol Gel PatchÒ) No. (199/05) Novartis 9 September 2005 The Scottish Medicines Consortium (SMC) has completed its assessment of the above product and advises NHS Boards and Area Drug and Therapeutic Committees (ADTCs) on its use in NHS Scotland. The advice is summarised as follows: ADVICE: following a full submission Diclofenac 1% gel patch (Voltarol Gel PatchÒ) is not recommended for use within NHS Scotland for the local symptomatic treatment of pain in epicondylitis and ankle sprain. Diclofenac gel patch provides analgesia similar to that obtained with a topical gel formulation of this drug. However, on a gram per gram basis, patches cost over 40% more than the gel formulation. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium 1 Diclofenac 1% gel patch (Voltarol Gel Patch®) Licensed indication under review Local symptomatic treatment of pain in epicondylitis and ankle sprain in adults. Dosing information under review Epicondylitis: one application morning and night for up to fourteen days. Ankle sprain: one application per day for up to three days. UK launch date 1 October 2005 Comparator medications Conditions included in the indications of diclofenac 1% gel patch, epicondylitis (tennis elbow) and ankle sprain could be treated topically with gel formulations of other non-steroidal anti- inflammatory drugs (NSAIDs), including diclofenac, ibuprofen, piroxicam, ketoprofen and felbinac or systemically with oral formulations of these drugs or simple analgesics such as paracetamol. Cost per treatment period and relevant comparators Daily dose Cost per course (£)* 3 days 14 days Diclofenac 1% gel patch one patch once 7.05 - Diclofenac 1% gel patch one patch twice - 42.30 Diclofenac 1% gel 2g to 4g three to four times 7.00 14.00- 21.00 Felbinac 3% gel 1g two to four times 7.00 7.00 Ketoprofen 2.5% gel 2.5g to 5 g two to four times 3.39-5.85 5.85-17.55 Piroxicam 0.5% gel 1g three to four times 3.63 3.63 Ibuprofen 10% gel 0.5g to 1.25g up to three times 3.22 3.22 *costs from submission and eVadis database accessed in July 2005 for the following preparations: Voltarol (diclofenac 1%) Gel Patch, sealed pouch of 5 patches £7.05; Voltarol (diclofenac 1%) EmulgelÒ or generic diclofenac 1% gel 100g £7; ketoprofen 2.5% gel 50g £3.39, 100g £5.85; piroxicam 0.5% gel 60g £3.63, 112g £6.19; Traxam (felbinac 3%) gel 100g £7.00; ibuprofen 10% 50g £3.22 2 Summary of evidence on comparative efficacy Diclofenac is an NSAID that reduces pain and inflammation by inhibiting an enzyme that produces some of the prostaglandins involved in inflammatory processes. Topical application of diclofenac is thought to produce a local effect, with minimal systemic absorption. An open-label trial randomised 190 patients with localised inflammations, including peri- arthropathies (n=100), epicondylitis or styloiditis (n=41) and tendonitis or bursitis (n=59), to fourteen days’ treatment with a diclofenac 1% patch twice daily or 2g of diclofenac 1% gel four times daily. All patients completed the study and their data were included in chi-squared analyses of pain. Mean spontaneous pain (assessed via 10cm visual analogue scale (VAS) and via 4-point categorical scale) and pain on pressure (assessed via 4-point categorical scale) were significantly improved from baseline at fourteen days and the improvements were significantly greater with the patch compared to the gel. These results are summarised in the table below. Investigators’ and patients’ assessments of efficacy significantly favoured the patch compared to the gel. Good or excellent ratings of efficacy were assigned to the patch by 85% and 82% of the investigators and patients, respectively, compared to 44% and 22% for the gel. Mean pain scores in patients with localised inflammations, including epicondylitis, styloiditis, peri-arthropathies, tendonitis and bursitis. Diclofenac 1% patch Diclofenac 1% gel Day 0 Day 7 Day 14 Day 0 Day 7 Day 14 Mean spontaneous pain (0-10)a 7.9 3.8 3.1*+ 7.6 4.7 4.5* Mean spontaneous pain (0-3)b 2.36 1.17 0.99*+ 2.2 1.4 1.33* Pain on pressure (0-3) b 2.6 1.3 1.1**+ 2.4 1.6 1.5* a = 10cm visual analogue scale; b = 4-point categorical scale; * p<0.001 versus baseline; ** p<0.01 versus baseline; + p<0.001 change from baseline to day 14 versus change from baseline to day 14 with diclofenac 1% gel The active comparator study described previously included many patients with conditions which are not included in the licensed indications of diclofenac 1% gel patch. Two double- blind, randomised, placebo-controlled studies have recruited patients with conditions which could be treated with this preparation and these are described below. A study included 140 patients with acute, mild, post-traumatic ankle sprain, located at the external lateral (lateral collateral) ligament, originating less than 48 hours previously who had pain ³50mm on a 100mm VAS. Diclofenac 1% gel patch applied once daily for seven days, compared with placebo, was associated with significantly lower mean spontaneous pain scores (assessed via 100mm VAS), the primary outcome, at three, four and five hours and three and seven days after initiation of treatment. Assessments of pain at rest, on stretching, in response to pressure and when standing on one leg (assessed via 4-point categorical scales) were also significantly improved with the patch compared to placebo. Patients’ and investigators’ global assessments of efficacy significantly favoured the patch. Consumption of paracetamol was permitted if required during this study and was low in both groups, with no significant difference between them. A study included 85 adults with humero-radial epicondylitis and tendon pain. Degree of pain was not specified as an inclusion criterion. However, 90% and 71% of patients in the placebo and active treatment groups, respectively, presented with spontaneous pain described on a 5- 3 point categorical scale as moderate, severe or very severe. Diclofenac 1% gel patch applied twice daily for 14 days was associated with significant improvements in spontaneous pain score (assessed via 100mm VAS) at days seven, fourteen and twenty-eight (at 14-day post- treatment follow-up) compared to baseline. Placebo was also associated with significant improvements compared with baseline at days fourteen and twenty-eight. Data were not available for the significance of the differences between active treatment and placebo at day seven, fourteen or twenty-eight. However, an analysis of covariance (ANCOVA) treatment by time interaction test found a significant difference between the groups over the whole study period. There was no significant difference between diclofenac 1% gel patch and placebo for mean spontaneous pain score (assessed via 5-point categorical scale) at day seven but this was significantly improved with the patch compared to placebo at day fourteen and twenty- eight. Patients’ global assessment of efficacy (assessed via 5-point categorical scale) significantly favoured the patch at day twenty-eight but was not significant at day fourteen. Investigators’ global assessment of efficacy (assessed via 5-point categorical scale) significantly favoured the patch at day fourteen but was not significant at day twenty-eight. Summary of evidence on comparative safety Common adverse effects associated with diclofenac 1% patch include local skin reactions, such as rash, pruritus and erythema. In the comparative trial described previously, which included 190 patients, five mild skin reactions were reported, with no significant difference in incidence between the patch and gel formulations. Summary of clinical effectiveness issues The comparison of diclofenac patch and gel formulations described previously included patients with a variety of localised inflammatory conditions, with many patients having a condition not included in the licensed indications for diclofenac 1% gel patches. This trial was not blinded to treatment allocation. This may have biased subjective assessments, such as pain and efficacy, especially if patients expected to achieve better pain relief with the novel patch formulation. In practice, it is possible that there may be no clinically significant difference between the formulations in the treatment of epicondylitis or ankle sprains. In the placebo-comparison in patients with epicondylitis there appears to be a difference in baseline pain severity, with more patients in the placebo group having moderate to very severe pain: 90% vs. 71%. This may have confounded assessments of treatment effect. The placebo-comparison in patients with epicondylitis did not report significant improvement with the patch compared to placebo in spontaneous pain on VAS and categorical scale at the seven-day time point and on VAS at day fourteen. However, as the report of this study did not define a primary endpoint and did not provide details about the power of the study, it is not possible to confirm that it had sufficient power to detect a significant difference between the patch and placebo at these time points. Summary of comparative health economic evidence The manufacturer submitted a cost minimisation study comparing diclofenac 1% gel patch with the gel equivalent. The purchase costs are: Gel patch: 1x 10 patches- £14.09 (2 x 5 patches in each sealed pouch) Comparator Diclofenac Emulgel: 1 x 100g tube - £7.00 4 Ankle sprain The submission assumed typically 1 patch would be applied per day for 3 days at a cost of £7.05; compared to 2-4g of gel, applied 3-4 times daily for typically 14 days, at a cost of £14.00–£21.00. Epicondylitis The submission assumed typically 1 patch would be applied twice daily for 7 days, with a maximum duration of 14 days. Cost for typical treatment duration of £21.15 and £42.30 for maximum duration.