Capsaicin cutaneous patch

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1 New Medicines Profile August 2010 Issue. 10/03 cutaneous patch Concise evaluated information to support the managed entry of new medicines in the NHS Summary cutaneous patch (Qutenza ) is licensed for the treatment of peripheral neuropathic pain in non-diabetic adults. It is applied to the affected area for 30 or 60 minutes (depending on body site and indication) as a single application and can be repeated every 90 days as necessary. Up to four patches can be applied at any one time. The mean treatment area in trials for post-herpetic neuralgia equated to the use of two patches per application. Two randomised active-led trials have shown mean improvements in pain scores of 23-30% over 12 weeks compared with 11-20% with a low-strength capsaicin patch (not commercially available). A reduction of at least 30% is considered a clinically moderately important improvement. Data on repeated use are limited. There have been no comparative trials against standard therapies for neuropathic pain. Trials have mostly included patients with post-herpetic neuralgia or painful HIV neuropathy. Clinical data presented to the European Medical Agency in support of an indication for diabetic neuropathy were considered not to be sufficient as only small numbers of patients were included. patches cause pain and erythema at the application site in the majority of patients. A local anaesthetic should be applied for 60 minutes prior to application. Pre- and post-treatment with an opioid may be required. Blood pressure should be monitored during the treatment process as transient increases may occur. In trials, the majority of patients were taking concomitant neuropathic pain medication and there is no indication that the use of capsaicin patches reduced the use of concomitant therapy. Patches will need to be applied in a clinic setting by suitably trained staff. It is expected they will initially be used exclusively by specialist pain clinics in secondary care. Brand Name, (Manufacturer): Qutenza (Astellas Pharma Ltd) BNF Therapeutic Class: Rubefacients and other topical antirheumatics Licensed Indications: Treatment of peripheral neuropathic pain in non-diabetic adults alone or in combination with other pain medications Dosage and Administration: After pretreatment with topical anaesthetic, up to 4 patches should be applied by a healthcare professional to painful areas for 30 minutes (feet) or 60 minutes (other areas), repeat after 90 days if necessary Marketed: July 2010 Cost Comparisons: Cost for 30 days treatment (prices from MIMs and Drug Tariff July 2010) Qutenza 1-4 patches Pregabalin mg bd Amitriptyline 75mg daily Gabapentin 600mg tds Lidocaine 1-3 plasters daily N.B. Doses shown for general comparison and do not imply therapeutic equivalence. N.B. Costs of clinic time, monitoring, PBR tariff and local anaesthetic or opioids not included for Qutenza. Introduction Peripheral neuropathic pain is an ongoing shooting, stabbing or burning pain initiated or caused by a primary lesion or dysfunction in the peripheral nervous system. 1 is a transient receptor potential vanilloid 1 (TRPV1) receptor agonist. Application of capsaicin topically causes initial excitation of primary sensory TRPV1 neurons, followed by prolonged desensitisation. 1 Topical capsaicin formulated as a low-strength, 0.075% cream (Axsain ) has been used with limited success in this condition. 2 A high-strength (8%) cutaneous patch has recently been launched (Qutenza ). Evidence Four phase III trials of similar design (2 in post-herpetic neuralgia (PHN) and 2 in painful HIV-related neuropathy (HIVN)) have supported the licence application. Only two have been published to date. One trial 3 included 402 patients who had had PHN for at least 6 months and had an average numeric pain rating scale (NPRS) score of 3-9 [NPRS is an eleven point scale from 0-10 where 0 is no pain and 10 is worst pain possible]. After a 14 day baseline screening period patients were assigned to either a highstrength (8%, Qutenza )) or a lowstrength (0.04%, ) capsaicin patch. As topical capsaicin causes erythema and burning, use of a placebo would have unmasked participants to treatment allocation. Efficacy was assessed by daily NPRS scores ( average pain for the past 24 hours ) for 12 weeks after patch application. Patient Global Impression of Change (PGIC) assessments, in which patients compare how they feel before and after treatment on a scale of 3 points (very much worse) to +3 (very much improved), were taken in addition to other quality of life and pain measurements. The primary endpoint was the percentage change in mean NPRS score during weeks two to eight compared with baseline. A 29.6%

2 cutaneous patch reduction in NPRS score was found with Qutenza compared with a 19.9% reduction in the group. A reduction in NPRS score of at least 30% is considered a clinically moderately important improvement and a reduction of 10-20% a clinically minimally important improvement. 4 In the Qutenza group 42% of patients achieved at least 30% reduction in NPRS score in the first eight weeks compared with 32% of the group (P=0.03). There were no statistically significant differences in the percentages of patients who achieved a 50% reduction in pain score, in changes in the majority of quality of life scores or in the proportion of patients with changes in concomitant neuropathic pain medication use although actual results were not reported. See Appendix I for further results. A further trial randomised 307 patients with painful HIV-associated distal sensory polyneuropathy to either Qutenza or capsaicin patch applied to painful areas of the feet for 30, 60 or 90 minutes. 5 The primary endpoint was the percentage change in the mean NPRS score during weeks two to twelve compared with baseline. Results for all patients receiving Qutenza showed a 22.8% reduction in NPRS score during weeks 2-12 compared with a reduction of 10.7% with (P=0.0026). The 30- and 90- minute, but not the 60-minute application, resulted in a statistically significant reduction in NPRS score compared with. In the Qutenza group 34% achieved at least 30% reduction in NPRS score compared with 18% of the group (P<0.01). See Appendix I for further results. Details of the two unpublished phase III trials are available from the licensing documentation. 6 Results were broadly comparable with those discussed above (see Appendix I) although the results in the trial in HIVN did not reach statistical. Data on repeated use of capsaicin patch are limited. Forty-week openlabel extensions to 12 week studies in PHN (n=24) and HIVN (n=272, unpublished) have allowed up to 3 further applications. Pain relief appears to have been maintained although details are very limited. 1,7 Comparative studies against other therapies are not available and would be methodologically difficult. A Cochrane systematic review and meta-analysis pooled data from the two published studies to calculate an NNT of 12 to provide a 30% or greater improvement in pain over 12 weeks. 8 This compares with a NNT of approximately 5 for at least 50% pain relief with duloxetine or pregabalin over weeks. However, capsaicin was compared against an active rather than placebo, and the patient population, in terms of previous agents already tried, may not be comparable. Safety Overall in led trials, adverse events occurred in 84% of patients treated with Qutenza. 6 The most common effects were application site reactions, including erythema (in up to 94% of patients with PHN), burning, dryness, pain, swelling and pruritus. These were mostly transient and resolved within seven days. The incidence of application-site reactions was greater in patients with PHN than those with HIVN. A topical local anaesthetic should be applied to the treatment area for 1 hour before patch administration. 9 Acute pain can be treated with local cooling and oral analgesics- in trials oxycodone was given as necessary during the application, followed by hydrocodone/paracetamol use for up to 5 days: 48-55% of patients receiving the Qutenza required some analgesic rescue medication. Transient increases in blood pressure may occur on the day of application- which may be due to the pain of application. There is minimal systemic absorption, 10 thus systemic adverse effects or interactions are unlikely. Further details can be found in the Summary of Product Characteristics. 9 NHS Impact Peripheral neuropathic pain is usually a chronic condition that can be difficult to treat. In the UK, the incidence of PHN is estimated to be 28 per 100,000 personyears. 11 HIVN is reported to affect 30-60% of patients with HIV infection or AIDS. 1 Drugs used in the management of neuropathic pain include antidepressants, anticonvulsants, opioid analgesics, topical lidocaine patch or 0.075% capsaicin cream. n-pharmacological approaches have also been tried, including neuro-stimulation, surgical and chemical sympathectomy or acupuncture. The evidence base for these therapies is weak. 11 Recent NICE guidance on the management of neuropathic pain in non-specialist settings recommends amitriptyline (unlicensed use) or pregabalin as first line treatment with the alternative agent or their combination as a second-line options. 12 Other suggested thirdline options include tramadol or lidocaine plasters. Qutenza was not included or appraised as the guidance was produced prior to its launch. The NICE guidance was intended for use by nonspecialists. It is envisaged that Qutenza will be used by specialist pain clinics only for patients who have not responded to other, more established agents. It is likely to be used in conjunction with other neuropathic pain medications. Appendix I: Table of Clinical Trials Risk Management Issues: Wear nitrile, NOT latex, gloves when handling the patch and treatment area. Apply patches to clean, intact skin, not mucous membranes. Do not apply to the face. Hairs can be clipped (not shaved) if necessary. Used patches should be disposed of according to the instructions. The cleansing gel provided may cause local skin reactions or irritation of eyes or mucous membranes. Produced for the UK Medicines Information Service By Vanessa Chapman, Trent Medicines Information Centre, Leicester LE1 5WW Tel The information contained in this document will be superseded in due course. t to be used for commercial purposes. May be copied for use within the NHS.

3 cutaneous patch erences 1. to C, Pappagallo M & Szallasi A. NGX-4010, a high-concentration capsaicin dermal patch for lasting relief of peripheral neuropathic pain. Curr Opin Invest Drugs 2009; 10: CKS (2008) Post-herpetic neuralgia Version 1.2 Last revised in August Clinical Knowledge Summaries. [Accessed: 9th April 2010] 3. Backonja M, Wallace MS, Blonsky ER et al, for the NGX-4010 C116 Study Group. NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: a randomised, double-blind study. Lancet Neurol 2008; 7: Dworkin RH, Turk DC, Wyrwich KW et al. Interpreting the Clinical Importance of Treatment Outcomes in Chronic Pain Clinical Trials: IMMPACT Recommendations. Journal of Pain 2008; 9: Simpson DM, Brown S & Tobias J for the NGX C107 Study Group. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy Neurology 2008; 70: Derry S, Lloyd R, Moore RA, McQuay HJ. Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database of Systematic Reviews 2009, Issue 4. Art..: CD DOI: / CD pub2 Accessed 8th April Summary of Product Characteristics: Qutenza, Astellas Pharma Europe B.V May Accessed via on 6th August Babbar S, Marier J-F, Mouksassi M-S et al Pharmacokinetic analysis of capsaicin after topical administration of a high-concentration capsaicin patch to patients with peripheral neuropathic pain. Ther Drug Monit 2009; 31: Freynhagen R & Bennett MI. Diagnosis and management of neuropathic pain. BMJ 2009; 339: b National Institute for Health and Clinical Excellence (2010) Neuropathic pain: the pharmacological management of neuropathic pain in adults in nonspecialist settings. Clinical Guideline. 96 March 2010 London: National Institute for Health and Clinical Excellence. Available from: Accessed 9th April Qutenza, European Public Assessment Report Scientific discussion. Available at: Qutenza/H-909-en6.pdf Accessed 6th August Backonja MM, Malan TP, Vanhove GF et al for the C102/106 Study Group NGX-4010, a highconcentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind, led study with an open-label extension. Pain Med 2010; 11: Key papers are highlighted in bold

4 cutaneous patch Appendix I Post herpetic neuralgia Patients aged at least 18 years of age who were diagnosed with PHN and had an average numeric pain rating scale (NPRS) score of 3 9 (inclusive) were eligible if at least 6 months had passed since crusting of their shingles vesicles. Patients who took long-term pain medications were included if they had been on stable doses for at least 21 days before treatment and stayed on a stable dose during the study period. Longterm pain medications could include oral or transdermal opioids but could not exceed a total dose of 60 mg/day morphine equivalent. (n=196) (n=206) 3 Mean NPRS score at baseline t significant Concomitant neuropathic pain medication at baseline Opioids Anticonvulsants n-selective serotonin- 15% 25% 12% 50% 18% 14% P=0.021 t significant t significant t significant reuptake inhibitors Withdrawals (number) Percentage change in NPRS from baseline to the mean of weeks 2-8 Mean (95%CI) Percentage change in NPRS from Mean (95%CI) Percentage of patients with a reduction in NPRS score of >=30% over 12 weeks (Percentage slightly, much or very much -19.9% (-24.0 to -15.8) -20.4% (-24.6 to -16.2) -29.6% (-33.6 to -25.6) -29.9% (-34.0 to -25.8) P=0.001 P= % 44% P=0.05 (Odds ratio %CI ) 43% 55% P=0.04 (n=204) 8% patch (n=212) 6 Mean NPRS score at baseline Actual values not given. statistically significant differences between groups. Concomitant neuropathic pain medication at baseline Actual values not given. statistically significant differences between groups. Withdrawals (number) Mean percentage change in NPRS from -24.4% -32.0% P= baseline to the mean of weeks 2-8 Mean percentage change in NPRS from -25.0% -32.3% P= Percentage of patients with a reduction 47% P= in NPRS score of >=30% over 12 weeks (Percentage slightly, much or very much 47% 61% P=0.0047

5 cutaneous patch HIV neuropathy Eligible subjects had at least 2 months of moderate to severe neuropathic pain in both feet secondary to HIV distal sensory polyneuropathy or neurotoxic antiretroviral drugs (ARVs), with an average numeric pain rating scale (NPRS) score of 3 9 (inclusive). Patients receiving ARVs must have been on stable doses for at least 8 weeks. Doses of other neuropathic pain medications had to be stable for at least 21 days before treatment and throughout the study. Patients were excluded if they were using topical analgesics, had other causes for neuropathy, had abnormal cardiac, renal, hepatic or pulmonary function or were receiving more than 60mg morphine equivalent daily. 5 Mean NPRS score at baseline Concomitant neuropathic pain medication at baseline Opioids Anticonvulsants Antidepressants 0.04% patch (n=82) (all) (n=225) 30 mins (n=72) 60 mins (n=78) % 18% 39% Withdrawals (number) Percentage change in NPRS from baseline to the mean of weeks 2-12 Least squares mean (SD) Percentage of patients with a reduction in NPRS score of >=30% over 12 weeks Patient Global Impression of change overall (Percentage slightly, much or very much -10.7% (30.8) 68% 25% 43% -22.8% (30.6) 18% 34% 31% 67% 78% 29% 53% 40% -27.7% (30.9) 42% P<0.01 vs 66% 68% 26% 45% -15.8% (30.4) P=NS vs 24% P=NS vs 70% 90 mins (n=75) 63% 28% 28% very much improved 8% 12% 16% 11% 8% much improved 6% 21% 21% 17% 24% slightly improved 17% 34% 28% 42% 32% -24.7% (30.6) 36% P<0.01 vs 65% p<0.05 vs (n=162) 6 Withdrawals (number) Mean percentage change in NPRS from Percentage of patients with a reduction in NPRS score of >=30% over 12 weeks (Percentage slightly, much or very much t provided 8% patch (n=332) Approximately 30% t significant t provided t provided t significant t provided t provided t significant