Scottish Medicines Consortium Advice following an Independent Review Panel (IRP) Pregabalin 25, 50, 75, 100, 150, 200 and 300mg capsules (Lyrica ) Pfizer No. 157/05 7 July 2006 The Scottish Medicines Consortium 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 an Independent Review Panel Assessment pregabalin (Lyrica ) is not recommended for use within NHS Scotland for the treatment of peripheral neuropathic pain in adults. Comparative clinical and cost effectiveness have not been demonstrated. Further controlled data are needed to establish its place in therapy in patients refractory to or intolerant of other pharmacological treatments. Overleaf is the detailed advice on this product. Vice Chairman Scottish Medicines Consortium 1
Pregabalin 25, 50, 75, 100, 150, 200 and 300mg capsules (Lyrica ) Indication For the treatment of peripheral neuropathic pain in adults. Dosing information Initially 150mg daily, then increased to 300mg daily after 3 to 7 days according to individual patient response and tolerability, and increased again if needed to a maximum dose of 600mg daily after another 7 days. The daily dose may be given in two or three divided doses. UK launch date July 2004 Comparator medications Gabapentin is licensed for the treatment of neuropathic pain and carbamazepine is licensed for the treatment of the paroxysmal pain of trigeminal neuralgia. These are the main licensed comparators of pregabalin. Amitriptyline is commonly used for the treatment of neuropathic pain, but it is not licensed for this indication. A topical formulation of capsaicin is indicated for symptomatic relief of neuralgia associated with herpes zoster infections after open skin lesions have healed and for the symptomatic management of painful diabetic neuropathy (under supervision of hospital consultant). Cost of relevant comparators Drug Usual daily dose Annual cost Pregabalin 150-600mg 840-1259* Gabapentin 900-1800mg 249-497** Gabapentin (Neurontin ) 900-1800mg 580-1161 Carbamazepine 400-1600mg 89-374 Carbamazepine (Tegretol Retard ) 400-1600mg 69-270 Amitriptyline 25-75mg 23-49 Capsaicin 0.075% cream (Axsain ) Applied three to four times daily 138*** * Any dose of pregabalin (150-600mg daily) prescribed in two divided doses costs 64.40/28 days and prescribed in three divided doses costs 96.60/28 days. ** prices based on gabapentin 300mg capsules from the drug tariff April 2006 *** cost for capsaicin cream are based on the assumption that a 45g tube (costing 10.63) lasts 28 days Summary of evidence on comparative efficacy Pregabalin is an anti-epileptic that decreases central neuronal excitability by binding to an auxillary subunit of a voltage-gated calcium channel in the central nervous system. It also 2
reduced the release of several neurotransmitters including glutamate, noradrenaline and substance P, though the significance of the latter effects is unknown. The original submission to the Scottish Medicines Consortium (SMC), included data from ten double-blind studies. Five studies recruited patients with diabetes who had glycated haemoglobin (HbA 1C ) 11% and distal symmetrical sensorimotor polyneuropathy for one year and <5 years in three studies. Four studies recruited patients with postherpetic neuralgia of 3 and 6 months duration after healing of the herpes zoster skin rash. A further doubleblind trial recruited patients with either diabetic peripheral neuropathy or postherpetic neuralgia. In all studies patients had a score of 40mm on the 100mm visual analogue pain scale of the Short-Form McGill Pain Questionnaire (SF-MPQ) and during the week before randomisation, had at least four daily pain scores 4 assessed on an 11-point scale (where 0=no pain and 10=worst possible pain). Patients were randomised to placebo or pregabalin with one trial including amitriptyline as an active treatment arm. The primary endpoint, weekly mean pain score (assessed via the 11-point Likert scale) at endpoint, was compared in the intention to treat population between placebo and active treatments via an analysis of covariance which adjusted for weekly mean pain score at baseline. In the trial with an active comparator, pregabalin 600 mg daily was not associated with a significant difference from placebo in the primary analysis of pain scores at end-point. The difference between amitriptyline 75mg daily and placebo was significant. This pattern was repeated in two supplementary analyses of pain scores and in a number of secondary endpoints including the proportion of patients achieving a response ( 50% reduction in pain scores) and patients and clinicians global impression of pain. In no endpoint analysis was the result significant for pregabalin but not amitriptyline. Pregabalin 300mg and 600mg were associated with significantly lower weekly mean pain scores at endpoint compared with placebo in all other studies, except for the 300mg dose in a 12-week diabetic neuropathy study. Weekly mean pain scores with pregabalin 150mg were generally lower than placebo, but differences between this dose and placebo were not consistently significant. In these studies, responders were defined as patients who had a 50% reduction in mean weekly pain score compared with baseline. Similar efficacy patterns were observed in this secondary endpoint. The resubmission and IRP contains additional data from an interim, 15 month, analysis of an ongoing open-label safety study. Patients had participated in previous pregabalin studies and had a score of 40mm on the 100mm visual analogue pain scale of the SF-MPQ and were intolerant of or had experienced lack of efficacy after two weeks of at least minimum doses of tricyclic antidepressants, gabapentin 1800mg or other third line agents. Patients were given pregabalin 150-600mg daily and could continue to receive other analgesics, including those that may not have provided adequate pain control previously with titration at the investigator s discretion to optimise pain control. Pregabalin was discontinued quarterly for 3-28 days until patient s pain worsened before recommencing. If pain did not worsen or only slightly deteriorated, the patient was discontinued from the study. Interim analysis data from 45 patients with painful diabetic peripheral neuropathy and 36 patients with postherpetic neuralgia indicate that mean SF-MPQ scores decreased from respective baseline values of 73mm and 75mm to 47mm and 51mm at endpoint. A published systematic review, new to the IRP, calculates numbers needed to treat (NNT) to achieve a 50% reduction in pain scores and numbers needed to harm (NNH) and uses these as a basis for an evidence-based treatment algorithm. Data are included from five of the pregabalin studies from above: three in painful diabetic peripheral neuropathy and two in postherpetic neuralgia. The authors report a combined NNT for pregabalin at doses of 150-600mg in both pain models of 4.2 (3.4-5.4). 3
This is reported to be similar to the NNT for gabapentin at all doses and pain models (5.1 (4.1-6.8). The NNH for pregabalin was considered to represent a relatively high rate of withdrawal and was 11.7 (8.3-19.9) compared with 26.1 (14.1-170) for gabapentin. For a treatment algorithm in peripheral neuropathic pain based on pain relief, the NNT are lowest for tricyclic antidepressants, then opioids, then tramadol, then gabapentin/pregabalin. The IRP submission also presents other supportive evidence in the form of clinical audit results and clinician testimonies. Summary of evidence on comparative safety Pregabalin is commonly associated with central nervous system adverse events similar to most ant-epileptic drugs. It is not metabolised in vivo and is eliminated from the systemic circulation primarily by renal excretion of the unchanged drug. It does not bind to plasma proteins and does not induce or inhibit hepatic enzymes. It would thus not be expected to induce or be affected by hepatic pharmacokinetic interactions and did not interact with other anti-epileptic drugs or combined oral contraceptives in studies. Similarly gabapentin is eliminated renally and does not induce hepatic enzymes or interact with other anti-epileptics or oral contraceptives. However, carbamazepine is metabolised by and induces the production of hepatic enzymes, and, thus, may be involved in hepatic pharmacokinetic interactions. Summary of clinical effectiveness issues There are no direct trials of pregabalin with gabapentin in the treatment of neuropathic pain and so relative efficacy is uncertain. In addition, there are limited data in patients unresponsive to gabapentin since many of the double-blind studies excluded patients who had failed to respond to previous treatment with gabapentin 1200mg/day. Since the drugs are considered to act in the same way, this exclusion could potentially favour the results of the pregabalin studies. Data represented in the resubmission and IRP include interim results of an openlabel trial in patients intolerant of or refractory to other treatments. Although this indicates a reduction in pain with pregabalin, these results are difficult to interpret due to a number of limitations. The study was descriptive with no statistical testing to assess efficacy; patients could remain on other analgesic medication with doses titrated to optimise control. Results from a new systematic review would suggest comparable efficacy to gabapentin. The submission from the manufacturer seeks approval in patients who have failed to respond to amitriptyline and gabapentin. However, controlled data are needed to establish the place of pregabalin in this patient population. Summary of comparative health economic evidence The manufacturer presents an analysis of the mixed randomised control trial among post herpetic neuralgia patients and painful diabetic peripheral neuropathy patients. The manufacturer analyses the flexible dosing arm within this trial on the grounds that this is the most likely clinical implementation. The analysis is presented on the assumption that the patient group has already been treated with and failed on amitriptyline, gabapentin and other third line treatments. As a consequence, the appropriate comparator to assess pregabalin against within this patient group is placebo. 4
The average weekly reductions in pain scores across the flexible dosing arm and across the placebo arm are applied to the patient population, a common percentage reduction being applied to all patients in a given arm for a given week. This initial distribution of pain scores within this patient population is drawn from a separate external pain study rather than the trial itself. The resultant pain scores are mapped to utility values using a mapping function drawn from the same external pain study: No pain to mild pain being given the value 0.69 moderate pain being given the value 0.46 severe pain being given the value 0.16 Only the direct drug costs of treatment are included, there being no consideration of adverse events. This results in a cost effectiveness estimate of 8,800 for post herpetic neuralgia patients and 16,300 for painful diabetic peripheral neuropathy patients. There are a number of concerns with this analysis: The economic analysis focuses upon a single trial. While other trial data is used for sensitivity analyses the focus is upon twice daily dosing. However, the results of one, three times a day dosing trial for pregabalin and placebo are rejected despite it being of reasonable size and duration. Clinical effectiveness in this trial relative to placebo appears to have been somewhat less than that in the trial used for the base case. Quality of life data was collected in all the trials, but was not used to inform the analysis at all. In particular EQ5D data was collected within the trial used for the base case, but showed no statistical difference across the 5 dimensions between the placebo arm and the flexible dosing arm. The modelling approach adopted is a carry over from the original submission. This approach was to an extent necessary to facilitate the indirect comparison with an active comparator. But as the current comparator is the placebo of the pregabalin trial, it is not clear that the modelling approach remains justified. It might have been anticipated that individual patient level data on pain scores, rather than weekly average reductions, and quality of life could have been presented. It is unclear to what extent the results of the trial will apply to those having failed on amitriptyline, gabapentin and other third line treatments. Effectiveness in this patient group has not been demonstrated. As a consequence, the cost effectiveness of pregabalin has not been demonstrated. Patient and public involvement Patient Interest Group Submission: The Neuropathy Trust Patient Interest Group Submission: Pain Concern Correspondence from Action on Pain Budget impact The manufacturer estimates that 1,330 patients within NHS Scotland would fail on amitriptyline, gabapentin and other third line treatments and so be eligible for treatment with 5
pregabalin. Based upon the open label study, it is estimated that among these patients 678 (51%) would not respond to pregabalin so would discontinue treatment after one month. The remaining 652 patients would continue with treatment. Based upon 76% of patients receiving twice daily dosing and 24% of patients receiving three times a day dosing this results in an average drug cost of 2.58 per day and an annual direct drug cost of 650,000 in year one. This is anticipated to rise to 750,000 by year 5. Savings are also anticipated by the manufacturer in terms of reduced use of gabapentin and reduced numbers of secondary referrals. Guidelines and protocols The 2001 Scottish Intercollegiate Guidelines Network (SIGN) publication number 55: management of diabetes notes that there is good evidence that the tricyclic antidepressants amitriptyline, imipramine and desimpramine, the anticonvulsant carbamazepine and topical capsaicin are more effective than placebo in reducing symptoms of painful diabetic neuropathy. Gabapentin is superior to placebo in painful diabetic neuropathy and one trial indicated that it had fewer side effects than tricyclic antidepressants. It is recommended that tricyclic antidepressants should be used as first line therapy in painful diabetic neuropathy. Gabapentin is also recommended in painful diabetic neuropathy and is associated with fewer side effects than tricyclic antidepressants and older anticonvulsants. Topical capsaicin should be considered for the relief of localised neuropathic pain. The 2004 National Institute for Health and Clinical Excellence (NICE) clinical guideline number 15, type1 diabetes: diagnosis and management of type 1 diabetes in adults recommends that painful diabetic neuropathy should be initially treated with simple analgesics (paracetamol, aspirin) and local measures (bed cradles), which should not be continued if ineffective. The next step is a low- to medium-dose tricyclic antidepressant drug, timed to symptoms, with explanation that they are a trial of therapy. This can be followed by a trial of gabapentin, working up to the maximum tolerated dose or at least 1800mg per day. If gabapentin fails, carbamazepine and phenytoin are alternative choices. If continued chronic pain, consider opiate analgesia and referral to pain management service. In February 2006, NHS Quality Improvement Scotland published a best practice statement on the management of chronic pain in adults. This suggested that anticonvulsants should be considered for neuropathic pain with evidence noted for gabapentin. Additional information In February 2005, after consideration of a full submission, the SMC issued advice that pregabalin is accepted for restricted use within NHS Scotland as adjunctive therapy in adults with partial seizures with or without secondary generalisation. It should be initiated only by physicians who have appropriate experience in the treatment of epilepsy and should be used principally in patients who have not benefited from treatment with an older anti-convulsant drug such as carbamazepine or sodium valproate, or for whom these drugs are unsuitable because of contra-indications, interaction or poor tolerance. In February 2005, after consideration of a full submission, the SMC issued advice that pregabalin is not recommended for use within NHS Scotland for the treatment of peripheral neuropathic pain in adults. The comparative clinical and cost effectiveness have not been demonstrated. 6
In August 2005, after consideration of a full resubmission, the SMC reissued this advice for the treatment of peripheral neuropathic pain in adults. 7
Advice context: No part of this advice may be used without the whole of the advice being quoted in full. This advice represents the view of the Scottish Medicines Consortium and was arrived at after careful consideration and evaluation of the available evidence. It is provided to inform the considerations of Area Drug & Therapeutics Committees and NHS Boards in Scotland in determining medicines for local use or local formulary inclusion. This advice does not override the individual responsibility of health professionals to make decisions in the exercise of their clinical judgement in the circumstances of the individual patient, in consultation with the patient and/or guardian or carer. This assessment is based on data submitted by the applicant company up to and including 02 May, 2006 Drug prices are those available at the time the papers were issued to SMC for consideration. The undernoted references were supplied with the submission. Those shaded grey are additional to those supplied with the submission. Finnerup N, Otto M, McQuay H, et al. Algorithm for neuropathic pain treatment: an evidence based proposal. Pain. 2005: 1-17 Oct 4. Freynhagen R, Strojek K, Griesing T, et al. Efficacy of pregabalin in neuropathic pain evaluated in a 12 week, randomised, double blind, multicentre, placebo controlled trial of flexible and fixed dose regimens. Pain 2005: 115: 254-63. Pfizer. Interim research memo on the first fifteen months of an ongoing open-label pregabalin study., 1008-197. 4 March 2005. Rosenstock J, Tuchman M, LaMoreaux L, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial Pain 2004; 110: 628-638. Sabatowski R, Galvez R, Cherry D, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post herpetic neuralgia: results of a randomised, placebo controlled clinical trial. Pain 2004: 109, 26-35. European Medicines Agency. European Public Assessment Report for Lyrica, scientific discussion. [internet] www.emea.eu.int Richter RW, Portenoy R, Sharma U et al Relief of painful diabetic peripheral neuropathy with pregabalin: a randomised, placebo-controlled trial. J Pain 2005; 6: 253-260. Lesser H, Sharma U, LaMoreaux L et al. Pregabalin relieves symptoms of painful diabetic neuropathy. A randomised controlled trial. Neurology 2004; 63: 2104-2110. Van Seventer R, Feister HA, Young JP et al. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia; a 13-week, randomised trial. Curr Med Res Opin 2006; 22: 375-84. 8