pregabalin, 25mg, 50mg, 75mg, 100mg, 150mg, 200mg and 300mg capsules (Lyrica ) No. (157/05) Pfizer

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1 Scottish Medicines Consortium Re-Submission pregabalin, 25mg, 50mg, 75mg, 100mg, 150mg, 200mg and 300mg capsules (Lyrica ) No. (157/05) Pfizer 8 July 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 resubmission Pregabalin (Lyrica ) is not recommended for use within NHS Scotland for the treatment of peripheral neuropathic pain in adults. Clinical and cost effectiveness have not been demonstrated and the economic case for use in patients refractory to other treatments has also not been demonstrated. Overleaf is the detailed advice on this product. Chairman, Scottish Medicines Consortium 1

2 Pregabalin capsules (Lyrica ) Licensed indication under review Treatment of peripheral neuropathic pain in adults. Dosing information under review 150mg to 600mg daily 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 paroxysmal pain of trigeminal neuralgia. These are the main licensed comparators of pregabalin. Amitriptyline is commonly used for the treatment of neuropathic pain, but 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. Cost per treatment period and relevant comparators Usual daily dose range Annual cost ( )* Pregabalin mg All doses $ 840 Gabapentin mg Carbamazepine mg Amitriptyline # 25-75mg Capsaicin 0.075% cream small amount tid to qid 196 * costs from British National Formulary 49 th edition, except for amitriptyline and carbamazepine, which relate to generics listed in the March 2005 Scottish Drug Tariff. If modified release carbamazepine, Tegretol Retard, was used, costs would be ; Costs for capsaicin cream are based on the assumption that a 45g tube, costing 15.04, would be used per 28 days. # unlicensed for neuropathic pain; $ for all daily doses between 150mg and 600mg, which are given as two divided doses. Summary of evidence on comparative efficacy Pregabalin is an anti-epileptic that decreases central neuronal excitability by binding to an auxiliary subunit of a voltage-gated calcium channel in the central nervous system. It also reduces 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) for pregabalin in the treatment of neuropathic pain included data from nine double-blind trials. Five trials recruited patients with diabetes who had glycated haemoglobin (HbA 1c ) 11% and distal symmetrical 2

3 sensorimotor polyneuropathy for at least one year. Three trials recruited patients with postherpetic neuralgia of at least 3 months duration after healing of the herpes zoster skin rash and one trial recruited patients who had suffered this for at least 6 months. A further double-blind 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 an 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. Pregabalin 300mg and 600mg were associated with significantly lower weekly mean pain scores at endpoint compared with placebo in all studies, except for the 300mg dose in a 12- week diabetic neuropathy study and the 600mg dose in an 8-week diabetic neuropathy study. In the latter study, there was a significant difference between the active control arm, amitriptyline 75mg daily, and placebo. Weekly mean pain scores with pregabalin 150mg were generally lower than placebo, but differences were not consistently significant. The resubmission contains additional data from an interim, 15-month, analysis of an ongoing open-label safety trial, which recruited patients from open-label pregabalin trials and two placebo-controlled double-blind studies which terminated early. All patients 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 or more weeks treatment with at least minimum doses of a tricyclic antidepressant, gabapentin 1800mg and one other analgesic, which included other anticonvulsants or antidepressants, non-steroidal anti-inflammatory drugs (NSAIDs) or opioids. Patients were given pregabalin 150mg to 600mg daily and could continue to receive other analgesics, including those that may not have provided adequate pain control previously. Both pregabalin and non-study analgesics could be titrated to optimise pain control and minimise adverse effects at the discretion of the investigator throughout the study. Every three months pregabalin was discontinued for 3 to 28 days until patients pain had worsened and then recommenced. If a patient s pain did not worsen or only deteriorated slightly during this 28-day pregabalin-treatment holiday they were discontinued from the study. Interim analysis of 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, with last observations carried forward for missing data. During pregabalin-treatment holidays mean SF-MPQ scores in both groups returned to baseline levels. In the respective groups 78% and 58% of patients remained on treatment at this analysis. Numbers discontinuing in the respective groups for the following reasons were: lack of efficacy, 1 (2.2%) and 4 (11%); adverse effects, 6 (13%) and 4 (11%); failure to meet relapse criteria, 1 (2.2%) and 3 (8.3%) and other reasons, 2 (4.4%) and 4 (11%). Summary of evidence on comparative safety Pregabalin is commonly associated with central nervous system adverse effects similar to most anti-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. Similarly gabapentin is eliminated renally and does not induce hepatic enzymes or interact with other anti-epileptics or oral 3

4 contraceptives. However, carbamazepine is metabolised by and induces the production of hepatic enzymes. Thus, it may be involved in hepatic pharmacokinetic interactions. Summary of clinical effectiveness issues The majority of trials provided with the first submission to SMC excluded patients who had failed to respond to previous treatment with gabapentin at daily doses 1200mg. Thus data are limited on the efficacy of pregabalin in patients unresponsive to gabapentin. The additional trial provided with the resubmission, which suggests that pregabalin is effective in patients intolerant of or refractory to other treatments, has a number of limitations. It was primarily a safety study, not designed or powered to investigate the efficacy of pregabalin relative to placebo or active control in this group of patients. It was open-label, therefore patients knew when treatment was withdrawn and this may have biased subjective assessments of pain when receiving and not receiving study medication. Patients could remain on other analgesic medications, which had failed to control pain after two or more weeks treatment, and doses of these could be altered during the study. Full analgesic effects of antidepressants and anti-epileptics may take more than two weeks to become apparent. It was not possible to quantify the effects of these drugs on analgesia observed during the study. In the absence of randomised, controlled trial data within this subgroup of patients, it is difficult to estimate the clinical benefits of pregabalin for them in practice. Summary of comparative health economic evidence The manufacturer submitted a Markov model comparing pregabalin with placebo in patients with postherpetic neuralgia and diabetic peripheral neuralgia who are refractory to other third line treatments. The model simulated average daily changes in pain scores for a cohort of patients in moderate or severe pain at baseline. Utilities, from manufacturer sponsored research, and presented in abstract form only, were used (mild pain 0.67: moderate pain 0.47: severe pain 0.16). The incremental cost effectiveness ratio (ICER) was 8,800 for the postherpetic pain model and 16,300 for the diabetic peripheral neuropathy model. Sensitivity analysis using different trials and thrice daily rather than twice daily drug costs had ICERs of less than 20,000. The model had the following weaknesses: The clinical effectiveness data and patient groups in the model do not match The manufacturer notes clinical data cannot be extrapolated beyond 12 weeks yet the prescription could be lifetime The quality of life measure is not from pregabalin trials although European quality of life (EQ-5D) measures were reported in the results The model assumes full compliance although the observed drop-out rate was about 40%. Budget impact The manufacturer assumes that if 1,600 patients are prescribed pregabalin and that 83% will receive twice daily and 17% three times daily doses, then the gross additional annual cost of pregabalin is 1.5m; of which 1.1m might be saved if pregabalin displaces gabapentin, giving a net increase in drug costs of 0.4m. If pregabalin displaces amitriptyline or is used in refractory patients then there is virtually no saving, so additional cost is 1.5m. 4

5 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 of Clinical Excellence (NICE) clinical guideline number 15, type 1 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. Additional information In December 2004, 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. 5

6 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 17 June 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. Pfizer. Interim research memo on the first fifteen months of an on-going open-label pregabalin study, th March Backonja M, Bell D, Beydoun A et al. Synopsis of clinical study report A doubleblind placebo-controlled trial of pregabalin for the treatment of painful diabetic neuropathy. Hewitt D, Biesbroeck R, Blonsky ER at al. Synopsis of clinical study report A 5- week, double-blind, placebo-controlled trial of 3 dosages of pregabalin (75, 300 and 600mg/day) for treatment of patients with painful diabetic peripheral neuropathy. Rosenstock J, Schwartz SL, Pfeifer M et al. Synopsis of clinical study report An 8- week, double-blind, placebo-controlled trial of pregabalin (300mg/day) for relief of pain in patients with painful diabetic peripheral neuropathy. Laurent B, Lanteriminet M, Mick G et al. Synopsis of clinical study report A placebo-controlled trial of pregabalin and amitriptyline for the treatment of painful diabetic peripheral neuropathy. Yue D, Colagiuri S, Walter R et al. Synopsis of clinical study report A 12-week randomised, double-blind, multicenter, placebo-controlled trial of pregabalin twice a day (BID) for relief of pain associated with diabetic peripheral neuropathy. Abuabara F, Allen M, Backonja M et al. Synopsis of clinical study report A 5-week, double-blind, placebo-controlled parallel-group study of pregabalin (75 and 150mg/day) in patients with postherpetic neuralgia. Cherry D, Molloy A, O Brien T et al. Synopsis of clinical study report An 8-week, double-blind, placebo-controlled parallel-group study of pregabalin (150 and 300mg/day) in patients with postherpetic neuralgia. Bernick C, Blonsky ER, Brownstone PK et al. Synopsis of clinical study report An 8-week, double-blind, placebo-controlled parallel-group study of pregabalin in patients with postherpetic neuralgia. 6

7 Domzal T, Jastrzebski J, Kubler A et al. Synopsis of clinical study report A 13- week, randomised, double-blind, multicentre, placebo-controlled study of pregabalin twice a day (BID) in the treatment of postherpetic neuralgia. Rosenstock J, Tuchman M, LaMoreaux L, Sharma U. Pregabalin for the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled trial. Pain 2004; 110: Dworkin RH, Corbin AE, and Young JP et al. Pregabalin for the treatment of postherpetic neuralgia: a randomised placebo-controlled trial. Neurology 2003; 60: Sabatowski R, Galvez R, Cherry DA et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebocontrolled clinical trial. Pain 2004; 109: European Medicines Agency. European Public Assessment Report for Lyrica, Scientific Discussion. [internet] Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus. JAMA 1998; 280: Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia. JAMA 1998; 280: Rice ASC, Maton S, Postherpetic neuralgia study group. Gabapentin in postherpetic neuralgia: a randomised, double-blind, placebo controlled study. Pain 2001; 94: