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Scottish Medicines Consortium
pregabalin, 25mg, 50mg, 75mg, 100mg, 150mg, 200mg and 300mg
capsules (Lyrica)
No. (157/05)
Pfizer
4 February, 2005
The Scottish Medicines Consortium has completed its assessment of the above product and
advises NHS Boards and Area Drug and Therapeutic Committees on its use in NHS
Scotland. The advice is summarised as follows:
ADVICE: following a full submission
Pregabalin (Lyrica) 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.
The licence holder has indicated their decision to resubmit.
Overleaf is the detailed advice on this product.
Chairman,
Scottish Medicines Consortium
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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 for 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 (post-herpetic
neuralgia) after open skin lesions have healed and for the symptomatic management of
painful diabetic neuropathy.
Cost per treatment period and relevant comparators
Pregabalin
Gabapentin
Carbamazepine
Amitriptyline#
Capsaicin 0.075% cream
Usual daily dose range
150-600mg
900-1800mg
400-1600mg
25-75mg
small amount tid to qid
Annual Cost (£)*
All doses
840
580-1161
40-190
7.30-22
197
* costs from British National Formulary 48th edition, except for amitriptyline and carbamazepine, which
relate to generics listed in the Scottish Drug Tariff. If modified release carbamazepine, Tegretol Retard ,
was used costs would be £0.19-0.74; 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.
Summary of evidence on comparative efficacy
Five double-blind trials recruited per treatment arm approximately 70 to 100 patients with
diabetes who had glycated haemoglobin (HbA1c) ≤11% and distal symmetrical sensorimotor
polyneuropathy for at least one year and, in the three American studies, less than 5 years.
Four trials recruited patients with postherpetic neuralgia of at least 3 and 6 months duration,
respectively, after healing of the herpes zoster skin rash. A further double-blind trial recruited
patients with either diabetic peripheral neuropathy or postherpetic neuralgia. In all studies
patients had a score ≥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
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(assessed via the 11-point Likert scale described previously) 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 the 12week diabetic neuropathy study and the 600mg dose in one of the 8-week diabetic neuropathy
studies. 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. In these trials,
responders were defined as patients who had a 50% reduction in mean weekly pain score
compared with baseline and similar efficacy patterns were observed in this secondary
endpoint.
Summary of evidence on comparative safety
Pregabalin is commonly associated with central nervous system adverse effects similar to
most anti-epileptic drugs. Pregabalin 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 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 comparative trials of pregabalin with carbamazepine for the treatment of
trigeminal neuralgia or with gabapentin in the treatment of neuropathic pain and therefore
relative efficacy is uncertain. There are gabapentin trials with inclusion/exclusion criteria,
methodology and primary endpoints similar to the pregabalin studies described previously. In
one trial, which recruited 165 patients with diabetic peripheral neuropathy, gabapentin was
titrated above the licensed daily dose of 1800mg per day to 3600mg when possible (67% of
patients). It was associated with a significantly lower mean weekly pain score at endpoint
compared with placebo: 3.9 vs. 5.1. This appears similar to the mean weekly pain scores at
endpoint with the maximum dose of pregabalin in diabetic peripheral neuropathy: 3.6 to 4.3. In
two trials, which recruited 334 and 229 patients with postherpetic neuralgia, gabapentin
titrated, in the first study, to 1800mg or 2400mg per day and, in the second study, to 3600mg
per day was associated with significantly lower mean weekly pain scores at endpoint
compared to placebo: 4.3 and 4.2 vs. 5.3 in the first study and 4.2 vs. 6.0 in the second.
These appear similar to results achieved with the highest dose of pregabalin in postherpetic
neuralgia: 3.6 to 4.4.
The majority of trials excluded patients who had failed to respond to previous treatment with
gabapentin at daily doses ≥1200mg. Data are thus limited on the efficacy of pregabalin in
patients unresponsive to gabapentin.
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Summary of comparative health economic evidence
The evidence is cost utility analysis based on a Markov model. The model compares
pregabalin with gabapentin for treatment of post herpetic neuralgia and diabetic neuropathy.
The model uses indirect comparison based on data from placebo controlled trials. The model
suggests that both pregabalin and gabapentin are cost-effective in comparison with placebo
and that pregabalin may be more cost-effective than gabapentin. However, this result is
dependent on pregabalin being more effective than gabapentin and there is no direct evidence
to support this. Moreover the submission provides no information about the cost-effectiveness
of either drug in comparison with more commonly used treatments such as amitriptyline and
carbamazepine. The economic case was therefore not demonstrated.
Budget impact
Gabapentin is currently used for about 7% of patients treated for neuropathic pain. If
pregabalin were to replace gabapentin in all patients currently receiving the latter, the net
resource implication, in terms of drug acquisition costs to the NHS in Scotland, would be an
additional cost of between £1m and £2m over one year.
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 it to have fewer side effects than tricyclic antidepressants. SIGN recommends 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.
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Additional information
At its November 2004 meeting, after consideration of a full submission, the New Drugs
Committee of the Scottish Medicines Consortium recommended that pregabalin should be
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.
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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
12 January, 2005.
Drug prices are those available at the time the papers were issued to SMC for consideration.
The reference numbers in this document refer to the under-noted references. Those shaded
grey are additional to those supplied with the submission.
European Medicines Agency. European Public Assessment Report for Lyrica, Scientific
Discussion. [internet] www.emea.eu.int/humandocs/Humans/EPAR/lyrica/lyrica.htm
Backonja M, Bell D, Beydoun A et al. Synopsis of clinical study report 1008-014. 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 1008-029. A 5week, 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 1008-131. An 8week, 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 1008-040. 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 1008-149. 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 1008-030. 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 1008-045. 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 1008-127. An
8-week, double-blind, placebo-controlled parallel-group study of pregabalin in patients with
postherpetic neuralgia.
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Domzal T, Jastrzebski J, Kubler A et al. Synopsis of clinical study report 1008-196. A 13week, 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: 628-38.
Dworkin RH, Corbin AE, and Young JP et. al. Pregabalin for the treatment of postherpetic
neuralgia: a randomised placebo-controlled trial. Neurology 2003; 60: 1274-83.
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: 26-35
Backonja M, Beydoun A, Edwards KR et al. Gabapentin for the symptomatic treatment of
painful neuropathy in patients with diabetes mellitus. JAMA 1998; 280: 1831-6.
Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic
neuralgia. JAMA 1998; 280: 1837-42.
Rice ASC, Maton S, Postherpetic neuralgia study group. Gabapentin in postherpetic
neuralgia: a randomised, double-blind, placebo controlled study. Pain 2001; 94: 215-24
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