New Medicine DEXIBUPROFEN Report Document Status Decision made at Suffolk D&TC 7th September 2006 Traffic Light Decision Double Green Prescriber’s Rating Nothing New Date of Last Revision 11th September 2006

Approved Name Dexibuprofen Trade Name Seractil™ Manufacturer Genus Legal Status POM Indication Symptomatic treatment for the relief of pain and inflammation associated with osteoarthritis Acute symptomatic treatment of pain during menstrual bleeding (primary dysmenorrhoea) Symptomatic relief of other forms of mild to moderate pain such as muscular- skeletal or dental pain Dosage 600mg to 900mg daily divided in up to three single doses For treatment of mild to moderate pain – initially 200mg single dose and daily doses of 600mg are recommended (NB Half tablets are stated as not giving 200mg) Maximum single dose 400mg maximum daily dose 1200mg Not recommended <18 years of age Cost 300mg tablets 60 £9.47 400mg tablets 60 £9.97 Possible Number of Suffolk All patients in Suffolk Patients Number Needed to Treat Not calculated Treatment Alternatives Ibuprofen Other analgesics within BNF Future Alternatives None known Possible Future Indications None known but other uses for similar products

This is an NHS Suffolk document that has been adopted by the WSCCG.

Reviewer’s Comments

The release of dexibuprofen, S(+)-ibuprofen, in the UK adds another non- steroidal anti-inflammatory product to the list of available NSAIDs

It is the active isomer of ibuprofen and has been shown to be at least equivalent to double the dose of ibuprofen.

It has been shown that the onset of action is shorter (15 minutes less) than that for racemic ibuprofen and it is perhaps conceivable that this may be seen as an advantage in certain circumstances.

It has been suggested that some of the side effect profile, such as the interference with the triglyceride pathway, is specific to the R(-) isomer of ibuprofen and thus dexibuprofen is a “cleaner” drug. However the evidence suggests that the gastrointestinal effects, which are most common and cause the patients the majority of concern, at relative doses are similar.

Evidence Reviewed

Paper, Review, Abstract etc. Level of evidence Seractil™ Summary of Product Characteristics N/A Phleps W Overview on clinical data of dexibuprofen IV Clin Rheumatol (2001) Suppl 1 S15 – S21 Hawel R, Klein G, Singer F et al Comparison of the I efficacy and tolerability of dexibuprofen and celecoxib in the treatment of osteoarthritis of the hip Int J Clin Pharmacology & Therapeutics Vol41 No4/2003(153-164) Klein G, Neff H, Kullich W S(+) versus racemic I ibuprofen Letter Lancet March 14 1992 p 681 Dionne RA, McCullagh L Enhanced analgesia and I suppression of plasma β-endorphin by the S(+)-isomer of ibuprofen Clin Pharmacol Ther 1998;63:694-701 Tooley P Seractil™ Product Monograph Document IV Genus Level of evidence adapted from “Quick and Clean” : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995

Submitted for comment to: Date Medical Information Department, Genus 18.8.06 Dr M Bailey, The Ipswich Hospital 18.8.06 Dr G Cluney, The Ipswich Hospital Dr R Munglani, West Suffolk Hospital Dr W Notcutt, James Paget Hospital Dr Blossfelt, James Paget Hospital

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Review

Dexibuprofen has been available for prescription in Europe and other parts of the world since it was first introduced in Austria in 1994. Ibuprofen is a racemic mixture of R(-)-ibuprofen and S(+)-ibuprofen in roughly equal parts. The S(+) isomer, also known as dexibuprofen, is twice as soluble in both water and acid than the racemic mixture and as such permits rapid absorption by the body and extensive distribution into target tissues.

In the overview of the clinical data of dexibuprofen by Phleps several clinical trials and post-marketing surveillance studies were reviewed and a meta- analysis was performed. Six of the trials were double-blind studies and the others were a pharmacokinetic study and a long-term safety study both of which were open.

It was found that in a dosage ratio of 0.5:1 dexibuprofen was equally efficacious as racemic ibuprofen. In addition 75% of the maximum daily dose of dexibuprofen (300mg three times a day) was equally efficacious as the maximum daily dose (50mg three times a day) of diclofenac sodium.

In the paper by Dionne it is reported that the S(+) isomer of ibuprofen in an oral surgery model of acute pain provided faster onset and greater analgesic activity than the racemic mixture of ibuprofen. These results are shown in Table 1.

Table 1 To show median time to onset of pain relief and duration of relief.

S(+)-ibuprofen S(+)-ibuprofen Racemic 200mg 400mg ibuprofen 400mg n 51 50 50 Median time to onset of pain relief 22 23 35 (minutes) Median time to end of satisfactory 291 274 255 pain relief (minutes) Median time to request for rescue 5.8 6.1 5.4 medication (hours)

Adverse Effects etc.

For full information please refer to the Summary of Product Characteristics

Phleps reports a meta-analysis of five randomised trials of up to 21 treatment days duration in the dose range of 600-1200mg dexibuprofen and 1200- 2400mg racemic ibuprofen. Adverse events classified as possible, probable and very probable were included as adverse reactions and analysed. The results are shown in Table 2.

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Table 2 To show the meta-analysis concerning % ADRs in five randomised double- blind clinical studies

% of patients reporting symptoms NB Multiple counts possible S(+)-ibuprofen Racemic ibuprofen n 747 583 Gastrointestinal tract 9.37 9.78 Central nervous system 2.54* 4.63 Skin 0.67 0.86 Cardiovascular 0.00 0.00 Others 0.54 0.69 Changes in complete blood count 1.34 2.92 Changes in laboratory values 1.20 1.54 Total sum of ADRs 15.66* 20.41 Withdrawals from treatment 2.4 3.25 * p<0.05

Economic Information

A comparison of prices for a 28 day treatment course using ibuprofen, Brufen™ and Seractil™ is shown in Table 3.

Table 3 To show comparative prices for ibuprofen, Brufen™ and Seractil™

Medicine Dose No tablets Cost £ Ibuprofen 400mg tds 84 (OP) 3.80 Ibuprofen 600mg tds 84 (OP) 5.94 Ibuprofen 600mg tds 84 (ex 100) 3.77 Brufen 400mg tds 84 (ex 100) 6.85 Brufen 600mg tds 84 (ex 100) 10.28 Seractil 300mg bd 84 (ex 60) 8.84 Seractil 300mg tds 84 (ex 60) 13.26 Seractil 400mg bd 84 (ex 60) 9.31 Seractil 400mg tds 84 (ex 60) 13.96 Ibuprofen @ DT price August 2006, Brufen & Seractil @ MIMS price August 2006

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David Evans Specialist in Pharmaceutical Public Health Suffolk Public Health Network Suffolk House P.O.Box 170 Foxhall Road Ipswich Suffolk IP3 8LS

4th September 2006

Dear David,

Re: Dexibuprofen

Thank you for sending my colleague Kim Ellis a copy of your New Medicine Report for Seractil (dexibuprofen). We have the following comments:

Your summary review of the papers we sent you on dexibuprofen has excluded mention of the randomised, comparative endoscopic evaluation of patients with chronic degenerative and/or inflammatory disease by Gomez B.J., et al., (J Clin Pharmacol Ther., 44(4):154-162(2006)). In this study, 60 patients with various rheumatic diseases were treated for a period of 14 days and received either 1200mg dexibuprofen, 2400mg ibuprofen or 150mg diclofenac on the first three days and 800mg dexibuprofen, 1600mg ibuprofen or 100mg diclofenac on the remaining days. After the two-week treatment, gastrointestinal endoscopy was performed in all patients and in 7 patients of each treatment group, an additional capsule-endoscopy was done in order to evaluate the possible damage of each drug on the gastroduodenal and intestinal mucosa. Mucosal lesions were classified in three grades (Grade 0: normal mucosa, Grade 1: 1-5 erosions, Grade 2: >5 erosions, or active bleeding areas). The results showed a clear statistical superiority of dexibuprofen in comparison with ibuprofen (p=0.003), i.e. dexibuprofen caused significantly fewer lesions in the gastroduodenal area than ibuprofen. Furthermore, patients in the dexibuprofen group had significantly fewer lesions in the intestinal mucosa than patients treated with ibuprofen (p=0.0175).

Printed 14/11/12 ©David Evans Suffolk Public Health Network Not to be used for promotional purposes Page 5 of 9 May be freely copied by NHS agencies We feel this study demonstrates the superior tolerability of dexibuprofen compared to ibuprofen when used at higher doses.

In response to your request for our “view of who should prescribe” dexibuprofen, this should be restricted to general practitioners and hospital clinicians.

In light of the reduced prescribing options to clinicians to treat patients with mild to moderate pain and arthritic conditions following recent product withdrawals and prescribing restrictions, we feel Seractil (dexibuprofen) offers a valuable alternative option for the following:-

• Patients requiring higher doses of ibuprofen in which there are concerns of tolerability.

• Patients with dental pain where speed of onset of analgesia is required.

• Patients intolerant of other NSAIDs at high to maximum doses. This has been confirmed by clinical experience in Europe (75% of the maximum dose of dexibuprofen (900mg) was as 1 effective as the maximum dose of diclofenac (150mg) in patients with severe OA pain. Dexibuprofen (800mg) was as effective as celecoxib (200mg) in relieving OA pain2).

Our 3 year commercial expectation of Seractil (dexibuprofen) is: To achieve a national NSAID prescription market share of 0.5%.

Finally, your comparative price chart for ibuprofen, BrufenTM and Seractil doesn’t make it clear that the therapeutic equivalent dosage ratio for Seractil and ibuprofen is 0.5:1 i.e. Seractil 300mg should be compared to ibuprofen 600mg and Seractil 400mg should be compared to 2 x 400mg ibuprofen.

I hope our comments are useful. If you require any further information, please let me know.

Yours sincerely

Kelly Bird Pharmacovigilance and Medical Information

References: 1. Hawel, R., et al., Wien Klin Wochenschr.,109(2):53-59(1997). 2. Hawel, R., et al., Int J Clin Phar Ther., 41:153-164(2003).

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Charts to be used in the decision making process in Suffolk

Quality of Evidence categories Cost utility categories Per life year gained I Strong evidence from at least 1 RCT A Less than £3,000 II-1 Evidence from a well designed CT without randomisation B £3,000 to £20,000 II-2 Evidence from well designed cohort or case controlled study C > £20,000 II-3 Evidence from multiple time series or dramatic results D Negative life years III Opinions of respected clinicians or expert committees IV Evidence inadequate

Recommendations informed by cost utility and quality of evidence Key to Table at Right Quality of A B C D evidence ++ Strongly recommended I ++ (high) ++ - X + Recommended II ++ + - X - Beneficial but high cost III + - - X X Not recommended IV 0 0 0 0 (low) 0 Not proven

Adapted from

“Quick and Clean” : authorative health technology assessment for local health care contracting Andrew Stevens, Duncan Collin-Jones & John Gabbay Health Trends Vol 27 No 2 1995

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To Decide If A Medication Is To Be Used In Suffolk

Criterion Tends to 2 Medium 4 Tends to poor good Quality of evidence in the papers reviewed IV III II-2 II-1 Magnitude of effect inferred from the trials reviewed Low xxxx Medium xxxx High Known Side Effect Profile High xxxx Medium xxxx Low Known Interactions High xxxx Medium xxxx Low Concern re Possible Side Effects Not Yet Uncovered High xxxx Medium xxxx Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor xxxx Medium xxxx Good NNT High xxxx Medium xxxx Low Comparison Of Effectiveness With Other Medicines In Use For Poor xxxx Medium xxxx Good The Same Condition Severity of Condition to be Treated Trivial xxxx Medium xxxx Severe Cost Utility Score D C B ?A A Recommendations informed by cost utility and quality of 0 X - + ++ evidence

Prescriber’s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are “me-too” products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages.

With acknowledgement to Prescrire

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To Decide Where A Medication Is To Be Used In Suffolk

Criterion Red Amber Green D Green Skills of the Experience Of The Condition Specific Specific Specific Genera prescriber Diagnosis Specific Specific Specific Genera Monitoring Progress Of Treatment Difficult Specific Genera Genera

Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy

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