Diclofenac sodium with misoprostol, tablet, 50 mg–200 micrograms, Arthrotec® 50, November 2009
Public Summary Document for Diclofenac sodium with misoprostol, tablet, 50 mg–200 micrograms, Arthrotec® 50, November 2009
Page last updated: 05 March 2010
Public Summary Documents
Product: Diclofenac sodium with misoprostol,
tablet, 50 mg–200 micrograms, Arthrotec®
50
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
The submission sought an Authority Required (STREAMLINED) listing
for osteoarthritis or rheumatoid arthritis in patients who require
prophylaxis against non-steroidal anti-inflammatory drug
(NSAID)-induced peptic ulcers.
2. Background
The PBAC has considered four previous applications for listing of
the combination product diclofenac sodium with misoprostol.
3. Registration Status
Diclofenac sodium with misoprostol was TGA registered on 29 October
1997 for the treatment of patients who require a non-steroidal
anti-inflammatory drug (NSAID) together with misoprostol. The
diclofenac component is indicated for the treatment of
osteoarthritis and rheumatoid arthritis. The misoprostol component
is indicated for the prophylaxis of NSAID induced gastric and
duodenal ulceration. Known risk factors for NSAID induced
gastropathy include age in excess of 60 years, a history of peptic
ulcer disease, smoking, previous NSAID gastrointestinal intolerance
and the presence of a concomitant disease.
4. Listing Requested and PBAC’s View
Authority Required (STREAMLINED)
Osteoarthritis or rheumatoid arthritis in patients who require
prophylaxis against NSAID-induced peptic ulcers.
NOTE:
Known risk factors include age in excess of 60 years, a history of
peptic ulcer disease, smoking, previous NSAID gastrointestinal
intolerance, and serious co-morbid disease.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Gastric and duodenal ulcers and serious gastrointestinal (GI)
complications have been commonly reported in patients receiving
NSAIDs. These events can occur at any time during treatment, and in
the majority of cases, serious GI complications are asymptomatic
and result in hospitalisations and increased mortality.
The fixed dose combination of diclofenac sodium with misoprostol
may simplify the management of osteoarthritis and rheumatoid
arthritis in those patients where the use of diclofenac and
misoprostol concomitantly is appropriate.
6. Comparator
The submission nominated the individual components of the fixed
combination, diclofenac and misoprostol, as the main comparators.
This is in accordance with the PBAC Guidelines for Fixed
Combination Products. A supplementary analysis was undertaken with
a combination on an NSAID and proton pump inhibitor (PPI) as the
comparator, because this is the treatment regimen most prescribed
in clinical practice.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
The submission presented seven trials comparing Arthrotec with
diclofenac monotherapy for the treatment of the symptoms of
arthritis. Ulcer prevention was assessed using an indirect
comparison of one Arthrotec trial and two concomitant diclofenac
and misoprostol trials with diclofenac monotherapy as the common
reference. Supplementary evidence was based on three trials
comparing NSAID + PPI versus NSAID + misoprostol. Five
pharmacokinetic trials were provided as supportive evidence.
Details of the trial publications are presented in the table below.
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Arthrotec vs. diclofenac monotherapy – arthritis outcomes | ||
| Trial 289 Stead H et al (1992) Verdickt W et al (1992) | Gastroduodenal safety of Arthrotec in rheumatoid arthritis patients: subgroup analyses of the effects of age and gender. A double-blind comparison of the gastroduodenal safety and efficacy of diclofenac and a fixed dose combination of diclofenac and misoprostol in the treatment of rheumatoid arthritis. | Br J Rheumatol 1992a; 31(Suppl 2): 178 Scand J Rheumatol 1992; 21: 85-91 |
| Trial 292 De Queiroz MV et al (1994) Hannequin JR (1992) Woods EM et al (1992) | Double-blind comparison of the efficacy of diclofenac/misoprostol and diclofenac in the treatment of rheumatoid arthritis. Efficacy of Arthrotec in the treatment of rheumatoid arthritis. Antiarthritis efficacy of Arthrotec in rheumatoid arthritis patients: subgroup analyses of the effects of disease duration and functional capacity. | Eur J Rheumatol Inflamm 1994; 14: 5-13 Scand J Rheumatol Suppl 1992; 96: 7-14 Br J Rheumatol 1992; 31(Suppl 2): 179 |
| Trial 296 Bolten W et al (1992) Stead H et al (1992) | The gastroduodenal safety and efficacy of the fixed combination of diclofenac and misoprostol in the treatment of osteoarthritis. Gastroduodenal safety of Arthrotec in osteoarthritis patients: subgroup analyses of the effects of age and gender. | Br J Rheumatol 1992; 31: 753-758 Br J Rheumatol 1992b; 31(Suppl 2): 178 |
| Trial 298 Doherty M (1992) | The efficacy of Arthrotec in the treatment of osteoarthritis. | Scand J Rheumatol Suppl 1992; 96: 15-21 |
| Trial 349 Bocanegra TS et al (1998) | Diclofenac/misoprostol compared with diclofenac in the treatment of osteoarthritis of the knee or hip: a randomized, placebo-controlled trial. Arthrotec Osteoarthritis Study Group. | J Rheumatol 1998; 25:1602-11 |
| Trial 352 Bocanegra JA et al (1997) | Safety and tolerability of diclofenac/misoprostol (Arthrotec) versus diclofenac alone in the treatment of elderly osteoarthritis (OA) patients. | Gastroenterology 1997; 112 (Suppl): A74 |
| Trial 003 Kiff PS et al (1994) | Arthrotec, diclofenac and ibuprofen in general practice. | Eur J Rheumatol Inflammation 1994; 14: 31-7 |
| Arthrotec vs. diclofenac and misoprostol – prevention of NSAID-induced ulcers | ||
| Trials 289, 296, 349 | As above. | |
| Trial 269 Agrawal NM et al (1995) Geis GS et al (1991) Geis GS et al (1992) | Misoprostol coadministered with diclofenac for prevention of gastroduodenal ulcers. A one-year study. Prevalence of mucosal lesions in the stomach and duodenum due to chronic use of NSAID in patients with rheumatoid arthritis or osteoarthritis, and interim report on prevention by misoprostol of diclofenac associated lesions. Prevention of diclofenac-induced gastroduodenal mucosal ulcers by misoprostol: a one year study. | Dig Dis Sci 1995; 401125-31 J Rheumatol 1991; 18 (Suppl 28): 11-4 Br J Rheumatol 1992; 31 (Suppl 2): 180 |
| Misoprostol and NSAID vs. PPI and NSAID | ||
| Bianchi Porro et al (1994) | Misoprostol vs two different dosages of omeprazole in the prevention of NSAIDs-induced ulcers. | Gastroenterology 1994; 106 (Suppl 4): A51 |
| Hawkey C et al (1998) | Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. | NEJM 1998; 338: 727-34 |
| Stupnicki T et al (2003) | Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients. | Digestion 2003; 68: 198-208 |
8. Results of Trials
A meta-analysis using a random effects model was undertaken to
demonstrate non-inferiority of Arthrotec to diclofenac for the
treatment of the symptoms of arthritis.
The pooled results for all comparisons showed no statistically
significant difference between Arthrotec and diclofenac monotherapy
for arthritis outcomes. The re-submission used 0.8, a pre-defined
minimal clinically important difference (MCID) from the original
clinical trials, as the criteria for non-inferiority. This was
considered reasonable by the PBAC. As the lower confidence interval
around the relative risk for each comparison was greater than the
MCID, the re-submission claimed Arthrotec met the criterion for
non-inferiority to diclofenac. The PBAC noted that the
meta-analysis has low power for detecting heterogeneity if the
included number of trials is small.
The comparison of Arthrotec and concomitant misoprostol and
diclofenac for the prevention of NSAID-induced ulcers was based on
an indirect comparison using diclofenac as the common reference.
The indirect comparison only used trials in which patients had a
history of gastro-intestinal (GI) damage at trial enrolment. The
table below provides the results of this comparison.
Summary of results of the indirect comparison – ulcer
prevention
| Trial ID | Trial of proposed drug | Trials of main comparator | Indirect estimate of effect RR (95% CI) | ||||
| Arthrotec n/N (%) | Diclo n/N (%) | Tmt effect RR (95% CI) | Miso + Diclo n/N (%) | Diclo n/N (%) | Tmt effect RR (95% CI) | ||
| Gastric ulcer | |||||||
| 349 | 4/849 | 15/840 | 0.26 (0.09, 0.79) | — | — | — | — |
| Pooled results of 269 and 320 | 22/4,404 | 70/4,464 | 0.33 (0.20, 0.53) | 0.79 (0.24, 2.55) | |||
| Duodenal ulcer | |||||||
| 349 | 8/849 | 9/840 | 0.88 (0.34, 2.27) | — | — | — | — |
| Pooled results of 269 and 320 | 26/4,392 | 45/4,476 | 0.60 (0.37, 0.97) | 1.47 (0.51, 4.26) | |||
| Gastroduodenal ulcer | |||||||
| 349 | 12/849 | 23/840 | 0.52 (0.26, 1.03) | — | — | — | — |
| Pooled results of 269 and 320 | 46/4,404 | 108/4,464 | 0.44 (0.31, 0.62) | 1.18 (0.54, 2.57) | |||
Tmt = treatment; CI=confidence interval; n = number with
event; N = number in group; RR = relative risk; Miso=misoprostol;
Diclo=diclofenac
The re-submission claimed the results of the indirect comparison
indicated that Arthrotec is non-inferior to concomitant diclofenac
and misoprostol.
The re-submission undertook a direct comparison of the incidence of
ulcers with Arthrotec and diclofenac monotherapy in patients who do
not have a history of GI damage. The re-submission claimed that
this analysis demonstrated Arthrotec is superior to diclofenac
monotherapy for GI outcomes. However, the evaluation noted the
claimed advantage for Arthrotec was not consistent across trials
and so should be interpreted with caution.
The re-submission included a comparison of misoprostol and NSAID
versus PPI and NSAID as supplementary evidence to demonstrate that
misoprostol and PPIs are similar in terms of prevention of
NSAID-induced ulcers. The results of the misoprostol and PPI
comparison are shown in the table below.
Comparison of occurrence of GI ulcers with misoprostol +
NSAID vs. PPI + NSAID
| Trial ID | Misoprostol + NSAID n/N (%) | Omeprazole + NSAID n/N (%) | Misoprostol + NSAID versus omeprazole + NSAID | ||
| RR (95% CI) | RD (95% CI) | NNT (95% CI) | |||
| Gastric ulcer | |||||
| 4 weeks | |||||
| Bianchi Porro 1994 | 2/30 (6.7) | 1/30 (3.3) | 2.00 (0.19, 20.90) | 0.03 (-0.08, 0.14) | 33 |
| Hawkey 1998 | NR | NR | — | — | — |
| 24 weeks | |||||
| Bianchi Porro 1994 | NR | NR | — | — | — |
| Hawkey 1998 | 31/296 (10.5) | 35/274 (12.8) | 0.82 (0.52, 1.29) | -0.02 (-0.08, 0.03) | -50 |
| Duodenal ulcer | |||||
| 4 weeks | |||||
| Bianchi Porro 1994 | 0/30 (0) | 0/30 (0) | NA | NA | N/A |
| Hawkey 1998 | NR | NR | — | — | — |
| 24 weeks | |||||
| Bianchi Porro 1994 | NR | NR | — | — | — |
| Hawkey 1998 | 30/296 (10.1) | 7/274 (2.6) | 3.97 (1.77, 8.88) | 0.08 (0.04, 0.11) | 13 (9, 25) |
| Gastroduodenal ulcer | |||||
| 12 weeks | |||||
| Stupnicki 2003 | 1/258 (0.4) | 1/257 (0.4) | 1.00 (0.06, 15.84) | 0.00 (-0.01, 0.01) | N/A |
| 24 weeks | |||||
| Stupnicki 2003 | 1/258 (0.4) | 0/257 (0) | 2.99 (0.12, 73.02) | 0.00 (-0.01, 0.01) | N/A |
Abbreviations: GI = gastrointestinal; NR = not reported;
RR=relative risk; RD=risk difference; CI=confidence interval;
NNT=number needed to treat; NSAID=non-steroidal anti-inflammatory
drug; N/A=not applicable
The re-submission concluded that misoprostol and NSAID treatment is
similar to PPI and NSAID treatment. However, the PBAC considered
there was not a strong basis for the conclusion of similarity,
given the wide confidence intervals, which indicated some
uncertainty, the small number of trials included, and the greater
efficacy of the PPI omeprazole at 24 weeks in the Hawkey (1998)
trial. The re-submission did not present a meta-analysis of these
trials. The PBAC noted that the conclusions of the published trials
differed from those made in the re-submission.
The PBAC noted that all meta-analyses undertaken in the
re-submission combined in the least two and at most three trials.
As a result, there was substantial uncertainty about the effect of
heterogeneity in the clinical trials combined in the
meta-analysis.
The re-submission compared percentages of adverse effects and
concluded rates were similar. The re-submission did not conduct any
statistical analysis on the safety data, or attempt to prove that
the rates of adverse effects with Arthrotec were similar to those
with concomitant diclofenac and misoprostol. The PBAC considered
the methods used by the re-submission to assess safety data were
inappropriate given a non-inferiority claim should be demonstrated
with both efficacy and safety analyses.
For PBAC’s view, see Recommendation and
Reasons.
9. Clinical Claim
The re-submission claimed that Arthrotec is non-inferior to
diclofenac monotherapy for arthritis outcomes. With regard to the
reduction in NSAID-induced GI complications endpoints, the
re-submission claimed that Arthrotec is non-inferior to both
concomitant diclofenac and misoprostol and combination NSAID and
PPI.
The PBAC considered the evidence provided demonstrated that
Arthrotec is non-inferior to diclofenac monotherapy for treating
the symptoms of arthritis. However, the PBAC considered the
evidence did not conclusively prove Arthrotec is non-inferior to
concomitant diclofenac and misoprostol and combination NSAID and
PPI for the reduction of NSAID-induced ulcers.
The PBAC considered that the submission’s claim was not
reasonable because it failed to account for the higher
cardiovascular risk associated with diclofenac in comparison with
other NSAIDs.
10. Economic Analysis
The submission presented a cost-minimisation analysis.
Arthrotec taken twice daily was assumed to be equivalent to
concomitant treatment with diclofenac 100 mg and misoprostol
400-800 micrograms per day. Arthrotec taken three times daily was
assumed to be equivalent to concomitant treatment with diclofenac
150 mg and misoprostol 400-800 micrograms per day.
For the sensitivity analysis, Arthrotec taken twice daily was
assumed to be equivalent to concomitant treatment with diclofenac
100 mg and PPI 20 mg per day. Arthrotec taken three times daily was
assumed to be equivalent to concomitant treatment with diclofenac
150 mg and PPI 20 mg per day.
11. Estimated PBS Usage and Financial Implications
The submission asserted that the majority of patients prescribed
Arthrotec would receive a dose of one tablet twice daily for an
average duration of four months.
The submission estimated the likely number of patients per year to
be between 50,000 and 100,000 in Year 5 with an estimated financial
cost per year to the PBS of less than $10 million in Year 5.
For PBAC’s view, see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC agreed that the main comparators, the individual
components of the fixed combination diclofenac and misoprostol,
were appropriate and was in accordance with the PBAC Guidelines for
Fixed Combination Products. The PBAC noted that a supplementary
analysis was undertaken with a combination of a non-steroidal
anti-inflammatory drug (NSAID) and proton pump inhibitor (PPI) as
the comparator, because this is the treatment regimen most
prescribed in clinical practice which was also appropriate.
The PBAC noted that even though diclofenac is termed a
“traditional” NSAID, there is significant scientific
evidence to indicate that it is a relatively COX-2 selective drug
with a similar degree of COX-2 selectivity to celecoxib in some
studies. Diclofenac has also been shown to be associated with a
significant elevated risk of thrombotic cardiovascular events,
which appears to be similar to what was observed with rofecoxib,
and the increased vascular event risk for diclofenac is apparent at
commonly used doses (up to 150 mg/day).
The PBAC was concerned that the patient group targeted by the
proposed Arthrotec restriction was inappropriate given the
cardiovascular toxicity associated with diclofenac, and did not
consider that this issue had been adequately addressed in the
submission. In particular, there is the possibility that patients
might be switched from other NSAIDs to Arthrotec, which do not
carry the same cardiovascular risk as diclofenac. Should switching
occur, it would also increase the market compared to current
clinical practice.
The PBAC considered that the evidence from the trials does not
conclusively prove Arthrotec is non-inferior to concomitant
diclofenac and misoprostol and combination NSAID and PPI for the
reduction of NSAID-induced ulcers and that there is both clinical
and statistical uncertainty given the small patient numbers and
variability. The PBAC noted that the confidence intervals are wide
and there were a number of important differences in the underlying
trial populations of the trials included in the indirect
comparison.
The PBAC noted that both the individual components were currently
available on the PBS, which allows for dose titration of each drug.
However, the Arthrotec twice daily regimen results in misoprostol
dosing of 400mcg, which has been shown to be less effective than
higher doses (600-800mcg) of misoprostol (Raskin et al 1995) and
the three time daily regimen would mean an up-titration of
diclofenac to 150 mg which may lead to increased adverse events.
The PBAC also noted that proton pump inhibitors listed on the PBS
are a viable alternative to misoprostol. However, the patient would
have to pay two co-payments if prescribed with diclofenac.
The PBAC considered that there was not good evidence provided that
Arthrotec would be prescribed and used only as a four month course
as both osteoarthritis and rheumatoid arthritis are chronic
conditions and that the likely number of patients and the financial
costs to the PBS may have been underestimated.
The PBAC therefore, rejected the submission based on lack of
clinical need and the potential for unwanted clinical
outcomes.
The PBAC noted that the submission meets the criteria for an
independent review.
Recommendation:
Reject
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Pfizer Australia notes the PBAC recommendation but considers that there is an unmet need for the prevention of NSAID-induced gastroduodenal ulceration.
