Tocilizumab, solution for IV infusion, 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL, Actemra® - March 2010
Public Summary Document for Tocilizumab, solution for IV infusion, 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL, Actemra® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: TOCILIZUMAB, solution for IV infusion, 80
mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL,
Actemra®
Sponsor: Roche Products Pty Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application:
The submission sought a Section 100 (Highly Specialised Drugs
Program) listing for first line use in the treatment of severe
active rheumatoid arthritis.
Highly Specialised Drugs are medicines for the treatment of chronic
conditions, which, because of their clinical use or other special
features, are restricted to supply to public and private hospitals
having access to appropriate specialist facilities.
2. Background:
In July 2009, the PBAC recommended that tocilizumab solution for
infusion 80 mg in 4 mL, 200 mg in 10 mL and 400 mg in 20 mL be
listed as a Section 100 item, for the treatment of severe, active
rheumatoid arthritis in combination with methotrexate in patients
who have failed to demonstrate a response to at least one TNF-alfa
antagonist treatment on a cost-minimisation basis compared to
abatacept.
The PBAC was concerned with respect to comparative safety, in
particular long-term safety. Tocilizumab was associated with a
higher incidence of infection than abatacept, more than doubling of
incidence of malignancy in the long-term data compared to trial
data, sustained elevations in total cholesterol requiring
additional treatment, and 15 deaths reported in a post-marketing
surveillance study of Japanese patients. Therefore, given the
toxicity concerns of the increased risks of infection and raised
lipid profile the PBAC considered that a second-line listing on a
cost-minimisation basis with abatacept appropriate. The sponsor did
not proceed with listing.
At the same meeting, the PBAC noted that listing was also requested
for the treatment of severe active rheumatoid arthritis with
tocilizumab in combination with a non-biological disease modifying
anti-rheumatic drug (DMARD). The PBAC considered there was
uncertainty associated with the costings for the use of DMARDs in
combination with tocilizumab. The PBAC decided not to recommend
listing in combination with other DMARDs on the basis of uncertain
equivalent efficacy of tocilizumab in combination with
non-methotrexate DMARDs and the uncertain costs of non-methotrexate
DMARDs in the cost minimisation equation.
In November 2009, the PBAC recommended that tocilizumab be listed
as monotherapy for the treatment of severe active rheumatoid
arthritis in patients who have failed to demonstrate a response to
a TNF-alfa antagonist treatment on a cost-minimisation basis
compared to etanercept. With respect to the adverse event profile
of tocilizumab, the PBAC remained concerned. At the time, the
follow-up in trials was considered too short to adequately assess
the long-term toxicity risks. Therefore, the PBAC considered that
at that time the place of tocilizumab, both as combination therapy
with methotrexate, and as monotherapy, was second line to TNF-alfa
antagonists.
3. Registration Status:
Tocilizumab was TGA registered on 21 May 2009 for the treatment of moderate to severe active rheumatoid arthritis in adult patients:
- in combination with methotrexate or other non-biological DMARD in case of either an inadequate response or intolerance to previous therapy with one or more DMARDs; or
- as monotherapy in case of intolerance to methotrexate or where continued treatment with methotrexate is inappropriate.
4. Listing Requested and PBAC’s View:
The sponsor requested the same restrictions that apply to the
currently listed bDMARDs. The PBAC agreed that this approach was
appropriate.
5. Clinical place for the Proposed Therapy:
Rheumatoid arthritis is an inflammatory disorder, typically
featuring a combination of peripheral symmetrical inflammatory
arthritis and a number of well-described extra-articular symptoms.
Tocilizumab would provide another treatment option for adult
patients with severe active rheumatoid arthritis.
6. Comparator:
The submission nominated abatacept, infliximab, etanercept and
adalimumab as the main comparators. The previous submission
nominated abatacept and infliximab as the appropriate comparators
and this was agreed by the PBAC.
7. Clinical Trials
For the comparison of efficacy no changes were made to the trial
data presented in the July 2009 submission. The basis of the
re-submission was an indirect comparison of safety outcomes of four
tocilizumab trials (versus three trials in the July 2009
submission), four abatacept studies (versus two trials in the July
2009 submission), three infliximab studies (versus two trials in
the July 2009 submission), one randomised controlled trial of
abatacept and infliximab plus methotrexate (MTX) therapy (which was
identified in the July 2009 submission), four etanercept trials and
five adalimumab trials.
All of the trials presented in the re-submission had been published
at the time of submission, as follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Tocilizumab+MTX | ||
| Abatacept + MTX | ||
| OPTION | ||
| Smolen JS et al (2008) | Effect of interleukin-6 receptor inhibition with tocilizumab in patients with RA (OPTION study): a double-blind, placebo-controlled, randomised trial. | Smolen JS et al, Lancet 2008; 371(9617):987-997 |
| LITHE | ||
| Kremer JM et al (2008) | Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with an inadequate response to methotrexate: The LITHE study. | Kremer JM et al, American College of Rheumatology 2008 abstract/presentation number L11 |
| TOWARD | ||
| Genovese J et al (2008) | Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs. | Genovese J et al, Arthritis and Rheumatism 2008; 58 (10): 2968-2980 |
| RADIATE | ||
| Emery P et al (2008) | IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumor necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. | Emery P et al, Annals of the Rheumatic Diseases 2008; 67: 1516-1523 |
| AIM | ||
| Kremer JM et al (2008) | Results of a two-year follow up study of patients with rheumatoid arthritis who received a combination of abatacept and methotrexate. | Kremer JM et al, Arthritis & Rheumatism 2008; 58(4): 953-963 |
| ATTAIN | ||
| Genovese MC et al 2005) | Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition. | Genovese MC et al , New England Journal of Medicine 2005; 353 (11): 1114-1123 |
| Genovese MC et al 2008) | Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy. | Genovese MC et al , Annals of the Rheumatic Diseases 2008; 67: 547-554 |
| Wells G et al (2008) | Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis. | Wells G et al, Annals of the Rheumatic Diseases 2008; 67(2): 260-265 |
| Hassett AL et al (2008) |
The multi-faceted assessment of independence in patients with rheumatoid arthritis: preliminary validation from the ATTAIN study. | Hassett AL et al, Current Medical Research and Opinion 2008; 24(5): 1443-1453. |
| Westhovens R et al (2006) | Improved health-related quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. | Westhovens R et al,, Rheumatology 2006; 45 10): 1238-1246 |
| Infliximab +MTX | ||
|---|---|---|
| Etanercept +MTX | ||
| ASSURE | ||
| Weinblatt M et al (2006) | Safety of the selective co stimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. | Weinblatt M et al, Arthritis and rheumatism 2006; 54 (9): 2807-16 |
| ATTEST | ||
| Schiff M et al (2008) | Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. | Schiff M et al, Annals of the rheumatic diseases 2008; 67(8): 1096-103 |
| ATTRACT | ||
| Maini R et al (1999) | Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: A randomised phase III trial. | Maini R et al, Lancet 1999; 354 (9194): 1932-1939 |
| Breedveld FC et al (2004) | Infliximab in active early rheumatoid arthritis. | Breedveld FC et al, Annals of the Rheumatic Diseases 2004; 63(2): 149-155 |
| ASPIRE | ||
| St. Clair EW et al (2004) | Combination of infliximab and methotrexate therapy for early rheumatoid arthritis. | St. Clair EW et al, Arthritis and Rheumatism 2004; 50 (11): 3432-3443 |
| START | ||
| Westhovens R et al (2006) | The safety of infliximab, combined with background treatments, among patients with rheumatoid arthritis and various co morbidities: a large, randomized, placebo-controlled trial. | Westhovens R et al, Arthritis and rheumatism 2006; 54(4): 1075-86 |
| Weinblatt ME et al (1999) Bankhurst AD (1999) |
A trial of etanercept, a recombinant tumor necrosis
factor receptor: Fc fusion protein, in patients with rheumatoid
arthritis receiving methotrexate. Etanercept and methotrexate combination therapy. |
Weinblatt ME et al, New England Journal of Medicine
1999; 340(4): 253-259. Bankhurst AD, Clinical and Experimental Rheumatology 1999; 17 6, Suppl. 18): 69-72 |
| Combe B et al (2006) | Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. | Combe B et al, Annals of Rheumatic Diseases 2006; 65(10): 1357-1362 |
| Adalimumab +MTX | ||
|---|---|---|
| TEMPO | ||
| Klareskog L et al (2004) | Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. | Klareskog L et al, Lancet 2004; 363(9410): 675-681 |
| van der Heijde D et al (2006a) | Patient reported outcomes in a trial of combination therapy with etanercept and methotrexate for rheumatoid arthritis: the TEMPO trial. | van der Heijde D et al, Annals of Rheumatic Diseases 2006a; 65(3): 328-334 |
| van der Heijde D et al (2007) | Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. | van der Heijde D et al, Arthritis and Rheumatism 2007; 56(12): 3928-3939 |
| COMET Study | ||
| Emery P et al (2008) | Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. | Emery P et al, Lancet 2008; 372 (9636): 375-382 |
| Bejarano V et al (2008) | Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis. | Bejarano V et al, Arthritis and Rheumatism 2008; 59(10): 1467-1474 |
| ARMADA | ||
| Weinblatt ME et al (2003) | Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. | Weinblatt ME et al, Arthritis and Rheumatism 2003; 48(1): 35-45 |
| STAR Study | ||
| Furst DE et al (2003) | Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis: results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). | Furst DE et al, Journal of Rheumatology 2003;
30(12): 2563-2571 |
| DE019 Study | ||
| Keystone EC et al (2004) | Radiographic, clinical and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. | Keystone EC et al, Arthritis and Rheumatism 2004; 50(5): 1400-1411 |
| PREMIER | ||
| Breedveld FC et al (2006) | The PREMIER Study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate therapy. | Breedveld FC et al, Arthritis and Rheumatism 2006; 54(1): 26-37 |
8. Results of trials
The key results are summarised in the table below, and are the same
as those submitted in the July 2009 submission, however, with new
toxicity data comparing tocilizumab and the currently listed
first-line bDMARDs abatacept, infliximab, etanercept and
adalimumab.
Results of the indirect comparisons of tocilizumab and abatacept
and tocilizumab and infliximab for American College of Rheumatology
(ACR) response and Disease Activity Score including 28 joints
(DAS28) response at 6 months
| Outcome | Tocilizumab versus abatacept RR (95% CI) | Tocilizumab versus infliximab RR (95% CI) |
|---|---|---|
| ACR response | ||
| DAS28 response | ||
| ACR20 | 1.35 (1.14, 1.61) | 1.16 (0.79, 1.69) |
| ACR50 | 1.62 (1.19, 2.20) | 1.33 (0.75, 2.35) |
| ACR70 | 2.31 (1.13, 4.71) | 2.48 (1.38, 4.45) |
| DAS remission (DAS28 <2.6) | 3.34 (1.70, 6.54) | 4.76 (2.19, 10.36) |
| Low disease activity (DAS28 ≤3.2) |
3.54 (2.29, 5.49) | 3.60 (1.84, 7.06) |
Abbreviation: RR=relative risk
The results of the indirect comparisons showed that tocilizumab has
a statistically significant advantage over abatacept for all ACR
outcomes and DAS remission and low disease activity. Tocilizumab
also demonstrated a statistically significant advantage compared to
infliximab in proportion of patients achieving ACR70 response as
well as DAS remission and low disease activity.
The re-submission presented new toxicity data comparing tocilizumab
and the currently listed first-line bDMARDs abatacept, infliximab,
etanercept and adalimumab. Safety was assessed by the re-submission
at six months (by relative risks versus placebo and indirect
comparisons), one year (indirect comparisons) and two years
(summary of numerical comparisons). Statistically significant
results of the pooled comparisons of each drug compared to placebo
for all adverse events at six months are summarised below.
| Adverse event | Pooled tocilizumab trials RR(95%CI) | Pooled abatacept trials RR(95%CI) | Pooled infliximab trials RR(95%CI) | Pooled etanercept trials RR(95%CI) | Pooled adalimumab trials RR(95%CI) |
|---|---|---|---|---|---|
| Rash | 2.57 (1.50,4.41) | NR | 2.18 (1.07,4.41) | 1.98 (0.44,8.98) |
1.67 (1.00,2.78) |
| Infusion/injection site reactions | 1.55 (1.01,2.36) | 0.88 (0.28,2.82) |
1.82 (0.95,3.47) |
6.82 (2.20,21.1) | 1.76 (1.21,2.54) |
| Musculoskeletal and connective tissue disorders | 0.76 (0.63,0.93) |
NR | NR | 0.43 (0.10,1.81) |
3.40 (1.27,9.10) |
| Infection | 1.17 (1.05,1.30) | 1.02 (0.82,1.28) |
1.13 (0.86,1.49) |
0.92 (0.63,1.35) |
1.06 (0.91,1.23) |
| Headache | 1.50 (1.03,2.17) | 1.25 (0.55,2.84) |
1.85 (1.24,2.77) | 1.47 (0.73,2.97) |
1.02 (0.63,1.68) |
| Increased ALT levels | 4.09 (1.69,9.87) | NR | 1.30 (0.58, 2.93) |
NR | NR |
| Hypercholesterol-aemia defined as an adverse event | 25.15 (1.51,418.21) | NR | NR | NR | NR |
Note: Statistically significant differences between the treatment
groups are bolded
Abbreviations: ALT=alanine aminotransferase; RR=relative risk
The infection rates for tocilizumab and adalimumab at one year were
statistically significantly higher than MTX. Issues with increased
liver enzymes (ALT levels) and hypercholesterolemia were not
recorded for other first-line bDMARDs in the trials identified by
the re-submission. The table below presents statistically
significant adverse events at one year versus placebo.
| Adverse event | Pooled tocilizumab trials RR (95% CI) | Pooled abatacept trials RR (95% CI) | Pooled infliximab trials RR (95% CI) | Pooled etanercept trials RR (95% CI) | Pooled adalimumab trials RR (95% CI) |
|---|---|---|---|---|---|
| Infection | 1.30 (1.11, 1.53) | 1.03 (0.94, 1.13) |
Not calculable | 1.03 (0.91, 1.18) |
1.25 (1.04, 1.50) |
| Headache | 2.21 (0.97, 5.02) |
1.40 (1.13, 1.73) | 1.09 (0.70, 1.68) |
1.05 (0.67, 1.64) |
1.93 (1.10, 3.38) |
| Musculoskeletal and connective tissue disorders | 1.30 (0.91, 1.84) |
1.19 (0.73, 1.94) |
Not reported | 1.18 (0.67, 2.08) |
0.56 (0.36, 0.86) |
| Increased ALT levels | 3.44 (1.40, 8.43) | Not reported | Not reported | Not reported | Not reported |
| Hypertension | 1.88 (0.95, 3.73) |
4.05 (1.23, 13.29) | Not reported | Not reported | Not reported |
| Infusion/injection site reactions | 1.41 (0.76, 2.63) |
Not reported | 3.13 (0.14, 69.13) |
5.68 (1.99, 16.15) | 1.09 (0.78, 1.52) |
| Hypercholesterol-aemia based on ATPIIIa Guideline thresholds | 3.21 (2.20, 4.67) | Not reported | Not reported | Not reported | Not reported |
| Hyperlipidaemia based on ATPIIIa Guideline thresholds | 4.61 (2.69, 7.90) | Not reported | Not reported | Not reported | Not reported |
Note: Statistically significant differences between the treatment
groups are bolded
Abbreviations: ALT=alanine aminotransferase; RR=relative risk
The following table presents an indirect comparison of adverse
events at six months of special interest of tocilizumab versus all
four comparators.
Ratio of relative risks (95% CI) for adverse events of
special interest with 8 mg/kg tocilizumab and other bDMARDs at six
months and 12 months
| Adverse events | Time | 8 mg/kg tocilizumab versus abatacept | 8 mg/kg tocilizumab versus infliximab | 8 mg/kg tocilizumab versus etanercept | 8 mg/kg tocilizumab versus adalimumab |
|---|---|---|---|---|---|
| All infections and infestations | 6 mths 12 mths |
1.15 (0.90, 1.47) 1.26 (1.05, 1.52) | 1.04 (0.77, 1.39) Not calculable | 1.27 (0.86, 1.89) 1.26 (1.02, 1.55) | 1.11 (0.92, 1.33) 1.04 (0.81, 1.33) |
| Upper respiratory tract infection | 6 mths 12 mths |
1.24 (0.68, 2.25) 1.42 (0.76, 2.65) | 0.95 (0.42, 2.14) 1.42 (0.82, 2.44) | 1.33 (0.63, 2.77) Not calculable | 0.94 (0.61, 1.45) 1.18 (0.62, 2.25) |
| Serious infections | 6 mths 12 mths |
1.99 (0.58,6.77) 1.22 (0.38,3.90) | 1.74 (0.57, 5.31) 2.05 (0.18,23.62) | Not calculable 2.40 (0.73, 7.82) | 2.29 (0.58, 9.12) 0.53 (0.06, 4.99) |
| Neoplasms | 6 mths 12 mths |
2.26 (0.12,43.46) 3.28 (0.61,17.57) | 0.34 (0.02, 4.58) Not calculable | Not calculable 1.50 (0.17, 13.08) |
0.55 (0.05, 6.72) 0.34 (0.01, 9.41) |
| Infusion/injection site reactions | 6 mths 12 mths |
1.76 (0.51, 6.03) Not calculable | 0.85 (0.39, 1.85) 0.45 (0.02,10.59) |
0.23 (0.07, 0.76) 0.25 (0.07, 0.84) | 0.88 (0.50, 1.55) 1.30 (0.64, 2.64) |
Notes: Statistically significant results are shown in
bold
At both six (6) and 12 month time points, tocilizumab was
associated with a higher risk of infection, compared to other first
line bDMARDs. This was a statistically significant increased risk
as compared to abatacept and etanercept at 12 months. In addition,
it was associated with twice the rate of serious infections as
compared to infliximab and etanercept. These differences did not
reach statistical significance, however these events were rare and
hence it was not generally possible to prove statistically
significant differences in rare adverse events as studies were
powered to detect differences in efficacy between a drug and a
comparator and not for differences in adverse events. Tocilizumab
had a lower risk of infusion/injection site reactions, compared to
infliximab and etanercept.
The two year data presented in the re-submission was not comparable
as relative risks could not be calculated.
Extended assessment of safety was presented by the re-submission
and the rates and types of adverse events were similar to that
presented in the July 2009 submission.
The PBAC noted that the re-submission’s analysis of safety
data at one year showed that there was a statistically significant
increase in infections (but not for serious infections) for both
tocilizumab and adalimumab, a significantly higher incidence of
headache with abatacept and adalimumab, a significant increase in
hypertension with abatacept and a significant increase in
injection/infusion site reactions with etanercept, and no
significant difference in the incidence of malignancy for any of
the bDMARDs compared with placebo. The PBAC also accepted that
adverse events that are significantly higher for tocilizumab, but
not any of the other bDMARDs, compared to placebo are events for
which there are no reported data for the other bDMARDs: i.e. ALT
elevations, hyperlipidaemia and hypercholesterolaemia. The PBAC
noted that the Product Information for both infliximab and
tocilizumab similarly report the observation of mild or moderate
elevations of hepatic transaminases.
Whilst the safety results showed a higher rate of
hypercholesterolaemia with tocilizumab treatment compared to
placebo, the PBAC agreed that the 95 % confidence intervals around
these comparisons were wide. Further, the PBAC acknowledged the
evidence suggesting an association between hyperlipidaemia and
hypercholesterolaemia and treatment with other bDMARDs has also
been reported, including in a systematic review by Choy and Sattar
(2009) Choy E, Sattar N, Review Interpreting lipid levels in
the context of high-grade inflammatory states with a focus on
rheumatoid arthritis: a challenge to conventional cardiovascular
risk actions, Ann Rheum Dis., 2009;68:460-469.
9. Clinical Claim
The re-submission claimed tocilizumab was no worse than abatacept
and infliximab in terms of efficacy and no worse in terms of safety
than all first-line bDMARDs abatacept, infliximab, etanercept and
adalimumab in patients with severe, active rheumatoid arthritis
over a six-month, one-year and two-year treatment period.
10. Economic Analysis
The submission presented a cost minimisation analysis using
abatacept as the comparator. The equi-effective doses were
calculated to be tocilizumab 8mg/kg administered on days 1 and 29
and then every 28 days, and abatacept 10mg/kg administered on days
1, 15, 29 and then every 28 days. This was unchanged from the July
2009 submission.
Given the evidence in the literature suggesting that other bDMARDs
may have a similar effect on hyperlipidaemia and
hypercholesterolaemia as tocilizumab, the PBAC noted that the
inclusion of statin costs for a proportion of tocilizumab patients
was appropriate, and possibly conservative. Additionally, the PBAC
noted the sponsor’s advice that standard blood chemistry
tests are conducted for all patients with rheumatoid arthritis who
are receiving bDMARDs, so there would be no additional costs
associated with monitoring ALT levels specific to tocilizumab
treatment.
11. Estimated PBS Usage and Financial Implications:
The submission estimated the financial cost per year to the PBS to
be less than $10 million per year for Year 1 to Year 5, and
estimated the likely patient number to be less than 10,000 per
year.
12. Recommendation and Reasons:
The PBAC recommended amending the recommended restriction for the
section 100 (Highly Specialised Drugs Program) listing of
tocilizumab as a pharmaceutical benefit to allow first line use for
the treatment of severe active rheumatoid arthritis whether used as
monotherapy or in combination with methotrexate.
The PBAC noted that the re-submission’s analysis of safety
data at one year show that there was a statistically significant
increase in infections (but not for serious infections) for both
tocilizumab and adalimumab, a significantly higher incidence of
headache with abatacept and adalimumab, a significant increase in
hypertension with abatacept and a significant increase in
injection/infusion site reactions with etanercept, and no
significant difference in the incidence of malignancy for any of
the bDMARDs compared with placebo. The PBAC also accepted that
adverse events that are significantly higher for tocilizumab, but
not any of the other bDMARDs, compared to placebo are events for
which there are no reported data for the other bDMARDs: i.e. ALT
elevations, hyperlipidaemia and hypercholesterolaemia. The PBAC
noted that that the Product Information documents for both
infliximab and tocilizumab similarly report the observation of mild
or moderate elevations of hepatic transaminases.
Whilst the safety results showed a higher rate of
hypercholesterolaemia with tocilizumab treatment compared to
placebo, the PBAC agreed that the 95 % confidence intervals around
these comparisons were wide. Further, the PBAC acknowledged the
evidence suggesting an association between hyperlipidaemia and
hypercholesterolaemia and treatment with other bDMARDs has also
been reported, including in a systematic review by Choy and Sattar
(2009).
Given the evidence in the literature suggesting that other bDMARDs
may have a similar effect on hyperlipidaemia and
hypercholesterolaemia as tocilizumab, the PBAC noted that the
inclusion of statin costs for a proportion of tocilizumab patients
was appropriate, and possibly conservative. Additionally, the PBAC
noted the sponsor’s advice that standard blood chemistry
tests are conducted for all patients with rheumatoid arthritis who
are receiving bDMARDs, so there would be no additional costs
associated with monitoring ALT levels specific to tocilizumab
treatment.
The PBAC recommended that the restriction changes for bDMARDs for
the treatment of rheumatoid arthritis recommended at the December
2009 PBAC Special Meeting would also apply to tocilizumab’s
listing. These include revised eligibility criteria and a maximum
of five bDMARDs in a lifetime.
Recommendation:
TOCILIZUMAB, solution for I.V. infusion, 80 mg in 4 mL, 200 mg in
10 mL and 400 mg in 20 mL
Restriction: Section 100 listing (Highly
Specialised Drug)
Public and Private hospital authority required
Complex restriction to be finalised and will be available at www.pbs.gov.au from the date of listing.
Pack size: 1
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
The sponsor has no further comment.
