Zoledronic acid, solution for I.V. infusion, 5 mg (as monohydrate) in 100 mL, Aclasta®, (Paget), November 2009
Public Summary Document for Zoledronic acid, solution for I.V. infusion, 5 mg (as monohydrate) in 100 mL, Aclasta®, (Paget), November 2009
Page last updated: 05 March 2010
Public Summary Document
Product: Zoledronic acid, solution for I.V.
infusion, 5 mg (as monohydrate) in 100 mL,
Aclasta®
Sponsor: Novartis Pharmaceuticals Australia
Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
To request an extension to the current authority required PBS
listing for zoledronic acid to include an authority required
(STREAMLINED) listing for symptomatic Paget disease of bone.
2. Background
This drug had not previously been considered by the PBAC for this
indication.
3. Registration Status
Zoledronic acid 5 mg in 100 mL was TGA registered on 27 May 2009
for the treatment of Paget disease of bone.
Zoledronic acid 5 mg in 100 mL is also registered for the following
indications:
- Treatment of osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures, treatment should be restricted to three annual doses;
- Treatment of osteoporosis in patients over 50 years of age with a history of at least one low trauma hip fracture, to reduce the incidence of further fractures, treatment should be restricted to three annual doses;
- To increase bone mineral density in men with osteoporosis;
- To increase bone mineral density in patients with osteoporosis associated with long term glucocorticoid use; and
- To prevent glucocorticoid induced bone mineral density loss.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Symptomatic Paget’s disease of bone.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Paget disease is a chronic skeletal disorder characterised by
localised areas of increased bone remodelling, bone hypertrophy,
abnormal bone structure and structural weakness. It is
characterised by periods of active, symptomatic disease
interspersed with periods of disease remission. The aims of
treatment are to achieve clinical remission (relief of symptoms),
biochemical remission and radiological remission.
Therapy is aimed at decreasing abnormal bone turnover, and
therefore, treatment usually involves anti-resorptive therapy such
as alendronate, risedronate, tiludronate (oral therapy) and
pamidronate (intravenous therapy) as standard therapy.
Zoledronic acid would provide an alternative intravenous treatment
for Paget disease.
6. Comparator
The submission nominated risedronate as the main comparator (direct
comparison) and pamidronate as a secondary comparator (indirect
comparison).
For PBAC’s view see Recommendation and
Reasons.
7. Clinical Trials
The submission presented a direct comparison of zoledronic acid
with risedronate (pooled Trials 2304 and 2305), an indirect
comparison of zoledronic acid with pamidronate using risedronate as
common comparator (pooled data from Trials 2304/2305, and
pamidronate data from Rendina 2004), and an extension study of
treatment responders of Trials 2304 and 2305 (unpublished). The
outcomes of Merlotti 2007 (zoledronic dose of 4 mg) were included
in the evaluation as supplementary data.
The table below details the published trials presented in the
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Zoledronic acid 5 mg vs. risedronate | ||
| Trial 2304 Reid IR et al | Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Paget’s Disease. | NEJM 2005; 353(9):898-908 |
| Trial 2304 Reid IR | Zoledronate: Efficacy and Safety | J Bone & Mineral Research 2006; 21(Supp 2):P83-P87 |
| Trial 2305 Reid IR et al | Comparison of a Single Infusion of Zoledronic Acid with Risedronate for Paget’s Disease. | NEJM 2005; 353(9):898-908 |
| Trial 2305 Reid IR | Zoledronate: Efficacy and Safety | J Bone & Mineral Research 2006; 21(Supp 2):P83-P87 |
| Extension Study 2304/2305 (interim results) Hosking D et al | Long-Term Control of Bone Turnover in Paget’s Disease With Zoledronic Acid and Risedronate. | Journal of Bone and Mineral Research 2007, 22(1):142-148 |
| Pamidronate vs. risedronate | ||
| Rendina D et al | Risedronate and pamidronate treatment in the clinical management of patients with severe Paget’s disease of bone and acquired resistance to bisphosphonates. | Calcified Tissue International 2004 75:189-196 |
| Zoledronic acid 4 mg versus pamidronate | ||
| Merlotti D et al | Comparison of different intravenous bisphosphonate regimens for Paget’s disease of bone. | J Bone & Mineral Research 2007;22(10);1510-17 |
8. Results of Trials
The primary outcome of the Trials 2304 and 2305 was the proportions
of patients achieving ≥ 75% reduction from baseline in total
serum alkaline phosphatase (SAP) excess at baseline by 6 months.
This outcome has been previously accepted by the PBAC as an
adequate indicator of disease activity in Paget disease of
bone.
The primary outcomes at 6 months in the pooled Trials 2304 and 2305
for zoledronic acid compared with risedronate are summarised in the
table below.
Proportion of patients achieving ≥ 75% reduction from baseline
in total SAP excess at
6 months in pooled Trials 2304 & 2305
| Trial | Treatment | N | Proportion n (%) | Difference in proportions (95% CI) | Odds ratio (95% CI) | Relative risk* (95% CI) |
| 2304/ 2305* | Zoledronic acid | 176 | 169 (96) | 0.22 (0.14, 0.30) | 8.44 (3.90, 21.09) | 1.29 (1.19, 1.43) |
| Risedronate | 171 | 127 (74) |
* From Reid 2005
There were statistically significant differences in the proportion
of patients responding to zoledronic acid compared with risedronate
(relative risk 1.29 [95% CI 1.19, 1.43]).
The results of the indirect comparison of zoledronic acid with
pamidronate, via risedronate as common comparator, using the
secondary outcome of 100% reduction from baseline in total SAP
excess at 6 months are shown in the following table.
Indirect comparison of zoledronic acid and pamidronate via
risedronate: proportion of patients achieving 100% reduction from
baseline in total SAP excess at 6 months
| Trial | Zoledronic acid n/N (%) | Risedronate n/N (%) | Pamidronate n/N (%) | OR (95% CI) | RR (95% CI) |
| 2304/2305* | 156/176 (88.6) | 99/171 (57.9) | 5.7 (3.3,9.9) | 1.53 (1.33,1.76) | |
| Rendina 2004 | 13/15 (86.6) | 12/15 (80.0) | 0.6 (0.2,4.3) | 0.92 (0.67,1.27) | |
| Indirect odds ratio (95% CI) | 9.2 (1.2, 70.3) p = 0.032 | ||||
| Indirect Relative risk (95% CI) | 1.66 (1.17, 2.35) p = 0.046 | ||||
* From Reid 2005
There was a substantial difference in the proportions of responders
in the two risedronate study groups (57.9% and 86.6%) that made the
indirect comparison difficult to interpret. There was clinical
heterogeneity with sub-optimal dosing of risedronate in Trials 2304
and 2305, and possible risedronate resistance. The clinical
heterogeneity between studies and the wide confidence intervals
around the estimates (due to small sample sizes in Rendina 2004)
made this comparison difficult to interpret. The Rendina 2004 study
included patients with relatively high SAP levels, consistent with
relatively extensive and/or relatively active disease. In addition,
the inclusion criteria specified that the percent of total skeletal
volume involved in Paget’s disease of bone in each patient
was greater than 40%, which would not be common in clinical
practice.
The table below shows the proportions of responders in the
subgroups of patients with and without previous anti-pagetic
therapy in the pooled Trials 2304 and 2305.
Proportion of responders (i.e. patients achieving ≥ 75%
reduction from baseline in total SAP excess at 6 months) in pooled
Trials 2304 & 2305, and subgroups of patients with and without
previous anti-pagetic therapy
| Trial | Zoledronic acid n/N (%) | Risedronate n/N (%) | Odds ratio (95% CI) | Relative risk (95% CI) |
| Trials 2304/2305 combined* | 169/176 (96) | 127/171 (74) | 8.44 (3.90,21.09) | 1.29 (1.19,1.43) |
| Previous anti-pagetic therapy** | 89 /94 (95) | 62 /95 (65) | 9.47 (3.50,25.62) | 1.45 (1.24,1.69) |
| No previous anti-pagetic therapy** | 80 /82 (98) | 65 /76 (86) | 6.77 (1.45,31.63) | 1.14 (1.03,1.26) |
* From Reid 2005
** From Reid 2006
Patients in the risedronate group who had previous anti-pagetic
therapy were less likely to achieve a therapeutic response than
those who did not have previous therapy, which may be due to
risedronate resistance.
The table below shows the outcomes for zoledronic acid and
pamidronate from Merlotti 2007. Similar to the above table,
patients in the pamidronate group were less likely to respond to
treatment if they had a history of previous bisphosphonate therapy
compared with no previous therapy (26% vs. 81% response
respectively).
Proportion of patients achieving ≥ 75% reduction from
baseline in total SAP excess at 6 months in Merlotti 2007
| Trial | Zoledronic acid n/N (%) | Pamidronate n/N (%) | RR (95% CI) |
| All patients | 28 / 29 (97%) | 27 / 60 (45%) | 2.15 (1.64, 2.93) |
| Previous bisphosphonate therapy | Not reported* | 10 / 39 (26%) | - |
| No previous bisphosphonate therapy | Not reported* | 17 / 21 (81%) | - |
* Merlotti 2007 states that response rates in the zoledronic
acid group were not significantly different in the previous or no
previous treatment subgroups.
The clinical trial and post-marketing data suggested that
zoledronic acid may be similar to other bisphosphonates in adverse
event profile, with the exception of the acute phase reaction after
infusion.
For PBAC’s view see Recommendation and
Reasons.
9. Clinical Claim
The submission claimed non-inferiority of zoledronic acid compared
with other bisphosphonates in terms of comparative effectiveness,
but stated that this claim is conservative as superiority of
zoledronic acid was demonstrated compared with risedronate and
pamidronate. The submission described zoledronic acid as equivalent
in terms of safety compared with other bisphosphonates.
For PBAC’s view see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis compared with
risedronate, given that equi-effective doses of zoledronic acid and
pamidronate could not be calculated from the indirect analysis. The
equi-effective doses were estimated as 1 mg zoledronic acid to 627
mg risedronate. The submission calculated the equi-effective doses
solely by comparing the time to loss of therapeutic response in an
extension study of patients who were classified as
“responders” in Trials 2304 and 2305.
For PBAC’s view see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated less than 10,000 patients per year in
2010. This estimate was considered uncertain given that it was
back-calculated from the estimated cost of other substituted
bisphosphonates.
The submission estimated savings of less than $10,000 in 2010. The
estimate was considered uncertain, as they are based on assuming
that listing zoledronic acid would be cost neutral to the PBS, and
that the cost of administration of zoledronic would be included in
a specialist or GP consultation of less than 20 minutes.
12. Recommendation and Reasons
The PBAC recommended the listing of zoledronic acid for the
treatment of Paget disease on a cost-minimisation basis compared to
disodium pamidronate. The equi-effective doses in the context of
cost-minimisation were determined to be one infusion of zoledronic
acid 5 mg was equivalent to two infusions of disodium pamidronate
60 mg.
The submission nominated risedronate as the main comparator (direct
comparison) and pamidronate as a secondary comparator (indirect
comparison). The submission considered the main comparator would be
pamidronate based on similar indications and similar routes of
administration. However, the only direct trial evidence is against
risedronate, so this was presented as the primary comparison, with
the indirect comparison with pamidronate presented as a secondary
comparison. The PBAC considered that pamidronate was the
appropriate main comparator as is given by a similar route of
administration, and the most likely therapy to be replaced by
zoledronic acid.
In the indirect comparison the PBAC noted that the heterogeneity of
trials 2304/2305 and Rendina 2004, and the lack of power of Rendina
2004, hindered the interpretation of the results. However, the PBAC
considered that the evidence supported a conclusion of
non-inferiority between zoledronic acid and pamidronate.
In the direct comparison, the PBAC noted there were statistically
significant differences in the proportion of patients responding to
zoledronic acid compared to risedronate (relative risk 1.29 [95% CI
1.19, 1.43]). However, as re-treatment was not offered in the
risedronate group if the response was inadequate, as would occur in
clinical practice, and the study population may have included
patients who had been treated with bisphosphonates previously and
were resistant to risedronate, meant that the efficacy of
zoledronic acid compared to risedronate may have been
over-estimated.
The PBAC accepted that clinical trial and post-marketing data
indicated the adverse event profile of zoledronic acid is similar
to other bisphosphonates with the exception of acute phase reaction
after infusion. The PBAC noted that the incidence of osteonecrosis
of the jaw (ONJ) in patients treated for Paget disease is more
common that in those treated for osteoporosis, however zoledronic
acid has not been shown, to date, to be associated with an excess
risk of ONJ compared to other bisphosphonates.
The submission requested that the equi-effective doses be
determined by comparing the time to loss of therapeutic response in
an extension study of patients classified as
‘responders’ in trials 2304 and 2305. On this basis the
equi-effective doses were estimated in the submission as 1 mg of
zoledronic acid to 627 mg of risedronate.
However, on the basis that pamidronate is the appropriate
comparator, the PBAC considered the equi-effective doses to be one
infusion of zoledronic acid 5 mg was equivalent to two infusions of
sodium pamidronate 60 mg. In coming to this conclusion the PBAC
noted the following:
- time for re-treatment in the extension study was determined by biochemical parameters alone (serum alkaline phosphatase level) rather than symptomatic and suggested that re-treatment with zoledronic acid occurs every 3.4 years (1233 days) and with risedronate every 1.9 years (708 days);
- that Paget’s Disease management guidelines (Selby et al. Guidelines on the Management of Paget’s Disease of Bone, Bone 31,3, Sep 2002,10-19; 2002) suggest that symptoms drive treatment and this is confirmed in Walsh et al (Walsh JP et al Treatment of Paget’s disease of bone: A survey of clinical practice in Australia. Bone 42; 1219-1225; 2008) in its description of Australian practice; and
- in Walsh et al the re-treatment intervals for pamidronate were quoted as being between 3 and 12 months, suggesting that a 12 months re-treatment interval based on symptoms (with or without SAP level measurement) may be reasonable compared with a six months re-treatment interval for pamidronate.
- In addition, the Pricing Authority accepts that a 60 mg infusion of pamidronate = three months of alendronate =1.5 months of tiludronate = 1.5 months of risedronate; applying the Pricing Authority relativities to the extension study outcomes, it was calculated that time to re-treatment with one pamidronate infusion 60 mg would be 531 days (based on 60 days of risedronate providing 708 days, and one pamidronate 60 mg infusion being equivalent to 1.5 months of risedronate treatment), and two pamidronate infusions would provide treatment for 1062 days, which is close to the 1233 days time to treatment calculated for zoledronic acid.
The PBAC considered that given the variability in dosing and dosing
intervals with pamidronate and clinical practice in the treatment
of Paget’s disease that a therapeutic relativity of one 5 mg
zoledronic acid infusion to two 60 mg pamidronate infusions was
appropriate.
Recommendation:
ZOLEDRONIC ACID, solution for I.V. infusion, 5 mg (as monohydrate)
in 100 mL,
Extend the current restriction to include:
Restriction:
Authority required
Symptomatic Paget disease of bone.
Only 1 treatment each year per patient will be PBS-subsidised.
Maximum quantity: 1
Repeats: Nil
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 welcomes the PBAC’s decision to make zoledronic
acid 5 mg available on the PBS for the treatment of Paget’s
disease of bone.
