Zoledronic acid, solution for I.V. infusion, 5 mg (as monohydrate) in 100 mL, Aclasta®, (CIO) November 2009
Public Summary Document for Zoledronic acid, solution for I.V. infusion, 5 mg (as monohydrate) in 100 mL, Aclasta®, 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®
(CIO)
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 treatment of patients with
corticosteroid-induced osteoporosis (CIO).
2. Background
This drug had not previously been considered by the PBAC for this
indication.
3. Registration Status
On 2 July 2009 the TGA registration for zoledronic acid 5 mg in 100 mL was extended to include:
- To increase bone mineral density in patients with osteoporosis associated with long term glucocorticoid use;
- To prevent glucocorticoid induced bone mineral density loss.
- To increase bone mineral density in men with osteoporosis
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 nonvertebral 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;
- Treatment of Paget’s disease of bone.
4. Listing Requested and PBAC’s View
Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for
corticosteroid-induced osteoporosis in a patient currently on
long-term (at least 3 months), high-dose (at least 7.5 mg per day
prednisolone or equivalent) corticosteroid therapy with a Bone
Mineral Density (BMD) T-score of -1.5 or less.
The duration and dose of corticosteroid therapy together with the
date, site (femoral neck or lumbar spine) and score of the
qualifying BMD measurement must be documented in the patient's
medical records when treatment is initiated.
Only 1 treatment each year for 3 years per patient in a lifetime
will be PBS-subsidised.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Corticosteroids are widely used in a variety of chronic
non-infectious inflammatory diseases because of their
immunosuppressant and anti-inflammatory properties. However,
patients receiving high doses of corticosteroids are at increased
risk of significant bone loss and fractures. The two most serious
adverse events reported are osteoporosis and related
fractures.
Non-pharmacological treatments and management strategies include
adequate nutrition (particularly calcium and vitamin D) and
exercise to increase muscle strength and fall-prevention
strategies. Pharmacological treatment includes the bisphosphonates
which have shown to increase bone mineral density and reduce the
risk of vertebral fractures.
Zoledronic acid, an intravenous formulation, would provide an
alternative treatment to the current oral bisphosphonates for
corticosteroid-induced osteoporosis in patients on long term
corticosteroid therapy, who are at risk of fracture.
6. Comparator
The submission nominated risedronate, administered as an oral dose
of 5 mg daily, as the main comparator. The PBAC considered this
appropriate.
7. Clinical Trials
The submission presented one randomised trial that compared
zoledronic acid (5 mg annual infusion) with risedronate (5 mg
orally daily for 12 months) in patients on corticosteroid therapy
(equivalent to at least 7.5 mg of prednisone per day). The
‘treatment’ subpopulation of this trial consisted of
patients on corticosteroid therapy for more than 3 months at
randomisation. Results for patients who would be eligible under the
requested listing (baseline T-score ≤ -1.5) were drawn from a
post-hoc subgroup analysis of this treatment
subpopulation.
The table below details the published trial presented in the
submission:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Reid DM , et al. (Study 2306) | Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial. | Lancet 2009; 373(9671):1253-63 |
8. Results of Trials
The results for the trial’s primary outcome measure, percent change in lumbar spine
BMD at 12 months relative to baseline are shown in the following table, together with
the result at the 6 month time-point.
Change in lumbar spine BMD relative to baseline for the treatment subpopulation
| Zoledronic acid | Risedronate | LS mean difference (95% CI) a | P Value a | |||
| n | LS mean (%) | n | LS mean (%) | |||
| Change in baseline lumbar spine BMD at 12 months | ||||||
| MITT | 249 | 4.06 | 245 | 2.71 | 1.36 (0.67, 2.05) | 0.0001 |
| Per protocol | 235 | 4.03 | 230 | 2.70 | 1.33 (0.64, 2.03) | 0.0002 |
| Change in baseline lumbar spine BMD at 6 months | ||||||
| MITT | 249 | 3.43 | 245 | 2.39 | 1.04 (0.46, 1.62) | 0.0005 |
| Per protocol | 235 | 3.42 | 230 | 2.43 | 0.99 (0.40, 1.59) | 0.0011 |
a 95% confidence interval and P value are calculated from a three-way ANOVA with treatment,
region and gender in the model
BMD=Bone mineral density, CI=Confidence interval, LS=Least squares, MITT=Modified
intention-to-treat
The non-inferiority criterion was met as the lower bound of the 95% confidence interval
(CI) of the mean difference between zoledronic acid and risedronate for the primary
outcome of percent change in lumbar spine bone mineral density at 12 months was more
than the non-inferiority margin of -0.70%. Similar changes between treatment groups
were seen in the BMD at all anatomical sites at 6 and 12 months based on the modified
intention-to-treat population.
The non-inferiority criterion was also met for the post-hoc analysis for the treatment
subgroup with a baseline T-score of ≤ -1.5 for the primary outcome of percent change
in lumbar spine bone mineral density at 12 months. It was noted that numerically,
there was a smaller gain in lumbar spine bone mineral density at 12 months from baseline
in the subgroup with a baseline T-score of ≤ -1.5 versus the full treatment subpopulation
(0.88% vs. 1.36%, modified intention-to-treat population).
The submission presented limited fracture data and no differences were shown between
zoledronic acid and risedronate. No separate data were presented for patients on corticosteroid
therapy for > 3 months or for those with a baseline T-score of ≤ 1.5.
The PBAC recalled the Public Summary Document (PSD) for risedronate following the
July 2008 PBAC meeting stated: “The Committee further noted that Kanis (2007) pooled
and compared all available data for all bisphosphonates in CIO and post menopausal
osteoporosis (PMO) and concluded that the fracture risk reductions seen in the two
populations were of the same magnitude and that the lack of statistical significance
observed in CIO only reflected the smaller sample size within the CIO trials. The
overall conclusion from Kanis (2007) was that there was no evidence to support the
hypothesis that the effects of bisphosphonates (and risedronate in particular) on
fracture risks (including non-vertebral fractures) differ between CIO and PMO. Overall
the PBAC agreed that the relative risk reduction in this indication should be the
same if the baseline risk of fracture is equivalent.”
In addition, the PBAC has previously noted that “the clinical use of the bisphosphonates
in this condition (corticosteroid-induced osteoporosis) is widely accepted thus making
the availability of further studies unlikely on ethical grounds.”
Study 2306 showed no differences in quality of life between zoledronic acid and risedronate.
The trial results showed that adverse events suspected to be related to study drug
occurring in ≥ 2% of subjects were reported statistically significantly more frequently
in patients on zoledronic acid compared to patients on risedronate (38.2% vs. 18.3%,
P<0.0001). The submission stated that this difference was due to a higher incidence
of post-dose symptoms associated with zoledronic acid.
Trial reports of adverse events associated with zoledronic acid were considered to
be consistent with the known risk profile for this bisphosphonate. The PBAC noted
that in relation to osteonecrosis of the jaw, the submission stated that clinical
trials and post-marketing observations have not shown a greater risk of this condition
in osteoporosis.
9. Clinical Claim
The submission described zoledronic acid as non-inferior to
risedronate in terms of efficacy, and stated that this claim is
conservative because zoledronic acid was found to be superior to
risedronate for the primary outcome. Zoledronic acid was
significantly more likely to result in an adverse event due to the
post-dose syndrome, but was comparable in terms of serious or
significant adverse events over risedronate.
The PBAC noted that the trial had been designed as a
non-inferiority trial and accepted that zoledronic acid was
non-inferior to risedronate.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as zoledronic acid 5 mg
annually and risedronate 5 mg daily based on data from the pivotal
trial.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year as between 10,000 – 50,000 in Year 5 of listing. There was some uncertainty associated with submission’s estimate as:
- the requested listing of patients with a BMD T-score of ≤ -1.5 includes a proportion of patients with osteopenia whereas calculations were based on patients with osteoporosis;
- if the method used to estimate the likely number of patients excluded patients who may qualify for bisphosphonate therapy under current PBS listings; and
- uncertainty in the estimated market-share of zoledronic acid and market growth for bisphosphonates in CIO.
The estimated financial cost per year to the PBS was less than $10
million in Year 5 of listing.
12. Recommendation and Reasons
The PBAC recommended extending the listing of zoledronic acid to include treatment
for corticoid-induced osteoporosis in a patient on long-term, high-dose corticosteroid
therapy with a Bone Mineral Density (BMD) T-score of -1.5 or less on a cost-minimisation
basis with risedronate. The equi-effective doses are zoledronic acid 5 mg annually
and risedronate 5 mg daily, and the dispensed price maximum quantity should take account
of the administration costs associated with zoledronic acid.
The submission presented one randomised trial comparing zoledronic acid (5 mg annual
infusion) with risedronate (5 mg daily orally for 12 months) in patients on corticosteroid
therapy. The PBAC noted a post-hoc subgroup analysis of patients who would be eligible for treatment under the requested
listing showed that the non-inferiority criterion for the primary outcome of percent
change in lumbar spine BMD at 12 months was met.
While limited fracture data were presented in the submission, and no fracture data
for this sub-group, the PBAC noted its previous comments on this matter (July 2008
Risedronate Public Summary Document) and accepted that the trial was not powered to
evaluate differences in fracture rates.
Trial reports of adverse events associated with zoledronic acid were considered to
be consistent with the known risk profile for this bisphosphonate. The PBAC noted
that in relation to osteonecrosis of the jaw, the submission stated that clinical
trials and post-marketing observations have not shown a greater risk of this condition
in osteoporosis.
Recommendation:
ZOLEDRONIC ACID, solution for I.V. infusion, 5 mg (as monohydrate) in 100 mL,
Extend the current restriction to include:
Restriction:
Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for corticosteroid-induced osteoporosis in a patient currently on long-term (at least 3 months), high-dose (at least 7.5 mg per day prednisolone or equivalent) corticosteroid therapy with a Bone Mineral Density (BMD) T-score of -1.5 or less.
The duration and dose of corticosteroid therapy together with the date, site (femoral neck or lumbar spine) and score of the qualifying BMD measurement must be documented in the patient's medical records when treatment is initiated.
Only 1 treatment each year for 3 years per patient in a lifetime 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 this patient population.
