Zoledronic acid, solution for I.V infusion, 5 mg in 100 mL, Aclasta® , July 2008
Public summary document for Zoledronic acid, solution for I.V infusion, 5 mg in 100 mL, Aclasta® , July 2008
Page last updated: 31 October 2008
Public Summary Documents
Product: Zoledronic acid, solution for I.V
infusion, 5 mg in 100 mL, Aclasta®
Sponsor: Novartis Pharmaceuticals Australia Pty
Ltd
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought an Authority Required (Streamlined) listing
for zoledronic acid for the treatment of established osteoporosis
in patients with a hip fracture due to minimal trauma.
In a separate minor submission to the PBAC, the sponsor requested
that the listing also include the secondary prevention of
osteoporotic fractures in postmenopausal women with a low trauma
fracture.
2. Background
Zoledronic acid for the above requested indications or in this
formulation had not previously been considered by the PBAC.
3. Registration Status
Zoledronic acid was TGA registered on 23 June 2008 for the
following indications:
- 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 osteoporosis in postmenopausal women to reduce the incidence of hip, vertebral and non-vertebral fractures. Treatment should be restricted to three annual doses.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
established osteoporosis in patients with hip fracture due to
minimal trauma. The fracture must have been demonstrated
radiologically and the year of plain x-ray or CT-scan or MRI scan
must be documented in the patient's medical records when treatment
is initiated.
Authority required (STREAMLINED)
Treatment as the sole-subsidised anti-resorptive agent for
established postmenopausal osteoporosis in women with fracture due
to minimal trauma. The fracture must have been demonstrated
radiologically and the year of plain x-ray or CT-scan or MRI scan
must be documented in the patient’s medical records when
treatment is initiated.
A vertebral fracture is defined as a 20% or greater reduction in
height of the anterior or mid portion of a vertebral body relative
to the posterior height of that body, or, a 20% or greater
reduction in any of these heights compared to the vertebral body
above or below the affected vertebral body.
5. Clinical Place for the Proposed Therapy
Zoledronic acid 5 mg will provide an alternative treatment option
for post menopausal women who have established osteoporosis and
patients with a hip fracture which is due to minimal trauma.
6. Comparator
The submission nominated alendronate sodium as the main comparator
and risedronate sodium as an alternative main comparator.
For PBAC’s view, see Recommendation and
Reasons.
7. Clinical Trials
There were no head-to-head trials of zoledronic acid and either
alendronate or risedronate.
The submission presented:
One placebo-controlled trial of zoledronic acid 5 mg in patients
with surgical repair of a hip fracture within the previous 90 days
(Trial 2310).
One placebo-controlled trial of zoledronic acid in the treatment of
osteoporosis in postmenopausal women with either:
(1) radiological evidence of at least two mild or one moderate
existing vertebral fracture(s) and a femoral neck BMD T-score of
≤ -1.5, OR
(2) a femoral neck T-score of ≤ -2.5 with or without evidence of
an existing vertebral fracture (Trial 2301).
Two indirect comparisons are made with placebo as the common
reference:
a. one trial of alendronate 5 mg orally per day for the first 12
months, then 10 mg per day thereafter, compared with placebo, in
patients with a previous vertebral fracture (Black, based on
FIT-VFA)
b. a meta-analysis of two trials of risedronate 5 mg orally per day
with compared with placebo in patients with a previous vertebral
fracture (McClung, Reginster).
The trials and associated reports of randomised trials for the prevention of fractures in osteoporosis with zoledronic acid (with prior low-trauma hip fracture), alendronate (with prior vertebral fracture) and risedronate (with prior vertebral fracture) published at the time of submission are as follows:
| Trial/First author | Protocol title/Publication title | Publication citation |
| Zoledronic acid vs placebo | ||
| 2310 (Clinical trial report Study No. ZOL446H2310) Black 2007 | A multicenter, double-blind, randomized, placebo controlled, parallel group study to evaluate the safety and efficacy of zoledronic acid in the treatment of osteoporosis in post-menopausal women taking calcium and vitamin D | NEJM 2007; 356:1809-22 |
| Lyles 2007 | Multinational, multicenter, double-blind, randomized, placebo controlled, parallel group study assessing the efficacy of intravenous zoledronic acid in preventing subsequent osteoporotic fractures after a hip fracture. | NEJM 2007;357;1799-809 |
| Alendronate vs placebo: no trials in patient with hip fracture - inferred from Black (1996) | ||
| FIT-VFA (Fracture Intervention Trial -Vertebral Fracture Arm) | Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. | Lancet 1996; (348): 1535-1541. |
| Black 1999; Black 2000 Ensrud 1997; | ||
| Risedronate vs placebo : no trials in patient with hip fracture - inferred from pooled VERT-MN & HIP trials | ||
| VERT-MN (Vertebral Efficacy with Risedronate Therapy - Multinational) Reginster, 2000 | Randomised trial of the effects of risedronate on vertebral fractures in women with established post-menopausal osteoporosis. | Osteoporosis International 2000; 11:83-91 |
| HIP (Hip Intervention Program) McClung, 2001 | Effect of risedronate on the risk of hip fracture in elderly women. | NEJM 2001; 344:333-40 |
8. Results of Trials
The results of the indirect comparison, zoledronic acid (with prior hip fracture) vs. alendronate (with prior vertebral fracture) are summarised below:
| Trial ID | Zoledronic acid n/N (%) | Placebo n/N (%) | Alendronate n/N (%) | RR (95% CI) | Indirect RR (95% CI) |
| Any clinical fracture | |||||
| 2310 | 92/1065 (8.6) | 139/1062 (13.1) | 0.66 (0.51,0.85) | ||
| Black* | 183/1005 (18.2) | 139/1022 (13.6) | 0.75 (0.61,0.92) | 0.88 (0.64,1.22) | |
| Clinical vertebral fracture | |||||
| 2310 | 21/1065 (2.0) | 39/1062 (3.7) | 0.54 (0.32,0.91) | ||
| Black* | 50/1005(5.0) | 23/1022 (2.3) | 0.45 (0.28,0.74) | 1.19 (0.58,2.43) | |
| Non-vertebral fracture | |||||
| 2310 | 79/1065(7.4) | 107/1062 (10.1) | 0.74 (0.56,0.97) | ||
| Black* | 148/1005 (14.7) | 122/1022 (11.9) | 0.81 (0.65,1.01) | 0.91 (0.64,1.30) | |
| Hip fracture | |||||
| 2310 | 23/1065(2.2) | 33/1062 (3.1) | 0.70 (0.41,1.18) | ||
| Black* | 22/1005 (2.2) | 11/1022 (1.1) | 0.49 (0.24,1.01) | 1.41 (0.58,3.45) | |
* Black et al 1996, a report of the Fracture Intervention Trial
– Vertebral Fracture Arm
The PBAC considered that the results of the indirect comparison of
Study 2310 for zoledronic acid and the Vertebral Fracture Arm of
the Fracture Intervention Trial for alendronate (Black et al, 1996)
demonstrated that zoledronic acid is non-inferior to alendronate in
terms of its efficacy in preventing any new clinical fractures, new
clinical vertebral fractures, new non-vertebral fracture or new hip
fractures.
The PBAC was prepared to extrapolate the results of study 2310 to
the population of post-menopausal women with minimal trauma
fractures, as it has not previously made a distinction between
types of prior fracture in estimating the benefits of
bisphosphonate treatment in preventing future fractures. In this
context, the Committee was reassured by the data from the
unevaluated study 2301, which supports the conclusion that
zoledronic acid is at least non-inferior to alendronate in
preventing future osteoporotic fractures. Although the same
extrapolation argument could be applied to the population of males
with non-hip low trauma osteoporotic fractures, the current TGA
indication prevents the PBS listing from including this
group.
In the head to head trials comparing zoledronic acid and
alendronate, influenza-like illness in the three days following
zoledronic acid infusion (20.3% vs 5.1%), as well as myalgia (17.4%
vs 5.1% Saag 2007) and fatigue (9.7% vs 1.8% McClung 2007), were
significantly more likely to occur than with alendronate treatment,
which were consistent with known effects of zoledronic acid
post-infusion.
In Trial 2301 compared with placebo, there was an increased risk of
spontaneous reported serious atrial fibrillation (1.3% vs 0.5%),
cardiorespiratory arrest and death due to myocardial infarction,
and concerns were raised regarding death due to cerebrovascular
accident (though the relative risk did not reach statistical
significance). In trial 2310 compared with placebo, the incidence
of cardiovascular events was similar in the two groups: serious
atrial fibrillation was reported in 12 patients (1.1%) in the
zoledronic acid group and 14 patients (1.3%) in the placebo
group.
In the extended assessment of comparative harms other AEs of
interest included hypocalcaemia, osteonecrosis of the jaw (some
data has suggested that osteonecrosis of the jaw may occur more
frequently in patients treated with zoledronic acid than other
bisphosphonates), other osteonecrosis outside the maxillofacial
area, renal toxicity and ocular disorders.
9. Clinical Claim
The submission stated that, in patients who had already experienced
a hip fracture, zoledronic acid starting within 90 days after
surgical repair of a low-trauma hip fracture, is superior to
placebo.
The submission claimed that zoledronic acid is more effective than
alendronate sodium in reducing the risk of morphometric vertebral
and clinical vertebral fractures.
With respect to the comparison against alendronate in the
population with a prior hip fracture, the submission stated that
the indirect comparison demonstrated that zoledronic acid is no
worse than alendronate in terms of efficacy, but that, in light of
differences between trial 2310 (men and women who immediately after
post-hip fracture) and FIT-VFA (post-menopausal osteoporosis with a
prevalent vertebral fracture), the results of the indirect
comparison were inconclusive.
The submission further stated that zoledronic acid was superior to
alendronate in terms of increased utility due to patient preference
for the annual treatment, and was equivalent in terms of
comparative safety.
Finally, the submission claimed that there was no meaningful
difference in the safety profiles of zoledronic acid and
alendronate or risedronate.
For PBAC’s view, see Recommendation and
Reasons.
10. Premodelling studies:
The submission presented the results of an investigator initiated
time-trade-off (TTO) study funded by the sponsor to explore the
utility of Australian patients assigned to treatment with either an
annual I.V. bisphosphonate or a weekly oral bisphosphonate with
different adverse event profiles.
For PBAC’s view, see Recommendation and
Reasons.
11. Economic Analysis
The economic evaluation presented in the submission was based on
the secondary prevention post-menopausal osteoporosis population
(ie Trial 2301 vs FIT-VFA). The events included in the model were:
clinical vertebral fracture, proximal humerus fracture, wrist
fracture, hip fracture and death. The incremental cost per extra
quality adjusted life year gained was estimated to be less than
$15,000.
For PBAC’s view, see Recommendation and
Reasons.
12. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be between
10,000 – 50,000 patients in Year 5, including patients
switching from alendronate and risedronate.
The financial net cost per year to the PBS was estimated to be less
than $10 million in Year 5.
13. Recommendation and Reasons
The PBAC recommended the listing of zoledronic acid on the PBS for
the treatment of established osteoporosis in patients with a hip
fracture due to minimal trauma and in post-menopausal women with
other minimal trauma fractures on a cost-minimisation basis with
alendronate. The equi-effective doses for the purposes of setting
the listing price for zoledronic acid for these indications are
alendronate 70 mg weekly for 52 weeks versus zoledronic acid 5 mg
once per year, with the price to pharmacist of zoledronic acid
reduced to take into account an administration cost of
$49.95.
The PBAC reaffirmed its view, as expressed in listing
recommendations for other osteoporosis treatments, that, according
to its Guidelines, alendronate is the appropriate main comparator
as it is the treatment most likely to be replaced in clinical
practice.
For PBAC’s comments on the results, see ‘Results of
Trials’.
The Committee did not accept the results of the cost-effectiveness
analysis presented in the submission because the time-trade-off
study funded by the sponsor to explore the utilities associated
with annual IV versus weekly oral bisphosphonates had a number of
significant biases that favoured zoledronic acid.
The PBAC also agreed that the appropriate approach to modelling
osteoporosis is to use a Markov model, noting that all recently
published economic analyses, including those considered by NICE,
were Markov models.
Finally, the Committee agreed that the Quality Use of Medicine
(QUM) issues related to the prescribing of zoledronic acid were
important and that particular attention needs to be given to
establishing appropriate policies for administration of this agent
in hospitals. The PBAC requested the Secretariat alert the state
Health Departments to this issue.
Recommendation
ZOLEDRONIC ACID, solution for I.V infusion, 5 mg in 100 mL
Restriction: Authority required
Treatment as the sole PBS-subsidised anti-resorptive agent for
established osteoporosis in women with facture due to minimal
trauma.
Treatment as the sole PBS-subsidised anti-resorptive agent for
established osteoporosis in men with hip fracture due to minimal
trauma.
In all cases, the fracture must have been demonstrated
radiologically and the year of plain x-ray or CT-scan or MRI scan
must be documented in the patient's medical records when treatment
is initiated.
A vertebral fracture is defined as a 20% or greater reduction in
height of the anterior or mid portion of a vertebral body relative
to the posterior height of that body, or, a 20% or greater
reduction in any of these heights compared to the vertebral body
above or below the affected vertebral body.
Only one treatment each year for three consecutive years per
patient will be PBS-subsidised.
NOTE:
Anti-resorptive agents in established osteoporosis include
alendronate sodium, risedronate sodium, disodium etidronate,
raloxifene hydrochloride, strontium ranelate and zoledronic
acid.
Maximum quantity: 1
Repeats: Nil
14. 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.
15. Sponsor’s Comment
The sponsor chose not to comment.
