Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax® Once Weekly - July 2011
Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax® Once Weekly; ALENDRONATE SODIUM with Colecalciferol, tablet equivalent to 70 mg alendronic acid with 70 micrograms colecalciferol, Fosamax Plus™; Alendronate Sodium with Colecalciferol tablet equivalent to 70 mg alendronic acid with 140 micrograms colecalciferol, Fosamax Plus™ 70 mg/140 mcg; Alendronate Sodium with Colecalciferol and Calciuum Carbonate, pack containing 4 tablets containing the equivalent of 70 mg alendronic acid with 140 micrograms colecalciferol and 48 tablets calcium carbonate 1.25 g (equivalent to 500 mg elemental calcium), Fosamax Plus D-Cal® - July 2011
Page last updated: 28 October 2011
Public Summary Document
Product: Alendronate Sodium, tablet equivalent to 70 mg alendronic acid, Fosamax® Once Weekly;
Alendronate Sodium with Colecalciferol, tablet equivalent to 70 mg alendronic acid
with 70 micrograms colecalciferol, Fosamax Plus™; Alendronate Sodium with Colecalciferol
tablet equivalent to 70 mg alendronic acid with 140 micrograms colecalciferol, Fosamax
Plus™ 70 mg/140 mcg; Alendronate Sodium with Colecalciferol and Calciuum Carbonate,
pack containing 4 tablets containing the equivalent of 70 mg alendronic acid with
140 micrograms colecalciferol and 48 tablets calcium carbonate 1.25 g (equivalent
to 500 mg elemental calcium), Fosamax Plus D-Cal® - July 2011
Sponsor: Merck Sharp & Dohme (Australia) Pty Ltd
Date of PBAC Consideration: July 2011
1. Purpose of Application
The re-submission sought a change to the listing of these items
from patients aged 70 years of age or older with a BMD T-score of
-3.0 or less to patients aged 70 years of age or older with a BMD
T-score of -2.5 or less.
2. Background
At its March 2008 meeting, the PBAC rejected an application to change the listing
of Fosamax Once Weekly and Fosamax Plus (70 mg/70 mcg), from patients aged 70 years
of age or older with a bone mineral density (BMD) T-score of -3.0 or less to patients
aged 70 years of age or older with a BMD T-score of -2.5 or less, because of concerns
of a less favourable ratio of harms to benefits in this wider population and an unacceptable
cost-effectiveness ratio.
A copy of the Public Summary Document (PSD) from the March 2008 meeting is available.
3. Registration Status
Fosamax Once Weekly (alendronic acid 70 mg) was TGA registered on 9
February 2001 for the treatment of osteoporosis.
Fosamax Plus (70/70 and 70/140) were TGA registered on 8 March 2006
and 14 May 2008 respectively, for the treatment of osteoporosis in
select patients where vitamin D supplementation is
recommended.
Fosamax Plus D-Cal was TGA registered on 25 March 2010 for
treatment of osteoporosis in select patients where vitamin D and
calcium supplementation is recommended.
Prior to treatment with all presentations, osteoporosis must be
confirmed by the finding of low bone mass of at least 2 standard
deviations below the gender specific mean for young adults or by
the presence of osteoporotic fracture.
4. Listing Requested and PBAC’s View
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
osteoporosis in a patient aged 70 years of age or older with a Bone
Mineral Density (BMD) T-score of -2.5 or less.
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.
The PBAC agreed that the wording of the requested restriction was
appropriate.
5. Clinical Place for the Proposed Therapy
The submission stated that a change to a BMD T-score of -2.5 or
less will bring the PBS listing closer to meeting the clinical
needs of Australians with osteoporosis and align with the treatment
guidelines recommended by various professional organisations, such
as the Royal Australian College of General Practitioners and
Osteoporosis Australia.
6. Comparator
As previously, the submission nominated watchful waiting (patient
monitoring and standard management with calcium and vitamin D) as
the primary comparator.
The PBAC considered at its March 2008 meeting that the nominated
comparator was appropriate.
7. Clinical Trials
As previously, the resubmission presented data from all patients in
the Clinical Fracture Arm of the Fracture Intervention Trial
(FIT-CFA) and a post hoc analysis of results for those with BMD
T-score -2.5.
Publication details of the FIT-CFA trial have been previously
reported in the March 2008 PSD.
8. Results of Trials
Results from the FIT-CFA trial have been previously reported in the
March 2008 PSD.
The PBAC acknowledged that the results presented in the submission
indicated that there were clinical benefits associated with
alendronate treatment in the patients with BMD T-score ≤-2.5,
but remained concerned that the incremental benefit associated with
the requested change to alendronate’s PBS listing (i.e. any
benefit in patients with BMD T-score between -2.5 and -3.0)
remained unknown.
A post-hoc subgroup analysis for those patients with T-scores
between -3.0 and -2.5 from the pivotal FIT-CFA study was provided
by the sponsor in its pre-PBAC response. Statistically significant
reductions in outcomes for any clinical fracture and for hip
fracture were found for this sub-group that were similar to those
with T-score ≤-2.5. The test for interaction for the relative
risk (age at randomisation; T-score at femoral neck; fall history
in past 12 months) did not suggest treatment effect
variation.
The submission presented new safety data from the FIT-CFA trial
(all patients) on gastrointestinal events, as well as more detailed
analyses of events of interest in the published literature i.e.,
osteonecrosis of the jaw (ONJ), atypical subtrochanteric or
diaphyseal fractures of the femur and oesophageal cancer, focussing
on adverse events in adults taking alendronate for the management
of osteoporosis.
For PBAC’s comments on these results, see Recommendation
and Reasons.
9. Clinical Claim
The re-submission described alendronate as superior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over placebo.
For PBAC’s view, see Recommendation and
Reasons
10. Economic Analysis
An updated modelled economic evaluation from the previous
submission was presented with a base case population which included
the additional group for which listing was sought, i.e. patients
(aged ≥70 years) with a BMD T-score between -3.0 and -2.5. The
PBAC had previously considered this was the most appropriate
comparison. The submission used the Garvan Institute’s
fracture risk calculator to estimate baseline fracture risks. The
base case incremental cost effectiveness ratio (ICER) per quality
adjusted life year (QALY) was between $15,000 and $45,000 for the
alendronate combination products and lower but within the same
range for the alendronate only product.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients per year to
be between 10,000 and 50,000 in Year 5, at an estimated net cost 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 recommended listing of alendronate for patients aged 70
years and above with a BMD of -2.5 or less on the basis of
acceptable cost effectiveness and safety compared to placebo.
The PBAC agreed that the wording of the requested restriction was
appropriate. The comparator, watchful waiting (patient monitoring
and standard management with calcium and vitamin D) was also
considered appropriate.
As previously, the resubmission presented data from all patients in
the Clinical Fracture Arm of the Fracture Intervention Trial
(FIT-CFA) and a post hoc analysis of results for those with BMD
T-score -2.5. The PBAC agreed with the ESC that, although there
were clinical benefits associated with alendronate treatment in the
patients with BMD T-score -2.5, the relevant patients were those
aged 70 years or older with a BMD T-score between -3.0 and -2.5.
The PBAC considered that the key issue for the current submission
was to determine the cost effectiveness of alendronate treatment
specifically in patients who meet these criteria, rather than the
broader population who would be eligible under the proposed new PBS
restriction.
The PBAC noted that, in its Pre-PBAC Response following the ESC
Advice, the sponsor provided the requested post-hoc subgroup
analysis for those patients with T-scores between -3.0 and -2.5
from the pivotal FIT-CFA study. Statistically significant
reductions in outcomes for any clinical fracture and for hip
fracture were found for this sub-group that were similar to those
with T-score ≤-2.5. The test for interaction for the relative
risk (age at randomisation; T-score at femoral neck; fall history
in past 12 months) did not suggest treatment effect
variation.
Additionally, it was noted that the re-submission presented more
detailed analyses of the rare safety events of concern with
alendronate treatment (ONJ, atypical subtrochanteric or diaphyseal
fractures of the femur, and oesophageal cancer). The risk-benefit
assessment was an issue for PBAC consideration, given that the
additional patients who would be treated under the
submission’s proposed PBS listing would have a lower risk of
fracture but were likely to be at a similar risk of adverse events
as patients currently eligible. The extended safety assessment from
the sponsor covered changes to the approved Australian product
information for alendronate products since 2007, additional
observational studies and systematic reviews, together with the
most recently available Periodic Safety Update Reports. Although
the PBAC found these analyses reduced the uncertainty about these
adverse events, the argument of comparable safety and tolerability
of alendronate and placebo was not accepted by the PBAC, as in
previous submissions.
An updated modelled economic evaluation from the previous
submission was presented with a base case population which included
the additional group for which listing was sought, i.e. patients
(aged ≥70 years) with a BMD T-score between -3.0 and -2.5. The
PBAC had previously considered this was the most appropriate
comparison. The base case incremental cost effectiveness ratio
(ICER) per QALY was between $15,000 and $45,000 for the alendronate
combination products and lower but within the same range for the
alendronate only product.
The PBAC considered that there was uncertainty associated with the
baseline risk of fractures from the Garvan Institute’s
fracture risk calculator, as these were based on small numbers of
patients in the relevant populations from the Dubbo Osteoporosis
Epidemiology Study. In its Pre-PBAC Response, the sponsor stated
that these provided the best estimates of fracture risks in
Australia and were consistent with those that had guided previous
PBAC decisions. The PBAC considered that, as per the original
recommendation for primary prevention, the benefit of alendronate
depends on the baseline risk of the patients and that there will
likely be a smaller benefit in this new subgroup, based on the
clinical evidence presented. However, the comparable ICERs in this
submission to those which formed the basis of the previous
recommendations, particularly with the lower priced alendronate
monotherapy, alleviate some of the uncertainty in the model.
In response to previous PBAC concerns as to the likely extent to
which adverse events would offset gains in terms of fracture rate
reduction, sensitivity analyses were conducted to include the
impact of hypothetical ONJ and atypical subtrochanteric or
diaphyseal fractures. The PBAC noted that sensitivity analyses also
showed that the ICER was relatively stable with respect to fracture
risks and excess mortality.
The PBAC was advised that uptake in preventative population (70
years and over with a BMD of -3 or less) had not been as high as
had been anticipated and although a high proportion of the
population over 70 years would have a BMD of -2.5 or less, the
uptake may be less than predicted in the submission.
Recommendation:
ALENDRONATE SODIUM, tablet equivalent to 70 mg alendronic
acid;
ALENDRONATE SODIUM with COLECALCIFEROL, tablet equivalent to 70 mg
alendronic acid with 70 micrograms colecalciferol;
ALENDRONATE SODIUM with COLECALCIFEROL tablet equivalent to 70 mg
alendronic acid with 140 micrograms colecalciferol;
ALENDRONATE SODIUM with COLECALCIFEROL and CALCIUM CARBONATE, pack
containing 4 tablets containing the equivalent of 70 mg alendronic
acid with 140 micrograms colecalciferol and 48 tablets calcium
carbonate 1.25 g (equivalent to 500 mg elemental calcium).
Restriction:
Authority required (STREAMLINED)
Treatment as the sole PBS-subsidised anti-resorptive agent for
osteoporosis in a patient aged 70 years of age or older with a Bone
Mineral Density (BMD) T-score of -2.5 or less.
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.
Maximum quantity: 4 (alendronate sodium, alendronate sodium with
colecalciferol)
‡1 (alendronate sodium with colecalciferol and calcium
carbonate)
Repeats: 5 (all presentations)
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
Merck Sharp and Dohme Australia welcomes the PBAC’s decision
and is pleased that alendronate will now be available for more
patients over the age of 70 who have osteoporosis without a
fracture.
