Calcipotriol with betamethasone dipropionate, ointment, 50 micrograms-500 micrograms (base) per g, Daivobet®, July 2009
Public summary document for Calcipotriol with betamethasone dipropionate, ointment, 50 micrograms-500 micrograms (base) per g, Daivobet®, July 2009
Page last updated: 30 October 2009
Public Summary Document
Product: Calcipotriol with betamethasone
dipropionate, ointment, 50 micrograms-
500 micrograms (base) per g, Daivobet®
Sponsor: CSL Biotherapies Limited
Date of PBAC Consideration: July 2009
1. Purpose of Application
To request a restricted benefit listing for chronic stable plaque
type psoriasis vulgaris patients in whom treatment with either
calcipotriol or a potent topical corticosteroid alone is
inadequate.
2. Background
The combined presentation of calcipotriol and betamethasone
dipropionate had not previously been considered by the PBAC.
3. Registration Status
Daivobet® 50/500 has been registered by the TGA since 20 August
2004 for the once daily topical treatment of plaque type psoriasis
vulgaris amenable to topical therapy.
4. Listing Requested and PBAC’s View
Restricted Benefit
Chronic stable plaque type psoriasis vulgaris patients in whom
treatment with either calcipotriol or a potent topical
corticosteroid alone is inadequate.
See Recommendation and Reasons for PBAC’s
view.
5. Clinical place for the proposed therapy
The ability to apply calcipotriol and a potent corticosteroid at
the same time, rather than at different times of the day, leads to
a less complicated treatment regimen and thereby potentially
improved compliance.
6. Comparator
The submission nominated the individual constituents given as
single agents, and the two constituent agents given in combination
as the main comparators. The PBAC considered the comparators
appropriate.
7. Clinical Trials
The submission presented nine randomised trials comparing calcipotriol/betamethasone combination ointment with calcipotriol or/plus potent corticosteroids in patients with psoriasis vulgaris. Details of the trials are presented in the following table. Each of the trials utilised various dosing regimens for each of the medications not all of which were within their TGA approved dosage regimens.
| Trial ID | Publication title | Publication citation |
| Direct randomised trials | ||
| Trial 9802 Papp KA, et al | Early onset of action and efficacy of a combination of calcipotriene and betamethasone dipropionate in the treatment of psoriasis. | Journal of the American Academy of Dermatology 2003; 48: 48-54. |
| Trial 9904 Douglas WS, et al. | A new calcipotriol/betamethasone formulation with rapid onset of action was superior to monotherapy with betamethasone dipropionate or calcipotriol in psoriasis vulgaris. | Acta Derm Veneral 2002; 82: 131-135. |
| Trial 0003 Kaufmann R, et al. | Calcipotriol/betamethasone dipropionate once daily in psoriasis vulgaris. A new calcipotriol/betamethasone dipropionate formulation (Daivobet™) is an effective once-daily treatment for psoriasis vulgaris. | Dermatology 2002; 205: 389-393. |
| Trial 9905 Guenther L, et al. Van de Kerkhof PC. | Efficacy and safety of a new combination of calcipotriol and betamethasone dipropionate (once or twice daily) compared to calcipotriol (twice daily) in the treatment of psoriasis vulgaris: a randomized, double-blind, vehicle-controlled clinical trial. The impact of a two-compound product containing calcipotriol and betamethasone dipropionate (Daivobet/Dovobet) on the quality of life in patients with psoriasis vulgaris: a randomised controlled trial. | British Journal of Dermatology 2002; 147: 316–323. British Journal of Dermatology 2004; 151(3): 663-8. |
| Trial 0002 Kragballe K, et al. | Efficacy of once-daily treatment regimens with calcipotriol/betamethasone dipropionate ointment and calcipotriol ointment in psoriasis vulgaris. | British Journal of Dermatology 2004; 150(6): 1167-73. |
| Saraceno R, et al | Efficacy, safety and quality of life of calcipotriol/betamethasone dipropionate (Dovobet) versus calcipotriol (Daivonex) in the treatment of psoriasis vulgaris: A randomised, multicentre, clinical trial. | J Dermatol Treat 2007; 18(6): 361-5. |
| Kragbelle K et al | Calcipotriol cream with or without concurrent topical corticosteroid in psoriasis: tolerability and efficacy. | British Journal of Dermatology 1998; 139(4): 649-54. |
| Ruzicka T et al | Comparison of calcipotriol monotherapy and a combination of calcipotriol and betamethasone valerate after 2 weeks’ treatment with calcipotriol in the topical therapy of psoriasis vulgaris: a multicentre, double-blind, randomised study. | British Journal of Dermatology 1998; 138(2): 254-8. |
8. Results of Trials
The results of the primary outcome of all trials (percent change PASI- Psoriasis Area and Severity Index) are presented in the table below.
| Trial | Tx, weeks | Mean difference percent change PASI (95% CI) |
| Trial 9905 | 4 | Combination ointment od v Calcipotriol bd: -9.8 (-15.2, -4.3) Combination ointment od v Vehicle bd: -42.0 (-47.5, -36.4) Combination ointment bd v Vehicle bd: -47.3 (-52.3, -42.4) Combination ointment bd v Combination ointment od: -5.4 (-10.8, 0.1) |
| Trial 9802 | 4 | Combination ointment bd v Calcipotriol bd: -24.4 (-28.9, -20.0) Combination ointment bd v Betamethasone dipropionate bd: -10.3 (-14.7, -5.8) Combination ointment bd v Vehicle bd: -44.6 (-50.8, -38.4) |
| Trial 9904 | 4 (8 b ) | Combination ointment bd v Calcipotriol bd: -19.0 (-22.8, -15.2) Combination ointment bd v Betamethasone dipropionate bd: -13.1 (-16.9, -9.3) |
| Trial 0003 | 4 | Combination ointment od v Calcipotriol od: -25.3 (-28.7, -21.9) Combination ointment od v Betamethasone dipropionate od: -14.2 (-17.6, -10.8) Combination ointment od v Vehicle od: -48.3 (-53.2, -43.4) |
| Trial 0002 | 8 (12 c ) | Combination ointment od 8/4d v Calcipotriol bd after 8 weeks: -9.2 (-13.7, -4.7) Combination ointment od 4/8e v Calcipotriol bd after 8 weeks: -4.4 (-8.9, 0.1) |
| Kragbelle (1998) | 8 (10 f ) | Calcipotriol od less effective than other treatments Calcipotriol bd as effective as Calcipotriol + Clobetasone Calcipotriol + Betamethasone valerate 0.1% more effective than Calcipotriol bd Calcipotriol + Clobetasone no different to Calcipotriol + Betamethasone valerate 0.1% |
| Saraceno (2007) | 12 | No difference between combination ointment once daily for 4 weeks and calcipotriol twice daily for 8 weeks compared with calcipotriol twice daily for 12 weeks |
| Ruzicka (1998) | 4 (16 i ) | Statistically significant difference between calcipotriol + betamethasone valerate 0.1% concomitant treatment and calcipotriol twice daily treatment following 2 and 4 weeks of randomised treatment (P<0.001). No difference between groups 8 weeks after cessation of treatment. |
Bolded typography indicates statistically significant differences
Tx=treatment duration, od=once daily, bd=twice daily,
b double-blind treatment period of 4 weeks, then all patients switch to calcipotriol
twice daily for 4 weeks, results for 4 week double-blind period
c 12 weeks total treatment: see footnotes “d” and “e” – results reported here at the
treatment effect at 8 weeks
d Calcipotriol with betamethasone dipropionate combination ointment once daily for
8 weeks then calcipotriol once daily for 4 weeks
e Calcipotriol with betamethasone dipropionate combination ointment once daily for
4 weeks then for 8 weeks, used calcipotriol once daily on weekdays and calcipotriol
with betamethasone dipropionate combination ointment once daily on weekends
f 10 weeks total: 2 weeks wash-out, 8 weeks randomised treatment
g values for % mean change calculated from mean change provided in publication
h Calcipotriol with betamethasone dipropionate combination ointment once daily for
4 weeks then calcipotriol twice daily for 8 weeks
i 2 week wash-out (ointment base applied), 2 weeks calcipotriol twice daily, then patients
randomised to concomitant calcipotriol and betamethasone valerate or calcipotriol
twice daily for 4 weeks, then follow-up to 8 weeks after cessation of treatment (applied
ointment only)
The PBAC noted the heterogeneity of the clinical data submitted in support of listing;
each of the trials utilised various dosing regimens for each of the medications not
all of which are within their TGA approved dosage regimens. However, the PBAC noted
the trend across the trials was for an improvement in psoriasis as measured by a change
in PASI score when comparing the combination product to the monotherapies.
The submission also presented an indirect comparison of the results (mean percent
change in PASI) from Trial 9904 and Kragbelle (1998) in order to demonstrate non-inferiority
of combination ointment compared with its individual components used concomitantly.
The results of this indirect comparison are presented below.
| Trial | Combination ointment twice daily | Calcipotriol twice daily | Concomitant calcipotriol and betamethasone valerate 0.1% |
| Trial 9904 | -74.4 (22.3) | -55.3 (29.1) | NA |
| Kragbelle 1998 | NA | -53.3 (NR) | -59.5 (NR) |
With respect to toxicity, statistically significantly fewer total adverse events were
reported for the combination ointment compared with calcipotriol monotherapy in trials
9802, 9904, 0003 and 0002 (the 8 week combination/4 week calcipotriol arm v calcipotriol).
No differences in this outcome were observed in Trial 9905, Saraceno (2007), Ruzicka
(1998) or Trial MCB 0102 INT), and the outcome was not reported in Kragbelle (1998).
Statistically significantly fewer lesional/perilesional adverse events were reported
for the combination ointment compared with calcipotriol monotherapy in trials 9802,
0003, 9905, 0002, Kragbelle (1998) and Trial MCB 0102 INT. No differences in this
outcome were observed in Trial 9904 or Ruzicka (1998), and the outcome was not reported
in Saraceno (2007).
9. Clinical Claim
The submission claimed that calcipotriol/betamethasone dipropionate
combination ointment was equivalent in terms of comparative
effectiveness to calcipotriol and betamethasone topical products
given concomitantly, and that the combination product may have
safety advantages over the two agents given concomitantly.
The submission claimed that the combination product was superior in
terms of comparative effectiveness over calcipotriol and
betamethasone monotherapies.
For PBAC’s views, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis.
Given the data from the direct randomised trials indicated that the
use of medication was similar when the combination ointment was
used and when the individual components were used, the
equi-effective doses were estimated as combination ointment 30 g
was equi-effective with calcipotriol 30 g and potent corticosteroid
2 x 15 g. These estimates were derived from an indirect comparison
of Trial 9904 and Kragbelle (1998), based on the effectiveness
observed and the amount of medication used in the respective
trials.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed per
year (accounting for market share as necessary) would be up to
100,000 in Year 5 of listing, with the financial cost per year to
the PBS of less than $1 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of calcipotriol with betamethasone
ointment
(50 micrograms-500 micrograms (base) per g) as a restricted benefit
on a cost minimisation basis compared with the individual
components for use in the treatment of chronic stable plaque type
psoriasis in a patient not adequately controlled with either
calcipotriol or potent topical corticosteroid monotherapy. One 30 g
tube of the combination product was considered to be of equivalent
comparative effectiveness to one 30 g tube of calcipotriol ointment
50 micrograms per g and two 15 g tubes of betamethasone
dipropionate ointment 500 micrograms (base) per g. The PBAC noted
the product met the requirements of the Guidelines for the listing
of fixed combination products. However, there was concern that the
combination product could result in continuous use of a steroid,
which is not recommended by the TGA, and thus would not represent
quality use of medicine.
The PBAC noted the heterogeneity of the clinical data submitted in
support of listing; each of the trials utilised various dosing
regimens for each of the medications not all of which were within
their TGA approved dosage regimens. However, the PBAC noted the
trend across the trials was for an improvement in psoriasis as
measured by a change in PASI score when comparing the combination
product to the monotherapies and accepted the claim that the
combination product was superior in terms of comparative
effectiveness over calcipotriol and betamethasone monotherapies.
The Committee considered that Trial 9905 presented the most
relevant comparison in terms of TGA approved dosages of combination
ointment and calcipotriol monotherapy.
The PBAC noted that the Therapeutic Guidelines Dermatology 2009
listed methylprednisolone aceponate as being a corticosteroid of
‘moderate’ potency, and given the heterogeneity of the
clinical data, considered the requested listing on a
cost-minimisation basis of one 30 g tube of the combination
ointment being equivalent to one 30 g tube of calcipotriol ointment
plus twice the weighted average price of 15 g potent topical
corticosteroid product was not adequately demonstrated.
Recommendation
CALCIPOTRIOL with BETAMETHASONE DIPROPIONATE, ointment, 50
micrograms – 500 micrograms (base) per g (0.005 % - 0.05 %),
30 g
Restriction: Restricted Benefit
Chronic stable plaque type psoriasis vulgaris in a patient who is
not adequately controlled with either calcipotriol or potent
topical corticosteroid monotherapy.
Max qty: 1
Repeats: 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 comment.
