LOSARTAN, tablets, 25 mg and 50 mg (as potassium), Cozavan®
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Public Summary Document
Product: LOSARTAN, tablets, 25 mg and 50 mg (as
potassium), Cozavan®
Sponsor: Alphapharm Pty Ltd
Date of PBAC Consideration: July 2010
1. Purpose of Application
The submission requested an unrestricted benefit listing, intended
for the treatment of hypertension.
2. Background
At the December 1995 meeting, the PBAC recommended an unrestricted
listing for losartan potassium 50 mg tablets on a cost-minimisation
basis compared with enalapril with the equi-effective doses being
87 mg losartan and 17 mg enalapril. Listing was effective 1
November 1997.
Losartan was deleted from the PBS effective 1 August 1998 due to
issues with pricing arrangements.
3. Registration Status
Cozavan 25 mg and 50 mg tablets were TGA registered on 2 February
2010 for the treatment of hypertension, alone or in combination
with other antihypertensives.
It is also registered for the treatment of hypertensive type 2
diabetics with proteinuria, defined as urinary albumin creatinine
ratio greater than or equal to 300 mg/ g to delay the progression
of renal disease.
4. Listing Requested and PBAC’s View
Unrestricted benefit.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Persistent hypertension is one of the risk factors for strokes,
heart attacks, heart failure and arterial aneurysm, and is a
leading cause of chronic renal failure. Even moderate elevation of
arterial blood pressure may lead to shortened life
expectancy.
Losartan will provide an additional choice of angiotensin II
receptor antagonist for the treatment of hypertension.
6. Comparator
The submission nominated irbesartan as the main comparator. This
was considered appropriate by the PBAC.
7. Clinical Trials
The submission presented six randomised comparative trials (Oparil 1998, Dang 2006,
Fogari 2001, Kassler-Taub 1998, Koh 2004 and Oparil 2001) comparing losartan 50 mg
to 100 mg and irbesartan 150 mg to 300 mg in patients with essential hypertension.
It also presented two clinical outcome studies, one in hypertensive patients with
left ventricular hypertrophy (LIFE), and the other in patients with type 2 diabetes
and nephropathy (RENAAL).
The submission presented a published meta-analysis (Conlin 2000) of 43 randomised
trials comparing an AIIRA or an AIIRA/hydrochlorothiazide (HCTZ) combination with
other AIIRAs, other classes of antihypertensive, or placebo.
During the evaluation two clinical outcome trials (INDT and IRMA-2) were reviewed
comparing irbesartan and placebo in hypertension with type 2 diabetic nephropathy.
These trials are described in the irbesartan PI.
These trials had been published at the time of the submission as shown in the table
below:
| Trial ID/ First author | Protocol title/ Publication title | Publication citation | |
| Trials measuring changes in blood pressure as outcome | |||
| Optional titration trials measuring blood pressure | |||
| Oparil 1998 Oparil et al. | An optional -titration study of the comparative effectiveness of two angiotensin II-receptor blockers, irbesartan and losartan. | Clin Ther 1998; 20(3):398-409. | |
|
Dang 2006 Dang A et al. Dang A et al. |
Effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia in Chinese population. The effects of angiotensin II receptor blockers in hypertensive patients complicating hyperuricaemia. |
J Hum Hypertens 2006; 20(1):45-50. Zhonghua Xin Xue Guan Bing Za Zhi [Chinese Journal of Cardiovascular Diseases] 2006; 34(10):882-885. |
|
| Fogari 2001 Fogari et al. | Effects of four angiotensin II-receptor antagonists on fibrinolysis in postmenopausal women with hypertension. | Curr. Ther. Res. Clin. Exp. 2001; 62(1):68-78. | |
| Fixed dose trials measuring blood pressure | |||
| Kassler-Taub 1998 Kassler-Taub K et al. | Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators | Amer J Hypertens 1998; 11(4 Pt 1): 445-453. | |
| Koh 2004 Koh K et al. | Comparison of effects of losartan, irbesartan, and candesartan on flow-mediated brachial artery dilation and on inflammatory and thrombolytic markers in patients with systemic hypertension. | Amer J Cardiol 2004; 93(11):1432-1435, a10. | |
|
Oparil 2001 Oparil S et al. (2001) Smith D et al. (2005) |
Comparative efficacy of olmesartan, losartan, valsartan, and irbesartan in the control of essential hypertension. Use of 24-hour ambulatory blood pressure monitoring to assess antihypertensive efficacy: a comparison of olmesartan medoxomil, losartan potassium, valsartan, and irbesartan. |
J Clin Hypertens 2001; 3(5):283-291+318. American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions 2005; 5(1):41-50. |
|
| Trials with clinical outcomes | |||
|
LIFE Dahlof B et al. (2002) Okin P et al |
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Baseline characteristics in relation to electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan intervention for endpoint reduction (LIFE) in hypertension study. |
Lancet 2002; 359:995-1003. Hypertension 2000; 36:766-773 |
|
|
RENAAL Brenner B et al. (2001) Brenner B et al. (2000) |
Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. The losartan renal protection study – rationale, study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan. |
N Engl J Med 2001; 345:861-869. J Renin-Angiotensin-Aldosterone System 2000; 1(4):328-335. |
|
| Published meta-analysis presented in the submission | |||
| Conlin et al (2000) | Meta-analysis of 43 published studies (up to October 1998) investigating the antihypertensive efficacy losartan, irbesartan, valsartan and candesartan. Angiotensin II Antagonists for Hypertension: Are There Any Differences in Efficacy? | American Journal of Hypertension, 2000; 13:418-426 | |
The two clinical outcome trials identified during the evaluation are shown in the table below:
| Trials with clinical outcomes identified during the evaluation | ||
| Irbersartan vs Placebo | ||
|
IDNT Berl T et al. (2003) Lewis E et al. (2001) |
Cardiovascular outcomes in the irbesartan diabetic nephropathy trial of patients with type 2 diabetes and overt nephropathy. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. |
Ann Int Med 138:542-9. N Engl J Med 345:851-60. |
| IRMA-2 Parving H et al. (2001) | The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. | N Engl J Med 345:870-8 |
8. Results of Trials
From the results of change from baseline diastolic blood pressure
(DBP) the PBAC noted that in the optional titration trials, two of
the three comparisons (Dang 2006, Fogari 2001) showed no
statistically significant differences between treatments in
diastolic blood pressure (DBP), and one (Oparil 1998) showed a
statistically significant difference, with irbesartan producing
larger blood pressure reductions than losartan (-10.2 mmHg vs -7.9
mmHg, p<0.02). There were four comparisons in the three fixed
dose trials (Kassler-Taub 1998 compared losartan 100 mg with
irbesartan 300 mg and irbesartan 150 mg). Three of the four
comparisons (Kassler-Taub 1998: losartan 100 mg v irbesartan 300
mg, Koh 2004: losartan 100 mg v irbesartan 300 mg, and Oparil 2001:
losartan 50 mg v irbesartan 150 mg) used a losartan to irbesartan
ratio of 1 to 3. Koh and Oparil (2001) showed no statistically
significant difference between treatments and Kassler-Taub (1998;
losartan 100 mg v irbesartan 300mg) showed a statistically
significant difference in favour of irbesartan. The fourth
comparison (Kassler-Taub 1998: losartan 100 mg v irbesartan 150 mg)
used a losartan to irbesartan ratio of 1 to 1.5 and showed no
statistically significant difference.
The results of change from baseline systolic blood pressure (SBP)
in all three optional titration trials showed no statistically
significant differences between losartan and irbesartan in systolic
blood pressure (SBP). In the fixed dose trials, three of the four
comparisons (Kassler-Taub 1998: losartan 100 mg v irbesartan 300
mg, Koh 2004: losartan 100 mg v irbesartan 300 mg, Oparil 2001:
losartan 50 mg v irbesartan 150 mg) used the same dose relativities
(1:3) as the optional titration trials. Of these Koh (2004) and
Oparil (2001) showed no statistically significant difference and
Kassler-Taub (1998; losartan 100 mg v irbesartan 300 mg) showed a
statistically significant difference in favour of irbesartan. There
was no statistically significant difference in mean reductions in
SBP for the fourth comparison (Kassler-Taub 1998; losartan 100mg v
irbesartan 150 mg).
Only two trials (Oparil 1998 and Kassler-Taub 1998) reported the
proportion of patients responding, defined as attaining a DBP <
90 mmHg or a DBP reduction of at least 10 mmHg, or proportion
normalising DBP, defined as attaining a DBP < 90 mmHg. None of
the between-drug comparisons in these analyses showed a
statistically significant difference. Only one trial (Oparil 2001)
reported ambulatory BP monitoring, showing no statistically
significant difference in changes in DBP or SBP between losartan 50
mg and irbesartan 150 mg.
In the Conlin meta-analysis, there were no statistically
significant differences in DBP reduction in comparisons of losartan
and any of the other three angiotensin II receptor antagonists
(AIIRAs). In SBP reduction there was a statistically significant
difference in the titrated dose comparison of losartan and
irbesartan, favouring irbesartan. Overall, these results show
similar DBP and SBP reductions between losartan 50mg compared to
irbesartan 150 mg and between losartan 100 mg and irbesartan 300
mg.
In the LIFE trial, a 4.8-year, randomised trial comparing
losartan-based treatment with atenolol-based treatment in 9,193
patients with hypertension and left ventricular hypertrophy,
losartan demonstrated a statistically significant benefit compared
to atenolol in the composite primary outcome (cardiovascular death,
stroke, and myocardial infarction), driven mainly by the 25% risk
reduction in stroke (HR 0.75, 95% CI 0.63, 0.88). There was also a
statistically significant reduction in new-onset diabetes for
patients treated with losartan compared to atenolol. Other
events (revascularisation, resuscitated cardiac arrest,
hospitalisation for unstable angina, or hospitalisation for heart
failure) occurred in 6% or less of patients and showed no
difference across arms.
The RENAAL trial was a 3.4-year, randomised trial comparing
losartan with placebo in 1513 patients with type 2 diabetes and
proteinuria, with or without hypertension (over 90% of patients had
a history of hypertension treatment), which demonstrated a
statistically significant 16% risk reduction for losartan in the
primary composite outcome of creatinine-doubling, development of
end-stage renal disease or death, an effect seen in both
creatinine-doubling and development of end-stage renal disease.
These results were confirmed by analysis of renal progression and
proteinuria. A reduction in cardiovascular events was not
demonstrated.
The INDT trial was a 3-arm, 2.6-year, randomised trial comparing
irbesartan with amlodipine and placebo in 1715 patients with
hypertension and type 2 diabetes with proteinuria which
demonstrated a statistically significant 20% risk reduction
associated with irbesartan treatment compared to placebo in the
same primary composite outcome as used in RENAAL (doubling of
baseline creatinine, end-stage renal disease, or death), an effect
most pronounced in creatinine-doubling. The results were confirmed
by the results of renal progression and proteinuria reduction.
Although RENAAL and INDT enlisted somewhat different patient
populations and showed different placebo rates for the primary
outcome (47.1% v 39%, RENAAL v INDT) and for creatinine-doubling
(26.0% v 23.7%), the trials overall suggest similar effects on the
delay of renal progression in patients with hypertension and type 2
diabetes.
The IRMA-2 trial was a 24-month randomised trial comparing
irbesartan and placebo in 590 patients with hypertension and type 2
diabetes which showed a statistically significant reduction in
progression to overt nephropathy for irbesartan 300 mg compared to
placebo, supported by statistically significant reductions in
urinary albumin excretion. These results are consistent with those
of the INDT trial.
For PBAC’s view of these results, see Recommendation and
Reasons.
The PBAC noted that losartan and irbesartan have similar safety
profiles as shown in the short term trials measuring blood
pressure.
9. Clinical Claim
The submission described losartan as no worse than irbesartan in
terms of comparative effectiveness and safety. The PBAC considered
this claim to be reasonable.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated by the submission as losartan
100 mg daily and irbesartan 150 mg daily (i.e., a ratio of
1:1.5).
Based on the trial data presented in the submission, between 51.6%
and 61% of patients might be expected to be prescribed the 100 mg
dose. Based on 2008/2009 Medicare Australia data, the
pre-sub-committee response conservatively estimated that 75% of
patients will be uptitrated to the 100 mg dose and proposed a
weighted price for the 50 mg tablet based on the expected
utilisation split between the 50 mg and 100 mg doses.
For PBAC’s view, see Recommendation and
Reasons.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated in the
submission to be greater than 200,000 in Year 5. The PBAC noted
there was an error in the submission’s calculations that
resulted in an underestimate of usage predictions by 10.5%.
The financial savings per year to the PBS were estimated by the
submission to be less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended listing losartan on the PBS as an unrestricted
benefit listing on a cost-minimisation basis compared with
irbesartan, at the prices proposed by the sponsor. The PBAC
accepted the sponsor’s pre-Sub Committee response offer of a
weighted price to account for patients who require a dose of 100 mg
in the absence of a 100 mg strength tablet. This weighted price is
based on 75% patients taking a 100 mg dose and 25% taking a 50 mg
dose. The sponsor based this on 2008/2009 Medicare Australia data
of the utilisation of irbesartan 75 mg and 150mg, which showed that
75% patients within these two strengths were prescribed the higher
dose.
The PBAC agreed the approach of the submission for the dose
relativity was conservative as the dose relativity implied by the
optional titration studies were 1:2.85 (Oparil 1998) and 1:2.6
(Fogari 2001). Overall, the relativity of the equi-effective doses
from these trials was accepted as 1:2.8, using the number of
participants in each trial still taking the compared drugs at
steady state in each trial as the weighting factor.
The PBAC noted that in the optional titration trials, two of the
three comparisons (Dang 2006, Fogari 2001) show no statistically
significant differences between treatments in diastolic blood
pressure (DBP), and one (Oparil 1998) showed a statistically
significant difference, with irbesartan producing larger reduction
in diastolic blood pressure than losartan. However, there was no
statistically significant difference in systolic blood pressure
(SBP) in any of these three trials. There were four comparisons in
the three fixed dose trials (Kassler-Taub 1998 compared losartan
100mg with irbesartan 300mg and irbesartan 150mg). Three of the
four comparisons (Kassler-Taub 1998: losartan 100mg v irbesartan
300mg, Koh 2004: losartan 100mg v irbesartan 300mg, and Oparil
2001: losartan 50mg v irbesartan 150mg) used a losartan to
irbesartan ratio of 1:3. Koh and Oparil (2001) showed no
statistically significant difference in DBP or SBP between
treatments and Kassler-Taub (1998; losartan 100mg v irbesartan
300mg) showed a statistically significant difference in favour of
irbesartan for both DBP and SBP. The fourth comparison
(Kassler-Taub 1998: losartan 100mg v irbesartan 150mg) used a
losartan to irbesartan ratio of 1:1.5 and showed no statistically
significant difference in DBP or SBP.
In the Conlin meta-analysis, there were no statistically
significant differences in DBP reduction in comparisons of losartan
and any of the other three angiotensin II receptor antagonists
(AIIRAs). In SBP reduction there was a statistically significant
difference in the titrated dose comparison of losartan and
irbesartan, favouring irbesartan. Overall, these results show
similar DBP and SBP reductions between losartan 50mg compared to
irbesartan 150mg and between losartan 100mg and irbesartan 300mg.
The authors of the meta-analysis note that, whilst some
head-to-head studies comparing losartan with other AIIRAs
(including the study reported by Oparil 1998) suggest differences
in efficacy between the agents tested, these direct comparative
studies contribute only a small proportion of the available
evidence, and that a meta-analysis such as that presented provides
a stronger basis for understanding the comparative efficacy of the
drugs.
The PBAC also noted that the clinical outcome data of the four
trials presented in the submission (LIFE, RENAAL, INDT and IRMA-2)
support the conclusion that losartan is similar to other drugs in
the AIIRA class in terms of the most clinically relevant outcome of
survival. In other published studies, losartan is shown to be
superior to atenolol in a composite outcome of stroke, myocardial
infarction and death (Dahlof 2002) and similar to enalapril in
reduction of all cause mortality (ELITE 2).
The PBAC considered that based on the evidence presented in the
submission and the totality of the published literature for blood
pressure reduction and long term benefits, the claim that losartan
is no worse than irbesartan in terms of comparative effectiveness
and safety was reasonable. The longer term risk/benefit of losartan
and irbesartan also appeared similar.
The PBAC considered that losartan was clinically similar to the
drugs currently in the AIIRA therapeutic group based on the
totality of the evidence presented in the submission. The PBAC is
therefore of the view that, on the basis of the material available
to it at this time, losartan should be treated as interchangeable
on an individual patient basis with the AIIRAs candesartan,
eprosartan, irbesartan, olmesartan, telmisartan and valsartan. The
appropriate delegate may therefore wish to consider it for
inclusion in the AIIRA Therapeutic Group.
The PBAC noted that determining equi-effective doses can be
difficult for drugs which have a flat dose-response curve, and that
this factor may in part explain the statistically significant
differences in DBP for irbesartan over losartan in one of the three
dose titration studies presented in the submission. The PBAC did
however note that there is evidence from the HEAAL (Konstam M
et al. Effects of high-dose versus low-dose losartan on clinical
outcomes in patients with heart failure (HEAAL study): a
randomised, double-blind trial. Lancet 2009, 374:1840-48)
study that up-titrating doses of losartan beyond 50mg confers
additional clinical benefit. In accordance with the Guidelines, the
PBAC considered that the direct optional dose titration studies
(Oparil 1998 and Fogari 2001) are most appropriate for estimating
equi-effective doses. Overall, the PBAC determined that the dose
relativity of losartan and irbesartan was 1:2.8 and accepted the
price offered by the Sponsor which is less than that based on dose
relativity.
The PBAC noted that the sponsor did not market a 100 mg strength
tablet but that the trial data showed that between 51.6% and 61% of
patients required a dosage of 100 mg. In its Pre-Sub-Committee
Response the sponsor offered a weighted price to account for the
additional cost of treating patients with 100 mg. The PBAC noted
that patients may be financially disadvantaged as those requiring
100 mg per day would require two scripts and hence two co-payments
per month as the maximum quantity proposed for the 50 mg tablets is
30. The PBAC therefore considered that the maximum quantity for the
50 mg tablets should be increased to 60 tablets
The PBAC requested the sponsor to provide information regarding
whether 100 mg strength tablets could be made available in the
future.
The PBAC recommended the Safety Net 20 Day Rule should apply.
Recommendation:
LOSARTAN, tablets, 25 mg and 50 mg (as potassium),
Cozavan®
Restriction: Unrestricted benefit
Maximum quantity:
30 (25 mg)
60 (50 mg)
Repeats: 5
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 further comment.
