Sibutramine hydrochloride, capsules, 10 mg and 15 mg, Reductil/Ectiva® March 2006
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Public Summary Document
Product: Sibutramine hydrochloride, capsules, 10 mg and 15 mg, Reductil/Ectiva®
Sponsor: Abbott Australasia
Date of PBAC Consideration: March 2006
1. Purpose of Application
The submission sought a Restricted Benefit listing on the Pharmaceutical Benefits
Scheme (PBS) for the treatment of severe obesity (body mass index (BMI) ? 35 kg/m²)
in the presence of two or more of the following risk factors: Type 2 diabetes, hypertension,
high triglycerides or low high density lipoproteins.
BMI is calculated by taking the patient's weight, in kg, and dividing by the patients
height, in metres, squared.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Sibutramine is TGA approved for the management of obesity, including weight loss and
maintenance of weight loss, and should be used in conjunction with a reduced calorie
diet. Sibutramine is recommended for obese patients with an initial body mass index
(BMI) greater than or equal to 30 kg per square metre or greater than or equal to
27 kg per square metre in the presence of other obesity-related risk factors (e.g.
diabetes, dyslipidaemia, hypertension). Sibutramine may only be prescribed to patients
who have not adequately responded to an appropriate weight-reducing regimen alone
(hypocaloric diet and/or exercise) i.e. patients who have difficulty achieving or
maintaining greater than 5% weight loss within 3 months. Sibutramine is not intended
for use in obese children under 18 years of age as safety and efficacy in this population
has not been established. Sibutramine is not intended for use in elderly patients
over 65 years of age as safety and efficacy in this population has not been established.
4. Listing Requested and PBAC’s View
Restricted Benefit:
For the treatment of severe obesity (BMI?35 kg/m2) with two or more of the following
risk factors:
- Type 2 diabetes
- Adequately controlled hypertension (< 145/90)
- Triglycerides > 150 mg/dL
- HDL < 50 mg/dL (females) or < 40 mg/dL (males)
See Recommendations and Reasons for PBAC’s View.
5. Clinical Place for the Proposed Therapy
Sibutramine provides an alternative for obese patients with other risk factors who
have exhausted all other options to lose weight.
6. Comparator
The submission nominated placebo for standard medical management as the comparator.
Standard medical management consists of lifestyle modification; specifically a reduced
calorie diet and/or exercise. The PBAC did not accept that placebo for standard medical
management was the only appropriate comparator. See Recommendations and Reasons.
7. Clinical Trials
The submission presented data from 42 randomised controlled trials of sibutramine
versus placebo, investigating weight loss in overweight or obese individuals with
a range of co-morbidities and risk factors and patient level analyses for 23 of the
double-blind trials as primary evidence of efficacy and safety. In addition the submission
presented supportive data from 3 double-blind randomised controlled trials of sibutramine
vs placebo investigating the long-term maintenance of weight loss in overweight or
obese individuals.
The trials which had been published at the time of submission are as follows:
|
Trial/First author |
Protocol/Publication title |
Publication citation |
|---|---|---|
| Appolinario (2003) | Appolinario JC et al. A randomized, double-blind, placebo-controlled study of sibutramine in the treatment of binge-eating disorder. | Archives of General Psychiatry 2003; 60:1109-16. |
| Ballard (2001) | Abstract: Ballard RD et al. Efficacy of sibutramine for promoting weight loss in the treatment of obstructive sleep apnea. | International Journal of Obesity 2001; 25(Suppl 2):S109 |
| BPI 852 | Trial BPI 852: A multicenter double-blind, repeated dose placebo-controlled, parallel
group dose-ranging study to evaluate the weight-reducing efficacy, safety and tolerability
of sibutramine hydrochloride (1, 5, 10, 15, 20 and 30mg daily) in obese patients for
up to 24 weeks.
|
|
|
Obesity Research 1996; 4:263-70. | |
| BPI 858 | Trial BPI 858: A double-blind, placebo-controlled study to evaluate the acute and
chronic effects of sibutramine 10 and 30mg on resting metabolic rate in healthy obese
women. Seagle HM, et al. Effects of sibutramine on resting metabolic rate and weight loss in overweight women. |
Obesity Research 1998; 6:115-21. |
| Cuellar (2000) | Six-month treatment of obesity with sibutramine 15mg; A double-blind, placebo-controlled monocenter clinical trial in a Hispanic population. | Obesity Research 2000; 8:71-82. |
| Fanghanel (2000) |
|
International Journal of Obesity 2000; 24:144-50 |
|
International Journal of Obesity 2001; 25:741-7. | |
| Fanghanel (2003) | Safety and efficacy of sibutramine in overweight Hispanic patients with hypertension. | Advances in Therapy 2003; 20:101-13. |
| Faria (2002, 2005) |
|
Diabetes, Obesity and Metabolism 2005; 7(3):246-53. |
|
Arquivos Brasileiros de Cardiologia 2002; 78:172-80. |
|
Trial/First author |
Protocol/Publication title |
Publication citation |
|---|---|---|
| Hainer (2001) |
|
International Journal of Obesity and Related Metabolic Disorders 2001; 25(Suppl 2):S107. |
|
International Journal of Obesity & Related Metabolic Disorders 2005; 29(2):208-16. | |
| Halpern (2002) | Evaluation of efficacy, reliability, and tolerability of sibutramine in obese patients, with an echocardiographic study. | Revista do Hospital das Clinicas 2002; 57:98102. |
| Hauner (2004) |
|
Experimental and Clinical Endocrinology and Diabetes 2004; 112:201-7. |
|
Pharmacogenetics 2003; 13:453-9 | |
| Hwu (2003)/ Hung (2005) |
|
Journal of Parenteral and Enteral Nutrition 2003; 27:S12-S13. |
|
Diabetic Medicine 2005; 22(8):1024-30. | |
| Kaya (2004)/ Aydin (2004) |
|
Biomedicine and Pharmacotherapy 2004; 58:582-7. |
|
Tohoku Journal of Experimental Medicine 2004; 202:173-80. | |
| Kim (2001) | Abstract: Efficacy of sibutramine in preobese and obese class I | International Journal of Obesity 2001; 25(Suppl 2):S117. |
| Milano (2005) | Use of sibutramine, an inhibitor of the reuptake of serotonin and noradrenaline, in the treatment of binge eating disorder: A placebo-controlled study. | Advances in Therapy 2005; 22(1):25-31. |
| Porter (2004) * | The Long-term Outcomes of Sibutramine Effectiveness on Weight (LOSE Weight) study: Evaluating the role of drug therapy within a weight management program in a group-model health maintenance organization. | American Journal of Managed Care 2004; 10:369-76. |
| Redmon (2003) | One-year outcome of a combination of weight loss therapies for subjects with type 2 diabetes: A randomized trial. | Diabetes Care 2003; 26:2505-11. |
| Sanchez-Reyes (2004) | Use of sibutramine in overweight adult Hispanic patients with type 2 diabetes mellitus: A 12-month, randomized, double-blind, placebo-controlled clinical trial. | Clinical Therapeutics 2004; 26:1427-35. |
|
Trial/First author |
Protocol/Publication title |
Publication citation |
|---|---|---|
| SB 104 | Trial SB 104: Multicentre, randomised, double-blind, placebo-controlled study to assess
the effects of sibutramine on left ventricular mass in obese patients during weight
reduction.
|
|
| SB 1043 | Trial SB 1043: A double-blind, placebo-controlled, dose-ranging study to evaluate
the weight reducing activity of sibutramine hydrochloride in obese patients.
|
|
| SB 1047 | Trial SB 1047: Long-term treatment of mild to moderate obese patients with sibutramine.
|
|
| SB 2057 | Trial SB 2057: A double-blind, placebo-controlled study to evaluate the weight reducing
and anorectic activity of sibutramine in obese hypertensive subjects and to determine
the anti-hypertensive effects of weight reduction.
|
|
| SB 3051 | Trial SB 3051: Sibutramine versus placebo in obese patients with stage II diabetes.
|
|
| SB 5075 | Trial SB 5075: A randomised, double-blind, placebo-controlled, parallel group, multicentre
trial with sibutramine in the treatment of obese type II diabetic patients receiving
sulphonylureas.
|
|
| SB 5078 | Trial SB 5078: A multicentre, double-blind, placebo-controlled trial, followed by
an open treatment phase, to evaluate the effects of treatment with sibutramine upon
obese Type II diabetic subjects currently untreated with antidiabetic medication.
|
|
|
Obesity Research 1999; 7:363-9 | |
| SB 5084 | Trial SB 5084: A single centre, double-blind, placebo-controlled trial to evaluate
the effect of treatment with sibutramine on energy expenditure in healthy obese subjects.
|
|
| SB 6085 | Trial SB 6085: A randomised, double-blind, placebo-controlled, parallel group, multicentre
trial with sibutramine in the treatment of obese Type II diabetic patients receiving
metformin.
|
|
| SB 6087 | Trial SB 6087: A study of the effects of sibutramine on the insulin sensitivity of
obese patients with non-insulin dependent diabetes mellitus.
|
|
| SB 6090 | Trial SB 6090: A double-blind, parallel-group, placebo-controlled study of the safety
and efficacy of sibutramine in the treatment of obese patients.
|
|
| Tambascia (2003) | Sibutramine enhances insulin sensitivity ameliorating metabolic parameters in a double-blind, randomized, placebo-controlled trial. | Diabetes, Obesity and Metabolism 2003; 5:338-44 |
| Tankova (2003, 2004) |
|
Acta Diabetologica 2004; 41:146-53. |
|
Endocrinologia 2003; 8:257-65 | |
| Wadden (2005) | Randomized trial of lifestyle modification and pharmacotherapy for obesity. | New England Journal of Medicine 2005; 353:2111-20. |
| Walsh (1999) | The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. | International Journal of Obesity 1999; 23:1009-15. |
|
Supportive trials |
||
| KD 9618 | Trial KD 9618: Multicentre, double-blind, placebo-controlled, randomised parallel-group
comparison to show the equivalence of weight reduction of continuous therapy with
sibutramine 15mg and an interval therapy over 48 weeks in obese patients.
|
|
| SB 1048 | Trial SB 1048: A randomised, placebo-controlled, double-blind, parallel group, multicentre
trial of the effects on maintenance of weight loss, of treatment with sibutramine
in combination with a recommended diet and exercise programme.
|
|
|
Lancet 2000; 356: 2119-25. | |
|
Lakartidnengen 2001; 98:1802-3 | |
|
Ugeskrift for Laeger 2001; 163:2935-40. | |
|
American Journal of Clinical Nutrition 2003; 78:209-14 | |
|
International Journal of Obesity and Related Metabolic Disorders 2001; 25(Suppl 2):S104 | |
| SB 1049 | Trial SB 1049: Efficacy and tolerability of sibutramine versus placebo in maintenance
or improvement of weight loss, in obese patients, following a very low calorie diet.
|
|
* Data from this trial are presented as key and supportive evidence.
The submission presented meta-analyses of 40 of the head-to-head randomised trials.
Two trials (Ballard, et al 2001; and Hainer et al, 2001) contained inadequate data
to be included in the meta-analyses.
8. Results of Trials
In the three analyses presented, a trial based meta analysis, a patient level analysis
of all patients and analysis of patients eligible under the requested patient level
PBS restriction, the proportion of patients achieving a ? 5% weight loss was consistently
higher in the sibutramine plus lifestyle modification group (approximately 50%) than
in the lifestyle modification alone group (approximately 20%).
Other weight-loss outcomes presented in the submission were changes from baseline
in BMI and weight.
Treatment with sibutramine was associated with significant increases in systolic and
diastolic blood pressure and increases in pulse rate. Sibutramine was also associated
with higher rates of headache, constipation, and dry mouth compared with placebo.
9. Clinical Claim
The submission claimed that sibutramine has significant clinical advantages over standard
medical management, but has more toxicity. The PBAC had doubts about the extent of
clinical benefit claimed in the submission.
10. Economic Analysis
A preliminary trial-based economic evaluation was presented. The choice of the cost-effectiveness
approach was considered valid. The resources included were drug costs over six months.
The trial-based incremental cost/extra patient achieving a ? 5% reduction in body
weight was < $15,000.
A modelled economic evaluation was presented. The choice of the cost-utility approach
was considered valid. The resources included were drug costs, and the costs associated
with cardiovascular events and stroke, type 2 diabetes and diabetes-related complications.
The base case modelled incremental discounted cost per extra discounted quality adjusted
life year (QALY) gained was between $15,000 - $45,000. The model was sensitive to
assumptions regarding long-term weight loss and the duration of the model, about which
there is considerable uncertainty.
The PBAC noted that there were a number of issues with the modelled economic analysis.
11. Estimated PBS Usage and Financial Implications
The submission estimated that the cost to Government would be around $30 to 60 million
by year 3. The PBAC was concerned about the cost of listing sibutramine due to usage
uncertainty and considered the net financial cost was underestimated.
12. Recommendation and Reasons
The PBAC noted that the restriction proposed by the submission appropriately attempted
to target a population at high risk of cardiovascular disease. An outstanding matter
with the restriction was how often people would be eligible for re-treatment with
sibutramine. The modelled economic evaluation assumed that patients who do not respond
after 6 months of therapy received no further treatment and were not allowed any further
attempts at weight loss with sibutramine. However, the restriction did not limit therapy
to any specific duration.
The PBAC was concerned about total cost to the PBS of listing sibutramine and the
large potential for use outside of the restriction. The PBAC agreed that the submission’s
estimate of a net financial cost to the PBS of $30-$60 million in Year 3 of listing
was likely to be an underestimate. Potential for use beyond the restriction exists
in: patients with a BMI < 35 kg/m2 (especially as according to the WHO classification
a person with BMI of > 30 is considered obese); patients without two of the specified
risk factors; and patients who have not tried diet and exercise and patients over
65 years of age.
The PBAC did not accept that placebo for standard medical management (consisting of
lifestyle modification; ie a reduced calorie diet and/or exercise) was the only appropriate
comparator. Surgical interventions such as gastric banding are also an appropriate
comparator. The Committee noted that this procedure is one of the most rapidly expanding
surgical procedures at the present time, and although not yet a standard practice
for treating obesity, it is rapidly becoming so.
The Committee considered that the clinical trial evidence that sibutramine plus lifestyle
modification is more effective at producing a ?5% weight loss than life style modification
alone is reasonable, but remained unconvinced that this is a sufficient weight loss
in the very obese patient group targeted by the restriction, especially in the absence
of evidence that this benefit is sustained in the long term. The Committee also questioned
how the benefit of sibutramine treatment would compare against other treatments such
as gastric banding. Furthermore, the PBAC considered that the clinical importance
of the treatment effects demonstrated on physiological variables need to be balanced
against the potential for higher blood pressure, pulse rate and other adverse events.
The submission did not provide an analysis of the proportion of patients achieving
different levels of weight loss above the 5% or 10% levels. The weight-loss distribution
would be more informative than the meta-analysis which shows that the mean weight
loss, after 6 months of therapy, for an average size person with a BMI of 35 (approximately
105 kg) is 3.8kg. Other issues were the long term safety of sibutramine, and that
any positive results of therapy are conditional upon having successful lifestyle modification
at the same time as taking the drug.
The PBAC noted that there were a number of issues with the modelled economic analysis,
which extrapolated the surrogate outcomes in the trials to final endpoints, in particular,
the implausibly high diabetes mortality by use of the UKPDS risk engine, which overestimates
the Australian mortality rates by 2-3 times. The Committee accepted that the model
appropriately did not omit the direct effects of sibutramine in increasing blood pressure.
Overall, the model was considered to overestimate the potential benefits that are
likely to accrue from the drug therapy. The incremental cost per Quality Adjusted
Life Year (QALY) was considered to be high when compared to other lifestyle modifications,
although it was noted that the intended population is at high risk of adverse events.
The PBAC rejected the submission because of doubts about the extent of clinical benefit,
the resulting uncertain cost-effectiveness and a high potential for use outside the
restriction.
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 sought listing in a patient population at high risk of cardiovascular disease and diabetes and this was acknowledged by the PBAC. The sponsor believes that drug treatment for severe obesity is an effective part of a holistic approach that also includes diet and life style modification and that there is a clinical role for the use of sibutramine to treat severe obesity prior to surgical intervention. The sponsor is working to understand and resolve the issues outlined by the PBAC in order to demonstrate that sibutramine is a cost-effective treatment in patients with severe obesity.
