Nicotine, transdermal patch, releasing 15 mg per 16 hours, Nicorette® - March 2010
Public Summary Document for Nicotine, transdermal patch, releasing 15 mg per 16 hours, Nicorette® - March 2010
Page last updated: 02 July 2010
Nicotine, transdermal patch, releasing 15 mg per 16 hours, Nicorette® (PDF 55 KB)
Public Summary Document
Product: NICOTINE, transdermal patch, releasing 15
mg per 16 hours, Nicorette®
Sponsor: Cancer Council Australia, National Heart
Foundation of Australia, Australian Council on Smoking and Health
and Quit Victoria.
Date of PBAC Consideration: March 2010
1.Purpose of Application
The submission sought to extend the current Pharmaceutical Benefits
Scheme (PBS) listing for Aboriginal and Torres Strait Islanders to
include patients in the general community that are either
concession card holders or have a contraindication, precaution or
adverse reaction that prevents them using other PBS listed smoking
cessation pharmacotherapies.
2. Background
The PBAC had previously considered and rejected submissions for the
listing of Nicorette® in December 2001 and June 2003. These two
submissions were submitted by the Sponsor and the current
submission was submitted by a consortium of not-for-profit
agencies. Thus, any outstanding matters of concern to the PBAC
would not have been available to the consortium and thus could not
be addressed.
At the March 2008 meeting, the PBAC recommended an Authority
required listing as the sole PBS-subsidised therapy for nicotine
dependence in an Aboriginal or Torres Strait Islander person. The
PBAC recommended only 2 courses of PBS-subsidised nicotine
replacement therapy be authorised per year, noting that this
population eschews oral aids for smoking cessation.
3. Registration Status
Nicorette patches are registered with the Therapeutic Goods
Administration (TGA) for the treatment of tobacco dependence by
relieving nicotine craving and withdrawal symptoms thus
facilitating smoking cessation in smokers motivated to quit.
4.Listing Requested and PBAC’s View
Authority required
Nicotine dependence in concessional patients, or patients for whom
other smoking cessation pharmacotherapies should not be prescribed
because of contraindications, precautions or adverse reactions, or
an Aboriginal or a Torres Strait Islander person, as the sole
PBS-subsidised therapy.
Note:
Only two courses of PBS-subsidised nicotine replacement therapy
will be authorised per year. No applications for increased maximum
quantity and/or repeats will be authorised. Benefit is improved if
used in conjunction with a comprehensive support and counselling
program.
The PBAC referred to the legal advice received from the Department
stating that a pharmaceutical benefit cannot be listed on the PBS
conditional on supply of that pharmaceutical benefit being
restricted to persons of concession status. Therefore the PBAC
considered the listing of nicotine patches for the total
population. See Recommendation and Reasons.
5.Clinical place for the Proposed Therapy
Use as an alternative smoking cessation aid, particularly in
patients for whom the current PBS-subsidised pharmacotherapies
(bupropion and varenicline) are not suitable.
6.Comparator
The submission nominated varenicline as the main comparator because
it is the product most likely to be replaced on the PBS. The PBAC
agreed that varenicline is an appropriate comparator, but also as
nicotine replacement therapy (NRT) is accepted as a first line
pharmacotherapy for smoking cessation, then, an appropriate
comparator was placebo for all patients. The PBAC considered that a
comparison with bupropion was also appropriate.
7. Clinical Trials
The submission presented one randomised open-label trial comparing nicotine patch and varenicline in smokers motivated to quit smoking (Aubin et al. 2008). The dose regimens were:
- varenicline uptitrated to 1mg twice daily for 12 weeks or;
- transdermal nicotine replacement therapy (21 mg/day for 6 weeks, 14 mg/day for 2 weeks, then 7 mg/day for 2 weeks). This differs to the dose regimen proposed in the requested restriction of 15 mg/16 hour for 12 weeks.
The submission referred to results in a meta-analysis by Hughes et
al. (2009) which included three trials (Goreka et al. 2003, Jorenby
et al. 1999 and Uyar et al. 2007) comparing bupropion and nicotine
transdermal patch (NTP). The results from a further trial (Piper et
al. 2009) had since become available. During the evaluation a
meta-analysis was conducted using all 4 trials.
The submission did not include a detailed comparison of NTP and
placebo. However the submission referred to a published
meta-analysis of randomised trials of NRT compared to placebo or to
no treatment (Stead et al. 2008) in making the therapeutic claim
that the comparative effectiveness of nicotine patch is superior to
no pharmacological treatment.
The trials presented in the submission are shown below:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Aubin H-J et al. (2008) | Varenicline versus transdermal nicotine patch for smoking cessation: Results from a randomised, open-label trial. | Thorax 2008; 63(8): 717-724. |
The dose regimens in the requested restriction and the key clinical
trial were inconsistent with the TGA approved dose regimen for
Nicorette® (in terms of patch strength, tapering and duration
of therapy). The consortium pointed out that a Cochrane
Collaboration review by Stead et al. concluded that ‘Eight
weeks of patch therapy is as effective as longer courses and there
is no evidence that tapered therapy is better than abrupt
withdrawal’. Nonetheless the consortium encouraged the PBAC
to view favourably any applications to have additional strengths of
nicotine patch listed and thereby enable tapering dosage where
preferred by prescribers or patients.
Overall, the PBAC considered that while the claim of equivalence
between dose regimens is uncertain, that based on the Cochrane
review (Stead et al. 2008) any difference in efficacy between the
different treatment regimens was likely to be small.
8. Results of Trials
The primary outcome was continuous abstinence rate (CAR) for the last 4 weeks of 12
weeks treatment. Secondary outcomes included CAR from the last 4 weeks of treatment
through weeks 24 and 52, and measures of craving, withdrawal and smoking cessation.
NTP versus varenicline
The key results of the NTP versus varenicline comparison (based on Aubin et al. 2008)
are summarised in the table below:
| Outcome | NTP n/N (%) | Varenicline n/N (%) | OR (95% CI)a NTP v varenicline | RR (95% CI) NTP v varenicline | ||||
|---|---|---|---|---|---|---|---|---|
| CAR in last 4 weeks of treatmentb | 160/370 (42.3) | 210/376 (55.9) | 0.60 (0.45, 0.80) | 0.77 (0.67, 0.90) | ||||
| CAR in last 4 weeks of treatmentc | 160/379 (42.2) | 210/378 (55.6) | 0.58 (0.44, 0.78) | 0.76 (0.66, 0.88) | ||||
| CAR at 52 weeks | 75/379 (19.8) | 98/378 (25.9) | 0.70 (0.50, 0.99) | 0.76 (0.59, 0.99) | ||||
| Primary analysis set: all randomised and treated patients | ||||||||
| CAR at 24 weeks | 101/370 (27.3) | 122/376 (32.4) | 0.78 (0.57, 1.07) | 0.84 (0.67, 1.05) | ||||
| CAR at 52 weeks | 75/370 (20.3) | 98/376 (26.1) | 0.72 (0.51, 1.02) | 0.78 (0.60, 1.01) | ||||
| ITT: all randomised patients | ||||||||
| CAR at 24 weeks | 101/379 (26.6) | 122/378 (32.2) | 0.76 (0.56, 1.04) | 0.83 (0.66, 1.03) | ||||
a estimated during the evaluation using Review Manager 5
b primary outcome in the trial: weeks 8-11 for NTP and weeks 9-12 for varenicline
c weeks 8-11 for NTP and weeks 9-12 for varenicline
Bold typography indicates statistically significant differences
The PBAC noted that Aubin et al. (2008) reported a statistically significantly greater
continuous abstinence rate, the primary outcome, for varenicline in the last 4 weeks
of 12 weeks of treatment in each of the per protocol (PP) and intention to treat (ITT)
populations. The PBAC also noted that although there was no statistical difference
between the continuous abstinence rates of nicotine patches and varenicline at 24
weeks in both the PP and ITT populations, and at 52 weeks in the PP population, there
was a statistically significant difference in favour of varenicline in the ITT population
at 52 weeks. The Committee also noted that these were secondary outcomes of the trial
and that the trial may not have been powered for these endpoints. The PBAC considered
that this evidence was insufficient to support the submission’s claim of non-inferiority
of nicotine patches to varenicline.
The consortium argued that the CARs at 24 weeks and 52 weeks were the patient-relevant
outcomes.
NTP versus bupropion
The PBAC noted that a meta-analysis of four trials (Gorecka et al. 2003, Jorenby et
al. 1999, Uyar et al. 2007, Piper et al. 2009) conducted during the evaluation showed
no significant difference between nicotine patches and bupropion and considered this
supported non-inferiority of nicotine patches to bupropion for sustained abstinence
at 6 months or greater.
NTP versus placebo
The submission presented no evidence to inform the comparison of NTP versus placebo
and only provided a therapeutic conclusion based on the results reported in the Stead
et al. (2008) meta-analysis: that the improvement in smoking cessation rate with nicotine
patches compared with no NRT is statistically significant (risk ratio was 1.51 (95%
CI: 1.35, 1.70)) for abstinence at 12 months. None of the placebo controlled trials
included in the meta-analysis reported by Stead et al. (2008) utilised the NTP dosing
regimen specified in the requested restriction, nor were any of the studies likely
to have been conducted in patients for whom other smoking cessation pharmacotherapies
should not be prescribed because of contraindications, precautions or adverse reactions.
The PBAC noted the Cochrane review (Stead et al. 2008) presented in the submission
to support the claim of superiority of nicotine patches to placebo. For the outcome
of sustained abstinence at 12 months the meta-analysis reported a statistically significant
result favouring nicotine patches over placebo (risk ratio 1.51), however the PBAC
noted that none of the trials in the meta-analysis included the dosage regimen requested
in the submission. The Committee also noted that the same review suggested that such
differences, including the use of different strength patches such as 21 mg for 24
hours or 15 mg for 16 hours, and gradual tapering compared with abrupt withdrawal,
are likely to result in minimal changes in clinical outcomes.
The submission did not provide a quantitative analysis of the comparative safety of
either the NTP versus varenicline or the NTP versus placebo comparison. The adverse
events reported in the direct randomised trial of NTP versus varenicline reported
by Aubin et al. (2008) were extracted during the evaluation and are presented in the
table below:
| Adverse event | NTP N=370 n (%) | Varenicline N=376 n (%) | RR (95% CI) a | |||
|---|---|---|---|---|---|---|
| Any adverse event | 260 (70.3) | 319 (84.8) | 0.83 (0.77, 0.90) | |||
| Treatment discontinuation due to AEb | 16 (4.3) | 30 (8.0) | 0.54 (0.30, 0.98) | |||
| Dose reductions or temporary withdrawal from study medication | 25 (6.8) | 44 (11.7) | 0.58 (0.36, 0.92) | |||
| Deaths | 0 (0.0) | 0 (0.0) | NC | |||
| Serious AEs | 8c (2.2) | 2d (0.5) | 4.06 (0.87, 19.01) | |||
| Severe AEs | 27 (7.3) | 37 (9.8) | 0.74 (0.46, 1.19) | |||
| Nausea | 0 (0.0) | 7 (1.9) | 0.07 (0.00, 1.18) | |||
| Insomnia | 1 (<1.0) | 5 (1.3) | 0.20 (0.02, 1.73) | |||
| Headache | 0 (0.0) | 5 (1.3) | 0.09 (0.01, 1.66) | |||
| Most frequent AEs | ||||||
| Nausea | 36 (9.7) | 140 (37.2) | 0.26 (0.19, 0.37) | |||
| Insomnia | 71 (19.2) | 80 (21.3) | 0.90 (0.68, 1.20) | |||
| Headache | 36 (9.7) | 72 (19.1) | 0.51 (0.35, 0.74) | |||
| Abnormal dreams | 31 (8.4) | 44 (11.7) | 0.72 (0.46, 1.11) | |||
| Constipation | 9 (2.4) | 31 (8.2) | 0.30 (0.14, 0.61) | |||
| Dizziness | 13 (3.5) | 28 (7.4) | 0.47 (0.25, 0.90) | |||
| Disturbance in attention | 5 (1.4) | 24 (6.4) | 0.21 (0.08, 0.55) | |||
| Vomiting | 4 (1.1) | 23 (6.1) | 0.18 (0.06, 0.51) | |||
| Diarrhoea | 10 (2.7) | 22 (5.9) | 0.46 (0.22, 0.96) | |||
| Flatulence | 5 (1.4) | 22 (5.9) | 0.23 (0.09, 0.60) | |||
| Dysgeusia | 4 (1.1) | 22 (5.9) | 0.18 (0.06, 0.53) | |||
| Abdominal pain (upper) | 4 (1.1) | 21 (5.6) | 0.19 (0.07, 0.56) | |||
| Fatigue | 9 (2.4) | 21 (5.6) | 0.44 (0.20, 0.94) | |||
NTP=nicotine transdermal patch, AE=adverse event, RR=relative risk, CI=confidence
interval, NC=not calculable.
a estimated during the evaluation using Review Manager 5
b most frequent AE leading to adverse event was nausea NTP=0.8 %, varenicline=2.1%,
no other AE resulted in treatment discontinuation in > 1 % of the population
c bile duct cancer and sepsis (n=1), gastrointestinal bleeding (n=1), myocardial infarction
(n=2), salivary gland tumour (n=1), chest pain (n=2), worsening of existing knee trauma
(n=1) – none attributable to NTP
d depression (n=1) and constipation (n=1) – depression attributable to varenicline
Bold typography indicates statistically significant differences
Numerous statistically significant differences in the incidence of adverse events
were observed between NTP and varenicline, however in each instance, the events were
less likely to occur in patients treated with NTP compared with varenicline.
The submission provided an analysis of the TGA-approved Product Information documents
for nicotine patch, bupropion and varenicline. This analysis noted that bupropion
and varenicline are either contraindicated or precautions are advised for certain
patients (for example those with seizure disorders or serious psychiatric illnesses)
but that nicotine patch is not contraindicated for these patients.
The PBAC considered that nicotine patches are less toxic than varenicline or bupropion.
The Committee noted the adverse events comparison of nicotine patches and varenicline
from Aubin et al. (2008) extracted during the evaluation, showing statistically significant
lower rates of adverse reactions for nicotine patches for the majority of the most
frequently reported adverse events in the trial. The PBAC noted that the Hughes et
al. (2009) meta-analysis did not report on the comparative safety of nicotine patches
versus bupropion, however in Piper et al. (2009) there was a higher incidence of skin
irritations with nicotine patches but overall nicotine patches were less toxic than
bupropion.
9. Clinical Claim
The submission stated that the comparative effectiveness of
nicotine transdermal patches to varenicline is uncertain and that
nicotine transdermal patches may be non-inferior or inferior and
that the comparative safety of nicotine transdermal patch relative
to varenicline is superior.
The submission also concluded that the comparative effectiveness of
nicotine patch relative to no pharmacological treatment is
‘superior’.
Based on the totality of the evidence, the PBAC considered that the
claim of non-inferiority of nicotine patches to varenicline to be
uncertain with the evidence suggesting that varenicline is more
effective and more toxic, that the evidence supports nicotine
patches being more effective and less safe than placebo, and that
nicotine patches are of non-inferior efficacy to bupropion and of
superior safety.
10. Economic Analysis
The submission provided a cost-analysis comparing NTP and
varenicline, assuming equi-effective doses of 12 weeks of 15 mg/16
hour NTP therapy as being equivalent to 12 weeks of varenicline
therapy.
The recent PBAC recommendation to allow for an additional 12 weeks
of treatment with varenicline in patients who successfully abstain
from smoking following the initial 12 week treatment period is
likely to have made NTP even less costly and less effective than
varenicline.
The PBAC noted that the cost-analysis did not take into account the
lower effectiveness of nicotine patches in comparison to
varenicline in Aubin et al. (2008). However the cost-analysis also
did not include any indirect costs such as those associated with
the management of adverse effects to varenicline which the PBAC
considered are likely to be greater for varenicline than for
nicotine patches. The PBAC hence considered the evidence indicated
that nicotine patches are less effective, of superior safety and
less expensive than varenicline based on the evidence
presented.
The PBAC also noted that the price requested in the submission for
nicotine patches is less than that for a PBS course of bupropion.
Based on the meta-analysis conducted during the evaluation the PBAC
considered that nicotine patches are non-inferior to bupropion. The
PBAC also considered that bupropion is more toxic than nicotine
patches. The Committee noted that if other costs were also taken
into account, including GP consultations for the management of
adverse events associated with bupropion, this would favourably
affect the cost effectiveness of nicotine patches.
11. Estimated PBS Usage and Financial Implications
The submission estimated the number of patients using PBS
subsidised NRT to be greater than 200,000 patients in all years of
listing.
The net financial cost/year to the PBS was estimated during the
evaluation to be a cost saving of less than $10 million in all
years of listing.
The PBAC considered that the submission’s estimate of the
utilisation of nicotine patches and overall cost to Government is
highly uncertain, and substantially underestimated. See
Recommendations and Reasons.
12. Recommendation and Reasons
The PBAC recommended the listing of nicotine transdermal patches on the PBS as an
Authority required listing as an aid to cessation of smoking in patients who have
entered or are entering a comprehensive support and counselling program in the context
of a public health priority area, noting that reduction of chronic disease caused
by smoking is one of the key focuses of the national health taskforce on prevention.
The PBAC recommended the listing of nicotine transdermal patches at the price requested
in the submission on the basis of (a) non-inferior efficacy, superior safety and lower
cost compared to bupropion, and (b) uncertain and possibly inferior efficacy, superior
safety and lower cost compared to varenicline. The PBAC recommended that the listing
of nicotine patches be limited a maximum of 12 weeks treatment in a 12 month period.
The PBAC referred to the legal advice received from the Department stating that a
pharmaceutical benefit cannot be listed on the PBS conditional on supply of that pharmaceutical
benefit being restricted to persons of concession status. Therefore the PBAC considered
the listing of nicotine patches for the total population.
The submission presented an open label randomised trial comparing nicotine transdermal
patch and varenicline in smokers motivated to quit smoking (Aubin et al. 2008). The
PBAC noted that the trial reported a statistically significantly greater continuous
abstinence rate, the primary outcome, for varenicline in the last 4 weeks of 12 weeks
of treatment in each of the per protocol (PP) and intention to treat (ITT) populations.
The PBAC also noted that although there was no statistical difference between the
continuous abstinence rates of nicotine patches and varenicline at 24 weeks in both
the PP and ITT populations, and at 52 weeks in the PP population, there was a statistically
significant difference in favour of varenicline in the ITT population at 52 weeks.
The Committee also noted that these were secondary outcomes of the trial and that
the trial may not have been powered for these endpoints. The PBAC considered that
this evidence was insufficient to support the submission’s claim of non-inferiority
of nicotine patches to varenicline.
The PBAC noted the Cochrane review (Stead et. al. 2008) presented in the submission
to support the claim of superiority of nicotine patches to placebo. For the outcome
of sustained abstinence at 12 months the meta-analysis reported a statistically significant
result favouring nicotine patches over placebo (risk ratio 1.51), however the PBAC
noted that none of the trials in the meta-analysis included the dosage regimen requested
in the submission. The Committee also noted that the same review suggested that such
differences, including the use of different strength patches such as 21 mg for 24
hours or 15 mg for 16 hours, and gradual tapering compared with abrupt withdrawal,
are likely to result in minimal changes in clinical outcomes.
The PBAC noted that a meta-analysis of four trials (Gorecka et al. 2003, Jorenby et
al. 1999, Uyar et al. 2007, Piper et al. 2009) conducted during the evaluation showed
no significant difference between nicotine patches and bupropion and considered this
supported non-inferiority of nicotine patches to bupropion for sustained abstinence
at 6 months or greater.
In terms of safety, the PBAC considered that nicotine patches are less toxic than
varenicline or bupropion. The Committee noted the adverse events comparison of nicotine
patches and varenicline from Aubin et al. (2008), extracted during the evaluation,
showing statistically significant lower rates of adverse reactions for nicotine patches
for the majority of the most frequently reported adverse events in the trial. The
PBAC noted that the Hughes et al. (2009) meta-analysis did not report on the comparative
safety of nicotine patches versus bupropion, however in Piper et al. (2009) there
was a higher incidence of skin irritations with nicotine patches but overall nicotine
patches was less toxic than bupropion.
The submission presented a cost-analysis comparing 12 weeks of treatment with nicotine
patches, at the current price, and varenicline. The PBAC noted that the cost-analysis
did not take into account the lower effectiveness of nicotine patches in comparison
to varenicline in Aubin et al. (2008). However the cost-analysis also did not include
any indirect costs such as those associated with the management of adverse effects
to varenicline which the PBAC considered are likely to be greater for varenicline
than for nicotine patches. The PBAC hence considered the evidence indicated that nicotine
patches are less effective, of superior safety and less expensive than varenicline
based on the evidence presented.
The PBAC also noted that the price requested in the submission for nicotine patches
is less than that for a PBS course of bupropion. Based on the meta-analysis conducted
during the evaluation the PBAC considered that nicotine patches are non-inferior to
bupropion. The PBAC also considered that bupropion is more toxic than nicotine patches.
The Committee noted that if other costs were also taken into account, including general
practitioner consultations for the management of adverse events associated with bupropion,
this would favourably affect the cost effectiveness of nicotine patches.
Hence, based on the totality of the evidence, the PBAC considered that the claim of
non-inferiority of nicotine patches to varenicline to be uncertain with the evidence
suggesting that varenicline is more effective and more toxic, that the evidence supports
nicotine patches being more effective and less safe than placebo, and that nicotine
patches are of non-inferior efficacy to bupropion and of superior safety.
The PBAC considered that the submission’s estimate of the utilisation of nicotine
patches is highly uncertain, and substantially underestimated. The PBAC considered
that the estimations of substitution of nicotine patches for varenicline were substantially
overestimated in the submission, and considered that a number of patients may try
more than one type of PBS subsidised smoking cessation therapy. The PBAC noted the
sensitivity analysis undertaken by the DUSC indicating the cost implications of variation
of the extent of substitution of nicotine patches for varenicline, variation in compliance
with 12-weeks therapy and potential ‘unmet need’ for NRT as a result of people not
being able to afford over-the-counter NRT.
Due to the highly uncertain utilisation and consequently highly uncertain overall
cost to the Government of the listing of nicotine patches, the PBAC recommended that
further advice on the utilisation and overall estimated cost of the listing of nicotine
patches be sought by the Department in order to adequately inform the Minister.
In considering the submission, the PBAC also noted the comments received from consumers,
health professionals and from a number of organisations in relation to the submission.
The PBAC requested that the Department write to each of the sponsors of nicotine transdermal
patches to invite the sponsors to list under this recommendation.
Recommendation:
NICOTINE, transdermal patch, releasing 15 mg per 16 hrs
Add the following indication to the current restriction:
Authority required:
Short-term sole PBS-subsidised therapy as an aid to achieving abstinence in a patient
who has indicated they are ready to cease smoking and
a. who has entered a comprehensive support and counselling program; or
b. who is entering a comprehensive support and counselling program during the consultation at which this authority is requested.
Details of the program must be specified in the initial authority application.
NOTE:
A maximum of 12 weeks of PBS-subsidised nicotine replacement therapy will be authorised
per year. No applications for increased maximum quantity and/or repeats will be authorised.
Maximum quantity: 28
Repeats: 2
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 Cancer Council Victoria and other consortium members thank the
PBAC and Departmental staff for their careful consideration of this
submission. We believe that listing of an NRT product on the PBS
will increase clinically appropriate use of NRT and improve quit
rates in Australian smokers, particularly in people living with
mental illness and other disadvantaged groups among whom smoking
rates are substantially higher than in the rest of the
population.
