All varenicline PBS listings will be streamlined

Varenicline (0.5 mg and 1 mg tablets) is listed on the PBS General Schedule for the treatment of adults with nicotine dependence, as an aid to achieving abstinence from smoking.1,2

From 1 May 2017 all varenicline PBS listings were amended from Authority required to Authority required (streamlined).3,4

The positive recommendation was made by the Pharmaceutical Benefits Advisory Committee (PBAC) at its November 2016 meeting.3

The PBAC advised that varenicline remains suitable for prescribing by nurse practitioners, in addition to medical practitioners.4

See the PBS website for varenicline PBS listings and restrictions.


The PBAC previously considered varenicline’s restriction level

Varenicline’s restriction level was previously reviewed by the PBAC in March 2015, as part of the Post-market Review of Authority Required PBS Listings.4

At that time, the PBAC recommended that varenicline remain as Authority required.4

The PBAC considered that the National Medicines Policy objective of medicines meeting appropriate standards of safety would be enhanced by keeping the non-streamlined listing.4

The PBAC was also concerned that a streamlined listing may have led to inappropriate continuous use of varenicline and that the market for smoking cessation aids had not yet stabilised.4

This latest PBAC decision – to recommend the streamlined listing of varenicline – followed its advice to the sponsor to make a formal submission to address safety concerns regarding psychiatric events with varenicline.4

A quick overview of varenicline’s history with the PBAC is summarised in Table 1 below.

Table 1: Varenicline's history with the PBAC4

Year PBAC action on varenicline
2007 TGA registered as an aid for smoking-cessation in adults.
2008 First listed on the PBS.
2009PBAC recommended change to PBS listing to allow a further 12 weeks of treatment in responders.
2012PBAC rejected request to permit a further course of treatment for people who did not stop smoking or relapsed after completing treatment.
2014PBAC recommended request (resubmission) for an additional course of treatment within 12 months, on the basis of cost effectiveness compared with bupropion, NRT and placebo.
2015PBAC recommended varenicline remain Authority Required, following the Post-market Review of Authority Required PBS Listings.

TGA Safety Update to the PI to include potential for psychiatric symptoms and alcohol to increase the risk of neuropsychiatric events during treatment with varenicline.a
2016Varenicline PBAC submission, following DUSC findings that changes to the restriction level of NRT therapies did not substantially impact the utilisation of RPBS subsidised NRT treatment.

a Further changes to the PI have since been made in 2017 to make information about psychiatric symptoms more prominent.5

DUSC: Drug Utilisation Sub Committee; NRT: nicotine replacement therapy; PBAC: Pharmaceutical Benefits Advisory Committee; PI: Product Information; R/PBS, Repatriation Pharmaceutical Benefits Scheme / Pharmaceutical Benefits Scheme; TGA: Therapeutic Goods Administration.


PBAC consideration of the EAGLES study

Results from a single study, the Phase IV EAGLES study (NCT01456936), were submitted to the PBAC to support the streamlined listing of varenicline.4

An overview of the EAGLES study is provided in Table 2 below.

The PBAC considered that results of the EAGLES study supported the comparative safety of varenicline, bupropion, nicotine replacement therapy (NRT) and placebo.4

The PBAC considered that varenicline was non-inferior to bupropion with regard to safety, and likely to be non-inferior to NRT and placebo.4 

Table 2: Key characteristics of the EAGLES study6

Category EAGLES study characteristics
  • Randomised, double-blind, placebo- and active-controlled study
  • Concerns regarding the neuropsychiatric safety of varenicline and bupropion
  • Efficacy of varenicline and bupropion compared with NRT largely relied on indirect comparisons
  • Limited data for varenicline and bupropion in smokers with psychiatric disorders
  • 8144 smokers aged 18–75 years
  • With and without pre-specified psychiatric diagnoses
  • Smoked an average of ≥ 10 cigarettes/day during the previous year and motivated to quit smoking
  • Clinically stable and on treatment for ≥ 3 months
  • No alcohol-/drug-use disorder within 12 months
  • Not at high risk of self-injury or suicidal behaviour


  • Varenicline 1 mg twice daily
  • Bupropion 150 mg twice daily
  • Nicotine patch 21 mg daily, with taper (active control)
  • All taken for 12 weeks, with a 12-week non-treatment follow-up period
Neuropsychiatric adverse eventsb
  • Higher in the psychiatric group (5.8%, 238/4074 participants) than the non-psychiatric group (2.1%, 84/3984 participants, p < 0.0001)
  • Similar with varenicline (4.0%, 80/2016 participants), bupropion (4.5%, 90/2006 participants), nicotine patch (3.9%, 78/2022 participants) and placebo (3.7%, 74/2014 participants)
Smoking cessation
  • Continuous abstinence rates at weeks 9–12 and weeks 9–24 were significantly higher in the psychiatric and non-psychiatric groups for:c
    • varenicline versus placebo 
    • varenicline versus nicotine patch
    • varenicline versus bupropion
    • bupropion versus placebo
    • nicotine patch versus placebo
Most frequent adverse events
  • Nausea (varenicline; 25%, 511/2016 participants)
  • Insomnia (bupropion; 12%, 245/2006 participants)
  • Abnormal dreams (nicotine patch; 12%, 251/2022 participants)
  • Headache (placebo; 10%, 199/2014 participants)

b The primary endpoint was a composite measure based on postmarketing reports of neuropsychiatric adverse events in smokers taking varenicline and bupropion. The primary endpoint was met when participants reported at least one event coding to any of 261 MedDRA-derived preferred terms across 16 symptom categories during treatment or within 30 days of treatment discontinuation that met pre-established severity criteria.

c For the significant associations, odds ratios ranged from 4.00 (3.20 to 5.00, p < 0.0001) with varenicline versus placebo at weeks 9–12 in the non-psychiatric cohort to 1.41 (1.11 to 1.79, p = 0.0047) with varenicline versus bupropion at weeks 9–24 in the psychiatric cohort.

PBAC consideration of 2016 DUSC data

The February 2016 DUSC review showed that the utilisation of smoking-cessation medicines subsidised by the Pharmaceutical Benefits Scheme and Repatriation Pharmaceutical Benefits Scheme did not substantially change when NRT products had their listings changed from 'Authority required' to 'Authority required (streamlined)' on 1 December 2013.7

Therefore, the PBAC considered that changing the authority level of varenicline was also unlikely to substantially impact utilisation trends.4

Other PBAC considerations

The PBAC noted that no new or increased safety signals with varenicline were identified in the latest TGA Periodic Safety Update Report and Risk Management Plans.4

The PBAC considered whether it was appropriate to include a caution for patients with a history of psychiatric disorders or alcohol/drug misuse to be monitored while taking varenicline.4

A caution was not recommended because risks of neuropsychiatric adverse events were well documented in the approved PI.4

In addition, other mechanisms, including practice software, already correlate medical records and prescribing history.

The PBAC noted that attempting to quit smoking may be associated with an increase in neuropsychiatric events in people with a history of neuropsychiatric disorders.4


Gaps in the evidence

The EAGLES study had several limitations, which potentially limit the study’s generalisability. These factors were acknowledged by the study authors.6

Due to eligibility criteria of the EAGLES study (see Table 2), the results may not be generalisable to:6

  • lighter, less dependent smokers (fewer than 10 cigarettes per day)
  • people with alcohol- or drug-use disorders
  • people with psychiatric conditions who are untreated
  • people with symptomatically unstable psychiatric conditions
  • people at high-risk of self-injury or suicidal behaviour.

In addition, the EAGLES study was not powered to detect differences in rare events (such as completed suicide), and the 24-week duration and monitoring requirements may not reflect real-life attempts to quit smoking.6


Practice points for managing side effects with varenicline

People who take varenicline may experience side effects, either due to the medicine or due to nicotine withdrawal.2,8

People who stop smoking, with or without varenicline, may experience dysphoric or depressed mood, insomnia, irritability, frustration, anger, anxiety, confusion, restlessness, decreased heart rate, and increased appetite or weight gain.2

People with pre-existing psychiatric illness are more likely to experience adverse events6 with post-marketing reports of neuropsychiatric symptoms, some serious, as well as worsening of pre-existing psychiatric illness.2

  • Assess the patient and family for any history of psychiatric illness prior to initiating treatment.2
  • Continue to monitor patients with pre-existing psychiatric illness for the development of neuropsychiatric symptoms, including suicidal ideation.2
    • Counselling should include the patient’s family, carers or friends depending on who the patient’s closest contacts are.
  • Counsel the patient about the increased risk of psychiatric symptoms.5
  • Advise patients and their families to stop varenicline immediately and seek urgent medical advice if the patient:2,8
    • experiences changes in mood, behaviour or thinking that are not usually typical for the patient
    • experiences suicidal ideation or behaviour
    • develops a rash or skin reaction
    • has existing heart or blood vessel problems and notices any changes in symptoms.
  • Inform patients that drinking alcohol while taking varenicline can increase their risk of experiencing changes in mood, behaviour or thinking.2,8
  • Inform patients that they may experience irritability, urge to smoke, depression, and/or insomnia when they finish taking varenicline:2
    • patients can be reassured that symptoms are likely to be temporary; they may want to have fast-acting NRT at hand in case they have an overwhelming urge to smoke.9
  • Remember that varenicline may lower the seizure threshold in people with a history of seizures.2,8
  • Be aware that physiological changes resulting from smoking cessation may alter pharmacokinetics or pharmacodynamics of some medicines (eg, theophylline, warfarin and insulin).2
  • Encourage smokers to stay motivated to quit, and advise them that varenicline should be used alongside a counselling program, such as the one offered by Quitline (137 848).