Most tobacco users live in low and middle income countries where stop smoking medicines are unavailable or unaffordable. There is an urgent need for action by key stakeholders to get cytisine licensed worldwide so that its life-saving potential can be realised.

1. Getting cytisine licensed for use world-wide: a call to
action
Most tobacco users live in low and middle income countries
where stop smoking medicines are unavailable or
unaffordable. There is an urgent need for action by key
stakeholders to get cytisine licensed worldwide so that its
life-saving potential can be realised.
Effective tobacco cessation medicines are needed in low-
and middle-income countries (LMICs), where most tobacco
users live, but are often unavailable or unaffordable [1].
Cytisine (an alkaloid found in some plants belonging to
the Leguminosae family) could be a solution to this prob-
lem. Cytisine, like varenicline, is a partial agonist at
nicotinic acetylcholine receptors (nAChRs) [2] with high
affinity for the alpha-4 beta-2 nAChRs subtype, and aids
cessation by reducing the severity of withdrawal and the
satisfaction associated with tobacco use [3]. However,
there are a number of key differences between the two
medications (Table 1).
Evidence for cytisine’s efficacy and effectiveness comes
from several sources. Four systematic reviews (five trials,
undertaken in central/eastern Europe, n = 3250) have
found cytisine to be superior to placebo for short- and
long-term abstinence from smoking [7–10], with a pooled
relative risk at ≥ 6 months of 3.29 (95% confidence inter-
vals = 1.84–5.90) [8]. A New Zealand non-inferiority trial
(n = 1310) found that cytisine was more effective than
combination nicotine replacement therapy (NRT) at
increasing 6-month quit rates [11]. Cytisine is well toler-
ated when taken according to the recommended dose: ad-
verse events reported in trials are typically non-serious and
self-limiting gastrointestinal and sleep disturbances [7–11].
Cytisine is cheaper than varenicline (Table 1), nortriptyline
(~US$95 for a 12-week course), NRT (~US$112–685 for
an 8–10-week course) and bupropion (~US$228–521 for
a 12-week course) [4]. Cytisine is affordable (even in
LMICs) [12], it has the lowest cost per quality-adjusted
life-year of all smoking cessation medications [13] and
may be more cost-effective than varenicline [14].
Since the 1960s cytisine has been available as a
prescription-only or non-prescription smoking cessation
treatment in central/eastern Europe. Cytisine is
manufactured according to the principles of European
Union (EU) Good Manufacturing Practice standards by
two companies: Sopharma (Bulgaria) and Aflofarm
(Poland), yet cytisine is currently authorized only by regu-
latory authorities for smoking cessation in four EU coun-
tries (Bulgaria, Poland, Latvia, Lithuania) and 13 non-EU
countries (Azerbaijan, Armenia, Belarus, Georgia,
Kazakhstan, Kyrgyzstan, Moldova, Russia, Serbia,
Tajikistan, Turkmenistan, Uzbekistan, Ukraine). Many
LMICs will not licence cytisine unless it is first licensed in
a reference country (namely Australia, Austria, Belgium,
Canada, Denmark, Germany, Finland, Iceland, France,
Ireland, Luxemburg, Holland, New Zealand, Norway, Swe-
den, Switzerland, United States, United Kingdom, Japan,
Italy, Spain, Portugal) or is on the World Health
Organization (WHO) Essential Medicines List.
If cytisine is effective, cost-effective, affordable and well
tolerated, why is it not licensed more widely? [4,13,15] A
key reason is that Sopharma and Aflofarm have not sought
regulatory approval actively outside central/eastern
Europe. This could be because regulatory authorities such
as the UK Medicines and Healthcare Products Regulatory
Agency (MHRA), the European Medicines Agency (EMA)
and the US Food and Drug Administration (FDA) may
require further placebo-controlled trials of cytisine to be
undertaken in western European and/or North American
populations. However, there is little incentive for pharma-
ceutical companies to conduct such research, as cytisine
is a generic drug. Potential investors may not see the oppor-
tunity for substantial return unless a patent can be
attached; this would almost certainly increase the cost to
consumers [15]. Interestingly, Extab has recently obtained
the rights from Sopharma to market a ‘new patent-
protected version of Tabex (cytisine)’ outside central and
eastern Europe, and is currently seeking regulatory
approval in the United States, Japan and other major mar-
kets (Archived by WebCite® at http://www.webcitation.
org/6iOWMRTDu). Extab’s website states: ‘Following
discussions with FDA and MHRA, a further large-scale
clinical trial is in planning’ (Archived by WebCite® at
http://www.webcitation.org/6iOWaLk4z). If regulatory
approval is obtained, it remains unknown where the new
version of Tabex will be priced in the market.
What can be done now to promote wider marketing
authorization and availability of the existing low-cost
cytisine? Without pharmaceutical industry investment, tri-
als required by the MHRA, EMA and FDA will rely upon
public good funding to progress; such funding is difficult to
obtain in a highly competitive research environment and
is often insufficient to cover the costs of studies that would
meet regulatory standards. For many LMICs, where cytisine
has the potential to have the greatest impact, there are addi-
tional barriers to accessing tobacco cessation products. For
example, tobacco cessation is not listed among the WHO
‘best buys’—a priority list of cost-effective interventions to
© 2016 Society for the Study of Addiction Addiction
EDITORIAL doi:10.1111/add.13464

2. tackle non-communicable diseases (NCDs) [16]—despite be-
ing a leading risk factor in the WHO target of a 25% relative
reduction in NCD mortality by 2025 [17]. Furthermore,
tobacco control is key to achieving Goal 3 (Good Health
and Well-Being) of the United Nations Sustainable Develop-
ment Goals (Archived by WebCite® at http://www.
webcitation.org/6iOWjGvM2). To date, international health
donors have shown limited interest in tobacco cessation.
In response, we propose the following:
1 We recommend to regulatory authorities that further
placebo-controlled trials of cytisine in its current form
are unnecessary (sufficient placebo-controlled trial data
exist and additional long-term safety data would
become available through post-marketing surveillance)
and unethical (people motivated to quit will be denied
a cessation treatment if randomised to placebo).
2 We encourage companies to explore alternative regula-
tory routes to licensing of cytisine, such as the ‘well-
established use’ procedure in Europe [18].
3 We plan to facilitate access to all relevant trial data. The
website www.stop-tabac.ch/cytisine contains the origi-
nal trial articles and English translations (where
needed). An up-to-date evidence summary for cytisine
is available at this website (Archived by WebCite® at
http://www.webcitation.org/6iOWsmKdp), and clinical
study reports from the two most recent trials [11,19]
can be obtained from the trial authors.
4 We encourage the WHO to update its position on
tobacco cessation to include cytisine.
5 We advocate that all governments signatory to the
WHO Framework Convention on Tobacco Control prior-
itize implementation of Article 14.
6 We encourage donors to support wider provision of low-
cost tobacco cessation interventions (such as cytisine)
in LMICs.
If cytisine became available more widely, the presence
of an in-class competitor to varenicline (which comes off
patent in 2020) could exert a downward pressure on the
price of both drugs. There is urgent need for action by
key stakeholders to get cytisine licensed worldwide so that
its life saving potential can be realized.
Declaration of interests
The editorial was drafted initially by N.W., with input from
all co-authors on subsequent versions. N.W. will act as
guarantor. N.W., C.B. and J.B. have been involved in a
clinical trial in which cytisine was supplied at no cost by
the manufacturer, Sopharma/Extab Ltd, Bulgaria. N.W.,
C.B. and J.S. have also accessed cytisine tablets for
pharmacokinetic/pharmacodynamic studies, which have
been provided free of charge from Aflofarm, Poland
and/or Sopharma/Extab Ltd, Bulgaria. In all instances the
companies have had no role in the study design, data col-
lection, analysis and writing and interpretation of the study
findings. N.W. has had funding for her research in the past
3 years from the University of Auckland, the Health
Research Council of New Zealand, the National Health
and Medical Research Council of Australia, the Auckland
Medical Research Foundation, the University of Malaya,
Social Code Ltd, Waitemata District Health Board, the
Heart Foundation of New Zealand and the New Zealand
Ministry of Health. She has also received support for travel,
accommodation, conference fees, honoraria and/or
expenses from the Heart Foundation of New Zealand, the
Society for Research into Nicotine and Tobacco and the
University of Malaya. C.B. has had funding for his research,
consultancy or travel as a speaker in the past 3 years from
the Health Research Council of New Zealand, Moffit Cancer
Centre, Commonwealth University of Virginia, University
of Hong Kong, National University of Taiwan, University
of Malaya and the New Zealand Ministry of Health. J.B.
has undertaken fee-paid work commissioned for the Uni-
versity of Otago, Curtin University, University of Queens-
land, University of Sydney and the Pharmaceutical
Society of New Zealand. She has been a paid speaker for
the Pharmaceutical Society of New Zealand and received
funding from the University of Auckland and University of
Auckland UniServices. She has also received support for
travel and conference fees and/or expenses from the
Auckland Medical Research Foundation, the Maurice and
Phyllis Paykel Trust, the University of Otago/International
Scientific Acupuncture and Meridian Symposium, the
Pharmaceutical Society of New Zealand and the National
Institute of Complementary Medicine (Australia). She has
also received royalties from Elsevier/Churchill Livingstone
and the Authors’ Licensing and Copyright Association. H.
M.R. has received investigator-led research funding and
honoraria for speaking at educational meetings from Pfizer
Inc. He has also received honoraria from Johnson and
Johnson for speaking at educational meetings and an advi-
sory board meeting. P.T. has undertaken paid consultancy
for Aflofarm, a manufacturer of cytisine. M.R. has no con-
flicts of interest to declare. J.-F.E. has no conflicts of interest
Table 1 Cytisine compared to varenicline.
Half-life Treatment period Cost for full course (US$) [4]
Cytisine 4.8 hours [5] Titrated down over 25 days $15–20
Varenicline 17 hours [6] Titrated up over 12 weeks $474–501
2 Editorial
© 2016 Society for the Study of Addiction Addiction

3. to declare. K.S. has received research funding from Pfizer
(GRAND 2014) to conduct a smoking cessation trial. R.J.
C. has had funding for his research in the past 3 years from
the National Health and Medical Research Council of
Australia and is supported by a Cancer Institute New South
Wales Early Career Research Fellowship (GNT14/ECF/1-
46). J.M.C.M. has been awarded a Pfizer Independent
Grant for Learning and Change (IGLC), managed by Global
Bridges (Healthcare Alliance for Tobacco Dependence
Treatment) and hosted at the Mayo Clinic, to support free
smoking cessation treatment training in addiction/mental
health care units in Brazil (grant IGLC 13513957). P.S.
has no conflicts of interest to declare. J.S. has had funding
for her research in the past 3 years from the University of
Auckland, Auckland Medical Research Foundation and
the New Zealand Education and Research Foundation.
She received research funding from Britannia Pharmaceu-
ticals in 1997 to undertake research. She has also attended
CME dinners sponsored by Reckitt Benckiser, Sanofi,
Janssen Cilag, AlphaPharm and Invidior and was sup-
ported to travel to the International Harm Reduction Asso-
ciation conference in 2005 by Schering Plough. She has
co-supervised a PhD student who had received funding
from Janssen-Cilag, Eli Lilly, Astra Zeneca, Roche Diagnos-
tics and Douglas Pharmaceuticals, but was not named on
any of these grant applications. Her personal investments
may include shares in pharmaceutical companies as part
of a managed portfolio. She was awarded a University of
Auckland Hood Fellowship in 2007. The Lion Foundation
http://www.lionfoundation.org.nz/, a gambling charity
which derives its money from gambling machines, is one
of the major donors to this fund. She has received funding
from the Alcohol Advisory Council (ALAC) of New Zealand
to conduct a literature review. A.L.A.C. received a hypoth-
ecated levy on the consumption of alcohol. She is a Co-
Principle Investigator on an investigator-initiated project
funded by the Health Promotion Agency (NZ) which is a
Crown Agency (http://www.hpa.org.nz/who-we-are). The
HPA is funded from Vote Health, the levy on alcohol pro-
duced or imported for sale in New Zealand (hypothecated
funding) and part of the problem gambling levy. N.A.R.
has received a research grant and been a consultant
(accepting no honorarium) to Pfizer.
Keywords Affordable, cost-effective, cytisine, regulatory
approval, smoking cessation, treatment.
NATALIE WALKER1
, CHRIS BULLEN2
, JOANNE BARNES3
,
HAYDEN MCROBBIE4
, PIOTR TUTKA5
, MARTIN RAW6
, JEAN-
FRANÇOIS ETTER7
, KAMRAN SIDDIQI8
, RYAN J. COURTNEY9
,
JOÃO MAURICIO CASTALDELLI-MAIA10
, PETER SELBY11
,
JANIE SHERIDAN12
& NANCY A. RIGOTTI13
National Institute for Health Innovation and Centre for Addiction
Research, School of Population Health, University of Auckland,
Auckland, New Zealand,1
National Institute for Health Innovation,
School of Population Health, University of Auckland, Auckland, New
Zealand,2
School of Pharmacy, University of Auckland, Auckland, New
Zealand,3
Queen Mary University of London, London, UK,4
Department of Pharmacology, Centre for Innovative Research for
Medical and Natural Sciences, University of Rzeszów, Rzeszów, Poland,5
UK Centre for Tobacco Control Studies, University of Nottingham,
Nottingham, UK,6
Faculty of Medicine, University of Geneva, Geneva,
Switzerland,7
Department of Health Sciences, University of York, York,
UK,8
National Drug and Alcohol, Research Centre, University of New
South Wales, Sydney, Australia,9
Department of Neuroscience, Medical
School, Fundação do ABC, Santo André, Brazil,10
Departments of
Family and Community Medicine, Psychiatry and Public Health
Sciences, University of Toronto, Toronto, Canada,11
School of Pharmacy
and Centre for Addiction Research, University of Auckland, Auckland,
New Zealand12
and Harvard Medical School, Tobacco Research and
Treatment Center, Massachusetts General Hospital, Boston, USA13
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4 Editorial
© 2016 Society for the Study of Addiction Addiction