TRAM5027JULL MCD YAT=
Is TM B%WXC PA= a SIMFICAM 2zCMnC1L ADVANCR an is IT LIMY To 09MArm
IN= A SAIAMZX MOO= PC& VMS MAZZ257
The technology for transdormal administration of ethical pharmaceuticals has been Lu
use for over ton years. Transdarmal nicotine patches (TM - 8) 0 which are marketed as
a major advance La smoking cessation therapy, are a refinement of this technology.
They were f irst introduced In Europe La 1990 and were Introduced In the US La I=*
1991. In the US, they are available only by prescription; however, in Ireland &:nd
Italy, they are available &a over-the-counter (OTC) products. TNP I a are =zw
available In thLrty-serven countries.
In the U.S., TNP's are marketed specifically as an aid for smoking cessation -'-a
with significant patient support programs that Include access to trained socic=9
cessation specialists via a tall-fr.* hotline, referrals to smoking cessaz.L=.
clinics, educational materials far families of sockars, and audio tapes. Ukaw=.am
there La substantial promotional activities for physicians and Pharmacists Lncludimq
sample kits and educational materials. There are also Joint programs with =be
American Medical Association and the American Lung Association.
The three major f Lrms In the US market are Ciba-Geigy (Rabitral brand), "r-
larrell Dow (Nl.coderm' brand, technology licensed from Alza), and L*d&=Ze
Laboratories division of American Cyanamid (Prost*p brand, technology licensed 0-.=
Elan). A fourth firm, Waxner-Lamb*rt, in expected to launch its YLectrol bz=nd
(technology licensed from Cygnus/K&bL Pharsacia), cam FDA approval La granted I
thin year.
The stowic patch may represent an advance over other TNP's based upon Its cla.Lned
ability to deliver aLectine at a constant rate that La independent of _@ts
concentration in the patch. it would appear that It could be develop" an a a
market basis.
0033 TM PA= (M) RXMMZM2 A SIGNIFICMU =RUM 20 2ZZ TOWCO =OS="
These products appear to represent a potential significant threat to the taboacc
Industry. Early volume indications are very concerning, however, the extent of =he
threat will depend upon the degree of the patch's success In enhancing long =mca
cigarette abstinence and safe usage. The Impact an Industry cigarette sales In %he
short term will not be significant, but the cumulative impact could have a major
effect an cigarette volume It early acceptance patterns of the patches couti,;s.
The threat will Increase If theme products are granted over-the-counter dLstribacmim
rights in major markets.
Analyst sales estimates continue to be surpassed. In the U.S. market, there !Lave
been numerous reports of supply shortages. Estimated first quarter sales Vows
reportedly in excess of $200 million (Rabitrol, $150 million; Kicaderm, $50
and Proatep, $15 Killion). Analysts estimates from earlier this year proj -
sales for the year 2000, to be $2 billion, based an such lower expectations for :292
sales. This should be compared to the sales of Micaretts gas, which was Lntrochamed
La 1964, and had 1991 sales of only $129 million. An additional threat could a=ise
If a related product Lo marketed by the pharmaceutical companies as an alternative
to smoking, leveraging on the beneficial properties of nicotine. Such threat would
grow dramatically it the product would become available an an over-tho-cou--sr
basis.
In terms of product characteristics, the dosage forms are typically 10, 20 or ZC1 Of
delivered nicotine per patch. Absorption Is slow and continuous. Peak blood levels CD
are attained after about 2 hours following application (9*e attachment A). 3Zzod
nicotine levels are maintained at a range of 17 to 24 ng/mL..
Ln
(A
4
BATCo document for Province of British Columbia 23 April 1999

2
The &=MM 24-hour blood nicotine concentrations resulting from use of a 21 mg
patch are somewhat lower but comparable to smoking a pack of Cigarettes. The
pattern of the blood nicotine concentrations attsiAod by smoking vs. the patch,
however, La different. With smoking, blood nicotine absorption is very rapid.
Blood nicotine concentrations go through a series of peaks and troughs with
successive cigarette smoking throughout the day (@am attachments 3-1, 11-2, 3-3).
With the patch, nicotine absorption La relatively slow and continuous and peak blood
levels are not as high as with cigarette smoking.
Skin irritation appears to be a persistent problem associated with use of the patch
for greater than 4 weeks. This could be a limiting factor La the prolonged use of
the skin patch, however, skin irritation can be overcome by rotation of the site of
patch application and it Ls likely that product improvements will be directed at
this issue.
Based on clinical trials of the nicotine patch, short tocia smoking cessation rates
aro generally twice the success rates of placebo groups. Longer term (one year)
abstinence rates drop substantially and range from 13% to 3S% which are comparable
to those of traditional behavioral modification therapies. Its long-term success
rate as a smoking cessation device therefore remains to be determined.
wux szomm u =z wAcTion, ir mr, ay B.A.T DmOsTam?
The pharmaceutical companies will undoubtedly so" over-the-counter status for the
TNP's very aggrossivoly. We have received reports of this strategic focus along
with indications that other forms of nicotine delivery are being developed.
we should closely monitor all technical and marketing developments related to the
skin patch and other nicotine delivery systems much as the nasal spray and the vapor
Inh-lar.
We need to carefully consider the product liability and regulatory issues associated
with any B.A.T involvement In nicotine delivery systems before extensive further
business analyses take place.
Increasing smoking restrictions will expand the market for an alternative to
cigarettes at work, on airplanes, *to. The broad area of non-ignitable,
tobacco-basod products represents a potential major business opportunity for the
Group. While the number of different forms such products might take is quite large,
a capsule, Lozenge or mint-typo product appears most promising at this time. The
attributes required to make such a decision viable are:
- Legal and social acceptability
- Good product taste/attribute delivery
- An acceptable business and product image
- Potential tie-La with current brand names
- Distribution channels similar to the cigarette business
- Retail placement in cigarette section
While there are a number of hurdles to overcome, we believe theme types of
opportunities should be explored aggressively as the marketplace changes.
4/27/92
Jh.
C)
4b.
Ln
L-4
BATCo document for Province of British Columbia 23 April 1999

4
RIBLIOGRAPHY
Abelin. T. ot.al. Controlled trial of transdermal nicotine patch in
tobacco withdrawal. The Lancet. Jan. 7, 7-9, 1989...,
Bannon, Y.S. Transdemal delivery of nicotine in normal human
volunteers: A single dose and multiple dose study. Eur. J. Clin.
Pharmacol.. 37:285--290, 1989.
Benowitz, N.L. Pharmacakinetics and pharmacodynamics of nicotine.
pp.3-18. In: N.J. Rand and K. 7hurad (eds.) The Pharmacology of
nicotine. IRL Press, Oxford-Washingtoi, DC, 1987.
Senowitz, N.L. Pharmacolgggical.aspects of cigarette smoking and
nicotine addiction. H. 1. J Ned., 319:1318-1330, 1988.
Benowitz. N.L. et.al. Comparison of plasma nicotine concentrations for
nicotine transdermals stem
.y cigarette smoking and nicotine polacrilex
(nicotine gum). Clin. Pharmacol. Thar. 51(2)iI29, 1992.
Daughton, D.M. et.al. --Effect of transdermal nicotine delivery as an
adjunct to low-intervention smoking cessation therapy. Arch. Intern.
Ned. 151:749-752, 1991.
Houezec, J.L. et.al. Nicotine enhances cognitive performance In
nonsmokers. Clin. Pharmacal. Thar. Sl(Z)U70, 1992.
Hurt, R.O. et.al. Nicotine-replacement therapy with use of a
truidermal nicotine patch-a. random doubl"lind placebo-controlled
trial. Mayo Clinic Proceedings. 65:IS29-IS37, 1990.
Md(endree E. and E. McNabb. Chewing nicotine gm for 3 month: What
happens to plas;ma nicotine levels? Can. W. Assoc. J., 131:589-692.
Iges.
Mulligan, S.C. et. al. Clinical and phamacokinetic properties of a
transdermal nicotine patch. Clin. Phirmacol. 7ber. 47:331-337, 1990.
Office an Smoking and Health, The health consequences of smoking:
Nicotine addictia-n. U.S. Department of Health -and Human Services.
Rockville, Maryland. 1988. -
Rose, J.E. et.al. Transdermal nicotine facilitates smoking cessation.
ClIn. Pharmacol. Ther., 47:323-330, 1990.
Russell, M.A.H. Nicotine intake by smokers: Are rates of absorption or
steady state levels mo ortant?. pp.375-402. In: N.J.'Rana and K.
.7hurau (eds.) The Phallla?v of nicotine. IRL Press,
Oxford-Vashin-9ton, DC, 1987.
Sachs, D.P. and S.J. Leischow. - Pharmacologic approaches to smoking
cessation. Clinics in Chest Red.. 12:76S49I.-1991.
Srivastava, E.K. et.al. Sensitivity and tolerance to nicotine In
smokers and nonsmokers. Psychopharizacology. IOS:63-68, 1991.
J:b.
Tonnesen, P. et.al. A double-blind trial of a 16-haur transdermal
nicotine patch in smoking cessation. H. En9l. J. Ned. 32S:311-315,
(-n
NJ
BATCo document for Province of British Columbia 23 April 1999

400453M
CL
CL
(Iwl0u) sleml VU)vvld

0
0
CL
0 ON (nolml)
C OLOOD NICOTINS OONOSNTRATI
.4 .4 .4
a #A
I
ir
da &
4A 0
Ir
cr
co
VILiSVOOV

400453715
CL
4
N
Cq
CL
Fir, v In
OW150) vujjQ;ju V@Jsvjd
c
E
0
C4
0
0

400453716
CL
cl
N
E
0
low
0
lot c
3
owl" $#la OM 110..
E
0
0