Clin Pharmacokinet

DOI 10.1007/s40262-015-0246-6

REVIEW ARTICLE

Drugs and Diseases Interacting with Cigarette Smoking in US

Prescription Drug Labelling
Haibo Li • Qiang Shi

 Springer International Publishing Switzerland (outside the USA) 2015

Abstract The US Food and Drug Administration (FDA) multiple-active-ingredient drugs, the labelling was found
draft guidance for industry on drug interaction studies to contain smoking-related information. The pharmacoki-
recommends, but does not mandate, that both cigarette netics of 29 and 21 single-active-ingredient drugs were
smokers and non-smokers can be used to study drug affected and unaffected, respectively, by smoking. For the
metabolism in clinical trials, and that important results remaining drugs, the provided information related to
related to smoking should be included in drug labelling to smoking affecting efficacy, safety or diseases but not
guide medication usage. This study aimed to provide a pharmacokinetics. Depending on the nature of specific
comprehensive review of drugs or diseases interacting drugs, the perturbation in pharmacokinetic parameters in
with smoking, as presented in all US drug labelling. The smokers ranged from 13 to 500 %, in comparison with
62,857 drug labels deposited in the FDA Online Label non-smokers. Dosage modifications in smokers are nec-
Repository were searched using the keywords ‘smoke’, essary for four drugs and may be necessary for six drugs,
‘smoker(s)’, ‘smoking’, ‘tobacco’ and ‘cigarette(s)’ on 19 but are unnecessary for seven drugs although the phar-
June 2014. The resultant records were refined to include macokinetic parameters of four of them are affected by
only human prescription drug labelling, for manual ex- smoking. Cigarette smoking is a risk factor for 16 types of
amination. For 188 single-active-ingredient drugs and 36 diseases or adverse drug reactions. For one single-active-
ingredient contraceptive drug and 10 multiple-active-in-
gredient contraceptive drugs, a black box warning (the
FDA’s strongest safety warning) is included in the la-
belling for increased risks of heart attacks and strokes in
Electronic supplementary material The online version of this female smokers, and ‘‘women are strongly advised not to
article (doi:10.1007/s40262-015-0246-6) contains supplementary
material, which is available to authorized users.
smoke’’ when using these drugs. This study presents the
first comprehensive overview of cigarette smoking inter-
H. Li acting with drugs and/or diseases, as presented in US drug
Department of Microbiology, Nantong Center for Disease labelling.
Control and Prevention, 189 South Gongnong Road,
Nantong 226007, Jiangsu, China

H. Li  Q. Shi (&)
Division of Systems Biology, National Center for Toxicological Key Points
Research, Food and Drug Administration, 3900 NCTR Road,
Jefferson, AR 72079, USA Information on drugs and diseases interacting with
e-mail: [email protected] cigarette smoking is present in some US Food and
Present Address:
Drug Administration (FDA)-approved drug
H. Li labelling.
Department of Clinical Laboratory Medicine,
Nantong Maternal and Child Health Hospital, Dosage adjustments on the basis of cigarette
399 Century Avenue, Nantong 226018, Jiangsu, China smoking are recommended by the FDA for ten drugs.
 H. Li, Q. Shi

1 Introduction coverage of relevant information. The resulting records

were downloaded and combined, and then duplicates were
removed. Labels for over-the-counter (OTC) medications,
Cigarette smoking poses significant health risks [1]. Its
unapproved drugs and animal drugs were excluded.
interactions with drugs and diseases have been extensively
The remaining labels were then downloaded directly
studied, and numerous literature reviews have been pub-
from DailyMed and manually examined to collect all in-
lished [2–7]. However, the relevant information in US
formation related to cigarette smoking. Though this study
Food and Drug Administration (FDA)-approved drug la-
was initiated to analyse smoking–drug interactions, it was
belling has not been analysed.
noted that a lot of information regarding smoking–disease
In an FDA document for new drug development [8], it is
interactions was also present in the labelling. We therefore
suggested that ‘‘a clinical study can be conducted in smokers
decided to scrutinize all of the information related to ci-
as compared to non-smokers (in lieu of an interaction study
garette smoking. The permanent link to each examined
with an inducer), when appropriate’’. In the FDA draft
label in DailyMed and the original statement relevant to
guidance for industry on drug interaction studies, published
cigarette smoking were recorded in an Excel table.
in 2006 [9] and 2012 [10], it is recommended that ‘‘for a
drug that is a substrate of CYP1A2, the evaluation of the
effect of induction of CYP1A2 can be carried out by com-
3 Number and Percentage of Labels Providing
parative pharmacokinetics (PK) studies in smokers vs. non-
Smoking-Related Information
smokers’’. Furthermore, these draft guidance documents
recommend that important drug interaction information,
As of 19 June 2014, a total of 62,857 labels were deposited
including information on smoking–drug interactions, should
in the FDALabel database. A complete list of all of these
be included in different sections of a drug label [9, 10].
labels is provided online in Supplementary Table 1 in the
We therefore carried out a comprehensive analysis of all
Electronic Supplementary Material. Using the keywords
FDA-approved drug labelling, aiming to assess if and how
‘tobacco’, ‘cigarette(s)’ and ‘smoke(r)(s)/smoking’ to
much information related to cigarette smoking is present in
query the database, 745, 1,245 and 6,695 labels were ob-
US drug labelling.
tained, respectively. Among these 8,685 labels, there were
1,726 duplicates. The remaining 6,959 unique labels rep-
2 Search Strategy resent 11 % of all 62,677 labels, and they are also pre-
sented in Supplementary Table 1.
The FDA Online Label Repository (at http://labels.fda. Among the 6,959 unique labels, 3,207 are for OTC drugs,
gov), the content of which is also deposited in DailyMed 215 are for unapproved products, 28 are for animal drugs,
(at http://dailymed.nlm.nih.gov/dailymed/about-dailymed. 14 are for dietary supplements/vaccines/medical devices
cfm) as an alternative interface, was chosen as the source and the remaining 3,495 are for human prescription drugs.
of US drug labelling. These websites provide the most Non-human prescription drug labels were excluded for
comprehensive coverage ([85 %) of FDA-approved pro- either of two reasons: (1) they were not reviewed or approved
duct labelling in the public domain [11]. by the FDA; or (2) the information was not relevant, as most
The FDALabel database, which allows a user to search of them are for safe handling or storage of the products.
the full text of all labels deposited in DailyMed (at http:// The 3,495 human prescription drug labels are for 371
www.fda.gov/ScienceResearch/BioinformaticsTools/ucm unique drugs, as a specific drug may have multiple labels
289739.htm), was used to collect relevant information. from different manufacturers. Further excluded were those
Though the FDALabel database is publically available providing information that was not relevant, such as those
(at https://rm2.scinet.fda.gov/druglabel/#simsearch-0), we dealing with safe handling or storage of flammable drugs
used the FDA intranet version (at http://ncsvmweb01.nctr. (such as oxybutynin chloride). A list of 188 single-active-
fda.gov/druglabel/#simsearch-0) because the latter is up- ingredient drugs and 36 multiple-active-ingredient drugs
dated more frequently. Nevertheless, our preliminary re- was finally chosen for detailed analysis, and the original
sults show that the final results were the same regardless of statement regarding cigarette smoking and the link to each
which version was used. label in DailyMed are presented in Supplementary Table 1.
The keywords ‘smoke’, ‘smoker(s)’, ‘smoking’, ‘tobac-
co’ and ‘cigarette(s)’ were used to search the FDALabel
database in the full text of all labels, using the ‘simple 4 Drugs with a Single Active Ingredient
search’ function. Any words in the label that match the
submitted query are recorded and the corresponding label is The summarized results for the 188 single-active-ingredi-
extracted. This strategy provides the most comprehensive ent drugs are presented in Tables 1 and 2.
Drugs and Diseases Interacting with Smoking in US Drug Labelling

Table 1 Effects of cigarette smoking on drug pharmacokinetics, efficacy and dosage modifications
Drug Effects of cigarette smokinga Dosage modification Labelling
according to smoking status sections

Alosetron hydrochloride Clearance : NA CP

Alprazolam (Blood) alprazolam concentrations ; 50 % NA CP
Aminophylline dihydrate Clearance : 50–80 % May be necessary CP; W; P; D&A
Aripiprazole No effects anticipated NA DI
Asenapine maleate No effects observed NA DI
Bendamustine hydrochloride Has ‘‘potential to ; plasma concentrations of NA DI
bendamustine and : plasma concentrations
of its active metabolites’’
Bupropion hydrochloride No effects on ‘‘Cmax, half-life, Tmax, AUC, or NA CP
clearance of bupropion or its active
metabolites’’
Chlorhexidine gluconate Efficacy ; NA CP
Cilostazol (Blood) cilostazol concentrations ; *20 % NA CP
Cimetidine Efficacy ; May be necessary D&A
Cimetidine hydrochloride Efficacy ; May be necessary D&A
Clozapine ‘‘[M]ay ; clozapine plasma level’’ NA DI
Desipramine hydrochloride Plasma levels ; NA CP
Diazepam No effects observed NA CP
Duloxetine hydrochloride AUC ; *33 % Not necessary UISP
Dyphylline No effects anticipated NA CP
Erlotinib hydrochloride Clearance : 24 %, AUC? ; 50–67 %, Necessary CP; DI; D&A
steady-state trough plasma concentrations ;
50 %
Estazolam Clearance :, t‘ ; NA CP; DI
Fluoxetine hydrochloride NA May be necessary D&A
Fluvoxamine maleate Metabolism : 25 % NA DI
Gefitinib Efficacy ; NA CS
Iloperidone No effects anticipated NA DI; UISP
Insulin Systemic insulin exposure : 2- to 5-fold; Necessary CP; D&A
efficacy :
Leflunomide Clearance : 38 %; no effects on efficacy NA CP
Lorazepam No effects observed NA UISP
Loxapine No effects observed Not necessary CP; UISP
Lurasidone hydrochloride No effects anticipated NA CP
Methysergide maleate May ‘‘result in enhanced vasoconstriction’’ NA DI
Naratriptan hydrochloride Clearance : 30 % NA CP
Olanzapine Clearance : 40 % or even : 300 % Not routinely recommended but may CP; DI; UISP
be necessary when multiple factors
are present
Olanzapine pamoate Clearance : Not routinely recommended but may CP; DI; UISP
be necessary when multiple factors
are present
Paliperidone No effects anticipated Not necessary CP
Paliperidone palmitate No effects anticipated Not necessary CP
Pemetrexed disodium No effects observed NA CP
Pomalidomide May ; pomalidomide exposure and ; efficacy NA DI
Prasugrel hydrochloride No effects observed NA CP
Propafenone hydrochloride May : plasma propafenone levels NA W&P
Propranolol hydrochloride May ; propranolol exposure and ; efficacy NA DI
Quetiapine fumarate No effects on clearance NA CP
 H. Li, Q. Shi

Table 1 continued
Drug Effects of cigarette smokinga Dosage modification Labelling
according to smoking status sections

Quinidine gluconate No effects observed NA P

Quinidine sulfate No effects observed NA P
Quinine sulfate AUC ; 44 %, Cmax ; 18 %, t‘ ; from 12 to Not necessary in malaria patients DI
7.5 h in healthy subjects; AUC ; 25 %,
Cmax ; 16.5 % in malaria patients; efficacy
not affected
Riluzole Elimination : 20 % Not necessary CP; DI
Riociguat Plasma concentrations ; 50–60 % Necessary CP
Rivastigmine tartrate Clearance : 23 % NA CP; DI; D&A
Roflumilast AUC of roflumilast ; 13 %, AUC of NA CP
roflumilast metabolite : 17 %; Cmax not
affected
Ropinirole hydrochloride Clearance :, Cmax ; 30 %, AUC ; 38 % NA CP; DI
Rosiglitazone maleate No effects observed NA CP
Tasimelteon Tasimelteon exposure ; *40 %; efficacy NA CP; UISP
may ;
Temozolomide No effects on clearance NA CP
Theophylline Clearance : 50–80 % Necessary W; CP; D&A
Tiagabine hydrochloride No effects on clearance NA CP
Ticagrelor Clearance : *22 % Not necessary CP
Varenicline tartrate No effects observed NA CP
Warfarin sodium Warfarin exposure ;; efficacy ; NA DI
Ziprasidone hydrochloride No effects observed NA UISP
: increase(d), ; decrease(d), AUC area under the plasma concentration–time curve, AUC? AUC from time zero to infinity, Cmax maximum
plasma drug concentration, CP clinical pharmacology, CS clinical studies, D&A dosage and administration, DI drug interactions, NA not
available, P precautions, t‘ half-life, Tmax time to reach Cmax, UISP use in specific populations, W warnings, W&P warnings and precautions
a
Wording in quotation marks is copied directly from the labelling

As shown in Table 1, smoking may affect the pharma- smoking is a risk factor for this type of adverse reaction.
cokinetics and/or efficacy of 34 drugs but shows no effect The labelling clearly states that gastrointestinal bleeding is
for 21 other drugs. For 18 drugs, the quantitative effects of more likely to occur in smokers receiving this class of
smoking on drug pharmacokinetics are specified. Depend- drugs. Another example concerns antihypertensive drugs.
ing on the nature of the specific drugs, smoking could in- As smoking is a well-established risk factor for cardio-
crease or decrease exposure levels, and the perturbations in vascular disease, it is suggested that usage of any of the
pharmacokinetic parameters range from 13 to 500 %. 22 antihypertensives ‘‘should be part of comprehensive
Dosage modifications in smokers are necessary for four cardiovascular risk management, including … smoking
drugs, including erlotinib hydrochloride, riociguat, theo- cessation’’.
phylline and insulin. For six drugs, including cimetidine Several drugs in Table 2 warrant discussion in detail.
and olanzapine, dosage modifications in smokers are nec- For the drug norethindrone, a black box warning (BBW),
essary only when multiple factors that may affect safety or the strongest warning about adverse drug reactions issued
efficacy are present. For seven drugs, dosage modifications by the FDA [12], is included in the labelling to highlight
in smokers are not necessary, although the pharmacokinetic the significantly increased risks of heart attacks and strokes
parameters of four of them are affected by smoking. This in female smokers using oral contraceptives, and ‘‘women
information is presented mainly in the ‘Clinical Pharma- who use oral contraceptives are strongly advised not to
cology’ and ‘Drug Interactions’ sections of the label. smoke’’. This is the only BBW for a single-active-ingre-
Table 2 shows that smoking is a risk factor for 16 types dient drug regarding smoking–drug interactions in all la-
of diseases or adverse drug reactions. One notable example belling. In contrast, for two drugs, doxycycline hyclate and
concerns nonsteroidal anti-inflammatory drugs (NSAIDs). calcitonin salmon, smoking appeared to have no effects on
All 22 NSAIDs may cause gastrointestinal bleeding, and adverse reactions.
Drugs and Diseases Interacting with Smoking in US Drug Labelling

Table 2 Effects of cigarette smoking on diseases or adverse drug reactions

Diseases or adverse drug reaction Drug name Labelling sections Effects of cigarette smokinga

CAD Abacavir sulfate W&P Smoking is a risk factor for CAD; these drugs
Almotriptan malate W&P (except for atorvastatin calcium, cholestyramine,
colestipol hydrochloride and fenofibrate) may also
Atorvastatin calcium I&U cause CAD, and they should be prescribed with
Cholestyramine I&U caution in smokers
Colestipol hydrochloride I&U
Dihydroergotamine mesylate W
Eletriptan hydrobromide W&P
Fenofibrate I&U
Frovatriptan succinate W&P
Methylergonovine maleate W
Naratriptan hydrochloride W&P; UISP
AVD Esterified estrogens W Smoking is a risk factor for AVD; these drugs
Estradiol W (except for norethindrone acetate) may also cause
AVD, and they should be prescribed with caution
Estradiol acetate W&P in smokers
Estradiol cypionate W
Estradiol hemihydrate W
Estradiol transdermal system W
Estradiol valerate W
Estrogens, conjugated W
Norethindrone acetate W
Ospemifene W&P
Progesterone W
CVD Rizatriptan benzoate W&P Smoking is a risk factor for CVD; these drugs
Rosuvastatin calcium I&U (except for rosuvastatin calcium) may also cause
CVD, and they should be prescribed with caution
Sumatriptan W&P in smokers
Sumatriptan succinate W&P
Varenicline tartrate W&P
Zolmitriptan W&P
High blood pressure Aliskiren hemifumarate I&U Smoking is among the cardiovascular risks; usage of
Amlodipine besylate I&U these drugs ‘‘should be part of comprehensive
cardiovascular risk management, including …
Atenolol I&U smoking cessation’’
Azilsartan kamedoxomil I&U
Doxazosin mesylate I&U
Enalapril maleate I&U
Eplerenone I&U
Felodipine I&U
Lisinopril I&U
Metoprolol succinate I&U
Nadolol I&U
Nebivolol hydrochloride I&U
Nifedipine I&U
Olmesartan medoxomil I&U
Prazosin hydrochloride I&U
Propranolol hydrochloride I&U
Quinapril hydrochloride I&U
Ramipril I&U
Spironolactone I&U
Telmisartan I&U
Valsartan I&U
Verapamil hydrochloride I&U
 H. Li, Q. Shi

Table 2 continued
Diseases or adverse drug reaction Drug name Labelling sections Effects of cigarette smokinga

Gastrointestinal bleeding Celecoxib W&P These drugs may cause gastrointestinal bleeding,
Diclofenac epolamine W&P and such a risk is higher in smokers
Diclofenac potassium W&P
Diclofenac sodium W&P
Diflunisal W
Etodolac W
Fenoprofen calcium W
Flurbiprofen W
Ibuprofen W
Indomethacin W
Ketoprofen W
Ketorolac tromethamine W
Meclofenamate sodium W
Mefenamic acid W
Meloxicam P
Nabumetone W
Naproxen sodium W
Oxaprozin W
Piroxicam W
Sulindac W
Tolmetin sodium W
Valdecoxib W
Serious blood clots Etonogestrel PI This drug may cause serious blood clots, and such a
risk is higher in smokers
Decreased bone mineral density/ Budesonide PI Smoking is a risk factor for decreased bone mineral
osteoporosis Desonide W&P density/osteoporosis; these drugs (except for
estropipate and ibandronate sodium) may also
Estropipate I&U cause decreased bone mineral density/
Flunisolide W&P osteoporosis, and they should be prescribed with
Goserelin acetate PI caution in smokers
Ibandronate sodium PI
Leuprolide acetate P
Medroxyprogesterone acetate W
Nafarelin acetate P
Prednisone P
Bacterial pneumonia Enfuvirtide W&P This drug may cause bacterial pneumonia, and such
a risk is higher in smokers
NAION Sildenafil citrate W&P These drugs may cause NAION, and such a risk is
Tadalafil W&P higher in smokers
Periodontal diseases Chlorhexidine gluconate CS Smoking is a risk factor for periodontal diseases;
smokers appear to show decreased efficacy of
chlorhexidine gluconate
Malignancies Adalimumab W&P Smoking is a risk factor for malignancies
Omalizumab W&P
Procarbazine hydrochloride AR ‘‘The risks of secondary lung cancer from
[procarbazine hydrochloride] treatment appear to
be multiplied by tobacco use’’
Asthma Cromolyn sodium PI Smoking is a ‘‘trigger’’ of asthma
COPD Tiotropium bromide PI ‘‘Most COPD is caused by smoking’’
Stroke Raloxifene hydrochloride W&P Smoking is a risk factor for stoke
Thyrotropin alfa W&P
Norethindrone BBW ‘‘Cigarette smoking greatly increases the possibility
of suffering heart attacks and strokes. Women
who use oral contraceptives are strongly advised
not to smoke’’
Drugs and Diseases Interacting with Smoking in US Drug Labelling

Table 2 continued
Diseases or adverse drug reaction Drug name Labelling sections Effects of cigarette smokinga

Erectile dysfunction Alprostadil PI ‘‘Excessive smoking’’ is a cause of erectile

dysfunction
Emphysema in patients with Alpha1-PI CP ‘‘Smoking is an important risk factor for the
Alpha1-PI deficiency development of emphysema in patients with
Alpha1-PI deficiency’’
Adverse events Doxycycline hyclate AR ‘‘[S]moking status did not appear to be correlated
with adverse events’’
Calcitonin salmon AR ‘‘Smoking did not have a contributory effect on the
occurrence of nasal adverse reactions’’
Alpha1-PI alpha-1-proteinase inhibitor (human), AR adverse reactions, AVD arteriovascular disease, BBW black box warning, CAD coronary artery
disease, COPD chronic obstructive pulmonary disease, CP clinical pharmacology, CS clinical studies, CVD cardiovascular disease, I&U indications and
usage, NAION non-arteritic anterior ischaemic optic neuropathy, P precautions, PI patient information, UISP use in specific populations, W warnings,
W&P warnings and precautions
a
Wording in quotation marks is copied directly from the labelling

5 Drugs with Multiple Active Ingredients label; each label includes about ten sections for different
types of information) poses a significant challenge for
As for the 36 multiple-active-ingredient drugs, none of manual review of all of the documents. The FDALabel
their labels include information regarding smoking affect- database provides the unique capability to search the full
ing pharmacokinetics. For 27 drugs, the smoking-relevant text of all labels deposited in the FDA Online Label Re-
information is the same as that for the individual active pository and allows the user to download the search results
ingredients (see Supplementary Table 1). Of note, the without limitations. To our knowledge, the FDALabel
combination drug norethindrone and mestranol has the database is the only publically available tool that provides
same BBW for smoking–drug interactions as does the these functionalities. This database is particularly suitable
single-active-ingredient drug norethindrone. The remaining for the present study, as the three keywords ‘cigarette(s)’,
nine multiple-active-ingredient drugs are for contraceptive ‘smoke(r)(s)/smoking’ and ‘tobacco’ effectively cover all
use, and all of them have a BBW stating that ‘‘smoking of the relevant information. In other words, as there are no
increases the risk of serious cardiovascular side effects alternative ways to describe the relevant information, these
from oral contraceptive use’’ and that ‘‘this risk increases three keywords are sufficient to extract all of the target
with age and with the extent of smoking (in epidemiologic information. This is in contrast to more complicated ap-
studies, 15 or more cigarettes per day was associated with a plications, such as a previous study of drug-induced liver
significantly increased risk) and is quite marked in women injury, for which a significant amount of unwanted infor-
over 35 years of age’’. The BBW concludes that ‘‘women mation was retrieved because of the lack of specific key-
who use oral contraceptives should be strongly advised not words, and extensive manual annotation was therefore
to smoke’’. These nine drugs are a combination of required [13]. For the current study, the use of three key-
ethinylestradiol with either desogestrel, drospirenone, words enabled us to quickly extract the relevant informa-
levonorgestrel, ethynodioldiacetate, etonogestrel, levo- tion with no false negatives and only a minimal number of
norgestrel, norelgestromin, norethindrone or norgestimate false positives. For example, we manually double-checked
(see Supplementary Table 1). the labelling of 100 drugs that were not picked up by
keyword searching, and we found no false negatives. We
believe our data present the most comprehensive and ac-
6 Discussion and Perspectives curate picture of cigarette smoking interacting with drugs
and/or diseases in US prescription drug labelling.
This is the first study to explore information regarding ci- Only a small number of drug labels were found to carry
garette smoking in FDA-approved drug labelling. By using information related to cigarette smoking. This is not nec-
the FDALabel database, we were able to address this issue essarily unexpected, for four possible reasons. First, in-
in a comprehensive and systematic manner. Specifically, clusion is advised by the FDA but is not mandatory. The
the enormous number of readily available drug labels FDA draft guidance clearly states that it is ‘‘for comment
(62,857 labels as of 19 June 2014; and the number is purposes only’’ [9, 10], and no specific inclusion criteria
growing on a daily basis in DailyMed) and the rich and are provided that define what types of interactions in-
diverse content in the labelling (averaging 20 pages per volving cigarette smoking are to be included in drug
 H. Li, Q. Shi

labelling. It is therefore possible that relevant studies were of the FAERS database, such as under-reporting [18],
performed in clinical trials during the drug development should be taken into consideration for these future
process, but the results were somehow not analysed or endeavours.
included in the labelling. Second, the first FDA draft The inclusion of smoking–drug interactions in drug la-
guidance that recommended inclusion of smokers as sub- belling appears not to be well recognized by many re-
jects in clinical trials and drug labelling was issued in 2006 searchers. Several elegant review articles [2–4, 14] and
[9]. It is therefore likely that drug labelling approved be- research papers [19, 20] on smoking–drug interactions
fore 2006 does not contain sufficient information regarding have been published, but none of them mentioned the
cigarette smoking. Third, the FDA draft guidance recom- possible inclusion of relevant information in drug labelling.
mended inclusion of smokers as subjects only in cy- There is an urgent need to increase the awareness of this
tochrome P450 (CYP) 1A2-related studies [9, 10]. The issue in the research community.
effects of smoking on other drug-metabolizing enzymes,
such as CYP1B1, CYP2A6, CYP2E1 and uridine 50 -
diphosphate-glucuronosyltransferases (UGT) enzymes [14, 7 Conclusion
15], are currently not included in FDA labelling docu-
ments. Lastly, drug labelling usually does not include Though the current study may represent an underestimate
animal-based data regarding smoking–drug interactions. of all smoking–drug interaction investigations in the drug
All of these are important reasons why, in comparison with development process, it presents an overview of this issue
literature reports [2, 3], only a small number of drugs were with regard to drug labelling. This information may be
identified in this study. useful to both regulatory agencies and the pharmaceutical
A significant difference between the literature reports industry for future action, such as revising or finalizing the
and the FDA drug labelling is that the latter does not tend FDA draft guidance [10]. The drug lists presented here may
to be exhaustive. Specifically, ‘‘only information that also help basic researchers to design future investigations,
would be useful to’’ clinical decisions should be included and may serve as a good reference source for physicians to
in drug labelling [9, 10]. While a recent analysis concluded better assess the risks of cigarette smoking in patient
that FDA drug labelling contains excessive information management.
that may ‘‘reduce physician comprehension of important It should be pointed out that the content of FDA-ap-
safety warning’’ [11], another report argued that the FDA is proved drug labelling, despite being ‘‘the official descrip-
not updating drug labelling consistently when new research tion of a drug product’’ (see http://www.fda.gov/Drugs/
findings become available [16]. Currently, the FDA is us- InformationOnDrugs/ucm079436.htm) and ‘‘the primary
ing its Adverse Event Reporting System (FAERS) to source for drug safety information for physicians’’ [11], is
monitor potential signals of serious adverse drug reactions, not perfect or static [13, 16]. Some authors even argue that
and the results may lead to a change in drug labelling the content in the BBW section needs to be improved [21].
[17] (see http://www.fda.gov/Drugs/GuidanceCompliance Part of the statement in the drug labelling, particularly that
RegulatoryInformation/Surveillance/AdverseDrugEffects/ related to pharmacokinetics, is based on limited sets of
ucm082196.htm). Analysis of the FAERS database may clinical trials and may not reflect the most recent findings
help identify potential smoking–drug reactions for regula- in the literature [16]. The information presented here may
tory considerations. This may be particularly important for serve as a useful reference but not definitive guidance. It is
drugs that were approved before the first FDA draft guid- likely that future studies will reveal additional important
ance recommending inclusion of smokers as subjects in smoking–drug interactions that may warrant a change in
drug development trials was issued in 2006. As the FAERS the labelling.
database contains mainly postmarketing information, the
Acknowledgments Dr. Haibo Li’s work was supported by the Re-
data would also be useful to validate some findings already
search Participation Program at the National Center for Toxicological
presented in the labelling, which are largely from clinical Research, administrated by the Oak Ridge Institute for Science and
trials. In addition, the newly established FDA Center for Education through an interagency agreement between the US
Tobacco Products (CTP) aims to reduce the adverse health Department of Energy and the US FDA. Dr. Li’s work was also
supported by the International Cooperation and Exchanges (2012)
impact for those who use tobacco products, and is col-
Program of the Department of Health in Jiangsu Province, China. Dr.
lecting safety reports involving tobacco products (at https:// Li now works in the Department of Clinical Laboratory Medicine,
www.safetyreporting.hhs.gov/fpsr/WorkflowLoginIO.aspx? Nantong Maternal and Child Health Hospital, 399 Century Avenue,
metinstance=0E1F229876AB85975D41F4FF60E512B19F Nantong, Jiangsu 226018, China.
F9C2BC). It can be expected that data accumulated by
Disclaimer The information in these materials is not a formal dis-
the FDA CTP will help improve drug labelling regarding semination of information by the US Food and Drug Administration
cigarette smoking in the future. However, the limitations (FDA) and does not represent agency position or policy.
Drugs and Diseases Interacting with Smoking in US Drug Labelling

References 12. Martin CM, Borgelt L. Black box warnings: what do they mean
to pharmacists and patients. Consult Pharm. 2012;27(7):482–92.
13. Chen M, Vijay V, Shi Q, Liu Z, Fang H, Tong W. FDA-approved
1. Thun MJ, Carter BD, Feskanich D, Freedman ND, Prentice R, drug labeling for the study of drug-induced liver injury. Drug
Lopez AD, et al. 50-year trends in smoking-related mortality in Discov Today. 2011;16(15–16):697–703.
the United States. N Engl J Med. 2013;368(4):351–64. 14. Petros WP, Younis IR, Ford JN, Weed SA. Effects of tobacco
2. Zevin S, Benowitz NL. Drug interactions with tobacco smoking: smoking and nicotine on cancer treatment. Pharmacotherapy.
an update. Clin Pharmacokinet. 1999;36(6):425–38. 2012;32(10):920–31.
3. Kroon LA. Drug interactions with smoking. Am J Health Syst 15. Villard PH, Herber R, Seree EM, Attolini L, Magdalou J,
Pharm. 2007;64(18):1917–21. Lacarelle B. Effect of cigarette smoke on UDP-glucuronosyl-
4. Kroon LA. Drug interactions and smoking: raising awareness for transferase activity and cytochrome P450 content in liver, lung
acute and critical care providers. Crit Care Nurs Clin N Am. and kidney microsomes in mice. Pharmacol Toxicol. 1998;82(2):
2006;18(1):53–62, xii. 74–9.
5. Schaffer SD, Yoon S, Zadezensky I. A review of smoking ces- 16. Seminerio MJ, Ratain MJ. Are drug labels static or dynamic?
sation: potentially risky effects on prescribed medications. J Clin Clin Pharmacol Ther. 2013;94(3):302–4.
Nurs. 2009;18(11):1533–40. 17. Fang H, Su Z, Wang Y, Miller A, Liu Z, Howard PC, et al.
6. Schein JR. Cigarette smoking and clinically significant drug in- Exploring the FDA Adverse Event Reporting System to generate
teractions. Ann Pharmacother. 1995;29(11):1139–48. hypotheses for monitoring of disease characteristics. Clin Phar-
7. Miller LG. Cigarettes and drug therapy: pharmacokinetic and macol Ther. 2014;95(5):496–8.
pharmacodynamic considerations. Clin Pharm. 1990;9(2):125–35. 18. Hoffman KB, Demakas AR, Dimbil M, Tatonetti NP, Erdman
8. US Food and Drug Administration. Drug development and CB. Stimulated reporting: the impact of US Food and Drug
drug interactions: table of substrates, inhibitors and inducers. Administration-issued alerts on the Adverse Event Reporting
2011. http://www.fda.gov/drugs/developmentapprovalprocess/ System (FAERS). Drug Saf. 2014;37(11):971–80.
developmentresources/druginteractionslabeling/ucm093664.htm. 19. Gagne JJ, Bykov K, Choudhry NK, Toomey TJ, Connolly JG,
Accessed 15 Sept 2014. Avorn J. Effect of smoking on comparative efficacy of an-
9. US Food and Drug Administration. Guidance for industry: drug tiplatelet agents: systematic review, meta-analysis, and indirect
interaction studies—study design, data analysis, and implications comparison. BMJ. 2013;347:f5307.
for dosing and labeling. Draft guidance. 2006. http://www.fda. 20. Zaverucha-do-Valle C, Monteiro SP, El-Jaick KB, Rosadas LA,
gov/OHRMS/DOCKETS/98fr/06d-0344-gdl0001.pdf. Accessed Costa MJ, Quintana MS, et al. The role of cigarette smoking and
15 Sept 2014. liver enzymes polymorphisms in anti-tuberculosis drug-induced
10. US Food and Drug Administration. Guidance for industry: drug hepatotoxicity in Brazilian patients. Tuberculosis. 2014;94(3):
interaction studies—study design, data analysis, implications for 299–305.
dosing, and labeling recommendations. Draft guidance. 2012. 21. Matlock A, Allan N, Wills B, Kang C, Leikin JB. A continuing
http://www.fda.gov/downloads/Drugs/GuidanceCompliance black hole? The FDA boxed warning: an appeal to improve its
RegulatoryInformation/Guidances/UCM292362.pdf. Accessed 15 clinical utility. Clin Toxicol. 2011;49(6):443–7.
Sept 2014.
11. Duke J, Friedlin J, Ryan P. A quantitative analysis of adverse
events and ‘‘overwarning’’ in drug labeling. Arch Intern Med.
2011;171(10):944–6.