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\begin{document}

\title{The association of chiral characteristic with drug withdrawal due to
safety: a comparative analysis}



\author[1]{Ayfer Bahar}%
\author[2]{Volkan Aydin}%
\author[1]{Caner Vizdiklar}%
\author[1]{Ahmet Akici}%
\affil[1]{Marmara University School of Medicine}%
\affil[2]{Istanbul Medipol University}%


\vspace{-1em}



  
  \date{June 05, 2024}


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\selectlanguage{english}
\begin{abstract}
Aim: Chirality of drugs might be associated with safety issues through
pharmacokinetic or pharmacodynamic variations, interactions, or direct
toxicological responses. This study aimed to examine chiral status of
the drugs withdrawn from the market. Methods: We searched the literature
regarding withdrawn drugs between 1950-2020 due to safety-related issues
and identified 395 drugs. We examined their chirality and assigned into
one of three categories: achiral compound, chiral mixture, and pure
enantiomer. We compared their distribution at ATC-1 level, duration on
the market, and adverse drug reactions leading to their withdrawal.
Results: We identified that 52.4\% (n=207) of withdrawn drugs were
achiral, whereas 27.6\% (n=109) were chiral mixtures and 20.0\% (n=79)
were pure enantiomers. The mean duration on the market was 24.6\selectlanguage{ngerman}±27.5
years. The groups did not differ in terms of mean duration on the
market. Chiral mixtures were significantly more withdrawn than were
achirals in cardiovascular system drugs (17.4\% vs. 7.7\%, p=0.01). In
musculoskeletal system drugs, pure enantiomers were significantly less
withdrawn (2.5\%) compared to achirals (12.6\%, p=0.01) and chiral
mixtures (11.9\%, p=0.03). Hepatotoxicity was significantly less common
in pure enantiomers (5.4\%) compared to chiral mixtures (12.7\%, p=0.04)
and achirals (17.0\%, p\textless{}0.01). Cardiovascular toxicity was
significantly more common in chiral mixtures (14.5\%) compared to that
in achiral drugs (7.5\%, p=0.02). Conclusion: Our study showed slightly
higher representation of chiral mixtures among withdrawn drugs over pure
enantiomers. The assessment of withdrawal reasons further indicates
higher tendency of chiral mixtures towards hepatotoxicity and
cardiovascular toxicity.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{The association of chiral characteristic with drug withdrawal
due to safety: a comparative analysis}

\textbf{Running title: Chiral status of withdrawn drugs}

Ayfer Bahar\textsuperscript{1*}, Volkan Aydin\textsuperscript{2*}, Caner
Vizdiklar\textsuperscript{1}, Ahmet Akici\textsuperscript{1}

Department of Medical Pharmacology, School of Medicine, Marmara
University, Istanbul, Turkey

Department of Medical Pharmacology, International School of Medicine,
Istanbul Medipol University, Istanbul, Turkey

* The authors equally contributed to this paper.

\textbf{Correspondence:} Prof Ahmet Akici, MD

Department of Medical Pharmacology, Marmara University School of
Medicine, Maltepe 34854, Istanbul, Turkey.

Phone: +902165557700; e-mail:\emph{aakici@marmara.edu.tr}

\textbf{Ethical approval:} This study was approved by Ethics Committee
for Non-interventional Clinical Studies of Marmara University Institute
of Health Sciences (Approval number: 16.11.2020-91).

\textbf{Acknowledgements} : We thank to Dr. Igho Onakpoya and his
co-workers for their tremendous efforts and earlier studies on withdrawn
drugs that inspired us to investigate another aspect of the subject.

\textbf{Competing Interests:} The authors declare they have no competing
or conflict of interest.

\textbf{Funding:} This research did not receive any specific grant from
funding agencies in the public, commercial, or not-for-profit sectors.

\textbf{Contributions:} Conception and design: AB, AA, VA; Acquisition
of data: AB, CV, VA; Analysis and interpretation of data: VA, AB, CV;
Writing first draft: VA, AB, CV, AA; Critical review and supervision:
AA, VA; Final approval to the submitted version of the manuscript: AB,
VA, CV, AA.

\textbf{Data availability:} The data that support the findings of this
study are available from the corresponding author upon reasonable
request.

\textbf{Keywords:} pharmacovigilance, pharmacoepidemiology, drug
regulation, stereoisomerism

\textbf{Word count:} 2682, \textbf{Table count:} 4, \textbf{Figure
count:} 1

\textbf{What is known about this subject}

Chiral status of drugs is postulated to be among factors that influence
drug safety through pharmacokinetic/pharmacodynamic changes, toxicities
or drug interactions.

There has not been any systematic analysis that investigated safety
issues/benefits attributed to chiral status.

\textbf{What this study adds}

Chiral distribution of the withdrawn drugs could differ by the reasons
for withdrawal, such as increased tendency of cardiovascular ADRs and
hepatotoxicity in chiral mixtures.

Further investigation of potential relationships between chirality of
drugs and ADR mechanisms might eventually lead to improvements of safety
standards in new drug development processes.

\textbf{ABSTRACT}

\textbf{Aim:} Chirality of drugs might be associated with safety issues
through pharmacokinetic or pharmacodynamic variations, interactions, or
direct toxicological responses. This study aimed to examine chiral
status of the drugs withdrawn from the market.

\textbf{Methods:} We searched the literature regarding withdrawn drugs
between 1950-2020 due to safety-related issues and identified 395 drugs.
We examined their chirality and assigned into one of three categories:
achiral compound, chiral mixture, and pure enantiomer. We compared their
distribution at ATC-1 level, duration on the market, and adverse drug
reactions leading to their withdrawal.

\textbf{Results:} We identified that 52.4\% (n=207) of withdrawn drugs
were achiral, whereas 27.6\% (n=109) were chiral mixtures and 20.0\%
(n=79) were pure enantiomers. The mean duration on the market was
24.6\selectlanguage{ngerman}±27.5 years. The groups did not differ in terms of mean duration on
the market. Chiral mixtures were significantly more withdrawn than were
achirals in cardiovascular system drugs (17.5\% vs. 7.7\%, p=0.01). In
musculoskeletal system drugs, pure enantiomers were significantly less
withdrawn (2.5\%) compared to achirals (12.6\%, p=0.01) and chiral
mixtures (11.9\%, p=0.03). Hepatotoxicity was significantly less common
in pure enantiomers (5.4\%) compared to chiral mixtures (12.7\%, p=0.04)
and achirals (17.0\%, p\textless{}0.01). Cardiovascular toxicity was
significantly more common in chiral mixtures (14.5\%) compared to that
in achiral drugs (7.5\%, p=0.02).

\textbf{Conclusion:} Our study showed slightly higher representation of
chiral mixtures among withdrawn drugs over pure enantiomers. The
assessment of withdrawal reasons further indicates higher tendency of
chiral mixtures towards hepatotoxicity and cardiovascular toxicity.



\textbf{INTRODUCTION}

Chirality is an important geometric characteristic of the objects within
biological systems including amino acids, carbohydrates, and lipids as
well as drugs . In the latter, chirality might be associated with safety
issues through pharmacokinetic or pharmacodynamic variations, drug
interactions, or direct toxicological responses . Chiral drugs consist
of racemic mixtures, non-racemic mixtures, or pure enantiomers . Unlike
achiral drugs with no chiral center, this stereoisomeric chemistry
allows the opportunity to manipulate their composition or molecular
chirality to enhance efficacy and/or overcome tolerability problems . A
typical example of improving clinical efficacy could be given as
selective H1-receptor antagonist, cetirizine, whose R-enantiomer
levocetirizine has 30-fold higher binding affinity and lower renal
clearance compared to its parent racemic mixture . On the other hand,
thalidomide represents a well-known dramatic example of drug-induced
toxicity, with R-enantiomer responsible for the intended sedative effect
and S-enantiomer for the tragic phocomelia .

Use of pure enantiomers offers advantages including dose reduction,
simplification of dose-response relationship, diminution of
interindividual variability and toxicity from inactive enantiomers . In
fact, regulatory drug authorities encourage such chemical designations
for novel drug development . In addition, some racemic mixtures were
undergone chiral switch, where their pure enantiomers were launched with
same/similar indication . These have led to increased share of pure
enantiomers worldwide though still many racemic and non-racemic mixtures
are present . While several clinical efficacy and/or safety benefits
have been attributed to pure enantiomer drugs, there has been no
systematic analysis that investigated these aspects with respect to
chirality. In this study, we aimed to examine chiral status of the drugs
withdrawn from the market.

\textbf{METHODS}

In this pharmacoepidemiologic study, we collected and analysed
retrospective descriptive drug safety data. Prior to data collection,
ethical approval was obtained from Marmara University Institute of
Health Sciences, Non-Interventional Clinical Studies Ethical Committee
(approval number: 16.11.2020-91).

We examined chemical structures regarding chirality status of the drugs,
which were withdrawn from market due to adverse effects. Drugs withdrawn
between 1950 and 2020 in the world due to safety-related issues were
identified via literature search. Those which were withdrawn between
1950 and 2014 were obtained from a systematic review conducted by
Onakpoya et al., including a total of 462 drugs/products .
Drugs/medicinal products that contain inorganic compounds, proteins,
vaccines, polymers, human tissue extracts, herbal and cell-based
preparations as active substances, and combinations of two active
substances that show different chiral status from each other were
excluded from the study. Remaining 389 drugs, i.e., the ones that
comprise single active substance (n=383) and the combinations of active
substances showing similar chiral characteristics (n=6), were included.
Using a methodology similar to the aforementioned review, literature
search was conducted for drugs withdrawn between 2015 and 2020, which
resulted in six drugs meeting those criteria (Supplementary Table 1).
Thus, a total of 395 drugs/medicinal products were included in the first
part of the study. Chiral characteristics and distribution of those
drugs at ATC-1 level, as well as the distribution of their duration on
the market, and adverse drug reactions (ADR) leading to their withdrawal
were examined.

Chirality status of the drugs were identified via information on the
``Inxight: Drugs'' database of U.S. National Institute of Health . For
the ones that are not available on that database, chirality status was
determined after literature search. The mean time to withdrawal (TtW)
and the duration (period from introduction to the calendar year of 2020)
and year of launch of drugs according to chirality status were examined.
According to chiral characteristics, the drugs were divided into three
main groups as ``achiral'', ``chiral mixture'' and ``pure enantiomer''.
Also, TtWs of drugs were evaluated categorically in six distinct time
periods as ``0-20/21-40/41-60/61-80/80-100/\selectlanguage{english}[?]100 years''.

Chiral distribution of the withdrawn drugs was evaluated and compared at
ATC-1 level. Before that, we re-classified drugs with multiple ATC codes
or without any code by adding them to the most appropriate ATC class
according to the indication led to withdrawal, whenever possible. Those
drugs were evaluated and compared first as ``achiral'' and ``chiral'',
and chiral ones were further separated into two to form three main
groups as ``achiral drugs'', ``chiral mixtures'' and ``pure
enantiomers'' to analyse in detail.

ADRs leading to withdrawal of drugs were evaluated in 20 subgroups
(i.e., cardiovascular, genitourinary, gastrointestinal, respiratory,
neurological, haematological, dermatological, psychiatric, endocrine,
ophthalmic, musculoskeletal, and other ADRs, along with hepatotoxicity,
nephrotoxicity, genotoxicity, drug abuse, carcinogenicity, and death).
These were distributed and compared by the chirality status
(achiral/chiral mixture/pure enantiomer) of the related drugs.

\emph{Statistical analysis}

All data were analysed using IBM SPSS Statistics for Windows, Version
22.0 (IBM Corp., Armonk, NY, USA) and GraphPad Prism version 5.0 for
Windows (GraphPad Software, San Diego, CA, USA) software. Analysed data
were expressed as numbers and percentages or mean +- standard deviation
values, where appropriate. Frequency analysis was used for statistical
evaluation and categorical variables were compared using chi-square
test. For continuous variables, normality of distribution was evaluated
by D'Agostino-Pearson and Shapiro-Wilk analyses. Normally distributed
data were compared using one-way analysis of variance (ANOVA) test with
Tukey's post-hoc test, whereas Kruskal-Wallis test was used with Dunn's
post-hoc test if normal distribution is not applicable. Statistical
significance was inferred by an overall 5\% of type-I error level.

\textbf{RESULTS}

\emph{Chirality Status of Withdrawn Drug Groups}

Of the 395 drugs withdrawn, 52.4\% (n=207) were achiral, 27.6\% (n=109)
were chiral mixtures, and 20.0\% (n=79) were pure enantiomers. The mean
TtW of all those drugs evaluated for safety were 24.6+-27.5 (0-226)
years, and the time after launch was 57.3+-30.1 (8-267) years.

``N-nervous system drugs'' had the highest share (26.3\%) when
distributed at ATC-1 level. Five of 13 ATC-1 classes were predominantly
chiral. Furthermore, the chiral predominance in ``C-cardiovascular
system drugs'' were statistically significant when compared to other
classes (p=0.02), (Figure 1).

Chiral mixtures were significantly higher in number than achirals in
cardiovascular system drugs (17.5\% vs. 7.7\%, p=0.01). In
musculoskeletal system drugs, pure enantiomers were significantly less
withdrawn (2.5\%) compared to achirals (12.6\%) and chiral mixtures
(11.9\%), (p=0.01 and p=0.03, respectively). On the contrary, pure
enantiomers were subject to withdrawal at a higher rate (8.9\%) compared
to chiral mixtures (1.8\%) in the genitourinary system drugs (p=0.04),
(Table 1).

\emph{Chirality Status by Adverse Drug Reactions}

A total of 583 ADRs were among the reasons of withdrawal of the drugs
evaluated. Fifty-two and a half percent (n=306) of those were related to
achiral drugs, 28.3\% (n=165) to chiral mixtures and 19.2\% (n=112) to
pure enantiomers. Among the most encountered ADRs, hepatotoxicity was
significantly less common in pure enantiomers (5.4\%) compared to chiral
mixtures (12.7\%, p=0.04) and achirals (17.0\%, p\textless{}0.01).
Cardiovascular ADRs were significantly more common in chiral mixtures
(14.5\%) compared to that in achiral drugs (7.5\%, p=0.02), with no
difference from pure enantiomers (11.6\%, p\textgreater{}0.05). Drug
abuse for a reason of withdrawal was found to be less common in achiral
drugs (5.2\%) than that in chiral mixtures (13.3\%, p\textless{}0.01)
and pure enantiomers (11.6\%, p=0.03). In addition, dermatological ADRs
were significantly less common in pure enantiomers compared to that in
achiral drugs (1.8\% vs. 8.8\%, p\textless{}0.01) for pure enantiomers
(Table 2).

\emph{Chirality Status by Temporal Patterns}

The drugs withdrawn were mostly launched between years of 1960-1980
(36.7\%) for all chiral groups. Achiral drugs had the highest share in
all time periods (48.3\%-70.8\%). Chiral mixtures were more commonly
withdrawn from the market than pure enantiomers in all time periods,
except those launched before the year 1920 (4.2\% vs. 25.0) and after
the year 2020 (5.6\% vs. 33.3\%), (Table 3).

Mean TtWs of achiral drugs, chiral mixtures and pure enantiomers were
similar (25.9+-29.1, 20.0+-16.9, and 27.9+-33.8 years respectively,
p\textgreater{}0.05). The drugs withdrawn due to abuse had the highest
mean TtW (35.1+-28.1 years) and those leading to death had the lowest
(11.4+-9.6 years). Achiral drugs withdrawn due to dermatological ADRs had
longer mean TtW (28.4+-20.4 years) compared to that in chiral mixtures
(9.3+-10.9 years, p=0.01), (Table 4).

\textbf{DISCUSSION}

We examined chirality of the drugs withdrawn from the market over the
last 70 years to uncover the potential reflections of such
characteristic on major safety issues that outweigh its intended
benefits. We observed that chiral status of withdrawn drug groups at
ATC-1 level seem to exhibit subtle differences. On the other hand,
assessment of ADRs by chiral category pointed out the tendency of
racemic/non-racemic chiral mixtures towards hepatotoxicity and
cardiovascular ADRs.

Drugs with a chiral characteristic, either in the form of
racemic/non-racemic mixtures or pure enantiomers, constitute more than
half (58\%) of the drugs used . This figure appeared to show modest
increments in favour of chiral drugs, as the annual new worldwide
approval rates of chiral drugs were reported to range between 50\% to
76\% . In our study, 47.6\% of the withdrawn drugs were of the chiral
type, which seems to imply that the withdrawal risk of chiral drugs may
be slightly less. Pure enantiomer drugs may offer advantage of less
complex pharmacological profile with a greater therapeutic index .
Nevertheless, our findings showed a comparable ratio of withdrawn chiral
mixtures (58\%) and pure enantiomers (42\%), questioning the relative
potential advantage of the latter on withdrawal. In fact, the
predominant composition among chiral drugs is racemic mixtures . While
scarce data was present in the literature, a recent nationwide study
from Tanzania reported that 74\% of all chiral drugs available on the
market between 2003-2018 were racemates . On the other hand, the upward
trend of chiral drugs appears to be mostly driven by up to 15-fold
higher introduction of pure enantiomers over racemic mixtures between
2000-2008 . Therefore, the inverse association of chiral drugs to
withdrawal might be partly attributed to the relatively higher share of
pure enantiomers among newly approved drugs. This was further supported
by our finding that those launched and withdrawn in the recent 20 years
revealed a comparably lesser predominance of pure enantiomers (33.3\%)
over chiral mixtures (5.6\%).

Chiral distribution of the withdrawn drug groups suggest that the
overall pattern was preserved across many of the groups at ATC-1 level
with several exceptions. One of these groups belonged to musculoskeletal
system drugs, where the rate of withdrawal was higher for chiral
mixtures (11.9\%) than that in pure enantiomers (2.5\%). Musculoskeletal
system drugs include a substantial part of non-steroidal
anti-inflammatory drugs (NSAIDs), whose majority is formed by racemates
. In fact, NSAIDs have been well-recognized to be associated with
important safety issues that may result in withdrawal. A study on
withdrawn drugs between 1960-1999 reported that 13\% of such drugs were
NSAIDs . In fact, NSAIDs were among the most commonly utilized drug
groups . This could suggest that putatively lower safety margin of
chiral mixtures compared to pure enantiomer drugs may be associated with
the emergence of important safety issues in frequently used medications.
This might have been contributed by possible over-the-counter or
non-prescription use of these drugs as self-medication since we did not
identify such difference in cardiovascular drugs, commonly used
prescription medicines. The top three best-selling drugs in the United
States in 2009 were reported to belong to cardiovascular category and
all were pure enantiomers . In addition, chirality-related
pharmacodynamic and pharmacokinetic characteristics of cardiovascular
drugs were also extensively reviewed in the literature . Nevertheless,
our findings suggest that a potential relationship of chirality to
withdrawal did not seem likely for cardiovascular mixed and pure
enantiomers.

ADRs have a very wide range of potential causes, including chemical
structure of the drugs, patient-related factors, concomitantly used
drugs or medicinal products, etc. . Possible underlying causes trigger
the incidence of drug-related problems of directly related tissues and
organs. Hepatotoxicity, the most common type of ADR in our study, was
the reason for withdrawal near 2.5-fold less likely in pure enantiomers
(5.4\%) than that in chiral mixtures (12.7\%). As the major organ for
drug biotransformation, the liver comprises majority of drug
metabolizing enzymes, which are chiral molecules. Due to
stereoselectivity, each drug enantiomer may be metabolized through
different pathways at different rates by these chiral enzymes . As the
metabolism of chiral mixtures may require different reactions for each
of the individual isomers, this may raise the possibility of additional
burden on the liver . Furthermore, one of the critical components of
drug-induced liver injury has been reported as drug biotransformation .
For instance, hepatotoxicity-related withdrawal of benoxaprofen, a
racemic NSAID, was reported to be mediated by the formation of reactive
acyl glucuronide metabolites . While our data was not empowered to infer
a causal association between chiral mixtures and liver injury, the
tendency of racemic/non-racemic mixture drugs towards
hepatotoxicity-driven withdrawal seems to have biological plausibility.
This warrants designation of further detailed studies with specific
racemic drugs to investigate such causal relationship. Another common
reason for withdrawal, cardiovascular ADRs were more frequently seen
with chiral mixtures compared to that of achiral drugs, but similar to
pure enantiomers. Though cardiovascular ADRs may also involve various
mechanisms, a recent machine learning-based computational model study
addressed biological binding and substructural chemical features of
drugs in predicting cardiovascular ADRs . The relative complexity of
chiral mixtures might have contributed to observed high share of
cardiovascular ADRs as a reason for withdrawal in our study.

Since the 1950s, the production of synthetic drugs has become widespread
and mostly racemates have been produced by this method . This might have
paved the way for the withdrawal of chiral drugs introduced in 1960-2000
to be predominantly mixtures. On the contrary, the limited number of
drugs withdrawn in the last 20 years are mostly pure enantiomers, which
might be related to their increasing share among newly approved drugs .
Additionally, drugs with different chiral characteristics in our study
had similar durations till withdrawal, and this pattern was mostly
maintained in sub-analyses based on the most common ADRs (only with one
exception in dermatological reactions). These results suggest that both
temporal parameters might be unrelated to chiral characteristics of the
drugs.

The results of the study should be interpreted considering the
limitations below. Chirality details of some drugs/medical products
included in the publication, which was used to determine the drugs
withdrawn between 1950 and 2014, could not be accessed. This resulted in
a partial reduction in the number of products evaluated. In addition,
ADRs that led to the withdrawal of the evaluated drugs were obtained
directly from the sources used to identify the drugs, so these should
not be considered as first-hand findings. Chiral characteristics-based
design of the study should not suggest that examined drugs were
withdrawn from the market solely due to their stereochemical properties.
We aimed to point out the possible effect of chirality on the
distribution of ADRs, which should be further addressed by detailed
future studies.

In conclusion, this study revealed that the stereochemical properties of
drugs are among the factors which should be considered for drug safety.
The chiral distribution of the withdrawn drugs could differ according to
the usage areas and the underlying reasons for withdrawal. While the
share of racemic/non-racemic mixtures in drugs withdrawn from the market
does not highly support the arguments in favour of them posing higher
risk, tendency of these drugs towards hepatotoxicity and cardiovascular
ADRs draws attention. The potential relationships between stereochemical
properties of drugs and ADR mechanisms should be investigated with
further experimental and epidemiological studies, which might eventually
lead to improvements of safety standards in new drug development
processes.

\textbf{Acknowledgements}

We thank to Dr. Igho Onakpoya and his co-workers for their tremendous
efforts and earlier studies on withdrawn drugs that inspired us to
investigate another aspect of the subject.

\textbf{Competing Interests}

The authors declare they have no competing or conflict of interest.

\textbf{Funding}

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Contributions}

AB, VA, and AA contributed to the study conceptualization and design.
AB, CV, and VA collected the data. Analyses were performed by AB, VA,
and CV. The first draft of the manuscript was written by VA, AB, and CV.
AA contributed to the critical review and supervision of the study. All
authors read and approved to the final version of the manuscript prior
to submission.

\textbf{Data availability}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

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\end{enumerate}



\textbf{Tables}

\textbf{Table 1.} Comparison of chiral distribution of the withdrawn
drugs at ATC-1 level.\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\textbf{ATC-1 Code} & \textbf{Total} & \textbf{Total} & \textbf{Achiral
drugs} & \textbf{Achiral drugs} & \textbf{Chiral mixtures} &
\textbf{Chiral mixtures} & \textbf{Pure enantiomers} & \textbf{Pure
enantiomers} & \textbf{p-value}\tabularnewline
& \textbf{n} & \textbf{\%} & \textbf{n} & \textbf{\%} & \textbf{n} &
\textbf{\%} & \textbf{n} & \textbf{\%} &\tabularnewline
A & 62 & 15.7 & 28 & 13.5 & 17 & 15.6 & 17 & 21.5 & 0.25\tabularnewline
B & 3 & 0.8 & 1 & 0.5 & - & - & 2 & 2.5 & 0.11\tabularnewline
C & 45 & 11.4 & 16 & 7.7 & 19 & 17.5 & 10 & 12.6 &
\textbf{0.03*}\tabularnewline
D & 15 & 3.8 & 11 & 5.3 & - & - & 4 & 5.1 & 0.05\tabularnewline
G & 16 & 4.0 & 7 & 3.4 & 2 & 1.8 & 7 & 8.9 &
\textbf{0.04\textsuperscript{+}}\tabularnewline
J & 30 & 7.6 & 16 & 7.7 & 6 & 5.5 & 8 & 10.1 & 0.50\tabularnewline
L & 8 & 2.0 & 5 & 2.4 & 3 & 2.8 & - & - & 0.35\tabularnewline
M & 41 & 10.4 & 26 & 12.6 & 13 & 11.9 & 2 & 2.5 &
\textbf{0.04\textsuperscript{++}}\tabularnewline
N & 104 & 26.3 & 56 & 27.1 & 33 & 30.3 & 15 & 19.0 & 0.21\tabularnewline
P & 18 & 4.6 & 13 & 6.3 & 2 & 1.9 & 3 & 3.8 & 0.19\tabularnewline
R & 26 & 6.6 & 12 & 5.8 & 10 & 9.2 & 4 & 5.1 & 0.43\tabularnewline
S & 6 & 1.5 & 2 & 1.0 & 1 & 0.9 & 3 & 3.8 & 0.18\tabularnewline
V & 9 & 2.3 & 5 & 2.4 & 1 & 0.9 & 3 & 3.8 & 0.42\tabularnewline
Miscellaneous & 12 & 3.0 & 9 & 4.3 & 2 & 1.9 & 1 & 1.3 &
0.28\tabularnewline
\textbf{Total} & 395 & 100.0 & 207 & 100.0 & 109 & 100.0 & 79 & 100.0 &
-\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}p=0.01 for achiral vs. racemic/non-racemic mixture
drugs. \textsuperscript{+}p=0.04 for racemic/non-racemic mixture vs.
pure enantiomers. \textsuperscript{++}p=0.01 and p=0.03 for pure
enantiomers vs. achiral and racemic/non-racemic mixture drugs,
respectively. \emph{A, Alimentary tract and metabolism; B, Blood and
blood forming organs; C, Cardiovascular system; D, Dermatological; G,
Genitourinary system and sex hormones; J, Anti-infectives for systemic
use; L, Antineoplastic and immunomodulating agents; M, Musculoskeletal
system; N, Nervous system; P, Antiparasitic products, insecticides and
repellents; R, Respiratory system; S, Sensory organs; V, Various.
Miscellaneous denotes drugs with multiple or undefined ATC codes.}

\textbf{Table 2.} Comparison of chirality status of drugs leading to
most common ADRs (n\textgreater{}30).\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\textbf{Adverse drug reaction} & \textbf{Achiral} & \textbf{Achiral} &
\textbf{Chiral mixture} & \textbf{Chiral mixture} & \textbf{Pure
enantiomer} & \textbf{Pure enantiomer} & \textbf{Total} & \textbf{Total}
& \textbf{p-value}\tabularnewline
& \textbf{n} & \textbf{\%} & \textbf{n} & \textbf{\%} & \textbf{n} &
\textbf{\%} & \textbf{n} & \textbf{\%} &\tabularnewline
Hepatotoxicity & 52 & 17.0 & 21 & 12.7 & 6 & 5.4 & 79 & 13.6 &
\textbf{0.008*}\tabularnewline
No hepatotoxicity & 254 & 83.0 & 144 & 87.3 & 106 & 94.6 & 504 & 86.4
&\tabularnewline
Cardiovascular & 23 & 7.5 & 24 & 14.5 & 13 & 11.6 & 60 & 10.3 &
\textbf{0.049\textsuperscript{+}}\tabularnewline
Non-cardiovascular & 283 & 92.5 & 141 & 85.5 & 99 & 88.4 & 523 & 89.7
&\tabularnewline
Drug abuse & 16 & 5.2 & 22 & 13.3 & 13 & 11.6 & 51 & 8.7 &
\textbf{0.006\textsuperscript{++}}\tabularnewline
No drug abuse & 290 & 94.8 & 143 & 86.7 & 99 & 88.4 & 532 & 91.3
&\tabularnewline
Neurological & 27 & 8.8 & 11 & 6.7 & 12 & 10.7 & 50 & 8.6 &
0.486\tabularnewline
Non-neurological & 279 & 91.2 & 154 & 93.3 & 100 & 89.3 & 533 & 91.4
&\tabularnewline
Haematological & 30 & 9.8 & 8 & 4.8 & 11 & 9.8 & 49 & 8.4 &
0.151\tabularnewline
Non-haematological & 276 & 90.2 & 157 & 95.2 & 101 & 90.2 & 534 & 91.6
&\tabularnewline
Carcinogenicity & 28 & 9.2 & 7 & 4.2 & 9 & 8.0 & 44 & 7.5 &
0.154\tabularnewline
No carcinogenicity & 278 & 90.8 & 158 & 95.8 & 103 & 92.0 & 539 & 92.5
&\tabularnewline
Dermatological & 27 & 8.8 & 9 & 5.5 & 2 & 1.8 & 38 & 6.5 &
\selectlanguage{greek}\textbf{0.029\textsuperscript{δ}}\selectlanguage{english}\tabularnewline
Non-dermatological & 279 & 91.2 & 156 & 94.5 & 110 & 98.2 & 545 & 93.5
&\tabularnewline
Immunological & 15 & 4.9 & 8 & 4.8 & 7 & 6.2 & 30 & 5.1 &
0.841\tabularnewline
Non-immunological & 291 & 95.1 & 157 & 95.2 & 105 & 93.8 & 553 & 94.9
&\tabularnewline
\textbf{Total} & 306 & 100.0 & 165 & 100.0 & 112 & 100.0 & 583 & 100
&\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}p\textless{}0.01 for pure enantiomer vs. achiral and
p=0.04 for pure enantiomer vs. chiral mixtures;\textsuperscript{+}p=0.02
for achiral vs. chiral mixtures;\textsuperscript{++}p\textless{}0.01 for
achiral vs. chiral mixtures and p=0.03 for achiral vs. pure
enantiomers;\selectlanguage{greek}\textsuperscript{δ}\selectlanguage{english}p\textless{}0.01 for pure enantiomer vs.
achiral drugs.

\subsection*{Table 3. Chiral distribution of the drugs by the time after
launch.}

{\label{table-3.-chiral-distribution-of-the-drugs-by-the-time-after-launch.}}\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{Year of launch} & \textbf{Achiral drugs} & \textbf{Achiral
drugs} & \textbf{Chiral mixtures} & \textbf{Chiral mixtures} &
\textbf{Pure enantiomers} & \textbf{Pure enantiomers} & \textbf{Total} &
\textbf{Total}\tabularnewline
& \textbf{n} & \textbf{\%} & \textbf{n} & \textbf{\%} & \textbf{n} &
\textbf{\%} & \textbf{n} & \textbf{\%*}\tabularnewline
Before 1920 & 17 & 70.8 & 1 & 4.2 & 6 & 25.0 & 24 & 6.1\tabularnewline
1920-1940 & 15 & 53.6 & 7 & 25.0 & 6 & 21.4 & 28 & 7.1\tabularnewline
1940-1960 & 48 & 51.6 & 24 & 25.8 & 21 & 22.6 & 93 & 23.5\tabularnewline
1960-1980 & 74 & 51.0 & 46 & 31.7 & 25 & 17.2 & 145 &
36.7\tabularnewline
1980-2000 & 42 & 48.3 & 30 & 34.5 & 15 & 17.2 & 87 & 22.0\tabularnewline
After 2000 & 11 & 61.1 & 1 & 5.6 & 6 & 33.3 & 18 & 4.6\tabularnewline
\textbf{Total} & 207 & 52.4 & 109 & 27.6 & 79 & 20.0 & 395 &
100.0\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}The column indicates relative share of the time
period for all withdrawn drugs.

\subsection*{Table 4. Comparison of time to withdrawal of chiral groups
for the most common
ADRs.}

{\label{table-4.-comparison-of-time-to-withdrawal-of-chiral-groups-for-the-most-common-adrs.}}\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\textbf{Adverse drug reactions (n[?]30)} & \textbf{Achiral} &
\textbf{Achiral} & \textbf{Chiral mixture} & \textbf{Chiral mixture} &
\textbf{Pure enantiomer} & \textbf{Pure enantiomer} & \textbf{Total} &
\textbf{Total} & \textbf{p-value}\tabularnewline
& \textbf{Mean} & \selectlanguage{ngerman}\textbf{± SD} & \textbf{Mean} & \selectlanguage{ngerman}\textbf{± SD} &
\textbf{Mean} & \selectlanguage{ngerman}\textbf{± SD} & \textbf{Mean} & \selectlanguage{ngerman}\textbf{± SD}
&\tabularnewline
Hepatotoxicity (n=79), yrs. & 19.1 & \selectlanguage{ngerman}± 25.8 & 13.8 & \selectlanguage{ngerman}± 12.7 & 12.3 & \selectlanguage{ngerman}±
19.6 & 17.2 & \selectlanguage{ngerman}± 22.6 & 0.550\tabularnewline
Cardiovascular (n=60), yrs. & 17.7 & \selectlanguage{ngerman}± 27.4 & 23.2 & \selectlanguage{ngerman}± 14.4 & 35.9 & \selectlanguage{ngerman}±
31.6 & 23.8 & \selectlanguage{ngerman}± 24.7 & \textbf{0.034*}\tabularnewline
Drug abuse (n=51), yrs. & 31.9 & \selectlanguage{ngerman}± 33.0 & 31.5 & \selectlanguage{ngerman}± 16.7 & 45.1 & \selectlanguage{ngerman}± 36.0
& 35.1 & \selectlanguage{ngerman}± 28.1 & 0.162\tabularnewline
Neurological (n=50), yrs. & 28.9 & \selectlanguage{ngerman}± 27.6 & 18.8 & \selectlanguage{ngerman}± 18.6 & 53.3 & \selectlanguage{ngerman}±
62.3 & 32.5 & \selectlanguage{ngerman}± 38.8 & 0.234\tabularnewline
Haematological (n=49), yrs. & 38.4 & \selectlanguage{ngerman}± 31.5 & 16.1 & \selectlanguage{ngerman}± 13.3 & 20.0 & \selectlanguage{ngerman}±
18.6 & 30.7 & \selectlanguage{ngerman}± 28.2 & 0.061\tabularnewline
Carcinogenicity (n=44), yrs. & 39.2 & \selectlanguage{ngerman}± 40.5 & 17.9 & \selectlanguage{ngerman}± 21.4 & 11.7 & \selectlanguage{ngerman}±
6.3 & 30.2 & \selectlanguage{ngerman}± 38.6 & 0.093\tabularnewline
Dermatological (n=38), yrs. & 28.4 & \selectlanguage{ngerman}± 20.4 & 9.3 & \selectlanguage{ngerman}± 10.9 & 18.0 & \selectlanguage{ngerman}±
14.1 & 23.4 & \selectlanguage{ngerman}± 19.8 & \textbf{0.018\textsuperscript{+}}\tabularnewline
Immunological (n=30), yrs. & 38.1 & \selectlanguage{ngerman}± 29.4 & 15.1 & \selectlanguage{ngerman}± 13.9 & 21.3 & \selectlanguage{ngerman}±
15.9 & 28.0 & \selectlanguage{ngerman}± 25.0 & 0.075\tabularnewline
\bottomrule
\end{longtable}

\textsuperscript{*}p\textgreater{}0.05 for each of the multiple
comparisons between pairs. \textsuperscript{+}p=0.01 for achiral drugs
vs. chiral mixtures.

\textbf{Figure Legends}

\textbf{Figure 1.} Chiral distribution of the withdrawn drugs at the
ATC-1 level. \textsuperscript{*}\emph{p=0.02 for achiral vs. chiral
drugs.} \emph{{[}A, Alimentary tract and metabolism (n=62); B, Blood and
blood forming organs (n=3); C, Cardiovascular system (n=45); D,
Dermatological (n=15); G, Genito urinary system and sex hormones (n=13);
J, Anti-infectives for systemic use (n=30); L, Antineoplastic and
immunomodulating agents (n=8); M, Musculoskeletal system (n=41); N,
Nervous system (n=104); P, Antiparasitic products, insecticides and
repellents (n=18); R, Respiratory system (n=26); S, Sensory organs
(n=6); V, Various (n=9); Others denotes drugs with multiple or undefined
ATC codes (n=12){]}}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/chiralitywithdrawn-figure1-BJCP/chiralitywithdrawn-figure1-BJCP}

\end{center}
\end{figure}

\selectlanguage{english}
\FloatBarrier
\end{document}

